Nivolumab (Opdivo) in combination with chemotherapy as a frontline treatment demonstrated a significant survival benefit in patients with metastatic gastric cancer, gastroesophageal junction (GEJ) cancer, or esophageal adenocarcinoma, according to findings from the phase 3 CheckMate-649 trial (NCT02872116).1
When compared with chemotherapy alone, the nivolumab combination met both primary end points of overall survival (OS) at a prespecified interim analysis of the trial, as well as progression-free survival at the time of the final analysis in patients whose tumors had PD-L1 expression with a combined positive score (CPS) of 5 or greater. Notably, the OS benefit achieved with the combination was also reported in the all-randomized patient population.
According to Bristol Myers Squibb (BMS), the developer of the agent, nivolumab is the first PD-1 inhibitor to show superior OS and PFS when used in combination with chemotherapy versus just chemotherapy alone in these patient populations. Moreover, the safety profiles observed with both nivolumab and chemotherapy in the trial were found to correlate with what has previously been reported with both approaches in the frontline treatment setting.
“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 5 years,” Yelena Y. Janjigian, MD, principal investigator and chief of Gastrointestinal Oncology at Memorial Sloan Kettering Cancer Center, stated in a press release. “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.”
For patients with metastatic gastric or GEJ cancer, the frontline standard of care is a combination comprised of platinum and fluoropyrimidine, and the median OS achieved with this approach ranges from 8 months to 14 months.2
Investigators hypothesized that nivolumab plus chemotherapy or ipilimumab (Yervoy) would result in stronger outcomes for patients with advanced or metastatic gastric/GEJ cancer over chemotherapy alone.
The goal of the multicenter, open-label, phase 3 trial was to compare the OS benefit achieved with nivolumab plus chemotherapy or nivolumab plus ipilimumab versus that of standard-of-care chemotherapy comprised of oxaliplatin and fluoropyrimidine in treatment-naïve patients with advanced or metastatic gastric/GEJ cancer and PD-L1–positive tumors.
To be eligible for participation, patients had to be 18 years of age or older and have advanced or metastatic gastric/GEJ cancer determined to be inoperable and predominant adenocarcinoma that was histologically confirmed.3
Patients also could not have received previous systemic treatment for advanced or metastatic disease and could not have had neoadjuvant or adjuvant treatment within the past 6 months. Moreover, to participate, they had to have an ECOG performance status ranging from 0 to 1 and they had to agree to provide a tissue sample so that investigators could determine their PD-L1 status.
Patients with known, untreated central nervous metastases, with active known or suspected autoimmune disease, grade 1 or higher peripheral neuropathy, HER2 positivity, a history of human immunodeficiency virus, or hepatitis B or C indicative of acute or chronic infection, were not permitted.
The primary end point of the trial was OS in participants with PD-L1–positive tumors, while key secondary end points included OS in all patients who underwent randomization, PFS in those whose tumors had PD-L1 positivity as well as all randomized patients, and time to symptom deterioration, which was evaluated via a GaCs questionnaire in both patients with PD-L1–positive tumors and all randomized patients.
For the trial, previously untreated patients with gastric/GEJ cancer were randomized to 1 of 3 treatment arms: 4 doses of nivolumab plus ipilimumab followed by nivolumab alone, nivolumab plus chemotherapy, either XELOX or FOLFOX, or XELOX or FOLFOX. All patients underwent post-treatment follow-up.
“The results from CheckMate-649, the largest study of gastric and esophageal cancers conducted to date, indicate the potential for [nivolumab] plus chemotherapy to change practice in the first-line setting and become a new standard of care for certain patients with gastric cancer, GEJ cancer, or esophageal adenocarcinoma,” Ian M. Waxman, MD, development lead of Gastrointestinal Cancers at BMS, added in the release. “We look forward to engaging health authorities worldwide with the goal of bringing this immunotherapy-based treatment option to patients as soon as possible.”
The pharmaceutical company plans to finish a full evaluation of the available data from the phase 3 trial, to work with investigators to present these data at an upcoming medical meeting, and to discuss the findings further with health authorities.
The company remains blinded to the data yielded in the nivolumab/ipilimumab arm and the trial will continue follow-up as planned to allow for the data to mature, according to BMS.
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/3aompB2.
2. Chau I, Cleary JM, Feeney K, et al. CheckMate 649: a randomized, multicenter, open-label, phase III study of nivolumab (NIVO) + ipilimumab (IPI) or nivo + chemotherapy (CTX) versus CTX alone in patients with previously untreated advanced (Adv) gastric (G) or gastroesphageal junction (GEJ) cancer. J Clin Oncol. 2018;36(suppl 4):TPS192. doi: 10.1200/JCO.2018.36.4_suppl.TPS192
3. Efficacy study of nivolumab plus ipilimumab or nivolumab plus chemotherapy against chemotherapy in stomach cancer or stomach/esophagus junction cancer (CheckMate649). ClinicalTrials.gov. Updated June 17, 2020. Accessed August 11, 2020. https://clinicaltrials.gov/ct2/show/NCT02872116
This article was originally posted on OncLive as, "Nivolumab Plus Chemotherapy Shows Significant Survival Benefit in Gastric and Esophageal Cancers."