Immune checkpoint inhibitors combined with chemotherapy have become an established first-line treatment option for patients with HER2-negative advanced gastric and gastroesophageal junction cancers. Given the complementary mechanisms of action of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4), investigators hypothesized that adding dual immunotherapy to chemotherapy could further enhance antitumor immunity and improve long-term clinical outcomes.

The Phase III ATTRACTION-6 study evaluated nivolumab plus ipilimumab combined with oxaliplatin-based chemotherapy versus chemotherapy alone in patients with previously untreated HER2-negative unresectable advanced or recurrent gastric/GEJ cancer across Japan, Korea, and Taiwan.

At a median follow-up of 31.3 months, the study did not meet its primary endpoint of overall survival.

Efficacy outcomes:

• Overall Survival:

• Median Overall Survival: 15.7 months with nivolumab + ipilimumab + chemotherapy versus 15.8 months with chemotherapy alone

• No statistically significant improvement in survival was observed

• Hazard Ratio (HR): 0.90 (95.8% CI: 0.74–1.09; p = 0.267)

• Progression-Free Survival (PFS):

• Median PFS: 8.9 months versus 7.7 months.

• HR: 0.83 (95% CI: 0.69–1.00).

• Objective Response Rate (ORR):

• ORR: 57.9% with nivolumab + ipilimumab + chemotherapy.

• ORR: 38.5% with chemotherapy alone.

Safety results:

• Grade ≥3 adverse events occurred in:

• 80.0% of patients receiving nivolumab + ipilimumab + chemotherapy

• 62.4% of patients receiving chemotherapy alone

• Grade ≥3 treatment-related adverse events occurred in:

• 64.8% of patients in the triplet arm

• 42.9% of patients in the chemotherapy arm

• Treatment-related deaths occurred in:

• 0.3% of patients receiving nivolumab + ipilimumab + chemotherapy

• The only treatment-related fatal event reported was gastroenteritis in the triplet therapy arm.

KOL Insights-

“ATTRACTION-6 highlights the complexity of combining dual immune checkpoint inhibition with chemotherapy in gastric cancer, where higher response rates do not necessarily translate into survival benefit.” – Expert Opinion

“The lack of overall survival improvement despite improved response underscores the need for better patient selection and biomarker-driven strategies in HER2-negative G/GEJ cancer.” – Expert Opinion

Conclusion- 

Around 50,000 individuals were diagnosed with gastroesophageal cancers in the United States in 2025. HER2 is overexpressed in about 30% of intestinal type gastric cancers, 15% of mixed type tumours, and about 5% of diffuse type.

For patients with HER2-negative advanced gastric or gastroesophageal junction cancer (G/GEJC), first-line treatment with a platinum-fluoropyrimidine chemotherapy doublet has traditionally resulted in a median overall survival of around one year. The introduction of nivolumab, approved in the United States in April 2021, improved survival outcomes, particularly among patients with a PD-L1 combined positive score (CPS) of ≥5. More recently, positive results from pivotal clinical trials have supported the approval of additional targeted and immunotherapeutic agents, including pembrolizumab, zolbetuximab, and tislelizumab, further expanding first-line treatment options.

The Phase III ATTRACTION-6 trial demonstrated that adding nivolumab and ipilimumab to standard chemotherapy did not improve overall survival in patients with previously untreated HER2-negative unresectable advanced or recurrent gastric/gastroesophageal junction cancer. Consequently, current PD-1 inhibitor-based chemotherapy regimens remain the preferred first-line treatment approach for HER2-negative advanced gastric and GEJ cancers.