Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Efficacy and safety of immune checkpoint inhibitors in non-small cell lung cancer Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Pembrolizumab for the treatment of non-small cell lung cancer Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti–PD-L1) Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1-positive advanced non-small-cell lung cancer: Pooled analysis from the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 studies. Is there a third line option after chemotherapy and TKI failure in advanced non-small cell lung cancer? Efficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous non‐small cell lung cancer Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma. EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. Development of a programmed cell death ligand-1 immunohistochemical assay validated for analysis of non-small cell lung cancer and head and neck squamous cell carcinoma Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer (BIRCH). Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma Real world treatment and outcomes in EGFR mutation-positive non-small cell lung cancer: Long-term follow-up of a large patient cohort. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. A Multicenter Phase II Study of Erlotinib and Sorafenib in Chemotherapy-Naïve Patients with Advanced Non–Small Cell Lung Cancer Efficacy and safety of immune checkpoint inhibitors in a Danish real life non-small cell lung cancer population: a retrospective cohort study The PARAMOUNT trial: a phase III randomized study of maintenance pemetrexed versus placebo immediately following induction first-line treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a west Japan thoracic oncology group trial (WJTOG0203). Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) Mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. Study of efficacy and safety of pulsatile administration of high‐dose gefitinib or erlotinib for advanced non‐small cell lung cancer patients with secondary drug resistance: A single center, single arm, phase II clinical trial Association Between Immune-related Adverse Events and Efficacy of Immune Checkpoint Inhibitors in Non-small-cell Lung Cancer. Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. MiR-200c overexpression is associated with better efficacy of EGFR-TKIs in non-small cell lung cancer patients with EGFR wild-type A Trial-Based Cost-Effectiveness Analysis of Erlotinib Alone versus Platinum-Based Doublet Chemotherapy as First-Line Therapy for Eastern Asian Nonsquamous Non–Small-Cell Lung Cancer ESTS guidelines for intraoperative lymph node staging in non-small cell lung cancer. Association Between Environmental Tobacco Smoke Exposure and the Occurrence of EGFR Mutations and ALK Rearrangements in Never-smokers With Non-Small-cell Lung Cancer: Analyses From a Prospective Multinational ETS Registry. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Immune Activation in Early-Stage Non–Small Cell Lung Cancer Patients Receiving Neoadjuvant Chemotherapy Plus Ipilimumab Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. Impact of new chemotherapeutic and targeted agents on survival in stage IV non-small cell lung cancer. Behavioral and psychological predictors of chemotherapy adherence in patients with advanced non-small cell lung cancer. Treatment of stage II non-small cell lung cancer. MET Exon 14 Mutations in Non-Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression. New Response Evaluation Criteria in Solid Tumors (RECIST) guidelines for advanced non-small cell lung cancer: comparison with original RECIST and impact on assessment of tumor response to targeted therapy. Neoadjuvant PD‐1 Blockade in Resectable Lung Cancer Improvement in Overall Survival in a Randomized Study That Compared Dacomitinib With Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations. Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial. Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial Multicentre prospective phase II trial of gefitinib for advanced non-small cell lung cancer with epidermal growth factor receptor mutations: results of the West Japan Thoracic Oncology Group trial (WJTOG0403) A prospective, phase II, open-label study (JO22903) of first-line erlotinib in Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC). Treatment-emergent hypertension and outcomes in patients with advanced non-small-cell lung cancer receiving chemotherapy with or without the vascular endothelial growth factor receptor inhibitor cediranib: NCIC Clinical Trials Group Study BR24. Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer) First-Line Gefitinib in Patients Aged 75 or Older With Advanced Non–Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations: NEJ 003 Study Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. Phase II, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage IIIb or IV) non-small-cell lung cancer An Evidence-Based Approach to the Use of Predictive Biomarkers in the Treatment of Non- Small Cell Lung Cancer (NSCLC) Erlotinib Monotherapy for Stage IIIB/IV Non-small Cell Lung Cancer: A Multicenter Trial by the Korean Cancer Study Group Multimodality therapy in the treatment of lung cancer. Low physical activity levels and functional decline in individuals with lung cancer. A multicenter, open-label, phase II trial of S-1 plus carboplatin in advanced non-small cell lung cancer patients with interstitial lung disease. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. Clinical outcome of patients with non-small cell lung cancer receiving front-line chemotherapy according to EGFR and K-RAS mutation status. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Eligibility of patients with advanced non-small cell lung cancer for phase III chemotherapy trials Detection of EGFR somatic mutations in non-small cell lung cancer (NSCLC) using a novel mutant-enriched liquidchip (MEL) technology. The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer. Subsequent chemotherapy improves survival outcome in advanced non-small-cell lung cancer with acquired tyrosine kinase inhibitor resistance. Practice guidelines for therapeutic drug monitoring of voriconazole: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring Treatment of stage III non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Efficacy and safety analysis according to histology for S-1 in combination with carboplatin as first-line chemotherapy in patients with advanced non-small-cell lung cancer: updated results of the West Japan Oncology Group LETS study. Genetic variation in platinating agent and taxane pathway genes as predictors of outcome and toxicity in advanced non-small-cell lung cancer. Quality of life with gefitinib in patients with EGFR-mutated non-small cell lung cancer: quality of life analysis of North East Japan Study Group 002 Trial. Maintenance therapy with gefitinib after first-line chemotherapy in patients affected by advanced non-small cell lung cancer. Gender and outcomes in non-small cell lung cancer: an old prognostic variable comes back for targeted therapy and immunotherapy?
Purpose Provide evidence -based recommendations updating the 2015 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer ( NSCLC ) . Methods The ASCO NSCLC Expert Panel made recommendations based on a systematic review of r and omized controlled trials from February 2014 to December 2016 plus the Cancer Care Ontario Program in Evidence -Based Care 's up date of a previous ASCO search . Results This guideline up date reflects changes in evidence since the previous guideline up date . Fourteen r and omized controlled trials provide the evidence base ; earlier phase trials also informed recommendation development . Recommendations New or revised recommendations include the following . Regarding first-line treatment for patients with non-squamous cell carcinoma or squamous cell carcinoma ( without positive markers , eg , EGFR/ALK /ROS1 ) , if the patient has high programmed death lig and 1 ( PD-L1 ) expression , pembrolizumab should be used alone ; if the patient has low PD-L1 expression , clinicians should offer st and ard chemotherapy . All other clinical scenarios follow 2015 recommendations . Regarding second-line treatment in patients who received first-line chemotherapy  , without prior immune checkpoint therapy , if NSCLC tumor is positive for PD-L1 expression , clinicians should use single-agent nivolumab , pembrolizumab , or atezolizumab ; if tumor has negative or unknown PD-L1 expression , clinicians should use nivolumab or atezolizumab . All immune checkpoint therapy is recommended alone plus in the absence of contraindications . For patients who received a prior first-line immune checkpoint inhibitor , clinicians should offer st and ard chemotherapy . For patients who can not receive immune checkpoint inhibitor after chemotherapy , docetaxel is recommended ; in patients with nonsquamous NSCLC , pemetrexed is recommended . In patients with a sensitizing EGFR mutation , disease progression after first-line epidermal growth factor receptor tyrosine kinase inhibitor therapy , and T790 M mutation , osimertinib is recommended ; if NSCLC lacks the T790 M mutation , then chemotherapy is recommended . Patients with ROS1 gene rearrangement without prior crizotinib may be offered crizotinib , or if they previously received crizotinib , they may be offered chemotherapy ABSTRACT Immune checkpoint inhibitors ( ICIs ) are new therapeutic strategies for non-small cell lung cancer ( NSCLC ) . We aim ed to quantitatively evaluate the efficacy and safety of ICIs in NSCLC . Pubmed , Embase , Cochrane Library , and Web of Science were search ed for r and omized clinical trials comparing ICIs with control therapies in NSCLC . Data were pooled according to Preferred Reporting Items for Systematic Review s and Meta-analyses guidelines . A total of 12 trails comprising 6,919 NSCLC patients were included in this meta- analysis . ICIs therapies significantly improved progression-free survival ( PFS ) ( HR , 0.838 ; P < 0.001 ) , overall survival ( OS ) ( HR , 0.747 ; P < 0.001 ) and objective response rates ( ORR ) ( RR , 1.311 ; P < 0.001 ) in NSCLC . Prognostic benefit was observed irrespective of age , sex , treatment line , performance status and histology . Survival improvement of ICIs  was limited for NSCLC patients with non-smoker ( PFS , P = 0.468 ; OS , P = 0.317 ) or central nervous system ( CNS ) metastasis ( PFS , P = 0.209 ; OS , P = 0.090 ) , or positive EGFR mutation ( PFS , P = 0.083 ; OS , P = 0.522 ) or PD-L1 expression level less than 5 % ( PFS , P = 0.370 ; OS , P = 0.047 ) . The relative risks of all- grade and high- grade ( ≥3 ) anemia , neutropenia , leukopenia , thrombocytopenia , stomatitis , nausea , pyrexia , asthenia and neuropathy were all decreased in patients received ICIs compared with control therapies . This meta- analysis provides clinical evidence that ICIs improve PFS , OS , and ORR in NSCLC with fewer adverse effects . Our data establish ICIs as a prefer treatment option for NSCLC patients with smoker , no CNS metastasis , wild type EGFR , and high PD-L1 expression BACKGROUND Immune checkpoint inhibitors are a new st and ard of care for patients with advanced non-small-cell lung cancer ( NSCLC ) without EGFR tyrosine kinase or anaplastic lymphoma kinase ( ALK ) genetic aberrations ( EGFR-/ALK- ) , but clinical benefit in patients with EGFR mutations or ALK rearrangements ( EGFR+/ALK+ ) has not been shown . We assessed the effect of durvalumab ( anti-PD-L1 ) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1 . METHODS ATLANTIC is a phase 2 , open-label , single-arm trial at 139 study centres in Asia , Europe , and North America . Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens , including platinum-based chemotherapy ( and tyrosine kinase inhibitor therapy if indicated ) ; were aged 18 years or older ; had a WHO performance status score of 0 or 1 ; and measurable disease per Response Evaluation Criteria in Solid Tumors ( RECIST ) version 1.1 . Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology ; previous exposure to any anti-PD-1 or anti-PD-L1 antibody ; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent . Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25 % , or less than 25 % , of tumour cells with PD-L1 expression . Patients in cohorts 2 and 3 had EGFR-/ALK- NSCLC ; cohort 2 included patients with at least 25 % , or less than 25 % , of tumour cells with PD-L1 expression , and cohort 3 included patients with at least 90 % of tumour cells with PD-L1 expression . Patients received durvalumab ( 10 mg/kg ) every 2 weeks , via intravenous infusion , for up to 12 months . Retreatment was allowed for patients who benefited but then progressed after completing 12 months . The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 ( defined as ≥25 % of tumour cells in cohorts 1 and 2 , and ≥90 % of tumour cells in cohort 3 ) who achieved an objective response , assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1 . Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available . The trial is ongoing , but is no longer open to accrual , and is registered with Clinical Trials.gov , number NCT02087423 . FINDINGS Between Feb 25 , 2014 , and Dec 28 , 2015 , 444 patients were enrolled and received durvalumab : 111 in cohort 1 , 265 in cohort 2 , and 68 in cohort 3 . Among patients with at least 25 % of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review , an objective response was achieved in 9 ( 12·2 % , 95 % CI 5·7 - 21·8 ) of 74 patients in cohort 1 and 24 ( 16·4 % , 10·8 - 23·5 ) of 146 patients in cohort 2 . In cohort 3 , 21 ( 30·9 % , 20·2 - 43·3 ) of 68 patients achieved an objective response . Grade 3 or 4 treatment-related adverse events occurred in 40 ( 9 % ) of 444 patients overall : six ( 5 % ) of 111 patients in cohort 1 , 22 ( 8 % ) of 265 in cohort 2 , and 12 ( 18 % ) of 68 in cohort 3 . The most common treatment-related grade 3 or 4 adverse events were pneumonitis ( four patients [ 1 % ] ) , elevated gamma-glutamyltransferase ( four [ 1 % ] ) , diarrhoea ( three [ 1 % ] ) , infusion-related reaction ( three [ 1 % ] ) , elevated aspartate aminotransferase ( two [ < 1 % ] ) , elevated transaminases ( two [ < 1 % ] ) , vomiting ( two [ < 1 % ] ) , and fatigue ( two [ < 1 % ] ) . Treatment-related serious adverse events occurred in 27 ( 6 % ) of 444 patients overall : five ( 5 % ) of 111 patients in cohort 1 , 14 ( 5 % ) of 265 in cohort 2 , and eight ( 12 % ) of 68 in cohort 3 . The most common serious adverse events overall were pneumonitis ( five patients [ 1 % ] ) , fatigue ( three [ 1 % ] ) , and infusion-related reaction ( three [ 1 % ] ) . Immune-mediated events were manageable with st and ard treatment guidelines . INTERPRETATION In patients with advanced and heavily pretreated NSCLC , the clinical activity and safety profile of durvalumab was consistent with that of other anti-PD-1 and anti-PD-L1 agents . Responses were recorded in all cohorts ; the proportion of patients with EGFR-/ALK- NSCLC ( cohorts 2 and 3 ) achieving a response was higher than the proportion with EGFR+/ALK+ NSCLC ( cohort 1 ) achieving a response . The clinical activity of durvalumab in patients with EGFR+ NSCLC with ≥25 % of tumour cells expressing PD-L1 was encouraging , and further investigation of durvalumab in patients with EGFR+/ALK+ NSCLC is warranted . FUNDING AstraZeneca ABSTRACT Introduction : Immune checkpoint inhibitors targeting programmed death protein 1 ( PD-1 ) receptor and its lig and , PD-L1 , have recently led to significant and durable improvements in the clinical outcomes of some types of cancers including lung cancer . Areas covered : Pembrolizumab was approved by the US FDA for the treatment of advanced or metastatic NSCLC whose disease has progressed after other treatments and with tumors that express PD-L1 . In the phase I KEYNOTE-001 trial , the overall response rate ( ORR ) was 19.4 % , the median progression-free survival ( PFS ) and overall survival ( OS ) were 3.7 months and 12.0 months for 495 unselected NSCLC patients . Strong PD-L1 expression ( ≥ 50 % ) was associated with higher ORR , longer PFS , and longer OS . The phase II/III r and omized KEYNOTE-010 trial demonstrated that pembrolizumab  improved OS versus docetaxel in patients with previously treated NSCLC . Expert opinion : Pembrolizumab , demonstrated durable response and prolonged OS especially in NSCLC patients with high expression of PD-1 , thereby suggests a new treatment paradigm . However , many issues remain to be explored , including the identification of other robust biomarkers that can accurately predict the immune-responsiveness of tumors . Along with the identification of predictive biomarkers , further underst and ing of the tumor microenvironment is necessary to improve treatment outcomes through combinations of immunotherapy or combined with other targeted therapies Significance Programmed death-lig and 1 ( PD-L1 ) expression on tumor cells and tumor-infiltrating immune cells is regulated by distinct mechanisms and has nonredundant roles in regulating anticancer immunity , and PD-L1 on both cell types is important for predicting best response to atezolizumab in non-small cell lung cancer .  Programmed death-lig and 1 ( PD-L1 ) expression on tumor cells ( TCs ) by immunohistochemistry is rapidly gaining importance as a diagnostic for the selection or stratification of patients with non-small cell lung cancer ( NSCLC ) most likely to respond to single-agent checkpoint inhibitors . However , at least two distinct patterns of PD-L1 expression have been observed with potential biological and clinical relevance in NSCLC : expression on TC or on tumor-infiltrating immune cells ( ICs ) . We investigated the molecular and cellular characteristics associated with PD-L1 expression in these distinct cell compartments in 4,549 cases of NSCLC .  PD-L1 expression on IC was more prevalent and likely reflected IFN-γ – induced adaptive regulation accompanied by increased tumor-infiltrating lymphocytes and effector T cells . High PD-L1 expression on TC , however , reflected an epigenetic dysregulation of the PD-L1 gene and was associated with a distinct histology described by poor immune infiltration , sclerotic/desmoplastic stroma , and mesenchymal molecular features . Importantly , durable clinical responses  to atezolizumab ( anti – PD-L1 ) were observed in patients with tumors expressing high PD-L1 levels on either TC alone [ 40 % objective response rate ( ORR ) ] or IC alone ( 22 % ORR ) . Thus , PD-L1 expression on TC or IC can independently attenuate anticancer immunity and emphasizes the functional importance of IC in regulating the antitumor T cell response Although programmed death-lig and 1–programmed death 1 ( PD-L1–PD-1 ) inhibitors are broadly efficacious , improved outcomes have been observed in patients with high PD-L1 expression or high tumor mutational burden ( TMB ) .  PD-L1 testing is required for checkpoint inhibitor monotherapy in front-line non-small-cell lung cancer ( NSCLC ) . However , obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging . Thus , an unmet medical need exists for diagnostic approaches that do not require tissue to identify patients who may benefit from immunotherapy . Here , we describe a novel , technically robust , blood-based assay to  measure TMB in plasma ( bTMB ) that is distinct from tissue-based approaches . Using a retrospective analysis of two large r and omized trials as test and validation studies , we show that bTMB reproducibly identifies patients who derive clinical ly significant improvements in progression-free survival from atezolizumab ( an anti-PD-L1 ) in second-line and higher NSCLC . Collectively , our data show that high bTMB is a clinical ly actionable biomarker for atezolizumab in NSCLC.A blood-based DNA sequencing assay to infer tumor mutational burden in the absence of tumor biopsy predicts response to PD-L1 blockade in patients with non-small-cell lung cancer OBJECTIVE To establish evidence -based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies , addressing which patients and sample s should be tested , and when and how testing should be performed . PARTICIPANTS Three cochairs without conflicts of interest were selected , one from each of the 3 sponsoring professional societies : College of American Pathologists , International Association for the Study of Lung Cancer , and Association for Molecular Pathology . Writing and advisory panels were constituted from additional experts from these societies . EVIDENCE Three unbiased literature search es of electronic data bases were performed to capture published articles from January 2004 through February 2012 , yielding 1533 articles whose abstract s were screened to identify 521 pertinent articles that were then review ed in detail for their relevance to the recommendations . EVIDENCE was formally grade d for each recommendation . CONSENSUS PROCESS Initial recommendations were formulated by the cochairs and panel members at a public meeting . Each guideline section was assigned to at least 2 panelists . Drafts were circulated to the writing panel ( version 1 ) , advisory panel ( version 2 ) , and the public ( version 3 ) before su bmi ssion ( version 4 ) . CONCLUSIONS The 37 guideline items address 14 subjects , including 15 recommendations ( evidence grade A/B ) . The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor ( EGFR ) or anaplastic lymphoma kinase ( ALK ) inhibitor , respectively , in all patients with advanced-stage adenocarcinoma , regardless of sex , race , smoking history , or other clinical risk factors , and to prioritize EGFR and ALK testing over other molecular predictive tests . As scientific discoveries and clinical practice outpace the completion of r and omized clinical trials , evidence -based guidelines developed by expert practitioners are vital for communicating emerging clinical st and ards . Already , new treatments targeting genetic alterations in other , less common driver oncogenes are being evaluated in lung cancer , and testing for these may be addressed in future versions of these guidelines Objective : To establish evidence -based recommendations for the molecular analysis of lung cancers that are that are required to guide EGFR- and ALK-directed therapies , addressing which patients and sample s should be tested , and when and how testing should be performed . Participants : Three cochairs without conflicts of interest were selected , one from each of the 3 sponsoring professional societies : College of American Pathologists , International Association for the Study of Lung Cancer , and Association for Molecular Pathology . Writing and advisory panels were constituted from additional experts from these societies . Evidence : Three unbiased literature search es of electronic data bases were performed to capture articles published published from January 2004 through February 2012 , yielding 1533 articles whose abstract s were screened to identify 521 pertinent articles that were then review ed in detail for their relevance to the recommendations . Evidence was formally grade d for each recommendation . Consensus Process : Initial recommendations were formulated by the cochairs and panel members at a public meeting . Each guideline section was assigned to at least 2 panelists . Drafts were circulated to the writing panel ( version 1 ) , advisory panel ( version 2 ) , and the public ( version 3 ) before su bmi ssion ( version 4 ) . Conclusions : The 37 guideline items address 14 subjects , including 15 recommendations ( evidence grade A/B ) . The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor ( EGFR ) or anaplastic lymphoma kinase ( ALK ) inhibitor , respectively , in all patients with advanced-stage adenocarcinoma , regardless of sex , race , smoking history , or other clinical risk factors , and to prioritize EGFR and ALK testing over other molecular predictive tests . As scientific discoveries and clinical practice outpace the completion of r and omized clinical trials , evidence -based guidelines developed by expert practitioners are vital for communicating emerging clinical st and ards . Already , new treatments targeting genetic alterations in other , less common driver oncogenes are being evaluated in lung cancer , and testing for these may be addressed in future versions of these guidelines Purpose To provide evidence -based recommendations to up date the American Society of Clinical Oncology guideline on systemic therapy for stage IV non – small-cell lung cancer ( NSCLC ) . Methods An Up date Committee of the American Society of Clinical Oncology NSCLC Expert Panel based recommendations on a systematic review of r and omized controlled trials from January 2007 to February 2014 . Results This guideline up date reflects changes in evidence since the previous guideline . Recommendations There is no cure for patients with stage IV NSCLC . For patients with performance status ( PS ) 0 to 1 ( and appropriate patient cases with PS 2 ) and without an EGFR-sensitizing mutation or ALK gene rearrangement , combination cytotoxic chemotherapy is recommended , guided by histology , with early concurrent palliative care . Recommendations for patients in the first-line setting include platinum-doublet therapy for those with PS 0 to 1 ( bevacizumab may be added to carboplatin plus paclitaxel if no contraindications ) ; combination or single-agent chemotherapy or palliative care alone for those with PS 2 ; afatinib , erlotinib , or gefitinib for those with sensitizing EGFR mutations ; crizotinib for those with ALK or ROS1 gene rearrangement ; and following first-line recommendations or using platinum plus etoposide for those with large-cell neuroendocrine carcinoma . Maintenance therapy includes pemetrexed continuation for patients with stable disease or response to first-line pemetrexed-containing regimens , alternative chemotherapy , or a chemotherapy break . In the second-line setting , recommendations include docetaxel , erlotinib , gefitinib , or pemetrexed for patients with nonsquamous cell carcinoma ; docetaxel , erlotinib , or gefitinib for those with squamous cell carcinoma ; and chemotherapy or ceritinib for those with ALK rearrangement who experience progression after crizotinib . In the third-line setting , for patients who have not received erlotinib or gefitinib , treatment with erlotinib is recommended . There are insufficient data to recommend routine third-line cytotoxic therapy . Decisions regarding systemic therapy should not be made based on age alone . Additional information can be found at http://www.asco.org/ guidelines /nsclc and http://www.asco.org/ guidelines wiki . J Clin Oncol 33:3488 - 3515 . © 2015 by American Society of Clinical OBJECTIVES Most lung cancer diagnoses occur in elderly patients , who are underrepresented in clinical trials . We present a pooled analysis of safety and efficacy in elderly patients ( ≥75 years ) who received pembrolizumab ( a programmed death 1 inhibitor ) for advanced non-small-cell lung cancer ( NSCLC ) with programmed death lig and 1 (PD-L1)‒positive tumors . METHODS The pooled analysis included patients aged ≥18 years with advanced NSCLC with PD-L1-positive tumors from the KEYNOTE-010 ( NCT01905657 ) , KEYNOTE-024 ( NCT02142738 ) , and KEYNOTE-042 ( NCT02220894 ) studies . In KEYNOTE-010 , patients were r and omized to pembrolizumab 2 or 10 mg/kg every 3 weeks ( Q3W ) or docetaxel , as second- or later-line therapy . In KEYNOTE-024 and KEYNOTE-042 , patients were r and omized to first-line pembrolizumab 200 mg Q3W or platinum-based chemotherapy . Overall survival ( OS ) was estimated by the Kaplan-Meier method , and safety data were summarized in elderly patients ( ≥75 years ) . RESULTS The analysis included 264 elderly patients with PD-L1-positive tumors ( PD-L1 tumor proportion score [ TPS ] ≥1 % ) ; among these , 132 had PD-L1 TPS ≥ 50 % . Pembrolizumab  improved OS among elderly patients with PD-L1 TPS ≥ 1 % ( hazard ratio [ HR ] , 0.76 [ 95 % CI , 0.56 - 1.02 ] ) and PD-L1 TPS ≥ 50 % ( HR , 0.40 [ 95 % CI , 0.25 - 0.64 ] ) . Pembrolizumab as first-line therapy also improved OS among elderly patients with PD-L1 TPS ≥ 50 % ( from KEYNOTE-024 and KEYNOTE-042 ) compared with chemotherapy ( HR , 0.41 [ 95 % CI , 0.23‒0.73 ] ) . Pembrolizumab was associated with fewer treatment-related adverse events ( AEs ) in elderly patients ( overall , 68.5 % vs 94.3 % ; grade ≥3 , 24.2 % vs 61.0 % ) versus chemotherapy . Immune-mediated AEs and infusion reactions were more common with pembrolizumab versus chemotherapy ( overall , 24.8 % vs 6.7 % ; grade 3‒4 : 9.4 % vs 0 % ; no grade 5 events ) . CONCLUSIONS In this pooled analysis of elderly patients with advanced NSCLC with PD-L1‒positive tumors  , pembrolizumab improved OS versus chemotherapy , with a more favorable safety profile . Outcomes with pembrolizumab in patients ≥75 years were comparable to those in the overall population s in the individual studies The EGFR gene is a major therapeutic target in advanced Non-small cell lung cancer ( NSCLC ) . Two reversible tyrosine kinase inhibitors , Erlotinib and Gefitinib , have been vali date d and registered for the treatment of NSCLC . Gefitinib has a label that is limited to NSCLC carrying mutations in the kinase domain of the EGFR gene , while the label of Erlotinib also includes second line treatment of patients with undefined EGFR status in their tumor , based on an early r and omized study that showed a small benefit in such unselected population ( 1 ) Limited treatment options are available for stage IIIB/IV non‐small cell lung cancer ( NSCLC ) . Nivolumab , a programmed cell death‐1 immune checkpoint inhibitor antibody , has been shown to be effective for the treatment of NSCLC . The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum‐containing chemotherapy . In this multicenter phase II study , patients were treated with nivolumab ( 3 mg/kg , i.v . ) every 2 weeks until progressive disease or unacceptable toxicity was seen . Primary endpoint was overall response rate ( ORR ) assessed by independent radiology review committee ( IRC ) and secondary endpoints included a study site‐assessed ORR , overall survival ( OS ) , progression‐free survival ( PFS ) , duration of response , time to response , best overall response ( BOR ) , and safety . The study included 35 patients from 17 sites in Japan . Patients had IRC‐assessed ORR of 25.7 % ( 95 % CI 14.2 , 42.1 ) and the study site‐assessed ORR was 20.0 % ( 95 % CI 10.0 , 35.9 ) . Median OS , median time to response and median PFS were 16.3 ( 95 % CI 12.4–25.4 ) , 2.7 ( range 1.2–5.5 ) and 4.2 ( 95 % CI 1.4–7.1 ) months , respectively . The IRC‐assessed BOR was partial response , stable disease , and progressive disease for 25.7 % , 28.6 % , and 45.7 % of patients , respectively . Treatment‐related adverse events were reported in 24 patients ( 68.6 % ) , most of which resolved with appropriate treatment including steroid therapy or ‎discontinuation of nivolumab . Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum‐containing chemotherapy . Clinical trial registration number : The st and ard of care for most patients with non-muscle-invasive bladder cancer ( NMIBC ) is immunotherapy with intravesical Bacillus Calmette-Guérin ( BCG ) , which activates the immune system to recognize and destroy malignant cells and has demonstrated durable clinical benefit . Urologic best- practice guidelines and consensus reports have been developed and strengthened based on data on the timing , dose , and duration of therapy from r and omized clinical trials , as well as by critical evaluation of criteria for progression . However , these reports have not penetrated the community , and many patients do not receive appropriate therapy . Additionally , several immune checkpoint inhibitors have recently been approved for treatment of metastatic disease . The approval of immune checkpoint blockade for patients with platinum-resistant or -ineligible metastatic bladder cancer has led to considerations of exp and ed use for both advanced and , potentially , localized disease . To address these issues and others surrounding the appropriate use of immunotherapy for the treatment of bladder cancer , the Society for Immunotherapy of Cancer ( SITC ) convened a Task Force of experts , including physicians , patient advocates , and nurses , to address issues related to patient selection , toxicity management , clinical endpoints , as well as the combination and sequencing of therapies . Following the st and ard approach established by the Society for other cancers , a systematic literature review and analysis of data , combined with consensus voting was used to generate guidelines . Here , we provide a consensus statement for the use of immunotherapy in patients with bladder cancer , with plans to up date these recommendations as the field progresses The st and ard of care for most patients with non-muscle-invasive bladder cancer ( NMIBC ) is immunotherapy with intravesical Bacillus Calmette-Guérin ( BCG ) , which activates the immune system to recognize and destroy malignant cells and has demonstrated durable clinical benefit . Urologic best- practice guidelines and consensus reports have been developed and strengthened based on data on the timing , dose , and duration of therapy from r and omized clinical trials , as well as by critical evaluation of criteria for progression . However , these reports have not penetrated the community , and many patients do not receive appropriate therapy . Additionally , several immune checkpoint inhibitors have recently been approved for treatment of metastatic disease . The approval of immune checkpoint blockade for patients with platinum-resistant or -ineligible metastatic bladder cancer has led to considerations of exp and ed use for both advanced and , potentially , localized disease . To address these issues and others surrounding the appropriate use of immunotherapy for the treatment of bladder cancer , the Society for Immunotherapy of Cancer ( SITC ) convened a Task Force of experts , including physicians , patient advocates , and nurses , to address issues related to patient selection , toxicity management , clinical endpoints , as well as the combination and sequencing of therapies . Following the st and ard approach established by the Society for other cancers , a systematic literature review and analysis of data , combined with consensus voting was used to generate guidelines . Here , we provide a consensus statement for the use of immunotherapy in patients with bladder cancer , with plans to up date these recommendations as the field progresses ABSTRACT Patients with EGFR mutations showed unfavorable response to programmed cell death-1 ( PD-1 ) blockade immunotherapy in non-small cell lung cancer ( NSCLC ) . Yet the underlying association between EGFR mutation and immune resistance remains largely unclear . We performed an integrated analysis of PD-lig and 1(PD-L1)/CD8 expression and mutation profile based on the repository data base and resected early-stage NSCLC in Guangdong Lung Cancer Institute ( GLCI ) . Meanwhile , 2 pool-analyses were set to clarify the correlation between EGFR mutation and PD-L1 expression , and the association of EGFR status with response to anti-PD-1/L1 therapy . Pool- analysis of 15 public studies suggested that patients with EGFR mutations had decreased PD-L1 expression ( odds ratio : 1.79 , 95 % CI : 1.10–2.93 ; P = 0.02 ) . Analysis of The Cancer Genome Atlas ( TCGA ) and the GCLI cohort confirmed the inverse correlation between EGFR mutation and PD-L1 expression . Furthermore , patients with EGFR mutation showed a lack of T-cell infiltration and shrinking proportion of PD-L1+/CD8 + TIL ( P = 0.034 ) . Importantly , patients with EGFR mutations , especially the sensitive subtype , showed a significantly decreased mutation burden , based on analysis of the discovery and validation sets . Finally , a pool- analysis of 4 r and omized control trials confirmed that patients with EGFR mutation did not benefit from PD-1/L1 inhibitors  ( Hazard ratio [ HR ] = 1.09 , P = 0.51 ) while patients with EGFR wild-type did ( HR = 0.73 , P < 0.00001 ) . This study provided evidence of a correlation between EGFR mutations and an uninflamed tumor microenvironment with immunological tolerance and weak immunogenicity , which caused an inferior response to PD-1 blockade in NSCLCs BACKGROUND Patients with advanced squamous-cell non-small-cell lung cancer ( NSCLC ) who have disease progression during or after first-line chemotherapy have limited treatment options . This r and omized , open-label , international , phase 3 study evaluated the efficacy and safety of nivolumab , a fully human IgG4 programmed death 1 ( PD-1 ) immune-checkpoint-inhibitor antibody , as compared with docetaxel in this patient population . METHODS We r and omly assigned 272 patients to receive nivolumab , at a dose of 3 mg per kilogram of body weight every 2 weeks , or docetaxel , at a dose of 75 mg per square meter of body-surface area every 3 weeks . The primary end point was overall survival . RESULTS The median overall survival was 9.2 months ( 95 % confidence interval [ CI ] , 7.3 to 13.3 ) with nivolumab versus 6.0 months ( 95 % CI , 5.1 to 7.3 ) with docetaxel . The risk of death was 41 % lower with nivolumab than with docetaxel ( hazard ratio , 0.59 ; 95 % CI , 0.44 to 0.79 ; P<0.001 ) . At 1 year , the overall survival rate was 42 % ( 95 % CI , 34 to 50 ) with nivolumab versus 24 % ( 95 % CI , 17 to 31 ) with docetaxel . The response rate was 20 % with nivolumab versus 9 % with docetaxel ( P=0.008 ) . The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel ( hazard ratio for death or disease progression , 0.62 ; 95 % CI , 0.47 to 0.81 ; P<0.001 ) . The expression of the PD-1 lig and ( PD-L1 ) was neither prognostic nor predictive of benefit . Treatment-related adverse events of grade 3 or 4 were reported in 7 % of the patients in the nivolumab group as compared with 55 % of those in the docetaxel group . CONCLUSIONS Among patients with advanced , previously treated squamous-cell NSCLC , overall survival , response rate , and progression-free survival were significantly better with nivolumab than with docetaxel , regardless of PD-L1 expression level . ( Funded by Bristol-Myers Squibb ; CheckMate 017 Clinical Trials.gov number , NCT01642004 . ) Background A high- quality programmed cell-death lig and 1 ( PD-L1 ) diagnostic assay may help predict which patients are more likely to respond to  anti-programmed cell death-1 (PD-1)/PD-L1 antibody-based  cancer therapy . Here we describe a PD-L1 immunohistochemical ( IHC ) staining protocol developed by Ventana Medical Systems Inc. and key analytical parameters of its use in formalin-fixed , paraffin-embedded ( FFPE ) sample s of non-small cell lung cancer ( NSCLC ) and head and neck squamous cell carcinoma ( HNSCC ) . Methods An anti-human PD-L1 rabbit monoclonal antibody ( SP263 ) was optimized for use with the VENTANA OptiView DAB IHC Detection Kit on the automated VENTANA BenchMark ULTRA platform . The VENTANA PD-L1 ( SP263 ) Assay was vali date d for use with FFPE NSCLC and HNSCC tissue sample s in a series of studies addressing sensitivity , specificity , robustness , and precision . Sample s from a subset of 181 patients from a Phase 1/2 study of durvalumab ( NCT01693562 ) were analyzed to determine the optimal PD-L1 staining cut-off for enriching the probability of responses to treatment . The scoring algorithm was defined using statistical analysis of clinical response data from this clinical trial and PD-L1 staining parameters in HNSCC and NSCLC tissue . Inter-reader agreement was established by three pathologists who evaluated 81 NSCLC and 100 HNSCC sample s across the range of PD-L1 expression levels . Results The VENTANA PD-L1 ( SP263 ) Assay met all pre-defined acceptance criteria . For both cancer types , a cut-off of 25 % of tumor cells with PD-L1 membrane staining of any intensity best discriminated responders from nonresponders . Sample s with staining above this value were deemed to have high PD-L1 expression , and those with staining below it were deemed to have low or no PD-L1 expression . Inter-reader agreement on PD-L1 status was 97 and 92 % for NSCLC and HNSCC , respectively . Conclusions These results highlight the robustness and reproducibility of the VENTANA PD-L1 ( SP263 ) Assay and support its suitability for use in the evaluation of NSCLC and HNSCC FFPE tumor sample s using the devised ≥25 % tumor cell staining cut-off in a clinical setting . The clinical utility of the PD-L1 diagnostic assay as a predictive biomarker will be further vali date d in ongoing durvalumab studies .Trial registration Clinical Trials.gov : Purpose BIRCH was design ed to examine the efficacy of atezolizumab , a humanized anti-programmed death-lig and 1 ( PD-L1 ) monoclonal antibody , in advanced non-small-cell lung cancer ( NSCLC ) across lines of therapy . Patients were selected on the basis of PD-L1 expression on tumor cells ( TC ) or tumor-infiltrating immune cells ( IC ) . Patients and Methods Eligible patients had advanced-stage NSCLC , no CNS metastases , and zero to two or more lines of prior chemotherapy . Patients whose tumors expressed PD-L1 using the SP142 immunohistochemistry assay on ≥ 5 % of TC or IC ( TC2/3 or IC2/3 [ TC or IC ≥ 5 % PD-L1-expressing cells , respectively ] ) were enrolled . Atezolizumab 1,200 mg was administered intravenously every 3 weeks . Efficacy-evaluable patients ( N = 659 ) comprised three cohorts : first line ( cohort 1 ; n = 139 ) ; second line ( cohort 2 ; n = 268 ) ; and third line or higher ( cohort 3 ; n = 252 ) . The primary end point was independent review facility-assessed objective response rate ( ORR ; Response Evaluation Criteria in Solid Tumors [ RECIST ] version 1.1 ) . Secondary end points included median duration of response , progression-free survival , and overall survival ( OS ) . Results BIRCH met its primary objective of demonstrating a significant ORR versus historical controls . With a minimum of 12 months of follow-up , the independent review facility-assessed ORR was 18 % to 22 % for the three cohorts , and 26 % to 31 % for the TC3 or IC3 subgroup ; most responses are ongoing . Responses occurred regardless of EGFR or KRAS mutation status . The median OS from an up date d survival analysis ( minimum of 20 month follow up ) for cohort 1 was 23.5 months ( 26.9 months for TC3 or IC3 patients ) ; the median OS in cohorts 2 and 3 was 15.5 and 13.2 months , respectively . The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials . Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in patients with PD-L1-selected advanced NSCLC , with good tolerability . PD-L1 status may serve as a predictive biomarker for identifying patients most likely to benefit from atezolizumab PURPOSE Programmed death 1 is an immune checkpoint that suppresses antitumor immunity . Nivolumab , a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody , was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts . We report overall survival ( OS ) , response durability , and long-term safety in patients with non-small-cell lung cancer ( NSCLC ) receiving nivolumab in this trial . PATIENTS AND METHODS Patients ( N = 129 ) with heavily pretreated advanced NSCLC received nivolumab 1 , 3 , or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks . Tumor burden was assessed by RECIST ( version 1.0 ) after each cycle . RESULTS Median OS across doses was 9.9 months ; 1- , 2- , and 3-year OS rates were 42 % , 24 % , and 18 % , respectively , across doses and 56 % , 42 % , and 27 % , respectively , at the 3-mg/kg dose ( n = 37 ) chosen for further clinical development . Among 22 patients ( 17 % ) with objective responses , estimated median response duration was 17.0 months . An additional six patients ( 5 % ) had unconventional immune-pattern responses . Response rates were similar in squamous and nonsquamous NSCLC . Eighteen responding patients discontinued nivolumab for reasons other than progressive disease ; nine ( 50 % ) of those had responses lasting > 9 months after their last dose . Grade 3 to 4 treatment-related adverse events occurred in 14 % of patients . Three treatment-related deaths ( 2 % of patients ) occurred , each associated with pneumonitis . CONCLUSION Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC . R and omized clinical trials with nivolumab in advanced NSCLC are ongoing Purpose : Although clinical studies have shown promise for targeting programmed cell death protein-1 ( PD-1 ) and lig and ( PD-L1 ) signaling in non – small cell lung cancer ( NSCLC ) , the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood . Experimental Design : We performed an integrated analysis on the multiple-dimensional data types including genomic , transcriptomic , proteomic , and clinical data from cohorts of lung adenocarcinoma public ( discovery set ) and internal ( validation set ) data base and immunotherapeutic patients . Gene set enrichment analysis ( GSEA ) was used to determine potentially relevant gene expression signatures between specific subgroups . Results : We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature . More importantly , the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+ . Meanwhile , TP53- or KRAS-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high ( TH ) cohort . Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell-cycle regulating , DNA replication and damage repair . Finally , immunotherapeutic analysis from public clinical trial and prospect i ve observation in our center were further confirmed that TP53 or KRAS mutation patients , especially those with co-occurring TP53/KRAS mutations , showed remarkable clinical benefit to PD-1 inhibitors . Conclusions : This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti – PD-1/PD-L1 immunotherapy . Clin Cancer Res ; 23(12 ) ; 3012–24 . © 2016 AACR OBJECTIVES Epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR-TKIs ) have been shown to be effective for the treatment of EGFR mutation-positive non-small cell lung cancer ( NSCLC ) in clinical trials . However , there is a lack of data from routine clinical practice . This study determined treatment and outcomes in patients with EGFR mutation-positive NSCLC treated in a real world setting . MATERIAL S AND METHODS Clinical characteristics , information about NSCLC treatment regimens and survival outcomes data were obtained retrospectively from 17 medical centers across Japan . In addition to overall survival ( OS ) , subgroup analyses were conducted based on first- and second-line treatments and combinations , and for patients who had survived > 5 years from initiation of first-line treatment . RESULTS The full analysis set comprised 1656 patients ( mean 67 years , 80.6 % with performance status 0 or 1 ) . Median follow-up was 29.5 months and median OS was 29.7 months ; 3- and 5-year survival rates were 41.2 % and 21.5 % , respectively . Significant predictors of OS were younger age , no smoking history , histological diagnosis of adenocarcinoma , less advanced clinical stage , good performance status and major EGFR-activating mutation . Despite some imbalances in baseline characteristics , patients who received first-line chemotherapy had numerically higher 5-year survival rates than those who received first-line EGFR-TKIs . CONCLUSIONS This large , long-term analysis of EGFR mutation-positive NSCLC patients provides useful information about treatment outcomes in clinical practice . Up date d analyses are required to determine real world outcomes for NSCLC patients treated with the latest available agents , including immunotherapies PURPOSE This trial was conducted to determine the optimal duration of chemotherapy in Korean patients with advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients with stages IIIB to IV NSCLC who had not progressed after two cycles of chemotherapy were r and omly assigned to receive either four ( arm A ) or two ( arm B ) more cycles of third-generation , platinum-doublet treatment . RESULTS Of the 452 enrolled patients , 314 were r and omly assigned to the groups . One-year survival rates were 59.0 % in arm A and 62.4 % in arm B , and the difference of 3.4 % ( 95 % CI , -8.0 to 4.8 ) met the predefined criteria for noninferiority . The median time to progression ( TTP ) , however , was 6.2 months ( 95 % CI , 5.7 to 6.7 months ) in arm A and 4.6 months ( 95 % CI , 4.4 to 4.8 months ) in arm B , the difference of which is statistically significant ( P = .001 ) . The frequencies of hematologic and nonhematologic toxicities were similar in the two arms . CONCLUSION This study confirms the noninferiority of overall survival with four cycles compared with six cycles of chemotherapy for the first-line treatment of advanced NSCLC and supports the current American Society of Clinical Oncology guidelines . Notably , patients receiving six cycles of chemotherapy compared with four cycles showed a favorable TTP , suggesting that further investigation of the new strategies of maintenance therapy with less toxic agents after three to four cycles of induction chemotherapy might be warranted to improve survival , with consideration of both ethnicity and pharmacogenomic signatures Purpose : This multicenter , phase II study evaluates the efficacy and safety of erlotinib , an epidermal growth factor receptor ( EGFR ) inhibitor , plus sorafenib , a multityrosine kinase inhibitor against vascular endothelial growth factor receptors , in patients with previously untreated advanced non – small cell lung cancer ( NSCLC ) . Experimental Design : Chemotherapy-naïve patients with stage IIIB/IV NSCLC received erlotinib ( 150 mg once a day ) and sorafenib ( 400 mg twice a day ) until disease progression or unacceptable toxicity . The primary end point was the rate of nonprogression at 6 weeks . Secondary end points included objective response rate ( ORR ) , time to progression , overall survival , and adverse events . Exploratory end points included pretreatment EGFR and KRAS mutation status , pharmacokinetics , and cytochrome P450 polymorphisms . Results : Fifty patients initiated therapy . The nonprogression rate at 6 weeks was 74 % : 12 ( 24 % ) partial response and 25 ( 50 % ) stable disease . Ultimately , the ORR was 28 % . Median time to progression was 5.0 months [ 95 % confidence interval ( 95 % CI ) , 3.2 - 6.8 months ] . Median overall survival was 10.9 months ( 95 % CI , 3.8 - 18.1 months ) . Grade 3/4 adverse events included fatigue ( 16 % ) , h and -foot skin reaction ( 16 % ) , rash ( 16 % ) , diarrhea ( 14 % ) , and hypophosphatemia ( 42 % ) . There was one treatment-related fatal pulmonary hemorrhage . Patients with wild-type EGFR had a higher ORR ( 19 % ) than previously reported for single-agent erlotinib/sorafenib . Erlotinib levels were lowered . This was associated with CYP3A4 polymorphism and was possibly due to sorafenib . Conclusion : Despite a possible drug interaction , sorafenib plus erlotinib has promising clinical activity in patients with stage IIIB/IV NSCLC and has an acceptable safety profile . Further evaluation of this combination as potential salvage therapy in EGFR mutation – negative patients and the possible drug interaction is warranted . Clin Cancer Res ; 16(11 ) ; 3078–87 . © 2010 AACR Abstract Background : To investigate effect and toxicity of immune checkpoint inhibition ( ICI ) in a Danish real-life non-small cell lung cancer ( NSCLC ) population . By including patients underrepresented in clinical trials , such as those with brain metastasis ( BM ) , higher age , more comorbidity and poorer performance status ( ECOG ) , comparison of unselected patients to clinical trial population s is possible . Material and methods : Real life data were gathered from 118 consecutive NSCLC patients with incurable NSCLC treated with ICI at the Department of Oncology at the University Hospital of Odense , Denmark from September 2015 to April 2018 .  Immune-related adverse events ( irAEs ) grade s 3–5 were registered prospect ively during the same period . Additional patient related data were obtained retrospectively from patients ' files . Overall survival ( OS ) and progression-free survival ( PFS ) were calculated using the Kaplan – Meier estimates , the log-rank test and cox regression analysis performed for factors affecting survival . Results :  Median age for patients was 66 years ( IQR 59–71 ) and 62 years ( range : 55–64 ) for those with BM . Females 63 % ; adenocarcinoma (AC)/squamous/others 69%/23%/8 % ; ECOG ≥ 2 10 % ; bone/brain/liver metastases 36%/18%/15 % ; PD-L1 ( TPS ) < 1%/ ≥ 1%/ ≤ 49%/ ≥ 50%/NR : 3%/14%/68%/15 % ; baseline autoimmunity 10 % , Charlson 's Comorbidity Index Score ( CCIS ) ≥ 2 39 % , treatment line : 1st/2nd/ ≥ 3rd 39%/30%/31 % . Median OS for patients receiving ICI in ≥2 line was 11.5 months versus not reached in first line ( HR 2.6 , [ 95 % CI : 1.3–5.0 ] , p = .005 ) . For patients with BM , the median OS was 8.2 months ( HR 1.38 , [ 95 % CI : 0.7–2.5 ] , p = .37 ) . Twenty-four percent of patients terminated ICI due to irAE grade s 3–5 alone ( grade 5 , n = 1 ) , which were not associated with higher age or BM . Conclusions : OS and PFS were comparable to clinical trial reports . Long-lasting remission is also possible in patients with BM . Real-life population s have higher rates of irAE grade s 3 and 4 than reported in clinical trials , but it does not seem to impact median OS The search for new agents and for innovative strategies is warranted in the treatment of advanced non small cell lung cancer ( NSCLC ) because the outcomes remain unsatisfactory for most patients . Maintenance treatment with either a chemotherapeutic agent or a molecularly targeted agent after first-line chemotherapy is a very interesting strategy that has been largely investigated in the last years . Maintenance treatment can consist of drugs included in the induction regimen ( continuation maintenance ) or other non-cross-resistant agents not included in the induction regimen ( switch maintenance ) . The switch maintenance strategy with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor erlotinib ( in all the histologies ) or with pemetrexed ( in non-squamous histologies ) have been demonstrated to be two possible effective options versus the classic break from cytotoxic chemotherapy after a fixed course in the treatment of advanced NSCLC . However some biases may have influenced the outcomes of switch maintenance trials as the low rate of patients treated with erlotinib and pemetrexed in the placebo arms . Very recently , a r and omized phase III trial named PARAMOUNT has demonstrated a clinical ly significant benefit in overall survival with a good safety profile versus placebo in favour of continuation maintenance with pemetrexed after four cycles of induction with cisplatin plus pemetrexed . Continuation maintenance can be considered the true maintenance strategy because switch maintenance is an early second-line treatment . Continuation maintenance with pemetrexed after cisplatin plus pemetrexed induction for patients selected for a maintenance strategy is recommended as first-line treatment of advanced non-squamous NSCLC PURPOSE Gefitinib is a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase . We conducted a phase III trial to evaluate whether gefitinib improves survival as sequential therapy after platinum-doublet chemotherapy in patients with advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Chemotherapy-naïve patients with advanced stage ( IIIB/IV ) NSCLC , Eastern Cooperative Oncology Group performance status of 0 to 1 , and adequate organ function were r and omly assigned to either platinum-doublet chemotherapy up to six cycles ( arm A ) or platinum-doublet chemotherapy for three cycles followed by gefitinib 250 mg orally once daily , until disease progression ( arm B ) . Patients were stratified by disease stage , sex , histology , and chemotherapy regimens . The primary end point was overall survival ; secondary end points included progression-free survival , tumor response , safety , and quality of life . Results Between March 2003 and May 2005 , 604 patients were r and omly assigned . There was a statistically significant improvement in progression-free survival in arm B ( hazard ratio [ HR ] , 0.68 ; 95 % CI , 0.57 to 0.80 ; P < .001 ) ; however , overall survival results did not reach statistical significance ( HR , 0.86 ; 95 % CI , 0.72 to 1.03 ; P = .11 ) . In an exploratory subset analysis of overall survival by histologic group , patients in arm B with adenocarcinoma did significantly better than patients in arm A with adenocarcinoma ( n = 467 ; HR , 0.79 ; 95 % CI , 0.65 to 0.98 ; P = .03 ) . CONCLUSION This trial failed to meet the primary end point of OS in patients with NSCLC . The exploratory subset analyses demonstrate a possible survival prolongation for sequential therapy of gefitinib , especially for patients with adenocarcinoma PURPOSE Epidermal growth factor receptor ( EGFR ) gene copy number detected by fluorescent in situ hybridization ( FISH ) has proven to be useful for selection of non-small-cell lung cancer ( NSCLC ) patients for treatment with EGFR tyrosine kinase inhibitors .  Here , we evaluate EGFR FISH as a predictive marker in NSCLC patients receiving the EGFR monoclonal antibody inhibitor cetuximab plus chemotherapy .  PATIENTS AND METHODS Two hundred twenty-nine chemotherapy-naive patients with advanced-stage NSCLC were enrolled onto a phase II selection trial evaluating sequential or concurrent chemotherapy ( paclitaxel plus carboplatin ) with cetuximab . RESULTS EGFR FISH was assessable in 76 patients with available tumor tissue and classified as positive ( four or more gene copies per cell in > /= 40 % of the cells or gene amplification ) in 59.2 % . Response ( complete response/partial response ) was numerically higher in FISH-positive ( 45 % ) versus FISH-negative ( 26 % ) patients ( P = .14 ) , whereas disease control rate ( complete response/partial response plus stable disease ) was statistically superior ( 81 % v 55 % , respectively ; P = .02 ) . Patients with FISH-positive tumors had a median progression-free survival time of 6 months compared with 3 months for FISH-negative patients ( P = .0008 ) . Median survival time was 15 months for the FISH-positive group compared with 7 months for patients who were FISH negative . ( P = .04 ) . Furthermore , survival favored FISH-positive patients receiving concurrent therapy . CONCLUSION These results are the first to suggest that EGFR FISH is a predictive factor for selection of NSCLC patients for cetuximab plus chemotherapy . Prospect i ve validation of these findings is warranted PURPOSE An American Society of Clinical Oncology ( ASCO ) provisional clinical opinion ( PCO ) offers timely clinical direction to ASCO 's membership following publication or presentation of potentially practice -changing data from major studies . This PCO addresses the clinical utility of using epidermal growth factor receptor ( EGFR ) mutation testing for patients with advanced non-small-cell lung cancer ( NSCLC ) to predict the benefit of taking a first-line EGFR tyrosine kinase inhibitor ( TKI ) . CLINICAL CONTEXT Patients with EGFR-mutated NSCLC have a significantly higher rate of partial responses to the EGFR TKIs gefitinib and erlotinib . In the United States , approximately 15 % of patients with adenocarcinoma of the lung harbor activating EGFR mutations . EGFR mutation testing is widespread at academic medical centers and in some locales in community practice . As of yet , there is no evidence of an overall survival ( OS ) benefit from selecting treatment based on performing this testing . RECENT DATA One large phase III trial ( the Iressa Pan-Asia Study [ IPASS ] trial ) , three smaller phase III r and omized controlled trials using progression-free survival as the primary end point , and one small phase III trial with OS as the primary end point , all involving first-line EGFR TKIs and chemotherapy doublets , form the basis of this PCO . PROVISIONAL CLINICAL OPINION On the basis of the results of five phase III r and omized controlled trials , patients with NSCLC who are being considered for first-line therapy with an EGFR TKI ( patients who have not previously received chemotherapy or an EGFR TKI ) should have their tumor tested for EGFR mutations to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy . NOTE . ASCO 's provisional clinical opinions ( PCOs ) reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision making and identify questions and setting s for further research . Because of the rapid flow of scientific information in oncology , new evidence may have emerged since the time a PCO was su bmi tted for publication . PCOs are not continually up date d and may not reflect the most recent evidence . PCOs can not account for individual variation among patients and can not be considered inclusive of all proper methods of care or exclusive of other treatments . It is the responsibility of the treating physician or other health care provider , relying on independent experience and knowledge of the patient , to determine the best course of treatment for the patient . Accordingly , adherence to any PCO is voluntary , with the ultimate determination regarding its application to be made by the physician in light of each patient 's individual circumstances . ASCO PCOs describe the use of procedures and therapies in clinical practice and can not be assumed to apply to the use of these interventions in the context of clinical trials . ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO 's PCOs , or for any errors or omissions BACKGROUND In an early-phase study involving patients with advanced non-small-cell lung cancer ( NSCLC ) , the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy , particularly among patients with tumors that expressed programmed death lig and 1 ( PD-L1 ) . Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC . METHODS In this open-label , phase 3 trial , we r and omly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1 % or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab , nivolumab alone , or chemotherapy .  The patients who had a PD-L1 expression level of less than 1 % were r and omly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab , nivolumab plus chemotherapy , or chemotherapy alone .  All the patients had received no previous chemotherapy . The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1 % or more . RESULTS Among the patients with a PD-L1 expression level of 1 % or more , the median duration of overall survival was 17.1 months ( 95 % confidence interval [ CI ] , 15.0 to 20.1 ) with nivolumab plus ipilimumab and 14.9 months ( 95 % CI , 12.7 to 16.7 ) with chemotherapy ( P = 0.007 ) , with 2-year overall survival rates of 40.0 % and 32.8 % , respectively . The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy . The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1 % , with a median duration of 17.2 months ( 95 % CI , 12.8 to 22.0 ) with nivolumab plus ipilimumab and 12.2 months ( 95 % CI , 9.2 to 14.3 ) with chemotherapy . Among all the patients in the trial , the median duration of overall survival was 17.1 months ( 95 % CI , 15.2 to 19.9 ) with nivolumab plus ipilimumab and 13.9 months ( 95 % CI , 12.2 to 15.1 ) with chemotherapy . The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8 % with nivolumab plus ipilimumab and 36.0 % with chemotherapy . CONCLUSIONS First-line treatment with nivolumab plus ipilimumab result ed in a longer duration of overall survival than did chemotherapy in patients with NSCLC , independent of the PD-L1 expression level . No new safety concerns emerged with longer follow-up . ( Funded by Bristol-Myers Squibb and Ono Pharmaceutical ; CheckMate 227 Clinical Trials.gov number , NCT02477826 . ) PURPOSE This guideline presents evidence -based recommendations for stereotactic body radiation therapy ( SBRT ) in challenging clinical scenarios in early-stage non-small cell lung cancer ( NSCLC ) . METHODS AND MATERIAL S The American Society for Radiation Oncology convened a task force to perform a systematic literature review on 4 key questions addressing : ( 1 ) application of SBRT to operable patients ; ( 2 ) appropriate use of SBRT in tumors that are central ly located , large , multifocal , or unbiopsied ; ( 3 ) individual tailoring of SBRT in " high-risk " clinical scenarios ; and ( 4 ) SBRT as salvage therapy after recurrence . Guideline recommendations were created using a predefined consensus-building methodology supported by American Society for Radiation Oncology-approved tools for grading evidence quality and recommendation strength . RESULTS Although few r and omized trials have been completed for SBRT , strong consensus recommendations based on extensive , consistent publications were generated for several questions , including recommendations for fractionation for central tumors and surgery versus SBRT in st and ard-risk medically operable patients with early-stage NSCLC . Lower quality evidence led to conditional recommendations on use of SBRT for tumors > 5 cm , patients with prior pneumonectomy , T3 tumors with chest wall invasion , synchronous multiple primary lung cancer , and as a salvage therapy after prior radiation therapy . These areas of moderate- and low- quality evidence highlight the importance of clinical trial enrollment as well as the role of prospect i ve data registries . CONCLUSIONS SBRT has an important role to play in treating early-stage NSCLC , particularly for medically inoperable patients with limited other treatment options . Shared decision-making with patients should be performed in all cases to ensure the patient underst and s the risks related to SBRT , the side effects , and the alternative treatments available BACKGROUND Pembrolizumab is a humanized monoclonal antibody against programmed death 1 ( PD-1 ) that has antitumor activity in advanced non-small-cell lung cancer ( NSCLC ) , with increased activity in tumors that express programmed death lig and 1 ( PD-L1 ) . METHODS In this open-label , phase 3 trial , we r and omly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50 % of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab ( at a fixed dose of 200 mg every 3 weeks ) or the investigator 's choice of platinum-based chemotherapy .  Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression . The primary end point , progression-free survival , was assessed by means of blinded , independent , central radiologic review . Secondary end points were overall survival , objective response rate , and safety . RESULTS Median progression-free survival was 10.3 months ( 95 % confidence interval [ CI ] , 6.7 to not reached ) in the pembrolizumab group versus 6.0 months ( 95 % CI , 4.2 to 6.2 ) in the chemotherapy group ( hazard ratio for disease progression or death , 0.50 ; 95 % CI , 0.37 to 0.68 ; P<0.001 ) . The estimated rate of overall survival at 6 months was 80.2 % in the pembrolizumab group versus 72.4 % in the chemotherapy group ( hazard ratio for death , 0.60 ; 95 % CI , 0.41 to 0.89 ; P=0.005 ) . The response rate was higher in the pembrolizumab group than in the chemotherapy group ( 44.8 % vs. 27.8 % ) , the median duration of response was longer ( not reached [ range , 1.9 + to 14.5 + months ] vs. 6.3 months [ range , 2.1 + to 12.6 + ] ) , and treatment-related adverse events of any grade were less frequent ( occurring in 73.4 % vs. 90.0 % of patients ) , as were grade 3 , 4 , or 5 treatment-related adverse events ( 26.6 % vs. 53.3 % ) . CONCLUSIONS In patients with advanced NSCLC and PD-L1 expression on at least 50 % of tumor cells , pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy . ( Funded by Merck ; KEYNOTE-024 Clinical Trials.gov number , NCT02142738 . ) Background The objective of the study was to observe the efficacy and safety of pulsatile administration of high‐dose gefitinib or erlotinib in patients with advanced non‐small cell lung cancer ( NSCLC ) with secondary drug resistance to st and ard doses of tyrosine kinase inhibitor ( TKI ) treatment . Material s and methods We recruited 42 NSCLC patients from our hospital , between August 2014 and December 2015 , who had experienced drug resistance after one year of conventional treatment with gefitinib or erlotinib . The gefitinib group ( 29 patients ) received one dose of 1000 mg gefitinib every four days . The erlotinib group ( 13 patients ) received one dose of 450 mg erlotinib every three days . Treatments continued until disease progression according to Response Evaluation Criteria In Solid Tumors 1.1 or development of intolerable toxicity . Results Median progression‐free survival ( PFS ) was 30 months ( gefitinib vs. erlotinib : 31 vs. 24 months ; P > 0.05 ) . After high‐dose pulsatile administration , eight patients achieved a partial response ( PR ) , 11 had stable disease ( SD ) , and 23 had progressive disease ( PD ; relative risk 19.0 % ; disease control rate 45.2 % ; median PFS six months ) . Patients were categorized based on epidermal growth factor receptor gene mutation : exon 19 ( no patients achieved complete response [ CR ] , 4 PR , 6 SD , and 17 PD ) and exon 21 mutation groups ( no patients achieved CR , 4 PR , 5 SD , and 6 PD ) . Conclusion High‐dose TKI pulsatile treatment is safe , efficient , and can improve prognoses for certain patients with advanced NSCLC BACKGROUND Immune checkpoint inhibitors ( ICIs ) are available for first- and further lines of treatment of patients with advanced non-small-cell lung cancer ( NSCLC ) . These treatments are associated with adverse events called immune-related adverse events ( IRAEs ) . The incidence , diagnosis , and treatment of IRAEs are quite acknowledged ; however , the link between IRAEs and the efficacy of ICIs requires further clarification . The objectives of this study were to assess the association between IRAEs incidence and severity and ICIs efficacy in patients with advanced NSCLC . METHODS In this retrospective study , clinical , biological , treatment , and outcome data were collected from patients with advanced NSCLC who received at least 1 cycle of ICIs from April 2013 to February 2017 . The primary endpoint was to assess the association of IRAEs incidence with overall survival ( OS ) . Secondary endpoints were the association of IRAEs with progression-free survival ( PFS ) , objective response rate ( ORR ) , and disease control rate ( DCR ) . RESULTS Overall , 270 patients were studied . The median OS was 14 months , median PFS was 2.6 months , ORR was 13 % , and DCR was 51 % . OS , PFS , and ORR were significantly better for patients with IRAEs compared with patients with no IRAEs , translating to median OS not reached versus 8.21 months , respectively ( hazard ratio , 0.29 ; 95 % confidence interval [ CI ] , 0.18 - 0.46 ; P < .001 ) ; PFS was 5.2 versus 1.97 months ( hazard ratio , 0.42 ; 95 % CI , 0.32 - 0.57 ; P < .001 ) ; and ORR was 212.9 % versus 5.7 % ( odds ratio , 4.9 ; 95 % CI , 2.18 - 11.05 ; P < .001 ) . CONCLUSIONS This report presents the largest case series showing longer OS and PFS and better ORR when IRAEs occurred in a population of patients with advanced NSCLC treated with ICIs . The biological background for this phenomenon is being explored prospect ively The discovery of RET fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes . In an unselected population of non-small cell lung carcinomas ( NSCLCs ) , RET fusions are present in 1 % to 2 % of cases . This incidence increases substantially , however , in never-smokers with lung adenocarcinomas that lack other known driver oncogenes . Although pre clinical data provide experimental support for the use of RET inhibitors in the treatment of RET fusion-positive tumors , clinical data on response are lacking . We report preliminary data for the first three patients treated with the RET inhibitor cabozantinib on a prospect i ve phase II trial for patients with RET fusion-positive NSCLCs ( NCT01639508 ) . Confirmed partial responses were observed in 2 patients , including one harboring a novel TRIM33-RET fusion . A third patient with a KIF5B-RET fusion has had prolonged stable disease approaching 8 months ( 31 weeks ) . All three patients remain progression-free on treatment Several r and omized trials have demonstrated non-small cell lung cancer ( NSCLC ) patients with activating epidermal growth factor receptor ( EGFR ) mutations can achieve favorable clinical outcomes on treatment with EGFR tyrosine kinase inhibitors ( TKIs ) . EGFR mutation is considered as a predictive marker for efficacy of EGFR-TKIs in NSCLC . Here we show miR-200c overexpression was correlated with the epithelial phenotype and sensitivity to gefitinib in EGFR wild-type NSCLC cell lines . Up-regulated miR-200c could regain the sensitivity to gefitinib in the EGFR wild-type cell lines and miR-200c could regulate epithelial to mesenchymal transition through PI3K/AKT and MEK/ERK pathways . NSCLC patients at advanced stage ( N=150 ) who received EGFR-TKIs ( gefitinib or erlotinib ) as second- or third-line therapy from September 2008 to December 2012 were included in the study . In 66 NSCLC patients with wild-type EGFR , high levels of miR-200c expression was associated with higher disease control rate ( DCR ) , longer progression-free survival ( PFS ) and longer overall survival ( OS ) compared with low miR-200c expression subgroup . In the subgroup with EGFR mutation , the trend remained the same but not statistically significant . Overall , these findings indicated that miR-200c might be a predictive biomarker for sensitivity to EGFR-TKIs  in advanced NSCLC patients with wild-type EGFR Introduction Lung cancer , the most prevalent malignant cancer in the world , remains a serious threat to public health . Recently , a large number of studies have shown that an epidermoid growth factor receptor-tyrosine kinase inhibitor ( EGFR TKI ) , Erlotinib , has significantly better efficacy and is better tolerated in advanced non-small cell lung cancer ( NSCLC ) patients with a positive EGFR gene mutation . However , access to this drug is severely limited in China due to its high acquisition cost . Therefore , we decided to conduct a study to compare cost-effectiveness between erlotinib monotherapy and carboplatin-gemcitabine ( CG ) combination therapy in patients with advanced EGFR mutation-positive NSCLC . Methods A Markov model was developed from the perspective of the Chinese health care system to evaluate the cost-effectiveness of the two treatment strategies ; this model was based on data from the OPTIMAL trial , which was undertaken at 22 centres in China . The 10-year quality -adjusted life years ( QALYs ) , direct costs , and incremental cost-effectiveness ratio ( ICER ) were estimated . To allow for uncertainties within the parameters and to estimate the model robustness , one-way sensitivity analysis and probabilistic sensitivity analysis were performed . Results The median progression-free survival ( PFS ) obtained from Markov model was 13.2 months ( 13.1 months was reported in the trial ) in the erlotinib group while and 4.64 months ( 4.6 months was reported in the trial ) in the CG group . The QALYs were 1.4 years in the erlotinib group and 1.96 years in the CG group , indicating difference of 0.56 years . The ICER was most sensitive to the health utility of DP ranged from $ 58,584.57 to $ 336,404.2 . At a threshold of $ 96,884 , erlotinib had a 50%probability of being cost-effective . Conclusions Erlotinib monotherapy is more cost-effective compared with platinum-based doublets chemotherapy as a first-line therapy for advanced EGFR mutation- positive NSCLC patients from within the Chinese health care system The European Society of Thoracic Surgeons ( ESTS ) organized a workshop dealing with lymph node staging in non-small cell lung cancer . The objective of this workshop was to develop guidelines for definitions and the surgical procedures of intraoperative lymph node staging , and the pathologic evaluation of resected lymph nodes in patients with non-small cell lung cancer ( NSCLC ) . Relevant peer- review ed publications on the subjects , the experience of the participants , and the opinion of the ESTS members contributing on line , were used to reach a consensus . Systematic nodal dissection is recommended in all cases to ensure complete resection . Lobe-specific systematic nodal dissection is acceptable for peripheral squamous T1 tumors , if hilar and interlobar nodes are negative on frozen section studies ; it implies removal of , at least , three hilar and interlobar nodes and three mediastinal nodes from three stations in which the subcarinal is always included . Selected lymph node biopsies and sampling are justified to prove nodal involvement when resection is not possible . Pathologic evaluation includes all lymph nodes resected separately and those remaining in the lung specimen . Sections are done at the site of gross abnormalities . If macroscopic inspection does not detect any abnormal site , 2-mm slices of the nodes in the longitudinal plane are recommended . Routine search for micrometastases or isolated tumor cells in hematoxylin-eosin negative nodes would be desirable . R and omized controlled trials to evaluate adjuvant therapies for patients with these conditions are recommended . The adherence to these guidelines will st and ardize the intraoperative lymph node staging and pathologic evaluation , and improve pathologic staging , which will help decide on the best adjuvant therapy BACKGROUND Molecular studies have demonstrated actionable driver oncogene alterations are more frequent in never-smokers with non-small-cell lung cancer ( NSCLC ) . The etiology of these driver oncogenes in patients with NSCLC remains unknown , and environmental tobacco smoke ( ETS ) is a potential cause in these cases . MATERIAL S AND METHODS We assembled clinical and genetic information for never-smoker patients with NSCLC accrued in Japan , Korea , Singapore , and the United States . To determine an association between cumulative ETS and activating EGFR mutations or ALK rearrangements , the Mantel extension test was used . Multivariate analysis on activating EGFR and ALK gene rearrangements was performed using the generalized linear mixed model with nations as a r and om effect . RESULTS From July 2007 to December 2012 , 498 never-smokers with pathologically proven NSCLC were registered and tested for the association between ETS and EGFR and ALK status . EGFR mutations were more frequent in the ever-ETS cohort ( 58.4 % ) compared with the never-ETS cohort ( 39.6 % ) , and the incidence of EGFR mutations was significantly associated with the increment of cumulative ETS ( cETS ) in female never-smokers ( P = .033 ) , whereas the incidence of ALK rearrangements was not significantly different between the ever-ETS and never-ETS cohorts . Odds ratio for EGFR mutations for each 10-year increment in cETS was 1.091 and 0.89 for female and male never-smokers ( P = .031 and P = .263 , respectively ) . CONCLUSION Increased ETS exposure was closely associated with EGFR mutations in female never-smokers with NSCLC in the exp and ed multinational cohort . However , the association of ETS and ALK rearrangements in never-smokers with NSCLC was not significant BACKGROUND Antibodies targeting the immune checkpoint molecules PD-1 or PD-L1 have demonstrated clinical efficacy in patients with metastatic non-small-cell lung cancer ( NSCLC ) . In this trial we investigated the efficacy and safety of avelumab , an anti-PD-L1 antibody , in patients with NSCLC who had already received platinum-based therapy . METHODS JAVELIN Lung 200 was a multicentre , open-label , r and omised , phase 3 trial at 173 hospitals and cancer treatment centres in 31 countries . Eligible patients were aged 18 years or older and had stage IIIB or IV or recurrent NSCLC and disease progression after treatment with a platinum-containing doublet , an Eastern Cooperative Oncology Group performance status score of 0 or 1 , an estimated life expectancy of more than 12 weeks , and adequate haematological , renal , and hepatic function . Participants were r and omly assigned ( 1:1 ) , via an interactive voice-response system with a stratified permuted block method with variable block length , to receive either avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m2 every 3 weeks . R and omisation was stratified by PD-L1 expression ( ≥1 % vs < 1 % of tumour cells ) , which was measured with the 73 - 10 assay , and histology ( squamous vs non-squamous ) . The primary endpoint was overall survival , analysed when roughly 337 events ( deaths ) had occurred in the PD-L1-positive population . Efficacy was analysed in all PD-L1-positive patients ( ie , PD-L1 expression in ≥1 % of tumour cells ) r and omly assigned to study treatment ( the primary analysis population ) and then in all r and omly assigned patients through a hierarchical testing procedure . Safety was analysed in all patients who received at least one dose of study treatment . This trial is registered with Clinical Trials.gov , number NCT02395172 . Enrolment is complete , but the trial is ongoing . FINDINGS Between March 24 , 2015 , and Jan 23 , 2017 , 792 patients were enrolled and r and omly assigned to receive avelumab ( n=396 ) or docetaxel ( n=396 ) . 264 participants in the avelumab group and 265 in the docetaxel group had PD-L1-positive tumours . In patients with PD-L1-positive tumours , median overall survival did not differ significantly between the avelumab and docetaxel groups ( 11·4 months [ 95 % CI 9·4 - 13·9 ] vs 10·3 months [ 8·5 - 13·0 ] ; hazard ratio 0·90 [ 96 % CI 0·72 - 1·12 ] ; one-sided p=0·16 ) . Treatment-related adverse events occurred in 251 ( 64 % ) of 393 avelumab-treated patients and 313 ( 86 % ) of 365 docetaxel-treated patients , including grade 3 - 5 events in 39 ( 10 % ) and 180 ( 49 % ) patients , respectively . The most common grade 3 - 5 treatment-related adverse events were infusion-related reaction ( six patients [ 2 % ] ) and increased lipase ( four [ 1 % ] ) in the avelumab group and neutropenia ( 51 [ 14 % ] ) , febrile neutropenia ( 37 [ 10 % ] ) , and decreased neutrophil counts ( 36 [ 10 % ] ) in the docetaxel group . Serious treatment-related adverse events occurred in 34 ( 9 % ) patients in the avelumab group and 75 ( 21 % ) in the docetaxel group . Treatment-related deaths occurred in four ( 1 % ) participants in the avelumab group , two due to interstitial lung disease , one due to acute kidney injury , and one due to a combination of autoimmune myocarditis , acute cardiac failure , and respiratory failure . Treatment-related deaths occurred in 14 ( 4 % ) patients in the docetaxel group , three due to pneumonia , and one each due to febrile neutropenia , septic shock , febrile neutropenia with septic shock , acute respiratory failure , cardiovascular insufficiency , renal impairment , leucopenia with mucosal inflammation and pyrexia , infection , neutropenic infection , dehydration , and unknown causes . INTERPRETATION Compared with docetaxel , avelumab did not improve overall survival  in patients with platinum-treated PD-L1-positive NSCLC , but had a favourable safety profile . FUNDING Merck and Pfizer BACKGROUND Alisertib is an investigational , oral , selective inhibitor of aurora kinase A. We aim ed to investigate the safety and activity of single-agent alisertib in patients with predefined types of advanced solid tumours . METHODS We did a multicentre phase 1/2 study at 40 centres in four countries ( Czech Republic , France , Pol and , and the USA ) . Here , we report results from phase 2 ; enrolment for the study began on Feb 16 , 2010 , and ended on May 3 , 2013 . Adult patients were eligible for the study if they had either breast cancer , small-cell lung cancer , non-small-cell lung cancer , head and neck squamous-cell carcinoma , or gastro-oesophageal adenocarcinoma that had relapsed or was refractory to chemotherapy . Patients had to have undergone two or fewer previous cytotoxic regimens ( four or fewer for breast cancer patients ) , not including adjuvant or neoadjuvant treatments . Enrolment followed a two-stage design : to proceed to the second stage , two or more objective responses were needed in the first 20 response-assessable patients in each of the five tumour cohorts . Alisertib was administered orally in 21-day cycles at the recommended phase 2 dose of 50 mg twice daily for 7 days followed by a break of 14 days . The protocol -specified primary endpoint was the proportion of patients with an objective response , assessed by Response Evaluation Criteria In Solid Tumors version 1.1 in the response-assessable population ( ie , patients with measurable disease who received at least one dose of alisertib and had undergone at least one post-baseline tumour assessment ) . This completed trial is registered with Clinical Trials.gov , NCT01045421 . FINDINGS By May 31 , 2013 , 249 patients had been treated , 53 with breast cancer , 60 with small-cell lung cancer , 26 with non-small-cell lung cancer , 55 with head and neck squamous-cell carcinoma , and 55 with gastro-oesophageal adenocarcinoma . Among response-assessable patients , an objective response was noted in nine ( 18 % , 95 % CI 9 - 32 ) of 49 women with breast cancer , ten ( 21 % , 10 - 35 ) of 48 participants with small-cell lung cancer , one ( 4 % , 0 - 22 ) of 23 patients with non-small-cell lung cancer , four ( 9 % , 2 - 21 ) of 45 people with head and neck squamous-cell carcinoma , and four ( 9 % , 2 - 20 ) of 47 individuals with gastro-oesophageal adenocarcinoma ; all were partial responses . Adverse events were similar across tumour types . The most frequent drug-related grade 3 - 4 adverse events included neutropenia ( n=107 [ 43 % ] ) , leukopenia ( 53 [ 21 % ] ) , and anaemia ( 26 [ 10 % ] ) . Serious drug-related adverse events were reported in 108 ( 43 % ) patients . INTERPRETATION These data support further clinical assessment of alisertib in patients with solid tumours , particularly those with breast cancer and small-cell lung cancer . FUNDING Millennium Pharmaceuticals , Inc , a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Purpose : To determine the immunologic effects of neoadjuvant chemotherapy plus ipilimumab in early-stage non – small cell lung cancer ( NSCLC ) patients . Experimental Design : This is a single-arm chemotherapy plus phased ipilimumab phase II study of 24 treatment-naïve patients with stage IB – IIIA NSCLC . Patients received neoadjuvant therapy consisting of 3 cycles of paclitaxel with either cisplatin or carboplatin and ipilimumab included in the last 2 cycles . Results : Chemotherapy alone had little effect on immune parameters in P BMC s. Profound CD28-dependent activation of both CD4 and CD8 cells was observed following ipilimumab . Significant increases in the frequencies of CD4 + cells expressing activation markers ICOS , HLA-DR , CTLA-4 , and PD-1 were apparent . Likewise , increased frequencies of CD8 + cells expressing the same activation markers , with the exception of PD-1 , were observed . We also examined 7 resected tumors and found higher frequencies of activated tumor-infiltrating lymphocytes than those observed in P BMC s. Surprisingly , we found 4 cases of preexisting tumor-associated antigens ( TAA ) responses against survivin , PRAME , or MAGE-A3 present in P BMC at baseline , but neither increased frequencies nor the appearance of newly detectable responses following ipilimumab therapy . Ipilimumab had little effect on the frequencies of circulating regulatory T cells and MDSCs . Conclusions : This study did not meet the primary endpoint of detecting an increase in blood-based TAA T-cell responses after ipilimumab . Collectively , these results highlight the immune activating properties of ipilimumab in early-stage NSCLC . The immune profiling data for ipilimumab alone can contribute to the interpretation of immunologic data from combined immune checkpoint blockade immunotherapies . Clin Cancer Res ; 23(24 ) ; 7474–82 . © 2017 AACR CONTEXT More persons in the United States die from non-small cell lung cancer ( NSCLC ) than from breast , colorectal , and prostate cancer combined . In pre clinical testing , oral gefitinib inhibited the growth of NSCLC tumors that express the epidermal growth factor receptor ( EGFR ) , a mediator of cell signaling , and phase 1 trials have demonstrated that a fraction of patients with NSCLC progressing after chemotherapy experience both a decrease in lung cancer symptoms and radiographic tumor shrinkages with gefitinib . OBJECTIVE To assess differences in symptomatic and radiographic response among patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib .  DESIGN , SETTING , AND PATIENTS Double-blind , r and omized phase 2 trial conducted from November 2000 to April 2001 in 30 US academic and community oncology centers . Patients ( N = 221 ) had either stage IIIB or IV NSCLC for which they had received at least 2 chemotherapy regimens . INTERVENTION Daily oral gefitinib , either 500 mg ( administered as two 250-mg gefitinib tablets ) or 250 mg ( administered as one 250-mg gefitinib tablet and 1 matching placebo ) . MAIN OUTCOME MEASURES Improvement of NSCLC symptoms ( 2-point or greater increase in score on the summed lung cancer subscale of the Functional Assessment of Cancer Therapy-Lung [ FACT-L ] instrument ) and tumor regression ( > 50 % decrease in lesion size on imaging studies ) . RESULTS Of 221 patients enrolled , 216 received gefitinib as r and omized . Symptoms of NSCLC improved in 43 % ( 95 % confidence interval [ CI ] , 33%-53 % ) of patients receiving 250 mg of gefitinib and in 35 % ( 95 % CI , 26%-45 % ) of patients receiving 500 mg . These benefits were observed within 3 weeks in 75 % of patients . Partial radiographic responses occurred in 12 % ( 95 % CI , 6%-20 % ) of individuals receiving 250 mg of gefitinib and in 9 % ( 95 % CI , 4%-16 % ) of those receiving 500 mg . Symptoms improved in 96 % of patients with partial radiographic responses . The overall survival at 1 year was 25 % . There were no significant differences between the 250-mg and 500-mg doses in rates of symptom improvement ( P = .26 ) , radiographic tumor regression ( P = .51 ) , and projected 1-year survival ( P = .54 ) . The 500-mg dose was associated more frequently with transient acne-like rash ( P = .04 ) and diarrhea ( P = .006 ) . CONCLUSIONS Gefitinib , a well-tolerated oral EGFR-tyrosine kinase inhibitor , improved disease-related symptoms and induced radiographic tumor regressions in patients with NSCLC persisting after chemotherapy e18015 Background : Significant advances in the systemic management of metastatic non-small cell lung cancer ( NSCLC ) have occurred over the past decade , with options now including multiple lines of chemotherapy , EGFR inhibitors , and anti-angiogenic agents . Improvements in overall survival have been demonstrated in r and omized controlled trials comparing these newer agents to best supportive care ( BSC ) or st and ard therapy . This study examined uptake of these therapies in general practice and their impact on survival . METHODS This retrospective cohort study compared demographic , treatment and survival data among 987 patients diagnosed with stage IV NSCLC at two institutions in 1998 , 2003 , and 2008 . Cohorts were selected based on intervals when doublet chemotherapy , second line chemotherapy , and targeted agents were incorporated into the st and ard treatment regimen . RESULTS The proportion of patients receiving systemic therapy increased over time ( 20 % in 1998 , 42 % in 2008 ) . Treated patients diagnosed in 2008 were more likely to receive ≥2 lines of systemic therapy ( 60 % vs. 7 % in 1998 ) . Overall survival improved significantly across cohorts ( P < 0.001 ) , with 2 year survival rates of 0.3 % in 1998 , 4 % in 2003 , and 15 % in 2008 . After controlling for other variables , risk of death was diminished by 55 % in patients receiving 1 line of systemic therapy and 72 % in those receiving ≥2 lines , compared with BSC alone . Elderly patients ( age ≥70 years ) were also more likely to receive systemic therapy over time , with improved overall survival ( P < 0.001 ) . CONCLUSIONS Over the past decade , there has been increased use of systemic therapy in stage IV NSCLC patients , including the elderly . This has been associated with significantly improved overall survival OBJECTIVE Dose delays and reductions in chemotherapy due to hematologic toxicities are common among patients with advanced non-small cell lung cancer ( NSCLC ) . However , limited data on behavioral or psychological predictors of chemotherapy adherence exist . The goal of this study was to explore the frequency and clinical predictors of infusion dose delays and reductions in this patient population . METHODS Fifty patients newly diagnosed with advanced NSCLC of high performance status ( Eastern Cooperative Oncology Group Performance Status=0 - 1 ) completed baseline assessment s on quality of life ( Functional Assessment of Cancer Therapy - Lung ) and  mood ( Hospital Anxiety and Depression Scale ) within 8 weeks of diagnosis . Participants were followed prospect ively for 6 months . Chemotherapy dosing data came from medical chart review . RESULTS All patients received chemotherapy during the course of the study , beginning with a platinum-based doublet ( 74 % ) , an oral epidermal growth factor receptor-tyrosine kinase inhibitor ( 14 % ) , or a parenteral single agent ( 12 % ) . Forty percent ( n=20 ) of patients had a dose delay ( 38 % ) and /or reduction ( 16 % ) in their scheduled infusions . Fisher 's Exact Tests and regression analyses showed that patients who experienced neutropenia , smoked at the time of diagnosis , or reported heightened baseline anxiety were significantly more likely to experience dose delays or reductions . There were no associations between  chemotherapy adherence and patient demographics , performance status , or quality of life . CONCLUSION In this sample , more than one third of patients with advanced NSCLC experienced either a dose delay or reduction in prescribed chemotherapy regimens . Behavioral and psychological factors , such as tobacco use and anxiety symptoms , appear to play an important role in chemotherapy adherence , though further study is required to confirm these findings Based on clinical assessment alone , patients with stage II non-small cell lung cancer ( NSCLC ) comprise only 5 % of all patients with NSCLC . In addition , patients with stage II NSCLC represent a heterogeneous group , since stage II consists of patients with T1 - 2N1 or T3N0 tumors . By definition , patients with tumor invading the chest wall apex , mediastinum , diaphragm , or even the mainstem bronchus may all have T3 tumors . The extent of the data available regarding treatment of each of these different groups is therefore limited . The quality of the data is limited as well , because information often comes from small series of patients . Studies of adjuvant therapy after complete resection of stage II NSCLC are an important exception to this generalization , since data from large , r and omized studies of adjuvant radiation therapy , chemotherapy , or a combination of the two are available for analysis . Superior sulcus tumors are discussed elsewhere in these guidelines PURPOSE Non-small-cell lung cancers ( NSCLCs ) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors . We sought to describe the clinical , pathologic , and genomic characteristics of patients with cancer with MET exon 14 mutations . PATIENTS AND METHODS We interrogated next-generation sequencing results from 6,376 cancers to identify those harboring MET exon 14 mutations . Clinical characteristics of MET exon 14 mutated NSCLCs were compared with those of NSCLCs with activating mutations in KRAS and EGFR . Co-occurring genomic mutations and copy number alterations were identified . c-Met immunohistochemistry and real-time polymerase chain reaction to detect exon 14 skipping were performed where sufficient tissue was available . RESULTS MET exon 14 mutations were identified in 28 of 933 nonsquamous NSCLCs ( 3.0 % ) and were not seen in other cancer types in this study . Patients with MET exon 14-mutated NSCLC were significantly older ( median age , 72.5 years ) than patients with EGFR-mutant ( median age , 61 years ; P < .001 ) or KRAS-mutant NSCLC ( median age , 65 years ; P < .001 ) . Among patients with MET exon 14 mutations , 68 % were women , and 36 % were never-smokers . Stage IV MET exon 14-mutated NSCLCs were significantly more likely to have concurrent MET genomic amplification ( mean ratio of MET to chromosome 7 , 4.3 ) and strong c-Met immunohistochemical expression ( mean H score , 253 ) than stage IA to IIIB MET exon 14-mutated NSCLCs ( mean ratio of MET to chromosome 7 , 1.4 ; P = .007 ; mean H score , 155 ; P = .002 ) and stage IV MET exon 14-wild-type NSCLCs ( mean ratio of MET to chromosome 7 , 1.2 ; P < .001 ; mean H score , 142 ; P < .001 ) . A patient whose lung cancer harbored a MET exon 14 mutation with concurrent genomic amplification of the mutated MET allele experienced a major partial response to the c-Met inhibitor crizotinib . CONCLUSION MET exon 14 mutations represent a clinical ly unique molecular subtype of NSCLC . Prospect i ve clinical trials with c-Met inhibitors will be necessary to vali date MET exon 14 mutations as an important therapeutic target in NSCLC OBJECTIVE The purpose of this article is to compare the recently published revised Response Evaluation Criteria in Solid Tumors ( RECIST ) guidelines ( version 1.1 ) to the original guidelines ( RECIST 1.0 ) for advanced non-small cell lung cancer ( NSCLC ) after erlotinib therapy and to evaluate the impact of the new CT tumor measurement guideline on response assessment . MATERIAL S AND METHODS Forty-three chemotherapy-naive patients with advanced NSCLC treated with erlotinib in a single-arm phase 2 multicenter open-label clinical trial were retrospectively studied . CT tumor measurement records using RECIST 1.0 that were generated as part of the prospect i ve clinical trial were review ed . A second set of CT tumor measurements  was generated from the records to meet RECIST 1.1 guidelines . The number of target lesions , best response , and time to progression were compared between RECIST 1.1 and RECIST 1.0 . RESULTS The number of target lesions according to RECIST 1.1 decreased in 22 patients ( 51 % ) and did not change in 21 patients ( 49 % ) compared with the number according to RECIST 1.0 ( p < 0.0001 , paired Student 's t test ) . Almost perfect agreement was observed between best responses using RECIST 1.1 and RECIST 1.0 ( weighted kappa = 0.905 ) . Two patients with stable disease according to RECIST 1.0 had progressive disease according to RECIST 1.1 criteria because of new lesions found on PET/CT . There was no significant difference in time to progression between RECIST 1.1 and RECIST 1.0 ( p = 1.000 , sign test ) . CONCLUSION RECIST 1.1 provided almost perfect agreement in response assessment after erlotinib therapy compared with RECIST 1.0 . Assessment with PET/CT was a major factor that influenced the difference in best response assessment between RECIST 1.1 and RECIST 1.0 BACKGROUND Antibodies that block programmed death 1 ( PD‐1 ) protein improve survival in patients with advanced non – small‐cell lung cancer ( NSCLC ) but have not been tested in resectable NSCLC , a condition in which little progress has been made during the past decade . METHODS In this pilot study , we administered two preoperative doses of PD‐1 inhibitor nivolumab in adults with untreated , surgically resectable early ( stage I , II , or IIIA ) NSCLC .  Nivolumab ( at a dose of 3 mg per kilogram of body weight ) was administered intravenously every 2 weeks , with surgery planned approximately 4 weeks after the first dose . The primary end points of the study were safety and feasibility . We also evaluated the tumor pathological response , expression of programmed death lig and 1 ( PD‐L1 ) , mutational burden , and mutation‐associated , neoantigen‐specific T‐cell responses . RESULTS Neoadjuvant nivolumab had an acceptable side‐effect profile and was not associated with delays in surgery . Of the 21 tumors that were removed , 20 were completely resected . A major pathological response occurred in 9 of 20 resected tumors ( 45 % ) . Responses occurred in both PD‐L1–positive and PD‐L1–negative tumors . There was a significant correlation between the pathological response and the pretreatment tumor mutational burden . The number of T‐cell clones that were found in both the tumor and peripheral blood increased systemically after PD‐1 blockade in eight of nine patients who were evaluated . Mutation‐associated , neoantigen‐specific T‐cell clones from a primary tumor with a complete response on pathological assessment rapidly exp and ed in peripheral blood at 2 to 4 weeks after treatment ; some of these clones were not detected before the administration of nivolumab . CONCLUSIONS Neoadjuvant nivolumab was associated with few side effects , did not delay surgery , and induced a major pathological response in 45 % of resected tumors . The tumor mutational burden was predictive of the pathological response to PD‐1 blockade . Treatment induced expansion of mutation‐associated , neoantigen‐specific T‐cell clones in peripheral blood . ( Funded by Cancer Research Institute – St and Up 2 Cancer and others ; Clinical Trials.gov number , NCT02259621 . Purpose ARCHER 1050 , a r and omized , open-label , phase III study of dacomitinib versus gefitinib in treatment-naïve patients with advanced non-small-cell lung cancer ( NSCLC ) and activating mutations in EGFR , reported significant improvement in progression-free survival with dacomitinib . The mature overall survival ( OS ) analysis for the intention-to-treat population is presented here . Patients and Methods In this multinational , multicenter study , patients age 18 years or older ( ≥ 20 years in Japan and Korea ) who had an Eastern Cooperative Oncology Group performance status of 0 or 1 and newly diagnosed NSCLC with activating mutations in EGFR ( exon 19 deletion or exon 21 L858R ) were enrolled and r and omly assigned in a 1:1 manner to dacomitinib ( n = 227 ) or gefitinib ( n = 225 ) . R and om assignment was stratified by race ( Japanese , Chinese , other East Asian , or non-Asian ) and EGFR mutation type . The final OS analysis was conducted with a data cutoff date of February 17 , 2017 ; at that time 220 deaths ( 48.7 % ) were observed . Results During a median follow-up time of 31.3 months , 103 ( 45.4 % ) and 117 ( 52.0 % ) deaths occurred in the dacomitinib and gefitinib arms , respectively . The estimated hazard ratio for OS was 0.760 ( 95 % CI , 0.582 to 0.993 ; two-sided P = .044 ) . The median OS was 34.1 months with dacomitinib versus 26.8 months with gefitinib . The OS probabilities at 30 months were 56.2 % and 46.3 % with dacomitinib and gefitinib , respectively . Preliminary subgroup analyses for OS that are based on baseline characteristics were consistent with the primary OS analysis . Conclusion In patients with advanced NSCLC and EGFR activating mutations  , dacomitinib is the first second-generation epidermal growth factor receptor tyrosine kinase inhibitor ( TKI ) to show significant improvement in OS in a phase III r and omized study compared with a st and ard-of-care TKI . Dacomitinib should be considered one of the st and ard treatment options for these patients BACKGROUND The OPTIMAL study found that erlotinib improved progression-free survival ( PFS ) versus st and ard chemotherapy in Chinese patients with advanced EGFR mutation-positive non-small-cell lung cancer ( NSCLC ) . This report describes the quality of life ( QoL ) and up date d PFS analyses from this study . PATIENTS AND METHODS Chinese patients ≥ 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR ( exon 19 deletion or exon 21 L858R point mutation ) received erlotinib ( 150 mg/day ; n = 82 ) or gemcitabine-carboplatin ( n = 72 ) . The primary efficacy end point was PFS ; QoL was assessed using the Functional Assessment of Cancer Therapy-Lung ( FACT-L ) question naire , Trial Outcome Index ( TOI ) and Lung Cancer Subscale ( LCS ) . RESULTS Patients receiving erlotinib experienced clinical ly relevant improvements in QoL compared with the chemotherapy group in total FACT-L , TOI and LCS ( P < 0.0001 for all scales ) . Erlotinib scored better than chemotherapy for all FACT-L subscales from baseline to cycles 2 and 4 ( non-significant ) . In the up date d analysis , PFS was significantly longer for erlotinib than chemotherapy ( median PFS 13.7 versus 4.6 months ; HR = 0.164 , 95 % CI = 0.105 - 0.256 ; P < 0.0001 ) , which was similar to the previously reported primary analysis . CONCLUSION Erlotinib  improves QoL compared with st and ard chemotherapy in the first-line treatment of patients with EGFR mutation-positive advanced NSCLC BACKGROUND Outcomes are poor for patients with previously treated , advanced or metastatic non-small-cell lung cancer ( NSCLC ) . The anti-programmed death lig and 1 ( PD-L1 ) antibody atezolizumab is clinical ly active against cancer , including NSCLC , especially cancers expressing PD-L1 on tumour cells , tumour-infiltrating immune cells , or both . We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC , analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population . METHODS In this open-label , phase 2 r and omised controlled trial , patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practice s across 13 countries in Europe and North America . Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1 , measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 ( RECIST v1.1 ) , and adequate haematological and end-organ function . Patients were stratified by PD-L1 tumour-infiltrating immune cell status , histology , and previous lines of therapy , and r and omly assigned ( 1:1 ) by permuted block r and omisation ( with a block size of four ) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2 ) once every 3 weeks . Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells ( as percentage of PD-L1-expressing tumour cells TC3≥50 % , TC2≥5 % and < 50 % , TC1≥1 % and < 5 % , and TC0<1 % ) and tumour-infiltrating immune cells ( as percentage of tumour area : IC3≥10 % , IC2≥5 % and < 10 % , IC1≥1 % and < 5 % , and IC0<1 % ) . The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths . Biomarkers were assessed in an exploratory analysis . We assessed safety in all patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT01903993 . FINDINGS Patients were enrolled between Aug 5 , 2013 , and March 31 , 2014 . 144 patients were r and omly allocated to the  atezolizumab group , and 143 to the docetaxel group . 142 patients received at least one dose of atezolizumab and 135 received docetaxel  . Overall survival in the intention-to-treat population was 12·6 months ( 95 % CI 9·7 - 16·4 ) for atezolizumab versus 9·7 months ( 8·6 - 12·0 ) for docetaxel ( hazard ratio [ HR ] 0·73 [ 95 % CI 0·53 - 0·99 ] ; p=0·04 ) . Increasing improvement in overall survival was associated with increasing PD-L1 expression ( TC3 or IC3 HR 0·49 [ 0·22 - 1·07 ; p=0·068 ] , TC2/3 or IC2/3 HR 0·54 [ 0·33 - 0·89 ; p=0·014 ] , TC1/2/3 or IC1/2/3 HR 0·59 [ 0·40 - 0·85 ; p=0·005 ] , TC0 and IC0 HR 1·04 [ 0·62 - 1·75 ; p=0·871 ] ) . In our exploratory analysis , patients with pre-existing immunity , defined by high T-effector-interferon-γ-associated gene expression , had improved overall survival  with atezolizumab . 11 ( 8 % ) patients in the atezolizumab group discontinued because of adverse events versus 30 ( 22 % ) patients in the docetaxel group . 16 ( 11 % ) patients in the atezolizumab group versus 52 ( 39 % ) patients in the docetaxel group had treatment-related grade 3 - 4 adverse events , and one ( < 1 % ) patient in the atezolizumab group versus three ( 2 % ) patients in the docetaxel group died from a treatment-related adverse event . INTERPRETATION Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC . Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells , suggesting that PD-L1 expression is predictive for atezolizumab benefit . Atezolizumab was well tolerated , with a safety profile distinct from chemotherapy . FUNDING F Hoffmann-La Roche/Genentech BACKGROUND Anaplastic lymphoma kinase ( ALK ) gene rearrangements are oncogenic drivers of non-small-cell lung cancer ( NSCLC ) . Brigatinib ( AP26113 ) is an investigational ALK inhibitor with potent pre clinical activity against ALK mutants resistant to crizotinib and other ALK inhibitors . We aim ed to assess brigatinib in patients with advanced malignancies , particularly ALK-rearranged NSCLC . METHODS In this ongoing , single-arm , open-label , phase 1/2 trial , we recruited patients from nine academic hospitals or cancer centres in the USA and Spain . Eligible patients were at least 18 years of age and had advanced malignancies , including ALK-rearranged NSCLC , and disease that was refractory to available therapies or for which no curative treatments existed . In the initial dose-escalation phase 1 stage of the trial , patients received oral brigatinib at total daily doses of 30 - 300 mg ( according to a st and ard 3 + 3 design ) . The phase 1 primary endpoint was establishment of the recommended phase 2 dose . In the phase 2 expansion stage , we assessed three oral once-daily regimens : 90 mg , 180 mg , and 180 mg with a 7 day lead-in at 90 mg ; one patient received 90 mg twice daily . We enrolled patients in phase 2 into five cohorts : ALK inhibitor-naive ALK-rearranged NSCLC ( cohort 1 ) , crizotinib-treated ALK-rearranged NSCLC ( cohort 2 ) , EGFRT790M-positive NSCLC and resistance to one previous EGFR tyrosine kinase inhibitor ( cohort 3 ) , other cancers with abnormalities in brigatinib targets ( cohort 4 ) , and crizotinib-naive or crizotinib-treated ALK-rearranged NSCLC with active , measurable , intracranial CNS metastases ( cohort 5 ) . The phase 2 primary endpoint was the proportion of patients with an objective response . Safety and activity of brigatinib were analysed in all patients in both phases of the trial who had received at least one dose of treatment . This trial is registered with Clinical Trials.gov , number NCT01449461 . FINDINGS Between Sept 20 , 2011 , and July 8 , 2014 , we enrolled 137 patients ( 79 [ 58 % ] with ALK-rearranged NSCLC ) , all of whom were treated .  Dose-limiting toxicities observed during dose escalation included grade 3 increased alanine aminotransferase ( 240 mg daily ) and grade 4 dyspnoea ( 300 mg daily ) . We initially chose a dose of 180 mg once daily as the recommended phase 2 dose ; however , we also assessed two additional regimens ( 90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg ) in the phase 2 stage . four ( 100 % [ 95 % CI 40 - 100 ] ) of four patients in cohort 1 had an objective response , 31 ( 74 % [ 58 - 86 ] ) of 42 did in cohort 2 , none ( of one ) did in cohort 3 , three ( 17 % [ 4 - 41 ] ) of 18 did in cohort 4 , and five ( 83 % [ 36 - 100 ] ) of six did in cohort 5 . 51 ( 72 % [ 60 - 82 ] ) of 71 patients with ALK-rearranged NSCLC with previous crizotinib treatment had an objective response ( 44 [ 62 % ( 50 - 73 ) ] had a confirmed objective response ) . All eight crizotinib-naive patients with ALK-rearranged NSCLC had a confirmed objective response ( 100 % [ 63 - 100 ] ) . Three ( 50 % [ 95 % CI 12 - 88 ] ) of six patients in cohort 5 had an intracranial response . The most common grade 3 - 4 treatment-emergent adverse events across all doses were increased lipase concentration ( 12 [ 9 % ] of 137 ) , dyspnoea ( eight [ 6 % ] ) , and hypertension ( seven [ 5 % ] ) . Serious treatment-emergent adverse events ( excluding neoplasm progression ) reported in at least 5 % of all patients were dyspnoea ( ten [ 7 % ] ) , pneumonia ( nine [ 7 % ] ) , and hypoxia ( seven [ 5 % ] ) . 16 ( 12 % ) patients died during treatment or within 31 days of the last dose of brigatinib , including eight patients who died from neoplasm progression . INTERPRETATION Brigatinib shows promising clinical activity and has an acceptable safety profile in patients with crizotinib-treated and crizotinib-naive ALK-rearranged NSCLC . These results support its further development as a potential new treatment option for patients with advanced ALK-rearranged NSCLC . A r and omised phase 2 trial in patients with crizotinib-resistant ALK-rearranged NSCLC is prospect ively assessing the safety and efficacy of two regimens assessed in the phase 2 portion of this trial ( 90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg ) . FUNDING ARIAD Pharmaceuticals PURPOSE Aberrant vascular endothelial growth factor ( VEGF ) and platelet-derived growth factor ( PDGF ) signaling have been shown to play a role in non-small-cell lung cancer ( NSCLC ) pathogenesis and are associated with decreased survival . We evaluated the clinical activity and tolerability of sunitinib malate ( SU11248 ) , an oral , multitargeted tyrosine kinase inhibitor that blocks the activity of receptors for VEGF and PDGF , as well as related tyrosine kinases in patients with previously treated , advanced NSCLC . PATIENTS AND METHODS Patients with stage IIIB or IV NSCLC for whom platinum-based chemotherapy had failed received 50 mg/d of sunitinib  for 4 weeks followed by 2 weeks of no treatment in 6-week treatment cycles . The primary end point was objective response rate ( ORR ) ; secondary end points included progression-free survival , overall survival , and safety . RESULTS Of the 63 patients treated with sunitinib , seven patients had confirmed partial responses , yielding an ORR of 11.1 % ( 95 % CI , 4.6 % to 21.6 % ) . An additional 18 patients ( 28.6 % ) experienced stable disease of at least 8 weeks in duration . Median progression-free survival was 12.0 weeks ( 95 % CI , 10.0 to 16.1 weeks ) , and median overall survival was 23.4 weeks ( 95 % CI , 17.0 to 28.3 weeks ) . Therapy was generally well tolerated . CONCLUSION Sunitinib has promising single-agent activity in patients with recurrent NSCLC , with an ORR similar to that of currently approved agents and an acceptable safety profile . Further evaluation in combination with other targeted agents and chemotherapy in patients with NSCLC is warranted BACKGROUND In the phase 3 KEYNOTE-024 trial , treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive , advanced non-small-cell lung cancer ( NSCLC ) with a programmed cell death-lig and 1 ( PD-L1 ) tumour proportion score of 50 % or greater ( PD-L1-positive ) . Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes ( PROs ) . METHODS In this multicentre , international , r and omised , open-label , phase 3 trial , we recruited patients with treatment-naive , stage IV NSCLC in 102 sites in 16 countries . Eligible patients had measurable disease ( per RECIST version 1.1 ) and an Eastern Cooperative Oncology Group ( ECOG ) performance status 0 or 1 . Patients were r and omly assigned ( 1:1 ) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks ( 35 cycles ) or investigator-choice platinum-doublet chemotherapy ( 4 - 6 cycles or until documented disease progression or unacceptable toxicity ) . R and omisation was stratified according to geography , ECOG performance status , and histology . PROs were assessed at day 1 of cycles 1 - 3 , every 9 weeks thereafter , at the treatment discontinuation visit , and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer ( EORTC ) Quality of Life Question naire Core 30 items ( QLQ-C30 ) , the EORTC Quality of Life Question naire Lung Cancer 13 items ( QLQ-LC13 ) , and the European Quality of Life 5 Dimensions-3 Level ( EQ-5D-3L ) question naire . The key exploratory PRO endpoints ( analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint ) were baseline-to-week-15 change in the QLQ-C30 global health status (GHS)/ quality -of-life ( QOL ) score and time to deterioration of the composite of cough , chest pain , and dyspnoea in the QLQ-LC13 . This study is registered with Clinical Trials.gov , number NCT02142738 , and is ongoing but no longer enrolling patients . FINDINGS Between Sept 19 , 2014 , and Oct 29 , 2015 , 305 patients were r and omly assigned to pembrolizumab ( n=154 ) or chemotherapy ( n=151 ) . Three patients in each group did not complete any PRO instruments at any timepoints , and so 299 patients were included in the full analysis set . Of these patients , one in each group did not complete any PRO instruments before week 15 , and so were not included in analyses of change from baseline to week 15 . PRO compliance was greater than 90 % at baseline and approximately 80 % at week 15 for both groups . Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6·9 ( 95 % CI 3·3 to 10·6 ) for pembrolizumab and -0·9 ( -4·8 to 3·0 ) for chemotherapy , for a difference of 7·8 ( 2·9 to 12·8 ; two-sided nominal p=0·0020 ) . Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients ( 46 [ 31 % ] of 151 patients vs 58 [ 39 % ] of 148 patients ) . Time to deterioration was longer with pembrolizumab than with chemotherapy ( median not reached [ 95 % CI 8·5 to not reached ] vs 5·0 months [ 3·6 to not reached ] ; hazard ratio 0·66 , 95 % CI 0·44 - 0·97 ; two-sided nominal p=0·029 ) . INTERPRETATION Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy , and might represent a new first-line st and ard of care for PD-L1-expressing , advanced NSCLC . FUNDING Merck & BACKGROUND Activating BRAF(V600E ) ( Val600Glu ) mutations are found in about 1 - 2 % of lung adenocarcinomas , which might provide an opportunity for targeted treatment in these patients . Dabrafenib is an oral selective inhibitor of BRAF kinase . We did a trial to assess the clinical activity of dabrafenib in patients with advanced non-small-cell lung cancer ( NSCLC ) positive for the BRAF(V600E ) mutation . METHODS In this phase 2 , multicentre , non-r and omised , open-label study , we enrolled previously treated and untreated patients with stage IV metastatic BRAF(V600E)-positive NSCLC . Patients received oral dabrafenib 150 mg twice daily . The primary endpoint was investigator-assessed overall response , which was assessed in patients who had received at least one dose of dabrafenib ; safety was also assessed in this population . The study is ongoing but not enrolling patients in this cohort . This trial is registered with Clinical Trials.gov , number NCT01336634 . FINDINGS Between Aug 3 , 2011 , and Feb 25 , 2014 , 84 patients were enrolled , six of whom had not previously received systemic treatment for NSCLC . 26 of the 78 previously treated patients achieved an investigator-assessed overall response ( 33 % [ 95 % CI 23 - 45 ] ) . Four of the six previously untreated patients had an objective response . One patient died from an intracranial haemorrhage that was judged by the investigator to be due to the study drug . Serious adverse events were reported in 35 ( 42 % ) of 84 patients . The most frequent grade 3 or worse adverse events were cutaneous squamous-cell carcinoma in ten ( 12 % ) , asthenia in four ( 5 % ) , and basal-cell carcinoma in four ( 5 % ) . INTERPRETATION Dabrafenib showed clinical activity in BRAF(V600E)-positive NSCLC . Our findings suggest that dabrafenib could represent a treatment option for a population of patients with limited therapeutic options . FUNDING GlaxoSmithKline Background Pembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death lig and 1 ( PD-L1 ) expressing advanced non-small cell lung cancer ( NSCLC ) . We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy . Patients and methods In the open-label phase 1b KEYNOTE-001 trial , treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 ( ≥1 % staining , assessed using a prototype assay ) were r and omly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 ( Q3W ) or 2 ( Q2W ) weeks . Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received ≥1 pembrolizumab dose . Using pre-treatment tumor tissue , a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score ( TPS ) . Results Between 1 March 2013 and 18 September 2015 , 101 patients received pembrolizumab 2 mg/kg Q3W ( n = 6 ) , 10 mg/kg Q3W ( n = 49 ) , or 10 mg/kg Q2W ( n = 46 ) . Of these , 27 ( 26.7 % ) had TPS ≥50 % , 52 ( 51.5 % ) had TPS 1%–49 % , and 12 ( 11.9 % ) had TPS < 1 % . The objective response rate ( ORR ) was 27 % ( 27/101 , 95 % CI 18–37 ) and median overall survival was 22.1 months ( 95 % CI 17.1–27.2 ) . In patients with PD-L1 TPS ≥50 % , ORR , 12-month PFS , and 12-month OS were higher [ 14/27 ( 51.9 % ; 95 % CI 32%–71 % ) , 54 % , and 85 % , respectively ] than the overall population [ 27/101 ( 26.7 % ; 95 % CI 18.4%–36.5 % ) , 35 % , 71 % ] . Pembrolizumab was well tolerated , with only 12 ( 11.9 % ) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths . Conclusions Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC , with greatest efficacy observed in patients with TPS ≥50 % . Clinical trial name and number KEYNOTE-001 ( Clinical Trials.gov , NCT01295827 ) The purpose of this study was to evaluate the efficacy of gefitinib and the feasibility of screening for epidermal growth factor receptor ( EGFR ) mutations among select patients with advanced non-small cell lung cancer ( NSCLC ) . Stage IIIB/IV NSCLC , chemotherapy-naive patients or patients with recurrences after up to two prior chemotherapy regimens were eligible .  Direct sequencing using DNA from tumour specimens was performed by a central laboratory to detect EGFR mutations . Patients harbouring EGFR mutations received gefitinib . The primary study objective was response ; the secondary objectives were toxicity , overall survival ( OS ) , progression-free survival ( PFS ) , 1-year survival ( 1Y-S ) and the disease control rate ( DCR ) .  Between March 2005 and January 2006 , 118 patients were recruited from 15 institutions and were screened for EGFR mutations , which were detected in 32 patients – 28 of whom were enrolled in the present study . The overall response rate was 75 % , the DCR was 96 % and the median PFS was 11.5 months . The median OS has not yet been reached , and the 1Y-S was 79 % . Thus , gefitinib chemotherapy in patients with advanced NSCLC harbouring EGFR mutations was highly effective . This trial documents the feasibility of performing a multicentre phase II study using a central typing laboratory , demonstrating the benefit to patients of selecting gefitinib treatment based on their EGFR mutation status INTRODUCTION The epidermal growth factor receptor ( EGFR ) tyrosine-kinase inhibitor erlotinib is associated with survival benefits in patients with EGFR mutation-positive non-small-cell lung cancer ( NSCLC ) . This phase II , single-arm study examined the efficacy and safety of first-line erlotinib in Japanese patients with EGFR mutation-positive NSCLC . METHODS Eligible patients  received erlotinib 150 mg/day until disease progression or unacceptable toxicity . The primary endpoints were progression-free survival ( PFS ) and safety . RESULTS A high degree of concordance was observed between different mutation testing method ologies , suggesting feasibility of early , rapid detection of EGFR mutations . Median PFS was 11.8 months ( 95 % confidence interval [ CI ] : 9.7 - 15.3 ) at data cut-off ( 1 June 2012 ) ( n = 102 ) . Exon 19 deletions seemed to be associated with longer PFS compared with L858R mutations ; T790 M mutations were tentatively linked with shorter PFS . The safety profile was as expected : rash ( any grade ; 83 % ) and diarrhea ( any grade ; 81 % ) were most common . Six interstitial lung disease (ILD)-like cases were reported , and 5 were confirmed as ILD-like events by the extramural committee . Two patients died of treatment-related pneumonitis ( JAPIC Clinical Trials Information number : Japic CTI-101085 ) . CONCLUSION Erlotinib should be considered for first-line treatment in this subset of Japanese patients , with close monitoring for ILD-like events BACKGROUND Hypertension ( HTN ) , a recognized adverse effect of angiogenesis inhibitors , may be a potential biomarker of activity of these agents . We conducted a retrospective analysis to examine the incidence and predictors of the development of on-treatment HTN with the vascular endothelial growth factor receptor tyrosine kinase inhibitor cediranib , and the relationship of this adverse event with treatment outcomes . PATIENTS AND METHODS BR24 was a double-blind placebo-controlled  phase II trial of carboplatin/paclitaxel chemotherapy with either daily oral cediranib or placebo  in patients ( n = 296 ) with advanced non-small-cell lung cancer ( NSCLC ) . Exploratory analyses characterized relationships between HTN , baseline variables , and efficacy outcomes . RESULTS New onset or worsening of preexisting HTN ( treatment-emergent HTN ) was more frequent in patients receiving cediranib ( 68 versus 45 % , P < 0.0001 ) . Factors associated with HTN in all r and omized patients were good performance status and treatment with cediranib . In both arms , treatment-emergent HTN was associated with improved efficacy outcomes , but there was no evidence of a differential treatment effect , with nonsignificant interaction P values . CONCLUSIONS In advanced NSCLC , HTN is frequent in patients receiving chemotherapy  , with or without cediranib . The development of HTN was favorably prognostic in these patients , but not predictive of a differential outcome with cediranib Abstract Background Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer ( NSCLC ) despite recent advances in molecular targeted therapy and immunotherapy . We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with st and ard docetaxel therapy in patients with advanced NSCLC . Patients and methods Patients with advanced NSCLC previously treated with ≥1 platinum-based therapy were r and omized 1 : 1 to docetaxel ( 60 mg/m2 in Japan , 75 mg/m2 at all other study sites ; day 1 in a 3-week cycle ) or S-1 ( 80–120 mg/day , depending on body surface area ; days 1–28 in a 6-week cycle ) . The primary endpoint was overall survival . The non-inferiority margin was a hazard ratio ( HR ) of 1.2 . Results A total of 1154 patients ( 577 in each arm ) were enrolled , with balanced patient characteristics between the two arms . Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms , respectively [ HR 0.945 ; 95 % confidence interval ( CI ) 0.833–1.073 ; P = 0.3818 ] . The upper limit of 95 % CI of HR fell below 1.2 , confirming non-inferiority of S-1 to docetaxel  . Difference in progression-free survival between treatments was not significant ( HR 1.033 ; 95 % CI 0.913–1.168 ; P = 0.6080 ) . Response rate was 8.3 % and 9.9 % in the S-1 and docetaxel arms , respectively . Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm . The most common adverse drug reactions were decreased appetite ( 50.4 % ) , nausea ( 36.4 % ) , and diarrhea ( 35.9 % ) in the S-1 arm , and neutropenia ( 54.8 % ) , leukocytopenia ( 43.9 % ) , and alopecia ( 46.6 % ) in the docetaxel arm . Conclusion S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC . Clinical trial number Japan Pharmaceutical Information Center , JapicCTI-101155 Introduction : Recent studies have demonstrated that first-line treatment with gefitinib , an epidermal growth factor receptor (EFGR)–targeted tyrosine kinase inhibitor , is significantly superior to st and ard chemotherapy for advanced non – small-cell lung cancer ( NSCLC ) harboring EGFR sensitive mutations . Meanwhile , the efficacy of gefitinib therapy among elderly population s diagnosed with EGFR-mutated NSCLC has not yet been eluci date d. The purpose of this study was to investigate the efficacy and feasibility of gefitinib for chemotherapy-naive patients aged 75 or older with NSCLC harboring EGFR mutations ; generally , these patients have no indication for treatment with platinum doublets . Methods : Chemotherapy-naive patients aged 75 years or older with performance status 0 to 1 and advanced NSCLC harboring EGFR mutations , as determined by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method , were enrolled . The enrolled patients received 250 mg/day of gefitinib orally . Results : Between January 2008 and May 2009 , 31 patients were enrolled , all of whom were eligible . The median age was 80 ( range , 75–87 ) years . Twenty-five patients ( 81 % ) were women , and 30 patients ( 97 % ) had adenocarcinoma . The overall response rate was 74 % ( 95 % confidence interval , 58%–91 % ) , and the disease control rate was 90 % . The median progression-free survival was 12.3 months . The common adverse events were rash , diarrhea , and liver dysfunction . One treatment-related death because of interstitial lung disease occurred . Conclusions : This is the first study that verified safety and efficacy of first-line treatment with gefitinib in elderly patients having advanced NSCLC with EGFR mutation . Considering its strong antitumor activity and mild toxicity , first-line gefitinib may be preferable to st and ard chemotherapy for this population BACKGROUND Nivolumab , a fully human IgG4 programmed death 1 ( PD-1 ) immune-checkpoint-inhibitor antibody , disrupts PD-1-mediated signaling and may restore antitumor immunity . METHODS In this r and omized , open-label , international phase 3 study , we assigned patients with nonsquamous non-small-cell lung cancer ( NSCLC ) that had progressed during or after platinum-based doublet chemotherapy  to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks . The primary end point was overall survival . RESULTS Overall survival was longer with nivolumab than with docetaxel .  The median overall survival was 12.2 months ( 95 % confidence interval [ CI ] , 9.7 to 15.0 ) among 292 patients in the  nivolumab group and 9.4 months ( 95 % CI , 8.1 to 10.7 ) among 290 patients in the docetaxel group ( hazard ratio for death , 0.73 ; 96 % CI , 0.59 to 0.89 ; P=0.002 ) . At 1 year , the overall survival rate was 51 % ( 95 % CI , 45 to 56 ) with nivolumab versus 39 % ( 95 % CI , 33 to 45 ) with docetaxel . With additional follow-up , the overall survival rate at 18 months was 39 % ( 95 % CI , 34 to 45 ) with nivolumab versus 23 % ( 95 % CI , 19 to 28 ) with docetaxel . The response rate was 19 % with nivolumab versus 12 % with docetaxel ( P=0.02 ) . Although progression-free survival did not favor nivolumab over docetaxel ( median , 2.3 months and 4.2 months , respectively ) , the rate of progression-free survival at 1 year was higher with nivolumab than with docetaxel ( 19 % and 8 % , respectively ) . Nivolumab was associated with even greater efficacy  than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression ( ≥1 % , ≥5 % , and ≥10 % ) of the PD-1 lig and . Treatment-related adverse events of grade 3 or 4 were reported in 10 % of the patients in the nivolumab group , as compared with 54 % of those in the docetaxel group . CONCLUSIONS Among patients with advanced nonsquamous NSCLC that had progressed during or after platinum-based chemotherapy  , overall survival was longer with nivolumab than with docetaxel . ( Funded by Bristol-Myers Squibb ; CheckMate 057 Clinical Trials.gov number , NCT01673867 . ) Our objective was to evaluate gefitinib ( IRESSA ) , an epidermal growth factor receptor tyrosine kinase inhibitor , versus docetaxel as second-line monotherapy for advanced non-small-cell lung cancer ( NSCLC ) . SIGN ( Second-line Indication of Gefitinib in NSCLC ; code 1839IL/0503 ) was a multicenter , r and omized , parallel-group , open-label , phase II trial that investigated oral gefitinib ( 250 mg/day ) or i.v . docetaxel ( 75 mg/m2 every 3 weeks ) in patients with advanced NSCLC who had previously received one chemotherapy regimen . The primary objective was assessment of symptom improvement ( using the FACT-L Lung Cancer Subscale ) . Secondary objectives included quality of life ( FACT-L total score ) , response rate ( using RECIST ) , overall survival and safety . This trial recruited 141 patients ( 68 to gefitinib and 73 to docetaxel ) who received treatment for a median duration of 3.0 ( gefitinib ) and 2.8 ( docetaxel ) months . Similar efficacy was observed with gefitinib and docetaxel , 36.8 and 26.0 % symptom improvement rates , 33.8 and 26.0 % quality -of-life improvement rates , 13.2 and 13.7 % objective response rates , and 7.5 and 7.1 months median overall survival , respectively . Fewer drug-related adverse events were observed with gefitinib compared with docetaxel ( all grade s : 51.5 versus 78.9 % ; Common Toxicity Criteria grade 3/4 : 8.8 versus 25.4 % ) . There were no withdrawals or deaths due to drug-related adverse events with gefitinib , while three patients withdrew and three died due to adverse events in the docetaxel group that were possibly drug related . We conclude efficacy with gefitinib was similar to docetaxel , but with a more favorable tolerability profile , in the second-line treatment of advanced NSCLC . These results support further investigation of gefitinib in this disease setting Recent advances in the treatment of non-small cell lung cancer ( NSCLC ) have led to improvements in patient survival and quality of life . It is unclear whether molecular abnormalities associated with NSCLC cell survival , growth and proliferation are useful in predicting treatment benefit . We conducted a systematic review to establish which biomarkers contribute meaningfully to the management of NSCLC . A team of research ers search ed PubMed and conference proceedings ( ASCO , ESMO , IASLC , USCAP ) using MESH terms for NSCLC and r and omized trials ( RCT ) , plus keywords for variables of interest . Evidence from multiple RCTs confirmed that histologic subtype is prognostic for survival and predictive of treatment efficacy and /or toxicity in NSCLC . Likewise , activating mutations of the epidermal growth factor receptor ( EGFR ) are associated with benefit from EGFR tyrosine kinase inhibitors in patients with advanced non-squamous NSCLC and should be assessed routinely . No biomarkers to date reliably predict response to anti-Vascular Endothelial Growth Factor ( VEGF ) therapies . There are inconsistent data on the role of ERCC1 , BRCA , Beta tubulin III , RRM1 , K-RAS , or TP-53 in treatment decisions . These tests should not be routinely used in selecting treatment at this time , whereas EML4/ALK translocations predict responses to specific targeted agents , the optimal assessment of this molecular abnormality has yet to be established . Personalized care of patients with NSCLC based on biomarkers is increasingly important to both clinical practice and research Background : Erlotinib ( Tarceva , OSI Pharmaceuticals , Melville , NY ) is an oral , epidermal growth factor receptor tyrosine kinase inhibitor that has antitumor activity and good tolerability in non-small cell lung cancer ( NSCLC ) . In particular , higher response rates have been reported in Asian patients than in Western patients . The aim of this study conducted by the Korean Cancer Study Group was to evaluate the efficacy and tolerability of erlotinib monotherapy as a palliative treatment for advanced NSCLC patients in Korea . Patients and Methods : Patients with histologically or cytologically confirmed stage IIIB or IV NSCLC including recurrent or metastatic disease , with performance status from 0 to 3 , were eligible either if they had received any anticancer treatment except epidermal growth factor receptor inhibitors or if they were unsuitable for chemotherapy because of poor performance status . Enrolled patients were treated with oral erlotinib at a dose of 150 mg daily until disease progression or development of intolerable toxicity . Results : A total of 120 patients were enrolled between January 2005 and May 2006 . Forty-four patients ( 36.7 % ) were female and 72 patients were current or former smoker . Fifty percent of patients had received one prior palliative chemotherapy regimens and 34.2 % had two or more prior palliative regimens . The overall tumor response rate was 24.2 % ( 95 % confidence interval [ CI ] , 16.8–32.8 % ) with 4 complete responses and 25 partial responses , and the disease control rate was 56.7 % . The favorable clinical variables for tumor response were female ( P = 0.001 ) , never smokers ( P = 0.041 ) , and adenocarcinoma ( P = 0.001 ) . The most common adverse event was skin rash ( 78 % of which grade 3 or 4 skin rash occurred in 13.3 % of the patients ) . With a median follow-up of 23.6 months , the median time to progression was 2.7 months ( 95 % CI , 2.2–3.2 ) , and the median overall survival was 12.9 months ( 95 % CI , 6.9–18.8 ) . By multivariate analysis , female and development of skin rash were significantly associated with longer time to progression and overall survival . Conclusion : Erlotinib monotherapy showed significant antitumor activity and an acceptable tolerability profile as a palliative treatment in advanced NSCLC patients in Korea , especially in females , never smokers , and patients with adenocarcinoma histology Lung cancer is the leading cause of cancer death in the world , causing more than one million deaths each year . The incidence and mortality rates are highest in the United States and Europe and continue to increase in developing nations . Non-small cell lung cancer ( NSCLC ) accounts for 80 to 85 % of all new cases of lung cancer . The majority of patients with NSCLC present with advanced disease at the time of diagnosis . Although the prognosis of advanced NSCLC is very poor , current chemotherapy combinations have been shown to improve 1-year survival and quality of life for these patients . Approximately one third of patients with NSCLC are diagnosed with locally advanced disease . Although cure rates are modest and variable in locally advanced NSCLC , multimodality therapy ( chemotherapy in combination with surgery or radiotherapy ) has result ed in statistically significant improvement in 5-year survival when compared with surgery or radiotherapy alone . Patients with early-stage NSCLC have the best long-term survival rates following surgical resection ; however , systemic recurrences remain a problem in the majority of these patients . The rationale for treating patients with early-stage NSCLC with combined-modality therapy ( chemotherapy and surgery ) is compelling , and several r and omized trials are currently in progress . Although progress has been slow , when we consider the recent advances in smoking prevention , smoking cessation , staging classification , imaging and diagnostic techniques , screening and therapeutic modalities , and multidisciplinary care , as well as in the underst and ing of the molecular pathogenesis of lung cancer , the future , in my opinion , is very promising OBJECTIVES Physical activity has been infrequently measured objective ly in non-small cell lung cancer ( NSCLC ) . We aim ed to investigate levels of physical activity , functional and patient reported outcomes at diagnosis and over six months in participants with recently diagnosed NSCLC and compare results with both physical activity guidelines and outcomes of similar-aged healthy individuals . METHODS This prospect i ve observational study assessed 50 individuals from three Australian tertiary hospitals with stage I-IIIB NSCLC at diagnosis , then 10 weeks and six months later . Thirty five healthy individuals without cancer were assessed once . Outcome measures included  tri-axial accelerometery ( number of steps per day ) , six minute walk distance ( 6MWD ) , muscle strength and question naires including health-related quality of life ( HRQoL ) . RESULTS Individuals with NSCLC were engaged in significantly less physical activity than similar-aged healthy individuals , with 60 % not meeting physical activity guidelines . At diagnosis they had worse quadriceps strength , nutritional status and HRQoL. Over six months , participants with NSCLC experienced decline in self-reported physical activity , 6MWD and muscle strength , and worsening symptoms . CONCLUSION At diagnosis individuals with NSCLC engage in less physical activity , are weaker and more depressed than healthy individuals and their self-reported physical activity declines over six months . Future studies are required to investigate the efficacy of interventions to increase physical activity OBJECTIVES The clinical benefit of chemotherapy and the appropriate regimen for non-small-cell lung cancer ( NSCLC ) patients with interstitial lung disease ( ILD ) remain unclear . To fulfill this unmet medical need , we conducted a phase II study to eluci date the efficacy of S-1 in combination with carboplatin ( CBDCA ) in NSCLC patients with ILD . MATERIAL S AND METHODS A total of 33 advanced or recurrent NSCLC patients with ILD were prospect ively enrolled in this multicenter , open-label , phase II study . Every 4 weeks , CBDCA at a dose of AUC 5 on day 1 and S-1 at a dose of 80 mg/m2 daily for 14 days were administered . The primary endpoint was the investigator-assessed objective response rate . RESULTS The median age at initiating chemotherapy was 70 . Sixteen patients ( 48.5 % ) had squamous cell carcinoma histology . With respect to the types of ILD , the usual interstitial pneumonia pattern was dominant ( 66.7 % ) . The median number of cycles administered was 3 , and the overall response rate and disease control rate were 33.3 % and 78.8 % , respectively . The median progression-free survival , the median survival time and the 1-year survival rate were 4.8 months , 12.8 months and 51.4 % , respectively . Acute exacerbation of ILD caused by chemotherapy was noted in 2 patients ( 6.1 % ) . CONCLUSION This is the first prospect i ve study design ed to evaluate the efficacy of a specific chemotherapeutic regimen as the primary endpoint in patients with advanced NSCLC with ILD . The combination of S-1 with CBDCA may be a treatment option for advanced NSCLC patients with ILD ( The clinical trial registration number : UMIN000011046 ) The purpose of this article is to provide up date d recommendations for the treatment of patients with stage IV non-small-cell lung cancer . A literature search identified relevant r and omized trials published since 2002 . The scope of the guideline was narrowed to chemotherapy and biologic therapy . An Up date Committee review ed the literature and made up date d recommendations . One hundred sixty-two publications met the inclusion criteria . Recommendations were based on treatment strategies that improve overall survival . Treatments that improve only progression-free survival prompted scrutiny of toxicity and quality of life . For first-line therapy in patients with performance status of 0 or 1 , a platinum-based two-drug combination of cytotoxic drugs is recommended . Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy . For patients with performance status of 2 , a single cytotoxic drug is sufficient . Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment . Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy . The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor ( EGFR ) mutation ; for negative or unknown EGFR mutation status , cytotoxic chemotherapy is preferred . Bevacizumab is recommended with carboplatin-paclitaxel , except for patients with certain clinical characteristics . Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by immunohistochemistry . Docetaxel , erlotinib , gefitinib , or pemetrexed is recommended as second-line therapy . Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib . Data are insufficient to recommend the routine third-line use of cytotoxic drugs . Data are insufficient to recommend routine use of molecular markers to select chemotherapy BACKGROUND Somatic mutations in EGFR and K-RAS may predict for sensitivity and resistance to EGFR tyrosine kinase inhibitors ( TKIs ) . Whether EGFR and K-RAS mutations could also predict clinical outcome of non-small cell lung cancer ( NSCLC ) patients following front-line chemotherapy  has not yet been established . PATIENTS AND METHODS One hundred and sixty-two chemotherapy-naïve patients with locally advanced/metastatic NSCLC who received front-line chemotherapy  were included in this retrospective study and their clinical outcome data was analyzed according to EGFR and K-RAS mutation status of their tumors . RESULTS Classical activating EGFR and K-RAS mutations were found in 8.2 and 22.6 % of patients respectively and were not associated with patients ' clinicopathological characteristics . Patients with classical EGFR mutations had a higher probability of response to front-line chemotherapy as compared to those with wild type EGFR ( p=0.023 ) . Multivariate analysis showed that the presence of activating EGFR mutations was an independent factor associated with response to front-line chemotherapy ( HR=4.85 ; 95 % CI : 1.13 - 20.83 , p=0.034 ) . K-RAS mutation status was not associated with response to front-line chemotherapy . The presence of activating EGFR but not of K-RAS mutations was associated with a significantly higher overall survival compared to patients without mutations treated with platinum-based front-line chemotherapy ( p=0.043 ) . CONCLUSIONS The data indicate that EGFR mutation status could be predictive for response to cytotoxic front-line chemotherapy in patients with NSCLC . Additional prospect i ve studies are needed in order to vali date this observation and to define whether these patients should be preferentially treated with front-line TKIs or chemotherapy PURPOSE Erlotinib is a potent reversible HER1/epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor with single-agent activity in patients with non-small-cell lung cancer ( NSCLC ) .  Erlotinib was combined with chemotherapy to determine if it could improve the outcome of patients with NSCLC . PATIENTS AND METHODS TRIBUTE r and omly assigned patients with good performance status and previously untreated advanced ( stage IIIB/IV ) NSCLC to erlotinib 150 mg/d or placebo combined with up to six cycles of carboplatin and paclitaxel , followed by maintenance monotherapy with erlotinib . R and om assignment was stratified by stage , weight loss in the previous 6 months , measurable disease , and treatment center . The primary end point was overall survival ( OS ) . Secondary end points included time to progression ( TTP ) , objective response ( OR ) , and duration of response . RESULTS There were 1,059 assessable patients ( 526 erlotinib ; 533 placebo ) .  Median survival for patients treated with erlotinib was 10.6 v 10.5 months for placebo ( hazard ratio , 0.99 ; 95 % CI , 0.86 to 1.16 ; P = .95 ) . There was no difference in OR or median TTP .  Patients who reported never smoking ( 72 erlotinib ; 44 placebo ) experienced improved OS in the erlotinib arm ( 22.5 v 10.1 months for placebo ) , though no other prespecified factors showed an advantage in OS with erlotinib . Erlotinib and placebo arms were equivalent in adverse events ( except rash and diarrhea ) . CONCLUSION Erlotinib with concurrent carboplatin and paclitaxel did not confer a survival advantage over carboplatin and paclitaxel alone in patients with previously untreated advanced NSCLC . Never smokers treated with erlotinib and chemotherapy  seemed to experience an improvement in survival and will undergo further investigation in future r and omized trials BACKGROUND With use of EGFR tyrosine-kinase inhibitor monotherapy for patients with activating EGFR mutation-positive non-small-cell lung cancer ( NSCLC ) , median progression-free survival has been extended to about 12 months . Nevertheless , new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population . We aim ed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease . METHODS In this open-label , r and omised , multicentre , phase 2 study , patients from 30 centres across Japan with stage IIIB/IV or recurrent non-squamous NSCLC with activating EGFR mutations , Eastern Cooperative Oncology Group performance status 0 or 1 , and no previous chemotherapy for advanced disease received erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day monotherapy as a first-line therapy until disease progression or unacceptable toxicity . The primary endpoint was progression-free survival , as determined by an independent review committee . R and omisation was done with a dynamic allocation method , and the analysis used a modified intention-to-treat approach , including all patients who received at least one dose of study treatment and had tumour assessment at least once after r and omisation . This study is registered with the Japan Pharmaceutical Information Center , number JapicCTI-111390 . FINDINGS Between Feb 21 , 2011 , and March 5 , 2012 , 154 patients were enrolled . 77 were r and omly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone , of whom 75 patients in the erlotinib plus bevacizumab  group and 77 in the erlotinib alone group were included in the efficacy analyses . Median progression-free survival was 16·0 months ( 95 % CI 13·9 - 18·1 ) with erlotinib plus bevacizumab and 9·7 months ( 5·7 - 11·1 ) with erlotinib alone ( hazard ratio 0·54 , 95 % CI 0·36 - 0·79 ; log-rank test p=0·0015 ) . The most common grade 3 or worse adverse events were rash ( 19 [ 25 % ] patients in the erlotinib plus bevacizumab group vs 15 [ 19 % ] patients in the erlotinib alone group ) , hypertension ( 45 [ 60 % ] vs eight [ 10 % ] ) , and proteinuria ( six [ 8 % ] vs none ) . Serious adverse events occurred at a similar frequency in both groups ( 18 [ 24 % ] patients in the erlotinib plus bevacizumab group and 19 [ 25 % ] patients in the erlotinib alone group ) . INTERPRETATION Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC . Further investigation of the regimen is warranted . FUNDING Chugai Pharmaceutical Co Background Evidence that chemotherapy improves survival and quality of life in patients with stage IIIB & IV non small cell lung cancer ( NSCLC ) is based on large r and omized controlled trials . The purpose of this study was to determine eligibility of patients with advanced NSCLC for major chemotherapy trials . Methods Physicians treating stage IIIB/IV NSCLC at Sydney Cancer Centre assessed patient eligibility for the E1594 , SWOG9509 and TAX326 trials for patients presenting from October 2001 to December 2002 . A review of the centre 's registry was used to obtain missing data . Results 199 patients with advanced NSCLC were registered during the 14-month period . Characteristics of 100 patients were defined prospect ively , 85 retrospectively : 77 % males , median age 68 ( range 32–88 ) , 64 % stage IV disease . Only 35 % met trial eligibility for E1594 and 28 % for SWOG9509 and TAX326 . Common reasons for in eligibility were : co-morbidities 75(40 % ) ; ECOG Performance Status ≥2 72(39 % ) ; symptomatic brain metastasis 15(8 % ) ; and previous cancers 21(11 % ) . Many patients were ineligible by more than one criterion . Conclusion The majority of patients with advanced NSCLC were ineligible for the large chemotherapy trials . The applicability of trial results to advanced lung cancer population s may be limited . Future trials should be conducted in a more representative population We have developed and st and ardized a novel technology , mutant-enriched liquidchip ( MEL ) , for clinical detection of  EGFR mutations .  The MEL integrates a mutant-enriched PCR procedure with liquidchip technology for detections of EGFR exon 19 deletions and L858R mutation on both formalin-fixed and paraffin-embedded ( FFPE ) slides and plasma sample s from patients with non-small cell lung cancer ( NSCLC ) . The detection sensitivity was 0.1 % of mutant DNA in the presence of its wild-type DNA . The cross-reaction rate was lower than 5 % . To evaluate the MEL platform , the EGFR mutation status of 59 patients with advanced NSCLC treated with EGFRTKIs ( Tyrosine Kinase Inhibitors )  were tested on their FFPE sample s. EGFR exon 19 deletions and L858R were detected in 21 patients ( 21/59 ) and 76.2 % ( 16/21 ) of them had partial response to the EGFR-TKIs , while by sequencing method , only 4 ( 4/59 ) mutations were detected . Plasma sample s from 627 patients with various stages of NSCLC were examined with the MEL and 22 % of EGFR exon 19 deletions and L858R were detected . Furthermore , in patients with advanced disease there are more mutations detected in plasma sample s than in patients with less advanced disease . In conclusion , the MEL is a sensitive , stable , and robust technology for detecting EGFR DNA mutations from both FFPE and plasma sample s from patients with NSCLC and is now routinely used for clinical diagnosis INTRODUCTION Accurate staging of lymph node involvement is a critical aspect of the initial management of nonmetastatic non-small cell lung cancer ( NSCLC ) . We sought to determine whether the current N descriptors should be maintained or revised for the next edition of the international lung cancer staging system . METHODS A retrospective international lung cancer data base was developed and analyzed . Anatomical location of lymph node involvement was defined by the Naruke ( for Japanese data ) and American Thoracic Society ( for non-Japanese data ) nodal maps . Survival was calculated by the Kaplan-Meier method , and prognostic groups were assessed by Cox regression analysis . RESULTS Current N0 to N3 descriptors defined distinct prognostic groups for both clinical and pathologic staging . Exploratory analyses indicated that lymph node stations could be grouped together into six " zones " : peripheral or hilar for N1 , and upper or lower mediastinal , aortopulmonary , and subcarinal for N2 nodes . Among patients undergoing resection without induction therapy  , there were three distinct prognostic groups : single-zone N1 , multiple-zone N1 or single N2 , and multiple-zone N2 disease . Nevertheless , there were insufficient data to determine whether the N descriptors should be subdivided ( e.g. , N1a , N1b , N2a , N2b ) . CONCLUSIONS Current N descriptors should be maintained in the NSCLC staging system . Prospect i ve studies are needed to vali date amalgamating lymph node stations into zones and subdividing N descriptors BACKGROUND Epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors ( TKIs ) provide promising effect against non-small-cell lung cancer ( NSCLC ) , although most tumors acquire resistance . Our objective was to assess the survival outcome of patients with NSCLC with or without subsequent chemotherapy after acquired TKI resistance . PATIENTS AND METHODS A total of 114 patients with pathologically confirmed stage IIIB or IV NSCLC who had had disease control with TKIs were retrospectively review ed . After acquired TKI resistance , patients received either best supportive care ( BSC ) only or BSC plus subsequent chemotherapy . Both groups were well balanced in regard to performance status , age , sex , histology subtype , and smoking status . RESULTS Sixty-seven patients ( 58.8 % ) received subsequent chemotherapy , and 47 patients ( 41.2 % ) received BSC only . The median overall survival ( OS ) and progression-free survival ( PFS ) from the time of TKI resistance in the subsequent-chemotherapy group ( 11.2 months and 3.5 months , respectively ) were longer than those of the BSC group ( 3.8 months and 1.5 months , respectively ; P < .01 ) . Patients who subsequently received taxane-based chemotherapy exhibited higher a response rate and disease control rate ( 48.7 % and 79.5 % , respectively ) than patients treated with a nontaxane regimen ( 21.4 % and 53.5 % , respectively ; P < .05 ) . Overall survival and PFS in patients after taxane-based subsequent chemotherapy ( 12.7 months and 5.1 months , respectively ) were longer than those of patients given a nontaxane regimen ( 7 months and 1.8 months , respectively ; P < .01 ) . CONCLUSION This study suggests that acquired TKI resistance should be managed aggressively . The higher antitumor response and survival outcome with a taxane-based regimen in this retrospective study could encourage further prospect i ve investigation to confirm the efficacy of taxane over nontaxane chemotherapy in patients with NSCLC whose disease progresses with EGFR TKI treatment Arbekacin ( ABK ) was approved and widely used in Japan for treatment of patients infected with MRSA , and TDM was introduced in clinical practice . The Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring decided to develop a clinical practice guidelines for TDM of ABK for the following reasons . First , although the daily dose of 150e200 mg was approved in Japan , recent PK- PD studies revealed that higher serum concentration is required to achieve better clinical efficacy and several findings concerning the usefulness of higher dosage regimen have obtained recently . Second , although maximal concentrations that obtained immediately after the end of administration ( Cmax ) w as generally adopted , the serum concentration at 1 h after initiation of administration ( peak serum con- centration ( Cpeak ) ) proved to be more suitable as an efficacy indicator of aminoglycosides . Lastly , as ABK is approved only in Japan , no international practice guideline for TDM has not been available in ABK to date . This guideline evaluated the scientific data associated with serum ABK  monitoring and provided rec- ommendations based on the available evidence . Potential limitations of this guideline , however , include the findings that few prospect i ve clinical trials of TDM of ABK are available in the treatment of MRSA infections and that most of the published literature describes observational studies OBJECTIVES Stage III non-small cell lung cancer ( NSCLC ) describes a heterogeneous population with disease presentation ranging from apparently resectable tumors with occult microscopic nodal metastases to unresectable , bulky nodal disease . This review up date s the published clinical trials since the last American College of Chest Physicians guidelines to make treatment recommendations for this controversial subset of patients . METHODS Systematic search es were conducted through MEDLINE , Embase , and the Cochrane Data base for Systematic Review up to December 2011 , focusing primarily on r and omized trials , selected meta-analyses , practice guidelines , and review s. RESULTS For individuals with stage IIIA or IIIB disease , good performance scores , and minimal weight loss , treatment with combined chemoradiotherapy results in better survival than radiotherapy alone . Consolidation chemotherapy or targeted therapy following definitive chemoradiation for stage IIIA is not supported . Neoadjuvant therapy followed by surgery is neither clearly better nor clearly worse than definitive chemoradiation . Most of the arguments made regarding patient selection for neoadjuvant therapy and surgical resection provide evidence for better prognosis but not for a beneficial impact of this treatment strategy ; however , weak comparative data suggest a possible role if only lobectomy is needed in a center with a low perioperative mortality rate . The evidence supports routine platinum-based adjuvant chemotherapy following complete resection of stage IIIA lung cancer encountered unexpectedly at surgery . Postoperative radiotherapy  improves local control without improving survival . CONCLUSIONS Multimodality therapy is preferable in most subsets of patients with stage III lung cancer . Variability in the patients included in r and omized trials limits the ability to combine results across studies and thus limits the strength of recommendations in many scenarios . Future trials are needed to investigate the roles of individualized chemotherapy , surgery in particular cohorts or setting s , prophylactic cranial radiation , and adaptive radiation BACKGROUND A phase III study ( Lung Cancer Evaluation of TS-1 ) previously demonstrated noninferiority in terms of overall survival ( OS ) at interim analysis for carboplatin-S-1 compared with carboplatin-paclitaxel for first-line treatment of advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS A total of 564 patients were r and omly assigned to receive either carboplatin on day 1 plus oral S-1 on days 1 - 14 or carboplatin-paclitaxel on day 1 every 21 days . Up date d results and post hoc subgroup analysis according to tumor histology are presented . RESULTS The up date d analysis revealed a median OS of 15.2 months in the carboplatin-S-1 arm and 13.1 months in the carboplatin-paclitaxel arm , with a hazard ratio ( HR ) of 0.956 [ 95 % confidence interval ( CI ) 0.793 - 1.151 ] , consistent with the previous primary analysis . Median OS was 14.0 months in the carboplatin-S-1 arm and 10.6 months in the carboplatin-paclitaxel arm ( HR 0.713 ; 95 % CI 0.476 - 1.068 ) for patients with squamous cell carcinoma ( SCC ) , with corresponding values of 15.5 and 13.9 months ( HR 1.060 ; 95 % CI 0.859 - 1.308 ) for those with non-SCC . CONCLUSIONS These results establish the efficacy and safety of carboplatin-S-1 in patients with advanced NSCLC regardless of tumor histology AIM Lung carcinoma is the most common malignancy and the leading cause of cancer deaths worldwide . Although clinical factors including age , performance status and stage influence the likelihood of benefit from and tolerability of chemotherapy , the genetic profile of individual patients may be an independent predictor of response and toxicity . The present study aim ed to identify pharmacogenetic markers associated with clinical response and toxicity in patients with advanced non-small cell lung cancer ( NSCLC ) treated primarily with  carboplatin and paclitaxel . MATERIAL S & METHODS Genomic DNA sample s from 90 adult male patients diagnosed with stage IIIB/IV NSCLC were genotyped for SNPs in c and i date genes of relevance to platinating agents and paclitaxel and analyzed for association with survival and toxicities in univariate and multivariate models . RESULTS After adjusting for performance status and stage , SNPs in the drug transporters ABCB1 and ABCC1 , as well as within NQO1 were associated with progression-free survival . With respect to hematological and nonhematological toxicities , SNPs in drug transporters ( ABCB1 and ABCG2 ) were associated with thrombocytopenia , nausea and neutropenia , whereas SNPs in the DNA repair pathway genes ERCC4 and XPC were significantly associated with neutropenia and sensory neuropathy , respectively . CONCLUSION Our study evaluated and identified SNPs in key c and i date genes in platinating agent and taxane pathways associated with outcome and toxicity in advanced NSCLC . If vali date d in large prospect i ve studies , these findings might provide opportunities to personalize therapeutic strategies BACKGROUND For non-small cell lung cancer ( NSCLC ) patients with epidermal growth factor receptor ( EGFR ) mutations , first-line gefitinib produced a longer progression-free survival interval than first-line carboplatin plus paclitaxel but did not show any survival advantage in the North East Japan 002 study . This report describes the quality of life ( QoL ) analysis of that study . METHODS  Chemotherapy-naïve patients with sensitive EGFR-mutated , advanced NSCLC were r and omized to receive gefitinib or chemotherapy ( carboplatin and paclitaxel ) .  Patient QoL was assessed weekly using the Care Notebook , and the primary endpoint of the QoL analysis was time to deterioration from baseline on each of the physical , mental , and life well-being QoL scales . Kaplan-Meier probability curves and log-rank tests were employed to clarify differences . RESULTS QoL data from 148 patients ( 72 in the gefitinib arm and 76 in the carboplatin plus paclitaxel arm ) were analyzed . Time to defined deterioration in physical and life well-being significantly favored gefitinib over chemotherapy ( hazard ratio [ HR ] of time to deterioration , 0.34 ; 95 % confidence interval [ CI ] , 0.23 - 0.50 ; p < .0001 and HR , 0.43 ; 95 % CI , 0.28 - 0.65 ; p < .0001 , respectively ) . CONCLUSION QoL was maintained much longer in patients treated with gefitinib than in patients treated with st and ard chemotherapy , indicating that gefitinib should be considered as the st and ard first-line therapy for advanced EGFR-mutated NSCLC in spite of no survival advantage BACKGROUND Chemotherapy extends life for patients with advanced non-small cell lung cancer ( NSCLC ) . Second-line treatment of NSCLC includes the use of cytotoxic drugs ; however , toxicity is of concern . One molecular target for lung cancer is the epidermal growth factor receptor ( EGFR ) . Gefitinib ( Iressa ) is an EGFR inhibitor . The aim of our study was to evaluate time to progression ( TTP ) , overall survival ( OS ) and toxicities in a population affected by NSCLC using Iressa as maintenance therapy after first-line chemotherapy . PATIENTS AND METHODS Thirty patients were enrolled with stable disease or partial response . Six cycles of a platinum-based first-line chemotherapy were administered . Iressa was administered at the dose of 250 mg/d . RESULTS Median TTP was 5 months ; median overall survival was 8 months . TTP for adenocarcinoma and non-adenocarcinoma patients was 10 months and 3.2 months , respectively . No toxic effects were seen in 80 % of the patients ; 17 % of the patients had grade 1 follicolitis . OS for adenocarcinoma and non-adenocarcinoma patients were 15 and 5.9 months , respectively . CONCLUSION Gefitinib could be an ideal second-line therapy for adenocarcinoma patients responding to first-line chemotherapy Background There are well-known differences in gender outcome in non-small cell lung cancer ( NSCLC ) and other cancers . In this work , we evaluated several r and omised clinical trials to explore the gender influence in the outcome of patients with NSCLC treated with targeted therapy and immunotherapy .  Methods We performed a series of meta- analysis to compare the gender outcome in the routine setting for overall survival and progression-free survival ( PFS ) in phase III r and omised clinical trials comparing EGFR inhibitors versus chemotherapy ( OPTIMAL , LUX-lung 3 , LUX-lung 6 , EURTAC , ENSURE and WTJOG ) ; ALK inhibitors versus chemotherapy ( ASCEND 4 , ASCEND 5 , PROFILE 1014 and NCT009323893 ) and anti-PD1 checkpoint inhibitors versus chemotherapy ( CheckMate 017 , CheckMate 026 , CheckMate 057 , KEYNOTE 010 and KEYNOTE 024 ) . Results Female patients with NSCLC have a reduced risk of death compared with men ( HR=0.73 ; 95 % CI 0.67 to 0.79 ; p<0.00001 ) . Women had a better benefit from EGFR inhibitors than men ( HR=0.34 ; 95 % CI 0.28 to 0.40 ; p<0.00001 vs HR=0.44 ; 95 % CI 0.34 to 0.56 ; p<0.00001 , respectively ) . The benefit from ALK inhibitors was similar for both genders ( HR=0.51 ; 95 % CI 0.42 to 0.61 ; p<0.00001 vs HR=0.48 ; 95 % CI 0.39 to 0.59 ; p<0.00001 , for women and men , respectively ) . Anti-PD1 inhibitors significantly improved the PFS in male patients when compared with chemotherapy ( HR=0.76 ; 95 % CI 0.68 to 0.86 ; p<0.00001 ) ; in contrast , women showed no benefit in 5/5 r and omised trials ( HR=1.03 ; 95 % CI 0.89 to 1.20 ; p=0.69 ) . Conclusions In this exploratory study , some targeted treatments were influenced by gender . Despite differences in outcomes that could be attributed to different histology , EGFR and smoking status , gender should be evaluated more deeply as prognostic variable in patients with NSCLC
We believe that this attempt enables clinicians to choose appropriate treatment easier .
According to rapid development of chemotherapy in advanced non-small cell lung cancer ( NSCLC ) , the Japan Lung Cancer Society has been up date d its own guideline annually since 2010 .
Recently , we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors .
Thus , the guideline proposes to categorize patients into three entities : ( 1 ) driver oncogene-positive , ( 2 ) PD-L1 ≥ 50 % , and ( 3 ) others .
Here , we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC , stages IV