Camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary tract cancer: a single-arm, open-label, phase II trial

Abstract

BackgroundImmune checkpoint inhibitors monotherapy has been studied in patients with advanced biliary tract cancer (BTC). The aim of this study was to assess the efficacy and safety of camrelizumab, plus gemcitabine and oxaliplatin (GEMOX) as first-line treatment in advanced BTC and explored the potential biomarkers associated with response.MethodsIn this single-arm, open-label, phase II study, we enrolled stage IV BTC patients. Participants received camrelizumab (3 mg/kg) plus gemcitabine (800 mg/m2) and oxaliplatin (85 mg/m2). Primary endpoints were 6-month progression-free survival (PFS) rate and safety. Secondary endpoints were objective response rate (ORR), PFS and overall survival (OS). Exploratory endpoints included association between response and tumor mutational burden (TMB), blood TMB, dynamic change of ctDNA and immune microenvironment.Results54 patients with advanced BTC were screened, of whom 38 eligible patients were enrolled. One patient withdrew informed consent before first dose treatment. Median follow-up was 11.8 months. The 6-month PFS rate was 50% (95% CI 33 to 65). Twenty (54%) out of 37 patients had an objective response. The median PFS was 6.1 months and median OS was 11.8 months. The most common treatment-related adverse events (TRAEs) were fatigue (27 (73%)) and fever (27 (73%)). The most frequent grade 3 or worse TRAEs were hypokalemia (7 (19%)) and fatigue (6 (16%)). The ORR was 80% in patients with programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) ≥1% versus 53.8% in PD-L1 TPS <1%. There was no association between response and TMB, blood TMB, immune proportion score or immune cells (p>0.05), except that PFS was associated with blood TMB. Patients with positive post-treatment ctDNA had shorter PFS (p=0.007; HR, 2.83; 95% CI 1.27 to 6.28).ConclusionCamrelizumab plus GEMOX showed a promising antitumor activity and acceptable safety profile as first-line treatment in advanced BTC patients. Potential biomarkers are needed to identify patients who might respond to camrelizumab plus GEMOX.Trial registration numberNCT03486678.

Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance

“…A recent study in advanced refractory BTC patients treated with nivolumab demonstrated that lower levels of PD-L1 in tumors were associated with reduced PFS, but not with lower OS [ 96 ]. A similar result was observed in advanced BTC patients treated with camrelizumab plus GEMOX as a first-line treatment since the ORR was worse in patients with lower PD-L1 levels in tumors than in those with higher levels [ 100 ]. However, in two clinical trials, including patients with advanced biliary cancer, most of them refractory to other therapies, no correlation between PD-L1 levels and response to pembrolizumab monotherapy was found [ 97 ]).…”

“…In another study with PD-L1-positive gemcitabine/cisplatin-refractory BTC patients, a durable efficacy of pembrolizumab with an ORR of 9.8% was found [ 99 ]. Camrelizumab, another PD-1 inhibitor, combined with chemotherapy as first-line treatment of BTCs, showed promising results with 50% ORR and a median OS of 11.8 months [ 100 ]. The combination of pembrolizumab and ramucirumab, an antibody that targets VEGFR-2, also seemed to be beneficial as a second-line treatment for patients with advanced BTC, showing a reduction of tumor size of 37.5% and a DCR of 38.5% [ 101 ].…”

“…In the KEYNOTE-158 study, a low tumor mutational burden correlated with a reduced response to pembrolizumab monotherapy [ 102 ]. In contrast, there was no association between the degree of response and this marker (determined in tissue or blood) in advanced BTC patients treated with camrelizumab plus GEMOX [ 100 ].…”

Independent Risk Factors of Early Recurrence After Curative Resection for Perihilar Cholangiocarcinoma: Adjuvant Chemotherapy May Be Beneficial in Early Recurrence Subgroup

“…Immunotherapy combined with chemotherapy (camrelizumab plus GEMOX [a gemcitabine and oxaliplatin regimen]) has been investigated and shown promising antitumor efficacy in biliary tract cancer. 45 Research focused on reported results for specific biliary tract subsites and high-risk patient subgroups is another avenue for future investigation.…”

Chemotherapy for Biliary Tract Cancer in 2021

“…Pembrolizumab provides durable antitumor activity in 6-13% of patients with advanced biliary tract cancer regardless of programmed cell death 1 ligand 1 (PD-L1) expression and has manageable toxicity. Other immune checkpoint inhibitors were also evaluated in phase I or II studies involving both naïve and refractory advanced biliary tract cancer [74][75][76][77][78][79]. The results of these studies were promising, and further large-scale evaluation is underway.…”