Editor’s Note: Recent years have witnessed significant breakthroughs in perioperative therapy for gastric cancer. Clinical studies, such as the RESOLVE trial, have demonstrated the efficacy and safety of neoadjuvant therapy in reducing tumor size, increasing resection rates, and improving patient survival. However, the quest for optimal treatment strategies remains pressing. As the year comes to a close, Oncology Frontier invited Dr. Chenghai Zhang from Dr. Xiangqian Su’s team at Peking University Cancer Hospital to provide a comprehensive review of advances in neoadjuvant and adjuvant therapies for gastric cancer in 2024.Advances in Neoadjuvant Therapy
Neoadjuvant therapy has become a critical strategy for locally advanced gastric cancer (LAGC), with increasing emphasis on the role of immunotherapy and targeted therapy.
1. Immunotherapy + Chemotherapy
KEYNOTE-585 Study:
- A global, randomized, double-blind, Phase III trial evaluating pembrolizumab + chemotherapy (FP/XP or FLOT) vs. placebo + chemotherapy as a perioperative therapy for locally advanced gastric/gastroesophageal junction (G/GEJ) cancer.
- Results: At 2024 ASCO GI: Pembrolizumab + FLOT improved pathological complete response (pCR) and event-free survival (EFS) compared to placebo, but there was no significant difference in overall survival (OS). At 2024 ESMO GI: The pCR rate was 13.4% vs. 2.0% in the main cohort and 14.2% vs. 2.8% when combining the main and FLOT cohorts. Median EFS was 44.4 months vs. 25.5 months, and median OS was 71.8 months vs. 55.7 months. Conclusion: While EFS and OS showed numerical improvement, they did not reach statistical significance, leaving current FLOT perioperative therapy unchanged.
MATTERHORN Study:
- A randomized, double-blind, placebo-controlled Phase III trial assessing durvalumab + FLOT vs. placebo + FLOT as a perioperative therapy for resectable G/GEJ cancer.
- Results: Durvalumab significantly improved pCR rates (19% vs. 7%, P<0.01), with combined near-complete pCR rates of 27% vs. 14%. Grade 3–4 treatment-related adverse events were comparable between groups.
DANTE/IKF-s633 Study:
- A Phase II trial evaluating PD-L1 antibody atezolizumab + FLOT vs. FLOT alone in resectable gastric/GEJ adenocarcinoma.
- Results: Adding atezolizumab improved post-operative staging and pathological regression, particularly in PD-L1 CPS ≥10 and MSI-H subgroups. Published in J Clin Oncol.
PANDA Study:
- A Phase II trial of atezolizumab + chemotherapy (docetaxel, oxaliplatin, capecitabine) in untreated resectable G/GEJ adenocarcinoma.
- Results: Pathological regression was improved, with a pCR rate of 45%. Responders had significantly prolonged DFS and OS.
NEOSUMMIT-01 Study:
- A randomized Phase II trial of perioperative PD-1 antibody + chemotherapy vs. chemotherapy alone in cT3–4aN+M0 resectable G/GEJ adenocarcinoma.
- Results: TRG 0/1 rate was 44.4% vs. 20.4%; pCR rate was 22.2% vs. 7.4%.
2. Dual Immunotherapy + Chemotherapy
ECOG-ACRIN EA2174 Study:
- Perioperative nivolumab + ipilimumab for resectable G/GEJ cancer.
- Results: No significant improvement in pCR rates (21.0% vs. 24.8%, P=0.27), suggesting a need to explore the impact of radiotherapy on immunotherapy outcomes.
3. Targeted Therapy (HER2 ADC)
EPOC2003 Study:
- Phase II trial of T-DXd as neoadjuvant therapy for HER2-positive G/GEJ adenocarcinoma.
- Results: MPR rate of 14.8% and pCR rate of 3.7%, indicating limited short-term efficacy.
4. Targeted Therapy + Immunotherapy + Chemotherapy
DRAGON-IV Study:
- Evaluated camrelizumab + low-dose apatinib + SOX vs. SOX alone in perioperative therapy for LAGC.
- Results: pCR rate was 18.3% vs. 5.0% (P<0.0001), demonstrating the potential of the combination therapy.
Advances in Adjuvant Therapy
1. Immunotherapy + Chemotherapy
ATTRACTION-5 Study:
- Evaluated nivolumab + chemotherapy vs. chemotherapy alone in postoperative Stage III G/GEJ cancer.
- Results: No significant improvement in DFS or OS, but patients with PD-L1 TPS ≥1% benefited from nivolumab.
2. Chemotherapy Alone
JCOG1104 Study (5-Year Follow-Up):
- Compared 4 vs. 8 cycles of S-1 for postoperative Stage II gastric cancer.
- Results: OS and DFS were slightly better in the 8-cycle group, supporting its use as the standard.
Conclusion
Neoadjuvant therapies, including immunotherapy + chemotherapy, dual immunotherapy, and targeted therapy combinations, have shown promise in improving pCR and survival outcomes in gastric cancer. In adjuvant therapy, the combination of immunotherapy and chemotherapy has not yet met its primary endpoints, highlighting the need for further exploration. As research continues, patient-centered endpoints and individualized approaches will remain critical to advancing gastric cancer care.
Dr. Chenghai Zhang
- Title: Chief Physician, Gastrointestinal Tumor Center, Peking University Cancer Hospital
- Specialty: Minimally invasive laparoscopic surgery for gastrointestinal cancers
- Research Achievements: Lead and participate in multiple basic and clinical studies; published several SCI papers (IF > 60) in the past three years; contributed to two medical textbooks
Professional Affiliations:
- Deputy Group Leader, Gastrointestinal Surgery Division, Integrative Medicine Experts Volunteer Committee
- Standing Committee Member, Robotics in Medicine Division, China Medical Education Association
- Member, Surgical Oncology Division, Chinese Research Hospital Association
- Youth Committee Member, Gastrointestinal Surgery Division, China International Medical Exchange Association
- Youth Committee Member, Colorectal Liver Metastasis Division, China International Medical Exchange Association
- Member, Organ Resection and Quality Control Group, Colorectal Cancer Division, China Medical Association
Member, Colorectal Committee, Beijing Integrative Medicine Association
