Jane Y. So

Purpose:Anti–PD-1/PD-L1 blockade combined with chemotherapy has become the first-line treatment for advanced biliary tract cancers. Combined anti–PD-1/CTLA-4 blockade using nivolumab and ipilimumab has shown encouraging activity in patients with intrahepatic cholangiocarcinoma (iCCA) and gallbladder carcinoma (GBC) in two trials (CA209–538 and SWOG1609). MoST-CIRCUIT further evaluated combined checkpoint blockade using nivolumab/ipilimumab in patients with advanced iCCA and GBC. Patients and Methods:Patients with a maximum of 1 line of prior systemic therapy were enrolled as cohort B into MoST-CIRCUIT, a single-arm, nonrandomized phase 2 trial. Patients received nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 480 mg every 4 weeks for 96 weeks. Response (RECIST 1.1) was assessed every 12 weeks. Coprimary endpoints were objective response rate (ORR) and 6-month progression-free survival (6-PFS), with the secondary endpoints being median overall survival (mOS), PFS, and treatment-related toxicity. Results:Sixty patients (37 iCCA and 23 GBC) were enrolled; 85% were pretreated, including 13 patients with durvalumab. The ORR was 12% (2% complete response, 10% partial response): 3% and 26% in the iCCA and GBC subgroups, respectively. The 6-PFS was 27% (iCCA 19%; GBC 39%), and mOS was 7 months. In the immunotherapy-naïve population, the ORR was 19% (iCCA 10%; GBC 38%). Severe immune-related adverse events were observed in 20% of patients. Conclusions:Efficacy was limited in what is the largest biliary tract cancer cohort treated to date with combined anti–CTLA-4/PD-1 blockade. Encouraging activity was observed in the GBC subgroup. Further evaluation of checkpoint inhibition in biliary tract cancer should focus on patients with GBC.

Representativeness of the Study population.

Purpose: Anti–PD-1/PD-L1 blockade combined with chemotherapy has become the first-line treatment for advanced biliary tract cancers. Combined anti–PD-1/CTLA-4 blockade using nivolumab and ipilimumab has shown encouraging activity in patients with intrahepatic cholangiocarcinoma (iCCA) and gallbladder carcinoma (GBC) in two trials (CA209–538 and SWOG1609). MoST-CIRCUIT further evaluated combined checkpoint blockade using nivolumab/ipilimumab in patients with advanced iCCA and GBC. Patients and Methods: Patients with a maximum of 1 line of prior systemic therapy were enrolled as cohort B into MoST-CIRCUIT, a single-arm, nonrandomized phase 2 trial. Patients received nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 480 mg every 4 weeks for 96 weeks. Response (RECIST 1.1) was assessed every 12 weeks. Coprimary endpoints were objective response rate (ORR) and 6-month progression-free survival (6-PFS), with the secondary endpoints being median overall survival (mOS), PFS, and treatment-related toxicity. Results: Sixty patients (37 iCCA and 23 GBC) were enrolled; 85% were pretreated, including 13 patients with durvalumab. The ORR was 12% (2% complete response, 10% partial response): 3% and 26% in the iCCA and GBC subgroups, respectively. The 6-PFS was 27% (iCCA 19%; GBC 39%), and mOS was 7 months. In the immunotherapy-naïve population, the ORR was 19% (iCCA 10%; GBC 38%). Severe immune-related adverse events were observed in 20% of patients. Conclusions: Efficacy was limited in what is the largest biliary tract cancer cohort treated to date with combined anti–CTLA-4/PD-1 blockade. Encouraging activity was observed in the GBC subgroup. Further evaluation of checkpoint inhibition in biliary tract cancer should focus on patients with GBC.

Purpose:Combination immunotherapy with anti–CTLA-4 and anti–PD-1 blockade has demonstrated significant clinical activity across several tumor types. Neuroendocrine tumors (NET) are a heterogeneous group of rare tumors with limited treatment options. CA209-538 is a clinical trial of combination immunotherapy with ipilimumab and nivolumab in rare cancers, including advanced NETs.Patients and Methods:CA209-538 is a prospective multicenter clinical trial in patients with advanced rare cancers. Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every three weeks for four doses, followed by nivolumab 3 mg/kg every two weeks and continued for up to 96 weeks, until disease progression or the development of unacceptable toxicity. Response was assessed every 12 weeks by RECIST 1.1. The primary endpoint was clinical benefit rate (CBR; complete remission + partial remission + stable disease).Results:Twenty-nine patients with advanced NETs received treatment. Three (10%) patients had low-, 13 (45%) had intermediate-, and 13 (45%) had high-grade tumors; lung was the most common primary site (39%). The objective response rate was 24% with a CBR of 72%; 43% of patients with pancreatic neuroendocrine neoplasms (NEN), and 33% of patients with atypical bronchial carcinoid achieved an objective response. The median progression-free survival was 4.8 months [95% confidence interval (CI): 2.7–10.5] and overall survival was 14.8 months (95% CI: 4.1–21.3). Immune-related toxicity was reported in 66% of patients with 34% experiencing grade 3/4 events.Conclusions:Combination immunotherapy with ipilimumab and nivolumab demonstrated significant clinical activity in subgroups of patients with advanced NETs including patients with atypical bronchial carcinoid and high-grade pancreatic NENs.

Purpose:Combination immunotherapy with anti–CTLA-4 and anti–PD-1 blockade has demonstrated significant clinical activity across several tumor types. Neuroendocrine tumors (NET) are a heterogeneous group of rare tumors with limited treatment options. CA209-538 is a clinical trial of combination immunotherapy with ipilimumab and nivolumab in rare cancers, including advanced NETs.Patients and Methods:CA209-538 is a prospective multicenter clinical trial in patients with advanced rare cancers. Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every three weeks for four doses, followed by nivolumab 3 mg/kg every two weeks and continued for up to 96 weeks, until disease progression or the development of unacceptable toxicity. Response was assessed every 12 weeks by RECIST 1.1. The primary endpoint was clinical benefit rate (CBR; complete remission + partial remission + stable disease).Results:Twenty-nine patients with advanced NETs received treatment. Three (10%) patients had low-, 13 (45%) had intermediate-, and 13 (45%) had high-grade tumors; lung was the most common primary site (39%). The objective response rate was 24% with a CBR of 72%; 43% of patients with pancreatic neuroendocrine neoplasms (NEN), and 33% of patients with atypical bronchial carcinoid achieved an objective response. The median progression-free survival was 4.8 months [95% confidence interval (CI): 2.7–10.5] and overall survival was 14.8 months (95% CI: 4.1–21.3). Immune-related toxicity was reported in 66% of patients with 34% experiencing grade 3/4 events.Conclusions:Combination immunotherapy with ipilimumab and nivolumab demonstrated significant clinical activity in subgroups of patients with advanced NETs including patients with atypical bronchial carcinoid and high-grade pancreatic NENs.

Best response according to histological grade

Best response according to histological grade