Journal of Clinical Oncology | Perioperative PD-1 inhibitor toripalimab plus chemotherapy significantly improves survival in patients with locally advanced gastric or gastroesophageal junction cancer

This study provides Level I evidence supporting the use of perioperative therapy for locally advanced gastric cancer, demonstrating that PD-1 inhibitor combined with chemotherapy can significantly extend event-free survival and overall survival. It has direct implications for optimizing multidisciplinary treatment strategies in gastric cancer.

 

Literature Overview

The article titled 'Perioperative Toripalimab Plus Chemotherapy Versus Chemotherapy Alone in Locally Advanced Gastric or Gastroesophageal Junction Cancer: 3-Year Follow-Up of NEOSUMMIT-01 Trial,' published in the Journal of Clinical Oncology, systematically investigates the long-term efficacy of adding the PD-1 inhibitor toripalimab to standard perioperative chemotherapy. Using a randomized controlled design, the study evaluates the impact of this combination regimen on 3-year event-free survival (EFS) and overall survival (OS), showing that the addition of toripalimab significantly improves outcomes. These findings provide critical evidence supporting the use of immunotherapy in resectable gastric cancer.

Background Knowledge

Gastric cancer and gastroesophageal junction cancer (GEJC) are highly prevalent gastrointestinal malignancies worldwide. Most patients are diagnosed at a locally advanced stage. Despite undergoing D2 radical surgery and perioperative chemotherapy, over 40% of patients experience recurrence or metastasis, highlighting the urgent need for more effective treatment strategies. Currently, PD-1 inhibitors have been established in first-line treatment for advanced gastric cancer; however, their application during the perioperative period in resectable disease lacks mature survival data. Although previous studies such as KEYNOTE-585 failed to significantly improve EFS, research like MATTERHORN suggests that PD-1 inhibitors combined with chemotherapy may increase pathological response rates. This study addresses this gap through a Phase III design, clarifying the long-term survival benefits of toripalimab combined with SOX/CapOX regimens in patients with cT3-4aN1M0 disease and exploring its impact on different recurrence patterns, thereby filling an evidence gap in immunotherapy for locally advanced gastric cancer. Additionally, the study examines the influence of dMMR status on treatment efficacy to rule out potential confounding effects from hyperprogressive populations.

 

 

Research Methods and Experiments

The study employed a multicenter, open-label, randomized Phase II design (NEOSUMMIT-01, NCT04250948), enrolling 108 patients with locally advanced gastric cancer or GEJC classified as cT3-4aN1M0, who were randomly assigned in a 1:1 ratio to receive either toripalimab plus chemotherapy (n=54) or chemotherapy alone (n=54). The chemotherapy regimen consisted of SOX or CapOX chosen by the investigator, delivered over six cycles perioperatively (three preoperatively and three postoperatively), with the combination group additionally receiving toripalimab, followed by maintenance therapy for up to six months post-surgery. The primary endpoints were 3-year EFS and OS. Analyses were performed using both intention-to-treat (ITT) and per-protocol (PP) populations, with sensitivity analyses conducted for pMMR and dMMR subgroups. Key evidence derived from Kaplan-Meier survival curves and Cox regression models showed that the combination group achieved a 3-year EFS of 74.7% versus 56.2% in the control group (HR=0.51, P=0.044), and a 3-year OS of 81.3% versus 72.2% (HR=0.45, P=0.036), with consistent results observed in both PP and pMMR subgroups.

Key Conclusions and Perspectives

• The addition of toripalimab significantly reduced the risk of events or death by 49%, indicating that PD-1 inhibitors can effectively delay disease progression and strongly support future study designs incorporating perioperative immunotherapy
• The combination regimen significantly reduced the risk of all-cause mortality at 3 years by 55%, with median OS not yet reached, suggesting that PD-1 blockade confers long-term survival benefits and supports its potential as a standard of care
• Subgroup analyses showed EFS and OS benefits regardless of PD-L1 CPS <5 or ≥5, suggesting that PD-L1 expression may not be a strong predictive biomarker in this population and requires further validation
• The combination group had significantly lower rates of peritoneal metastasis (15.0% vs 36.8%), suggesting that PD-1 inhibitors may enhance peritoneal immune surveillance to control micrometastases, offering new insights for developing therapies targeting peritoneal recurrence
• Survival benefits remained significant after excluding dMMR patients, indicating that the effect is primarily driven by the pMMR population and supporting the use of this regimen in routine clinical practice without mandatory dMMR screening

Research Significance and Prospects

This study sets a new benchmark for perioperative treatment of locally advanced gastric cancer, extending the application of PD-1 inhibitors from advanced to early-stage disease. Its results support toripalimab plus chemotherapy as one of the standard options for high-risk resectable gastric cancer, particularly offering important translational value in Asian populations. Future research should explore longer follow-up data, quality-of-life analyses, and associations between biomarkers (e.g., TMB, TILs) and treatment outcomes to enable precision therapy. Additionally, the safety profile of this regimen needs validation in larger cohorts, particularly regarding the risk of postoperative immune-related adverse events (irAEs).

 

 

Conclusion

The 3-year follow-up data from NEOSUMMIT-01 confirm that perioperative toripalimab combined with chemotherapy significantly improves event-free survival and overall survival in patients with locally advanced gastric or gastroesophageal junction cancer, providing the first Phase III evidence in a Chinese population validating the use of a PD-1 inhibitor in the perioperative setting. This study not only strengthens the role of immunotherapy in resectable gastric cancer but also reveals its unique advantage in controlling peritoneal metastasis, suggesting that PD-1 inhibitors may reshape recurrence patterns in locally advanced gastric cancer. From bench to bedside, this finding drives a paradigm shift from traditional chemotherapy to immune-combination strategies, laying a solid foundation for subsequent mechanistic studies (e.g., dynamic changes in the tumor microenvironment) and clinical applications (e.g., indication expansion). This regimen is poised to become one of the standard treatments recommended in future guidelines, significantly improving long-term survival rates and optimizing the comprehensive care system for gastric cancer.

 

Run-Cong Nie, Ying Jin, Cheng-Cai Liang, Rui-Hua Xu, and Shu-Qiang Yuan. Perioperative Toripalimab Plus Chemotherapy Versus Chemotherapy Alone in Locally Advanced Gastric or Gastroesophageal Junction Cancer: 3-Year Follow-Up of NEOSUMMIT-01 Trial. Journal of Clinical Oncology.