Nivolumab/Ipilimumab Improves Survival Outcomes in Metastatic Gastric/GEJ Cancers

Overall survival (OS) and progression-free survival (PFS) were improved with nivolumab (Opdivo) plus ipilimumab (Yervoy) and chemotherapy compared with chemotherapy alone as frontline treatment of patients with metastatic gastric cancer, gastroesophageal junction (GEJ) cancer, or esophageal adenocarcinoma, meeting the coprimary end points of the phase 3 CheckMate-649 clinical trial.

PFS benefit was reported in patients whose tumors expressed PD-L1 by a combined positive score of 5 or higher. The trial also demonstrated a consistent safety profile for nivolumab and chemotherapy used as frontline treatment of gastric and esophageal cancers. These findings were announced in a press release from Bristol Myers Squibb and full results will be presented at an upcoming medical conference and shared with health authorities.¹

“There is an urgent need to improve therapeutic options for patients with esophageal and stomach cancer. Responses to the current standard chemotherapy in patients are short-lived, and less than 6% of patients with metastatic disease survive beyond five years,” said principal investigator Yelena Y. Janjigian, MD, chief, Gastrointestinal Oncology, Memorial Sloan Kettering Cancer Center, in a statement. “Immunotherapy helped transform how we care for our patients across different tumor types, and the encouraging results from CheckMate-649 represent a new opportunity to improve survival for patients beyond standard chemotherapy.”

The purpose of CheckMate-649 is to uncover a new treatment option for the treatment of gastric/GEJ cancer. The current standard of care is the combination of oxaliplatin and fluoropyrimidine. In a study of patients in Asian countries, the combination demonstrated a median overall survival of 12 to 14 months. In a presentation at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, Janjigian et al stated the treatment landscape needed a new option that can improve survival.²

Based on preclinical research showing that PD-L1 expression is found in 22% to 40% of gastric/GEJ tumors, Janjigian et al hypothesized that PD-1 blockade may be the optimal strategy for improving survival in this patient population. Nivolumab, a fully human IgG4 monoclonal antibody targeting PD-1, and another immune checkpoint inhibitor ipilimumab, was hypothesized to be effective in enhancing T-cell function through specific mechanisms.

The hypothesis was tested in the phase 1/2 CheckMate-032 clinical trial of nivolumab plus ipilimumab in advanced and metastatic gastric cancer. The results shows a 6-month OS rate of 49% (95% CI, 35%-62%) among patients who received nivolumab 3 mg/kg every 2 weeks, 54% (95% CI, 39%-67%) in patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 43% (95% CI, 29%-57%) among those who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg.³

The 12-month OS rate was 36% (95% CI, 21%-51%) with nivolumab monotherapy, 34% (95% CI, 19%-50%) with the lower dose of nivolumab plus ipilimumab, and data were not available [NA] for the higher-dose nivolumab plus ipilimumab arm.

The median OS was 5.0 months (95% CI, 3.4-12.4) with nivolumab monotherapy, 6.9 months (95% CI, 3.5-NA) for the low-dose combination arm, and 4.8 months (95% CI, 3.0-9.1) for the higher-dose combination arm.

The study showed treatment-related adverse events (TRAEs) in 70% of the monotherapy arm, 84% of the low-dose combination therapy arm, and 75% of patients who received the higher-dose combination, with grade 3/4 events occurring in 17%, 45%, and 27% of patients, respectively. Serious TRAEs of any-grade occurred in 10% of the monotherapy group, 43% of the low-dose combination group, and 23% of the high-dose combination group. Overall, 12% of patients in the study discontinued treatment due to toxicity. Notably, there was one grade 5 event of tumor lysis syndrome in the higher-dose combination arm.

CheckMate-032 confirmed the clinical activity of nivolumab plus ipilimumab in patients with chemotherapy-refractory gastric cancer and CheckMate-649 was launched to further evaluate the combination with the inclusion of patients with GEJ cancer.

CheckMate-649 is a randomized, multicenter, open-label, phase 3 study of 870 patients with metastatic gastric/GEJ cancer with or without PD-L1 expression. In addition to PFS and OS, the study is evaluating OS in all randomized patients, PFS by blinded independent review committee, objective response rate, and time to symptom deterioration as secondary end points.

Eligible patients include those 18 years of age or older with gastric/GEJ cancer that is unresectable, who did not receive neoadjuvant or adjuvant chemotherapy or radiotherapy for their disease with 6 months of beginning study treatment. All patients are required to have tumor tissue samples available for testing.

Patients were ineligible if there was prescience of tumor cells in the brain or spinal cord, active known or suspected autoimmune disease, serious or uncontrolled medical condition or infections, history of positive immunodeficiency virus or acquired immunodeficiency syndrome, or positive test for hepatitis B or C.

In the trial, chemotherapy consisted of investigator’s choice of capecitabine and oxaliplatin (XELOX) or fluorouracil, leucovorin, and oxaliplatin (FOLFOX). PD-L1 status was determined using the Dako IHC 22C3 pharmDx assay.

“The results from CheckMate-649, the largest study of gastric and esophageal cancers conducted to date, indicate the potential for Opdivo plus chemotherapy to change practice in the first-line setting and become a new standard of care for certain patients with gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma,” said Ian M. Waxman, MD, development lead, Gastrointestinal Cancers, Bristol Myers Squibb, in a statement.1 “We look forward to engaging health authorities worldwide with the goal of bringing this immunotherapy-based treatment option to patients as soon as possible.”

_References:

_{1. CheckMate-649, a phase 3 trial evaluating opdivo (nivolumab) plus chemotherapy vs. chemotherapy, meets primary endpoints demonstrating superior overall survival and progression-free survival in first-line treatment of gastric and esophageal cancers. News release. Bristol Myers Squibb. August 11, 2020. Accessed August 11, 2020. https://bit.ly/2XRyHwx}

_{2. Moehler MH, Janjigian YY, Adenis A, et al. Checkmate 649: A randomized, multicenter, open-label, phase 3 study of nivolumab (Nivo) plus ipilimumab (Ipi) versus oxaliplatin plus fluoropyrimidine in patients (Pts) with previously untreated advanced or metastatic gastric (G) or gastroesophageal junction (GEJ) cancer. J Clin Oncol. 2018;36(suppl 4; abstr TPS192). doi:10.1200/JCO.2017.35.4_suppl.TPS213}

_{3. Janjigian YY, Bendell JC, Calvo E, et al. CheckMate-032: Phase I/II, open-label study of safety and activity of nivolumab (nivo) alone or with ipilimumab (ipi) in advanced and metastatic (A/M) gastric cancer (GC). J Clin Oncol. 2016;34(suppl 15):4010. doi:10.1200/JCO.2016.34.15_suppl.4010}