Phase III Trials Confirm Benefit of First-Line Anti–PD-1 Inhibition Plus Chemotherapy in Gastric Cancer

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Two phase III trials evaluating the addition of drugs targeting PD-1 to chemotherapy—RATIONALE 305 and CheckMate 649—confirmed the benefit of this approach as first-line therapy for advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma, in findings presented at the 2023 ASCO GI Cancers Symposium.

Markus Moehler, MD, Head of Gastrointestinal Oncology at Johannes Gutenberg–University Clinic, Mainz, Germany, reported that in the phase III RATIONALE 305 trial, tislelizumab (which is being developed in China) plus chemotherapy provided “a statistically significant and clinically meaningful improvement” in overall survival in patients with advanced PD-L1–positive gastric or gastroesophageal junction adenocarcinoma.1 This was an interim analysis performed in the study’s PD-L1–positive population.

“The overall survival benefit with tislelizumab plus chemotherapy was accompanied by improvements in progression-free survival, objective response rate, and duration of response.”
— Markus Moehler, MD

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“The overall survival benefit with tislelizumab plus chemotherapy was accompanied by improvements in progression-free survival, objective response rate, and duration of response,” Dr. Moehler said. “The RATIONALE 305 results offer tislelizumab plus chemotherapy as a new first-line treatment option for patients with PD-L1–positive, unresectable, locally advanced or metastatic gastric or gastroesophageal junction cancer.”

In addition, updated results of the global phase III CheckMate 649 trial upheld the benefit seen for nivolumab plus chemotherapy, according to Yelena Janjigian, MD, Chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, New York. She reported that at 3 years, this treatment resulted in a 30% reduction in the risk of death over chemotherapy alone in patients with tumors enriched for PD-L1 expression.2

“At 36 months, we still see a meaningful improvement in all efficacy endpoints, such as overall survival and progression-free survival—both in the first line and in subsequent therapies—and, of course, objective response rate,” Dr. Janjigian said. “These data, in conjunction with the safety data, continue to support the use of nivolumab plus chemotherapy in the first-line setting [in this population].”

“These data, in conjunction with the safety data, continue to support the use of nivolumab plus chemotherapy in the first-line setting [in this population].”
— Yelena Janjigian, MD

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In a panel discussion, Dr. Moehler commented that the field is clearly heading in the direction of first-line anti–PD-1 agents based on “clear” data with tislelizumab, nivolumab, and sintilimab (also being developed in China). “It is very important to test our patients for PD-L1 and integrate these new agents into classical therapy,” he said.

In April 2021, the U.S. Food and Drug Administration (FDA) approved nivolumab for use in combination with chemotherapy in the front-line treatment of advanced gastric or gastroesophageal junction cancer, based on the initial findings of CheckMate 649.3 The FDA is currently reviewing data for tislelizumab.

RATIONALE 305: Survival Benefit With Tislelizumab

RATIONALE 305 is a randomized, double-blind, placebo-controlled global phase III trial evaluating tislelizumab—an anti–PD-1 antibody engineered to minimize binding to Fc-gamma receptors R on macrophages. Tislelizumab was combined with chemotherapy (capecitabine plus oxaliplatin [XELOX] or cisplatin plus fluorouracil) and compared with chemotherapy alone as first-line treatment. More than 90% of patients received XELOX.

The study’s 997 patients were recruited from 13 countries, almost 50% of whom were from outside of China. Patients were randomly assigned to receive either tislelizumab and chemotherapy or placebo plus chemotherapy. The primary endpoint was overall survival in the 457 patients who were PD-L1–positive (PD-L1 score ≥ 5% of tumor cells), with hierarchical testing of the intention-to-treat population.

All Endpoints Improved With Tislelizumab

Median overall survival was 17.2 months with tislelizumab plus chemotherapy vs 12.6 months with chemotherapy alone (hazard ratio [HR] = 0.74; P = .0056 [statistical boundary = .0092]), yielding a 24-month survival rate of 38.3% vs 24.9%, respectively. “The Kaplan-Meier curves separated after 1 year and stayed nicely separated out to 2 years,” Dr. Moehler noted, adding that survival was improved across all prespecified subgroups.

Median progression-free survival in the PD-L1–positive population was 7.2 vs 5.9 months, respectively (HR = 0.67; 95% confidence interval [CI] = 0.55–0.83), with curves remaining separate. At 24 months, 22.3% and 8.7%, respectively, were free of disease progression. The combination was also associated with a numerically higher response rate (50.4% vs 43.0%) and longer median duration of response (9.0 vs 7.1 months).

Tislelizumab plus chemotherapy had a manageable safety profile, with treatment-emergent adverse events grade ≥ 3 observed in approximately 64% of each arm and serious treatment-emergent adverse events in 42.3% of the experimental arm and 36.8% of the control arm, respectively. Deaths considered treatment-related occurred in six patients (2.2%) given tislelizumab and two (0.7%) given chemotherapy alone. The control arm experienced more anemia, diarrhea, and neutropenia.

Health-related quality of life heavily favored tislelizumab plus chemotherapy. “The addition of tislelizumab to chemotherapy not only did not worsen health-related quality of life, but suggested it was better, as indicated by maintenance of [European Organisation for Research and Treatment of Cancer QLQ-C30] global health status/quality-of-life scores, physical functioning, and greater reduction in general stomach cancer symptoms,” Dr. Moehler reported. “There was also a trend toward reductions in fatigue, pain/discomfort, and upper gastrointestinal symptoms.”

CheckMate 649 Update: Overall Survival Benefit Maintained

Dr. Janjigian reported on the results of nivolumab plus XELOX or FOLFOX (fluorouracil, leucovorin, oxaliplatin, n = 789) vs XELOX or FOLFOX alone (n = 833). A third arm (not reported at the meeting) evaluated nivolumab plus ipilimumab (n = 409). Most patients (70%) had gastric cancer, 16% had PD-L1–positive disease, and 3% had microsatellite instability–high (MSI-H) tumors.

After a minimum follow-up of 36.2 months, median overall survival was 14.4 months with nivolumab plus chemotherapy and 11.1 months with chemotherapy alone in the subset of patients with a PD-L1 combined positive score (CPS) ≥ 5 (HR = 0.70; 95% CI = 0.61–0.81), with 3-year overall survival rates of 21% and 10%, respectively. Median progression-free survival was 8.3 vs 6.1 months, respectively (HR = 0.70; 95% CI = 0.60–0.81).

In the all-randomized population, the addition of nivolumab to chemotherapy resulted in a median overall survival of 13.7 months and 11.6 months, respectively (HR = 0.79; 95% CI = 0.71–0.88), with 3-year survival rates of 17% and 10%, respectively, and median progression-free survival of 7.7 months and 6.9 months, respectively (HR = 0.79; 95% CI = 0.71–0.89).


  • Updated 3-year analysis of the phase III CheckMate 649 trial confirmed the benefit of adding nivolumab to chemotherapy as a first-line treatment for advanced gastric cancer, gastroesophageal cancer, and esophageal adenocarcinoma.
  • The phase III RATIONALE 305 trial also showed an overall survival benefit with the anti–PD-1 agent tislelizumab plus chemotherapy given in the first line in advanced gastric and gastroesophageal cancers. In patients with PD-L1 ≥ 5%, median overall survival was 17.2 months vs 12.6 months with chemotherapy (hazard ratio = 0.74; P = .0056).

“Overall survival consistently favored nivolumab plus chemotherapy with longer follow-up across multiple prespecified subgroups in all randomized patients, and the benefit was enriched at higher PD-L1 cutoffs,” Dr. Janjigian said. She noted the benefit in the all-randomized population extended “to patients whom we would think would do poorly, such as [those with] liver metastasis, and irrespective of tumor location.”

Objective response rates were also higher vs chemotherapy alone across all PD-L1 CPS subgroups. In the CPS-enriched subset, the median duration of response was 9.6 months with nivolumab plus chemotherapy and 7.0 months with chemotherapy alone; among all randomly assigned patients, it was 8.5 vs 6.9 months, respectively.

Median time to second disease progression also favored the nivolumab/chemotherapy arm in patients with a PD-L1 CPS ≥ 5 (HR = 0.67; 95% CI = 0.58–0.77) and in the all-randomized population (HR = 0.76; 95% CI = 0.68–0.85).

Best Outcomes

“Clearly, the higher the PD-L1 status, the better patients do…, but it’s interesting to see that the response rates improved irrespective of PD-L1 status. Even in patients with lower levels of PD-L1 overexpression, we see higher response rates and improvement in duration of response as well,” Dr. Janjigian said.

“Also, the MSI-H patients in particular tend to do much better,” she added. In the MSI-H subset, nivolumab plus chemotherapy resulted in a median overall survival of 38.7 months vs 12.3 months with chemotherapy alone (HR = 0.34; 95% CI = 0.16–0.74). The microsatellite-stable subset, on the other hand, fared about the same as the all-randomized population, with median overall survival of 13.8 months and 11.5 months, respectively (HR = 0.79; 95% CI = 0.71–0.89).

“It’s critical to test patients for MSI, particularly if you’re going to restrict [therapy] by PD-L1 status,” Dr. Janjigian commented.

With longer follow-up, grade 3 or 4 treatment-related adverse events occurred in up to 5% of patients in the investigative arm. Most events in both arms presented within the first 6 months of treatment. 

DISCLOSURE: Dr. Moehler has received honoraria from Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Merck Serono, MSD Oncology, Pierre Fabre, Roche/Genentech, Sanofi, and Servier; has been a consultant or advisor to Amgen, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Lilly, Merck Serono, Pfizer, Roche, Servier, and Taiho Pharmaceutical; has received institutional research funding from Amgen, AstraZeneca, Leap Therapeutics, Merck Serono, and MSD; and has been reimbursed for travel, accommodations, or other expenses from Amgen, ASCO, Bayer, European Society for Medical Oncology, German Cancer Society, Merck Serono, MSD, and Roche. Dr. Janjigian has served as a consultant or advisor to AmerisourceBergen, Arcus Biosciences, AstraZeneca, Basilea Pharmaceutical, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Geneos, GlaxoSmithKline, Imedex, Imugene, Lilly, Lynx Health, Merck, Merck Serono, Michael J. Hennessy Associates, Paradigm, PeerView, Pfizer, Rgenix, Seattle Genetics, Silverback Therapeutics, and Zymeworks.


1. Moehler MH, Kato K, Arkenau HT, et al: RATIONALE 305: Phase 3 study of tislelizumab plus chemotherapy vs placebo plus chemotherapy as first-line treatment of advanced gastric or gastroesophageal junction adenocarcinoma. 2023 ASCO GI Cancers Symposium. Abstract 286. Presented January 19, 2023.

2. Janjigian YY, Shitara K, Moehler MH, et al: Nivolumab plus chemotherapy vs chemo as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: 3-year follow-up from CheckMate 649. 2023 ASCO GI Cancers Symposium. Abstract LBA291. Presented January 19, 2023.

3. Janjigian YY, Shitara K, Moehler M, et al: First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial. Lancet 398:27-40, 2021.

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