CheckMate-032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer

Abstract

Purpose: Metastatic esophagogastric cancer treatments after failure of second-line chemotherapy are limited. Nivolumab demonstrated superior overall survival (OS) versus placebo in Asian patients with advanced gastric or gastroesophageal junction cancers. We assessed the safety and efficacy of nivolumab and nivolumab plus ipilimumab in Western patients with chemotherapy-refractory esophagogastric cancers.

Patients and methods: Patients with locally advanced or metastatic chemotherapy-refractory gastric, esophageal, or gastroesophageal junction cancer from centers in the United States and Europe received nivolumab or nivolumab plus ipilimumab. The primary end point was objective response rate. The association of tumor programmed death-ligand 1 status with response and survival was also evaluated.

Results: Of 160 treated patients (59 with nivolumab 3 mg/kg, 49 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 52 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg), 79% had received two or more prior therapies. At the data cutoff, investigator-assessed objective response rates were 12% (95% CI, 5% to 23%), 24% (95% CI, 13% to 39%), and 8% (95% CI, 2% to 19%) in the three groups, respectively. Responses were observed regardless of tumor programmed death-ligand 1 status. With a median follow-up of 28, 24, and 22 months across the three groups, 12-month progression-free survival rates were 8%, 17%, and 10%, respectively; 12-month OS rates were 39%, 35%, and 24%, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 47%, and 27% of patients in the three groups, respectively.

Conclusion: Nivolumab and nivolumab plus ipilimumab demonstrated clinically meaningful antitumor activity, durable responses, encouraging long-term OS, and a manageable safety profile in patients with chemotherapy-refractory esophagogastric cancer. Phase III studies evaluating nivolumab or nivolumab plus ipilimumab in earlier lines of therapy for esophagogastric cancers are underway.

Trial registration: ClinicalTrials.gov NCT01928394.

Figures

Fig 1.

Changes in tumor burden per investigator assessment in individual patients. Percentage change from baseline in target lesions over time with (A) nivolumab 3 mg/kg (NIVO3), (B) nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1 + IPI3), (C) NIVO3 plus ipilimumab 1 mg/kg (NIVO3 + IPI1), and (D) the reduction in maximum percentage change from baseline in size of tumors by treatment group. Patients with 0% best reduction in target lesion are not shown on the plot (NIVO3, n = 2; NIVO1 + IPI3, n = 1; NIVO3 + IPI1, n = 1). Triangle indicates investigator-assessed confirmed complete or partial response, square indicates percent change truncated at 100%, closed circle represents patients off treatment, and cross represents first occurrence of a new lesion. (*) Indicates patients with a confirmed response (complete or partial response), and the bars representing patients with a percentage change in tumor burden that exceeds 100% have been truncated.

Fig 2.

Kaplan-Meier curves of (A) investigator-assessed progression-free survival (PFS) and (B) overall survival (OS) in all enrolled patients by treatment group: nivolumab 3 mg/kg (NIVO3), nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1 + IPI3), and NIVO3 plus ipilimumab 1 mg/kg (NIVO3 + IPI1). Hash marks indicate censored observations.

Fig A1.

CONSORT diagram for study design and patient disposition. (*) Increased ALT/AST (n = 1 patient) and pneumonitis (n = 1 patient). (†) Increased ALT/AST (n = 3 patients); colitis (n = 2 patients); diarrhea (n = 2 patients); colitis, cystitis, and transaminitis (n = 1 patient); and diarrhea and hyperthyroidism (n = 1 patient). (‡) Acute renal failure, autoimmune hepatitis, diarrhea, enteritis, increased ALT/AST, lymphocytic myocarditis, and pneumonitis (n = 1 patient each). AE, adverse event; IPI1, ipilimumab 1 mg/kg; IPI3, ipilimumab 3 mg/kg; NIVO1, nivolumab 1 mg/kg; NIVO3, nivolumab 3 mg/kg.

Fig A2.

Response characteristics in all responders by (A) investigator assessment and (B) blinded independent central review assessment. IPI1, ipilimumab 1 mg/kg; IPI3, ipilimumab 3 mg/kg; MSI, microsatellite instability; MSI-H, microsatellite instability–high; NIVO1, nivolumab 1 mg/kg; NIVO3 nivolumab 3 mg/kg; PDL, programmed death ligand; PD-L1+, programmed death-ligand 1–positive; PD-L1−, programmed death-ligand 1–negative.

Fig A3.

Changes from baseline in target lesions over time per blinded independent central review assessment in patients treated with (A) nivolumab 3 mg/kg monotherapy, (B) nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, or (C) nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. All data are based on the November 2016 database cutoff, except for the blinded independent central review data for the nivolumab 3 mg/kg group, which are based on the March 2016 database cutoff. The + signs indicate the occurrence of a new lesion, closed circles indicate off treatment, open squares represent percentage changes from baseline truncated at 100%, and red triangles indicate investigator-assessed confirmed complete or partial responses.

Fig A4.

Waterfall plot showing maximum percentage change from baseline in size of tumors in patients treated with nivolumab 3 mg/kg (NIVO3), nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1 + IPI3), and NIVO3 plus ipilimumab 1 mg/kg (NIVO3 + IPI1) per blinded independent central review. All data are based on the November 2016 database cutoff, except for the blinded independent central review data for the NIVO3 group, which are based on the March 2016 database cutoff. Patients with 0% best reduction in target lesion are not shown on the plot (NIVO1 + IPI3; n = 1). (*) Indicates patients with a confirmed response. Bars representing patients with a percentage change in tumor burden that exceeded 100% have been truncated.

Fig A5.

Kaplan-Meier curves of progression-free survival (PFS) in patients treated with nivolumab 3 mg/kg (NIVO3), nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1 + IPI3), and NIVO3 plus ipilimumab 1 mg/kg (NIVO3 + IPI1) per blinded independent central review. All data are based on the November 2016 database cutoff, except for the blinded independent central review data for the NIVO3 group, which are based on the March 2016 database cutoff.