The landscape of systemic therapies for advanced esophagogastric cancer (EGC) has evolved significantly with the integration of immunotherapeutic and targeted treatment strategies. This article summarizes the key findings from Dr. Markus H. Moehler’s presentation, which highlights recent clinical trial data and advancements in checkpoint inhibitors, antibody-drug conjugates, and emerging targeted therapies.KEYNOTE-811: PD-1 Inhibition in Advanced
EGC KEYNOTE-811 investigated the efficacy of pembrolizumab (PD-1 inhibitor) in combination with chemotherapy for the first-line (1L) treatment of unresectable, advanced, or metastatic EGC. The latest data with a follow-up of 38.5 months (IA3) confirm significant progression-free survival (PFS) benefits compared to chemotherapy alone. Median PFS for all patients was 10.0 months (95% CI: 8.6-12.2) compared to 8.1 months (95% CI: 7.1-8.6) for placebo (HR 0.73, 95% CI: 0.61-0.87). In PD-L1 CPS ≥1 patients, median PFS was 10.9 months (95% CI: 8.5-12.5) compared to 7.3 months (95% CI: 6.8-8.5) for placebo (HR 0.71, 95% CI: 0.59-0.86). The objective response rate (ORR) was 74.4% (95% CI: 66.2-81.6%) with pembrolizumab versus 51.9% (95% CI: 43.0-60.7%) for placebo (p = 0.00006).
CheckMate-649 and KEYNOTE-859: Expanding Immunotherapy in EGC
CheckMate-649 demonstrated that nivolumab (PD-1 inhibitor) plus chemotherapy significantly improved overall survival (OS) compared to chemotherapy alone in patients with PD-L1-positive tumors. Median OS was 15.0 months (95% CI: 13.7-16.7) compared to 10.9 months (95% CI: 9.9-12.0) for chemotherapy alone (HR 0.68, 95% CI: 0.58-0.79). The five-year OS rate for PD-L1 CPS ≥10 patients was 58% with nivolumab plus chemotherapy compared to 33% with chemotherapy alone. KEYNOTE-859 further validated the role of pembrolizumab in combination with chemotherapy in advanced gastric and gastroesophageal junction (GEJ) cancer, confirming robust survival benefits. The ORR was 51.3% (95% CI: 47.7-54.8%) with pembrolizumab compared to 42.0% (95% CI: 38.5-45.5%) for placebo (p = 0.00009). The median duration of response (DOR) was 8.0 months (range: 1.2 to 41.5+) compared to 5.7 months (range: 1.3 to 34.7+).
RATIONALE-305: Zolbetuximab + Chemotherapy T
his phase 3 trial evaluated zolbetuximab, a CLDN18.2-targeting monoclonal antibody, in combination with chemotherapy. Two positive phase 3 trials demonstrated improved OS. In the SPOTLIGHT trial, median OS was 18.23 months (95% CI: 16.43-22.90) compared to 15.54 months (95% CI: 13.47-16.53) for placebo (HR 0.750, 95% CI: 0.601-0.936; p = 0.0053). In the GLOW trial, median OS was 14.39 months (95% CI: 12.29-16.49) compared to 12.16 months (95% CI: 10.28-13.67) for placebo (HR 0.771, 95% CI: 0.615-0.965; p = 0.0118).
Oligometastatic Esophagogastric Cancer (OMEC) and Local Therapies
The OligoMetastatic Esophagogastric Cancer (OMEC) Consortium explored the role of local metastasis-directed treatments in conjunction with systemic therapy. Findings from the RENAISSANCE/FLOT5 trial suggested a potential benefit of integrating surgery with systemic therapy for select oligometastatic EGC patients. The meta-analysis from the OMEC group highlighted a significant overall survival (OS) advantage with local treatment in oligometastatic disease. Patients with any oligometastasis had an OS of 25 months with local therapy versus 11 months with systemic therapy alone, while liver oligometastasis patients showed an OS of 24 versus 8 months.
Further supporting these findings, the ESO-Shanghai 13 trial, conducted across six large hospitals in China, compared systemic therapy with or without local interventions in oligometastatic esophageal squamous cell carcinoma (ESCC). Results showed a median progression-free survival (PFS) of 15.3 months in the systemic plus local therapy group versus 6.4 months with systemic therapy alone. The study also demonstrated a significant overall survival (OS) benefit, with a hazard ratio of 0.42 (95% CI: 0.24-0.74; p = 0.0020), reinforcing the value of metastasis-directed therapy in selected cases.
Emerging Targeted Therapies: Anti-HER2 and FGFR2b
Approaches HER2-positive EGC remains a key area of targeted treatment, with ongoing trials evaluating novel anti-HER2 agents beyond trastuzumab. Bemarituzumab, an anti-FGFR2b antibody, is a promising new agent targeting FGFR2b-positive gastric cancer, currently under investigation in combination with chemotherapy and immunotherapy. The latest ESMO guidelines recommend the addition of PD-1 inhibitors for patients with CPS ≥5 and consider zolbetuximab for CLDN18.2-positive patients. Radical resection may be an option in highly selected cases.
Additional promising trials include DESTINY-Gastric03, which evaluates T-DXd (an antibody-drug conjugate) in combination with chemotherapy and IO agents, and LEAP-015, investigating pembrolizumab plus lenvatinib for advanced gastroesophageal cancer. Furthermore, the ASPEN-06 trial explores the efficacy of evorpacept, an anti-CD47 antibody, in combination with trastuzumab and chemotherapy for HER2-positive disease.
Ongoing and Future Clinical Trials
Several global studies continue to explore novel immunotherapeutic and targeted combinations to refine treatment approaches for advanced EGC. The FDZL-GC001 trial with camrelizumab and Nab-POF therapy reported an overall response rate (ORR) of 88.5%, a disease control rate (DCR) of 98%, and a 3-year OS rate of 63% regardless of HER2 status.
Conclusion
The integration of PD-1 inhibitors, monoclonal antibodies, and novel targeted therapies has transformed the treatment landscape for advanced esophagogastric cancer. The combination of systemic therapy with metastasis-directed local treatment continues to show promise in select patients. Ongoing research aims to further optimize these strategies, improving patient outcomes and expanding therapeutic options for this challenging malignancy.
