CheckMate 649 is the first global Phase III trial to successfully evaluate a first-line immunotherapy regimen (nivolumab + chemotherapy) for advanced gastric cancer. The study’s primary results were first unveiled at the 2020 European Society for Medical Oncology (ESMO) Congress, and the pre-specified China subgroup data were presented for the first time at the 2021 American Association for Cancer Research (AACR) meeting. The findings demonstrated even greater benefits in Chinese patients compared to the global population, generating significant academic interest and establishing first-line immunotherapy plus chemotherapy as the standard of care for advanced gastric cancer in China. Today, nivolumab in combination with chemotherapy has been approved as a first-line treatment for advanced or metastatic gastric cancer (GC), gastroesophageal junction cancer (GEJC), and esophageal adenocarcinoma (EAC) in more than 50 countries, including the United States and China.

At the 2025 ASCO Gastrointestinal Cancers Symposium (ASCO GI), the five-year follow-up data from the CheckMate 649 study in Chinese patients were presented, further reinforcing the pivotal role of nivolumab plus chemotherapy as the standard first-line treatment for advanced GC, GEJC, and EAC in China. This study provides the only five-year long-term survival data in this field of immunotherapy to date. During the conference, Oncology Frontier had the privilege of interviewing Dr. Zhi Peng from Peking University Cancer Hospital to discuss the key findings of the CheckMate 649 study and their clinical significance.

Oncology Frontier: Could you discuss the current first-line treatment landscape for advanced gastric and gastroesophageal junction adenocarcinoma, particularly in HER2-negative cases?

Dr. Zhi Peng: For HER2-negative gastric cancer or gastroesophageal junction adenocarcinoma, the standard first-line treatment is a combination of chemotherapy and immunotherapy. Given the high prevalence of this disease in China, Chinese researchers have conducted numerous clinical trials both domestically and internationally. These studies have explored the combination of immunotherapies targeting PD-1, CTLA-4, and TGF-β with chemotherapy in HER2-negative advanced gastric cancer, as well as novel targeted therapies against CLDN18.2 and FGFR2.

Looking ahead, as our understanding of molecular subtypes deepens and new drugs continue to emerge, the first-line treatment landscape for HER2-negative advanced gastric cancer will continue to evolve. On one hand, new treatment strategies based on specific biomarkers or molecular targets will become increasingly available. On the other hand, comprehensive treatment approaches that integrate multiple immunotherapy modalities will likely gain traction. These advancements will lead to more precise and personalized treatment options for specific patient subgroups.

Oncology Frontier: At ASCO GI, the five-year survival data for Chinese patients in the CheckMate 649 study were presented. Could you summarize the key findings and their clinical significance?

Dr. Zhi Peng: CheckMate 649 was the first global study in HER2-negative advanced gastric cancer to demonstrate a survival benefit with nivolumab plus chemotherapy. The five-year survival data presented at ASCO GI revealed that, with a median follow-up of 61.2 months, nivolumab plus chemotherapy continued to show clinically meaningful long-term benefits compared to chemotherapy alone in previously untreated Chinese patients with advanced GC, GEJC, or EAC. The key findings are as follows:

1. Clear Separation in Kaplan-Meier Curves, Five-Year Overall Survival (OS) Rate Reaches 24%

In the Chinese subgroup, nivolumab plus chemotherapy significantly improved overall survival (OS) compared to chemotherapy alone. The Kaplan-Meier survival curves showed a sustained separation (Figure 1). For patients with PD-L1 CPS ≥5, the five-year OS rate in the nivolumab plus chemotherapy group was three times higher than in the chemotherapy-only group (24% vs. 8%), with a 43% reduction in the risk of death. In the overall study population, a similar improvement in five-year OS was observed (20% vs. 7%), with a 37% reduction in the risk of death.

2. Enhanced Survival Benefit in PD-L1 CPS ≥5 Patients Across All Subgroups

In patients with PD-L1 CPS ≥5, the nivolumab plus chemotherapy group demonstrated a consistent overall survival (OS) advantage across all predefined subgroups (Figure 2). These findings align with the overall population results, further reinforcing the long-term efficacy of this treatment strategy in Chinese patients.

3. Sustained Progression-Free Survival (PFS) Benefit with Significant Risk Reduction

Compared to chemotherapy alone, nivolumab plus chemotherapy continued to provide long-term progression-free survival (PFS) benefits (Figure 3).

• In patients with PD-L1 CPS ≥5, the risk of disease progression or death was reduced by 49%.
• In the overall Chinese population, the risk of disease progression or death was reduced by 43%.

These results further confirm the durable efficacy of nivolumab plus chemotherapy in delaying disease progression in advanced gastric and gastroesophageal junction cancer.

4. Survival, PFS, and Response Rate Benefits Observed Regardless of PD-L1 CPS Expression

In the era of immunotherapy, patients with PD-L1 CPS <1 or CPS <5 have been a key focus of research. The CheckMate 649 study further explored the treatment benefits in these subgroups.

The newly released data from the Chinese cohort showed that:

• For patients with CPS <1, the OS hazard ratio (HR) was 0.72.
• For patients with CPS <5, the OS HR was 0.77.

These results show an improvement compared to the global population data previously analyzed by the FDA from three Phase III trials (OS HR: 0.91 for CPS <1 and 0.89 for CPS <5).

In addition to overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) also showed consistent benefits in these subgroups (Figure 4).

These findings highlight that nivolumab plus chemotherapy provides significant clinical benefits across all PD-L1 CPS expression levels, reinforcing its broad applicability in first-line treatment for advanced gastric and gastroesophageal junction cancer.

5. Patients Achieving Response at 18 Weeks Show Longer Median OS

As precision medicine in gastric cancer continues to evolve, there is an increasing need for reliable predictive markers of immunotherapy efficacy. CheckMate 649 has been at the forefront of this effort, first introducing a survival analysis based on response status at 18 weeks in its four-year follow-up data.

The newly updated five-year follow-up data now reveal that in the Chinese cohort, patients who achieved partial response (PR) or complete response (CR) at 18 weeks had a notably higher four-year overall survival (OS) rate compared to those with stable disease (SD) or progressive disease (PD).

• Among patients with PD-L1 CPS ≥5, those who had achieved PR/CR at 18 weeks demonstrated a four-year OS rate of up to 35% (Figure 5).

These findings further emphasize the strong correlation between early tumor response to nivolumab plus chemotherapy and long-term survival benefits, reinforcing the importance of response monitoring in clinical decision-making.

6. Manageable Safety Profile with No New Safety Concerns

In terms of safety, nivolumab plus chemotherapy did not present any new safety signals compared to chemotherapy alone. Among Chinese patients receiving nivolumab plus chemotherapy, the incidence of Grade 3/4 treatment-related adverse events (TRAEs) related to immune-mediated effects in various organ categories remained at 7% or lower. No Grade 5 events were observed in either treatment group. These findings were consistent with the four-year follow-up results.

Five-Year Survival Data: A Milestone in Gastric Cancer Treatment

The five-year survival results from CheckMate 649 mark a significant breakthrough in the treatment of HER2-negative advanced gastric cancer. For patients, this means a real possibility of reaching the five-year survival mark, which was nearly impossible before the introduction of immunotherapy. At least a portion of patients have now achieved this milestone, providing unprecedented hope for long-term survival.

Beyond survival outcomes, this study highlights the need for further research to determine which patients are most likely to benefit from this combination therapy. Identifying those with the highest likelihood of long-term survival will help refine treatment strategies in the future. As systemic therapies continue to evolve, multidisciplinary treatment approaches integrating surgery, systemic therapy, and radiation therapy will play an increasingly significant role in extending survival and potentially achieving a cure for more patients.

Identifying the Optimal Patient Population for Immunotherapy

Oncology Frontier: Based on the CheckMate 649 study, immunotherapy combined with chemotherapy is now the standard first-line treatment for advanced or metastatic GC, GEJC, and EAC. However, further analysis is needed to maximize patient benefit. Could you share insights into which patient groups are most likely to benefit from this regimen? What future research directions should be explored to expand treatment benefits?

Dr. Zhi Peng: From a biomarker perspective, several subgroups demonstrate significant survival advantages with immunotherapy. Microsatellite instability-high (MSI-H) patients, even in advanced stages, have the potential to achieve long-term survival and possibly a cure. Patients with high PD-L1 CPS levels tend to derive greater benefits from immunotherapy, while some Epstein-Barr virus (EBV)-positive patients also experience sustained survival benefits. Although less frequent, we occasionally observe long-term survival in a small subset of patients with low PD-L1 expression, suggesting that immunotherapy benefits may extend beyond PD-L1 status.

Clinical characteristics also play an essential role in predicting treatment response. Some patients with extensive lymph node involvement still achieve long-term survival with immunotherapy. In HER2-positive patients with liver metastases, systemic therapy can sometimes lead to complete remission, while in select cases, surgical removal of the primary tumor may significantly improve long-term outcomes.

While these observations lack conclusive evidence, subgroup analyses from ongoing trials continue to provide insights. By integrating biomarker testing and clinical pathology features, we aim to better predict which patients will achieve long-term, deep responses to treatment.

Oncology Frontier: How was your experience at ASCO GI this year?

Dr. Zhi Peng: This year’s ASCO GI was particularly remarkable for several reasons. One of the most striking aspects was the strong presence of Chinese researchers, with more than half of the oral presentations contributed by experts from China. Given the high incidence of gastric cancer in the country, it is clear that Chinese research in this field is leading the way on a global scale.

Another key takeaway from the conference was the growing importance of multimodal therapy in advanced gastric cancer treatment. The emergence of new drugs and combination strategies has significantly improved long-term outcomes, reinforcing the necessity of integrating various treatment modalities. The role of local treatments combined with systemic therapy is becoming increasingly relevant, especially for certain patient subgroups. For instance, some new therapies have demonstrated promising efficacy in HER2-positive patients with peritoneal metastases, an area where treatment options have historically been limited.

As a clinician, I feel that with the continuous advancement of treatment options, we are becoming increasingly confident in our ability to improve patient outcomes. Looking ahead, I believe that even more patients will benefit from these breakthroughs in gastric cancer treatment.

Dr. Zhi Peng

Peking University Cancer Hospital

Ph.D. Supervisor

• Chief Physician, Associate Professor, Department of Gastrointestinal Oncology
• Member, Chinese Anti-Cancer Association (CACA) Committee on Precision Oncology
• Member, CACA Committee on Cancer Metastasis
• Member, CACA Committee on Tumor and Microbiota
• Member, CSCO Oncology Nutrition Committee
• Member, Clinical Immunology Branch of the Chinese Society for Immunology
• Vice Chair, Beijing Anti-Cancer Society Committee on Gastrointestinal Precision Oncology
• Secretary-General, Beijing Anti-Cancer Society Committee on Gastric Cancer Prevention and Treatment
• Editorial Board Member, Chinese Medical Journal, Electronic Journal of Integrated Oncology Treatment
• Recipient of the First Prize from the Chinese Medical Association, Young Scientist Award from the Chinese Anti-Cancer Association, and First Prize from the Chinese Anti-Cancer Association