Discussion
DDR, nausea, gallbladder cancer, tumor, neutropenia, fatigue, vomiting,, anemia, heterogeneous disease, abnormal ECG
LEUKOCYTOPENIA, TUMOR, GALLBLADDER CANCER, NEUTROPENIA, THROMBOCYTOPENIA, DISEASE, ANEMIA, METASTASES, ADVANCED BILIARY TRACT CANCER
This study was the first to demonstrate that toripalimab in combination with lenvatinib and GEMOX chemotherapy yielded a high ORR (80%) and a median OS of 22.5 months in 30 subjects with locally advanced and metastatic ICC. Grade 3 or higher AEs were observed in 17 subjects and were easily manageable.Recently, many studies have investigated the clinical effects and safety of anti-PD-1/PD-L1 antibodies as first- and second-line therapy for BTC. A multicenter, open-label, phase 1 trial showed that nivolumab (PD-1 inhibitor) monotherapy had anti-tumor activity in Japanese patients with advanced BTC, yielding an ORR of 3.3%, a median OS of 5.2 months, and a median PFS of 1.4 months, while combination therapy of nivolumab and chemotherapy achieved more survival benefits in terms of higher ORR (33.3%), longer median OS (15.4 months), and median PFS (4.2 months).BTC is, however, a heterogeneous disease; ICC, ECC, and gallbladder cancer have distinct sites of origin, molecular phenotypes, and manifestations. The data from comprehensive analysis of Advanced Biliary Tract Cancer (ABC)-01, -02, and -03 studies also showed that patients with advanced ICC or liver-only ICC had a better OS-benefit from chemotherapy compared with other BTC.A combination therapy of lenvatinib with anti-PD-1 antibody also has utility in BTC. The LEAP-005 study recently showed that this combination yields an ORR of 10% as second-line treatment of advanced BTC.In addition to being beneficial, our triple treatments resulted in AEs that were tolerable and manageable. The common AEs observed in this study were increased AST or ALT levels, thrombocytopenia, anemia, neutropenia, leukocytopenia, abnormal ECG, vomiting, nausea, and fatigue, which were similar to those reported in a previous study of chemotherapy and an anti-PD-1 antibody.All patients with advanced ICC included in this study had stage IIIA disease or higher at baseline: 16.7% (5/30) had stage IIIA disease, 43.3% (13/30) had stage IIIB disease, and 40% (12/30) had stage IV disease. This means that the severity of the disease in the present study was similar to that in the ABC-02 trial (104/410 patients had locally advanced disease and 306/410 had metastases), which tested chemotherapy alone. Our combined therapy resulted in a much higher ORR and better mOS for advanced ICC than standard chemotherapy or any pairwise combination of PD-1 inhibitor with lenvatinib or chemotherapy. Moreover, this study showed that patients with positive staining for PD-L1in tumor cells tended to have a good response to this triple combination therapy. More importantly, our results also showed that patients presented with DDR-related gene mutations had a better response to this regimen than those without mutations. DDR is an important mechanism that enables cell survival in the face of genomic instability, replicative stress, and irreparable damage.This study has a few limitations. First, all patients were from a single center, potentially introducing an unknown selection bias and reducing the generalizability of the study. In particular, only relatively young patients (median 56.5 y, range 25–73 y) and those with good performance status were enrolled in this study, which may result in selection bias. Second, this was a single-arm, single-center and phase 2 trial and was designed without a control, which might weaken the reliability of evidence and increase the comparison error. Finally, the sample size in present trial was relatively small, which may result in selection bias and influence the estimation of ORR, PFS, and OS.Despite these limitations, this phase 2 study is, to the best of our knowledge, the first prospective trial of a PD1 inhibitor combined with GEMOX chemotherapy and lenvatinib for pure and advanced ICC patients. This study provides believable data demonstrating high efficacy, controllable AEs, and feasibility of this triple-combination therapy for ICC, which should be further explored in future well-designed prospective trials. To that end, we recently have developed a multicenter, double-blinded, randomized, phase 3 study to confirm the high efficacy of this combination therapy in patients with advanced ICC, and obtained NMPA approval (No 2021LP01825). That trial is also registered at Clinicaltrials.gov (number NCT05342194). It is expected that this new study will start to enroll patients in a few months.