Expert Point of View: David Wang, MD, PhD

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David Wang, MD, PhD

David Wang, MD, PhD

David Wang, MD, PhD, Associate Professor of Internal Medicine at UT Southwestern Medical Center and VA North Texas Health Care System, was invited to discuss the CheckMate 649 and RATIONALE 305 studies.

“CheckMate 649 was the first randomized controlled trial to demonstrate a significant survival benefit from the addition of an immune checkpoint inhibitor, specifically nivolumab, to chemotherapy as a first-line treatment for advanced gastric and gastroesophageal junction cancer. The current analysis now shows that the clinical benefit remains durable after 3 years, with no new toxicities,” Dr. Wang said.

The 3-year follow-up is significant, he said, because first-line trials of checkpoint inhibitors in gastric cancer have produced mixed results in regard to a significant overall survival benefit. Previous negative studies include KEYNOTE-062 with pembrolizumab,1 ATTRACTION-4 with nivolumab,2 and JAVELIN Gastric 100 with avelumab maintenance.3 Positive findings, on the other hand, have been reported for KEYNOTE-590 with pembrolizu-mab (esophageal, not gastric, cancer, and 12% gastroesophageal junction cancer),4 ORIENT-16 with sintilimab,5 RATIONALE 305 with tislelizumab (also presented at the 2023 ASCO GI Cancers Symposium),6 and, most recently, KEYNOTE-859, which demonstrated a 28% reduction in risk of death (P < .0001).7

CheckMate 649 Considerations

The CheckMate 649 population of 1,581 patients had gastric (70%) and gastroesophageal junction cancers (17%), were mostly non-Asian (76%), largely had a PD-L1 combined positive score (CPS) ≥ 5 (60%), and had no known HER2 positivity. Overall survival was significantly improved in patients with a CPS ≥ 5 as well as in all randomly assigned patients, with a median overall survival of approximately 14 months in both subsets.

“The survival benefit in CheckMate 649 is marked by continuous separation of the curves and some plateauing, demonstrating durable response at the tail end. The data are convincing because of the length of follow-up,” Dr. Wang said.

“The updated analysis also gives some idea of which patients may benefit most from nivolumab plus chemotherapy,” he continued. Not unexpectedly, higher expression of PD-L1 was associated with greater benefit, though durable benefit was seen even in patients with a CPS ≥1. “This is consistent with the qualifying statements that are included within the ASCO guidelines,”8 Dr. Wang said, noting that for patients with HER2-negative gastric adenocarcinoma with a CPS of 1 to 4, first-line treatment with nivolumab plus chemotherapy should be considered on an individual basis. For patients with a CPS of 0, however, chemotherapy alone is recommended. Microsatellite instability–high (MSI-H) status, high tumor burden, hypoalbuminemia, and liver metastases also heralded particular benefit from nivolumab plus chemotherapy in CheckMate 649, he added.

RATIONALE 305 Considerations

The findings of CheckMate 649 were bolstered by the results of RATIONALE 305. The positive overall survival benefit achieved with tislelizumab and chemotherapy showed that outcomes with other checkpoint inhibitors may be consistent with those achieved with nivolumab in CheckMate 649, and this consistency points to a class effect for checkpoint inhibitors, according to Dr. Wang. “In the first-line setting of gastric and gastroesophageal junction cancers, there are now three or four clinical trials showing some survival benefit.”

More granular findings from RATIONALE 305 will be important, as the current analysis lacks some important information, he said. Additional details will help in interpreting the findings vis à vis CheckMate 649 and the other trials of checkpoint inhibitors. At this point, some differences between the studies are clear from the baseline characteristics. Approximately three-quarters of RATIONALE 305 patients were Asian; generally speaking, their outcomes are better than for non-Asians. Also, the population did not include patients with esophageal adenocarcinoma (a particularly poor-prognosis cancer).

Findings were not reported specifically for the MSI-H subset, who derived particular benefit in CheckMate 649, nor for intestinal vs diffuse subtypes, which could also affect prognosis. Unlike CheckMate 649, outcomes in RATIONALE 305 were not separated by PD-L1 expression levels, and PD-L1 expression was determined using a different assay. Further analysis will help clinicians view this new agent in context with more familiar ones, he said.

The manufacturer of tislelizumab, BeiGene, has submitted a biologics license application to the U.S. Food and Drug Administration (FDA) as a second-line treatment for unresectable or metastatic esophageal squamous cell carcinoma, but FDA action has been deferred as a result of the COVID-19 pandemic. 

DISCLOSURE: Dr. Wang has served as a consultant to Novartis.


1. Shitara K, Van Cutsem E, Bang YJ, et al: Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: The KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol 6:1571-1580, 2020.

2. Kang YK, Chen LT, Ryu MH, et al: Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4). Lancet Oncol 23:234-247, 2022.

3. Moehler M, Dvorkin M, Boku N, et al: Phase III trial of avelumab maintenance after first-line induction chemotherapy versus continuation of chemotherapy in patients with gastric cancers: Results from JAVELIN Gastric 100. J Clin Oncol 39:966-977, 2021.

4. Sun JM, Shen L, Shah MA, et al: Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study. Lancet 398:759-771, 2021.

5. Xu J, Jiang H, Pan Y, et al: Sintilimab plus chemotherapy versus chemo as first-line treatment for advanced gastric or gastroesophageal junction adenocarcinoma (ORIENT-16). ESMO Congress 2021. Abstract LBA53. Presented September 17, 2021.

6. 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.

7. Rha SY, Wyrwicz LS, Yanez Weber PE, et al: Pembrolizumab plus chemotherapy as first-line therapy for advanced HER2-negative gastic or gastroesophageal junction cancer: Phase 3 KEYNOTE-859 study. ESMO Virtual Plenary. Presented February 16, 2023.

8. Shah MA, Kennedy EB, Alarcon-Rozas AE, et al: Immunotherapy and targeted therapy for advanced gastroesophageal cancer: ASCO Guideline. J Clin Oncol. January 05, 2023 (early release online).

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