Discussion
NSCLC, BOR of MR/SD, neuroblastoma, tumor, MR/SD, toxicities, ALK-driven, weight gain, psychiatric, NCSLC
NEUROBLASTOMA, TUMOR, MINOR, NSCLC, ONCOLOGY, SOFT TISSUE TUMOR, TUMORIGENESIS
Despite an exponential increase in discoveries related to neuroblastoma genomics and immune evasion, a child diagnosed with high-risk neuroblastoma today is subjected to a largely empiric and vastly intensive regimen of genotoxic chemotherapeutics, radiation and GD2-targeted immunotherapy that, although effective, has substantial acute and long-term side effectsThe RP2D of 115 mg/mOverall, younger patients treated with lorlatinib monotherapy, in particular those also harboring In the context of this phase 1 trial of safety and tolerability, we observed objective responses, and, of those, patients who achieved objective responses of CR/PR to lorlatinib as well as those with MR/SD went on to receive multiple courses of therapy owing to sustained responses. These response rates to lorlatinib compare favorably to previous trials of first-generation and second-generation ALK inhibitors crizotinib (15% CR/PR) or ceritinib (20% CR/PR) in children with ALK-driven neuroblastomaAlthough historical trials report CR/PR rates, there is now international consensus that minor response be used given the importance of MIBG response. Some patients with BOR of MR/SD were notable for having CR by functional imaging (MIBG or PET becoming non-avid) and bone marrow CRs achieved, with halted soft tissue tumor growth control that was not reflected in the BOR. In the era of targeted therapies such as lorlatinib, we are recognizing that durable metabolic responses result in sustained tumor control, supporting why the international community has added minor response in the overall response assessment. We speculate that The safety profile of lorlatinib across all ages was similar in scope and grade to those reported in NSCLC studies, with the unique toxicities of lorlatinib, such as weight gain and increased circulating lipids, manageable with supportive care, diet management and statins. Only one patient, who had a germline Lorlatinib was optimized to penetrate the blood–brain barrier, leading to improved CNS distribution as well as intracranial responses in patients with NCSLC with brain metastasesGrade 4 CNS AEs were limited to two adult patients, with one having a prior undisclosed psychiatric history, supporting the continued need for strict eligibility criteria to exclude those patients who are most at risk. Failure of certain patients to disclose prior psychiatric clinical history has also highlighted the need to identify more robust objective mechanisms to screen for pre-treatment psychiatric risk. Most importantly, CNS effects consistently improved with dose hold and reduction, allowing most to continue lorlatinib to benefit from its potent anti-tumor effects. Lorlatinib exposure was not affected by age nor by addition of chemotherapy.The source of tumor tissue used for The current therapeutic paradigm for patients with high-risk neuroblastoma is to treat with an intense and largely empiric multi-modal approach. The discovery of ALK as a biomarker of inferior prognosis and of these oncogenic mutations as drivers of tumorigenesis in a significant subset of newly diagnosed patients has shifted the paradigm to study ALK inhibition in frontline therapy. Based on the results of this phase 1 study, which supports the hypothesis that lorlatinib will be safe and effective for patients with newly diagnosed ALK-driven, high-risk neuroblastoma, we recently implemented a major amendment to replace crizotinib with lorlatinib in the Childrenʼs Oncology Group phase 3 trial (