Adding Opdivo (nivolumab) and Yervoy (ipilimumab) to chemotherapy did not improve how long patients with HER2-negative unresectable advanced or recurrent gastric or gastroesophageal junction (G/GEJ) cancer lived, compared with chemotherapy alone, according to results from the phase 3 ATTRACTION-6 trial presented at the 2026 ASCO Annual Meeting.
“The lack of (overall survival [OS]) benefit appears to be driven by multiple factors rather than a single cause,” Do-Youn Oh, MD, PhD, of Seoul National University College of Medicine in Seoul, Republic of Korea, explained during a presentation of the data.
In the overall population of 626 patients, median OS — the length of time from the start of treatment until death from any cause — was 15.7 months with the immunotherapy/chemotherapy combination, compared with 15.8 months for chemotherapy alone, reducing the risk for death by 10%. Therefore, the primary end point of overall survival was not met.
- Despite the primary end point not being met, favorable trends were observed in progression-free survival (how long patients lived without disease worsening) and in the proportion of patients whose tumors shrank with the combination regimen.
- Patients in the three-drug combination group experienced more side effects overall, including higher rates of serious adverse events and treatment discontinuations, compared with those receiving chemotherapy alone.
- A trend toward longer overall survival was observed in patients whose tumors had higher levels of PD-L1 protein expression (a score of 5 or greater), though no subgroup showed a definitive benefit.
Despite the negative OS result, the combination showed favorable signals in key secondary measures. Patients receiving the three-drug regimen had a median progression-free survival (PFS) — meaning the time from treatment until the cancer started to progress — of 8.9 months compared with 7.7 months for chemotherapy alone, reducing the risk for progression by 17%.
Further, the overall response rate (ORR), which captures the proportion of patients whose tumors shrank meaningfully with treatment, was 57.9% with the combination versus 38.5% with chemotherapy alone. The duration of response (DOR) — how long those responses lasted — was similar between the groups, at 10.6 months versus 9.0 months, but the Kaplan-Meier curves continued to show sustained separation, suggesting longer-lasting benefit in the combination arm.
Why should researchers evaluate the addition of an immunotherapy regimen to chemotherapy?
Immune checkpoint inhibitors — drugs that help the immune system recognize and fight cancer — combined with chemotherapy have become an established first-line treatment option for patients with HER2-negative advanced G/GEJ cancer. This benefit has been most evident in patients whose tumors express higher levels of the PD-L1 protein, Oh said.
Therefore, ATTRACTION-6 was designed to test whether a more intensive immunotherapy approach — combining both a PD-1 inhibitor (Opdivo) and a CTLA-4 inhibitor (Yervoy) alongside chemotherapy — could further improve outcomes in this patient population.
The open-label phase 3 trial enrolled 626 patients across Japan, Korea and Taiwan who had untreated, unresectable advanced or recurrent HER2-negative G/GEJ cancer. Patients were randomly assigned 1:1 to receive either nivolumab at a dose of 360 mg every three weeks plus ipilimumab at a dose of 1 mg/kg every six weeks plus chemotherapy, or chemotherapy alone.
The trial also included a subgroup analysis in patients with a PD-L1 combined positive score (CPS) of 5 or greater — a group that has previously shown stronger responses to immunotherapy in gastric cancer. Among this subgroup, a trend toward longer survival was observed: median OS was 18.4 months with the combination versus 15.3 months with chemotherapy; however, this did not reach statistical significance.
Oh noted that fewer patients in this trial had high PD-L1 expression (44%) compared with a prior pivotal trial (60%), and that chemotherapy dose intensity was lower in the combination arm.
What side effects occurred with the combination of Opdivo with Yervoy plus chemotherapy?
Side effects were more frequent in the Opdivo/Yervoy plus chemotherapy group than in the chemotherapy-only group. Grade 3 or higher side effects — those considered serious or severe — occurred in 80.0% of patients in the combination arm compared with 62.4% in the chemotherapy arm.
Treatment-related serious side effects were reported in 33.0% of patients in the combination arm versus 15.0% of patients in the chemotherapy-alone arm. Side effects leading to treatment discontinuation were also more common with the three-drug regimen (49.5% vs. 30.3%, respectively). One treatment-related death (0.3%) occurred in the combination arm, compared with none in the chemotherapy arm. Immune-related side effects — reactions linked specifically to the immunotherapy drugs — were more common with the combination, as expected, and included diarrhea, rash, and liver enzyme elevations.
"Grade ≥3 adverse events and treatment discontinuations were more frequent in the Opdivo plus Yervoy plus chemotherapy arm, highlighting the importance of tolerability when intensifying immunotherapy," Oh said, adding that no unexpected safety signals were identified.
Oh and colleagues concluded that in G/GEJ cancer, adding low-dose Yervoy to an Opdivo-based immunochemotherapy regimen did not lead to further improvement in overall survival, and that the clinical value of dual immunotherapy regimens in this setting warrants further investigation.
EDITORS_NOTE: Editor's note: This article is for informational purposes only and is not a substitute for professional medical advice, as your own experience will be unique. Use this article to guide discussions with your oncologist.
Reference
- Nivolumab plus ipilimumab combined with chemotherapy as first-line treatment for HER2-negative unresectable advanced or recurrent gastric/gastroesophageal junction cancer: A randomized phase 3 trial (ATTRACTION-6) Dr. Do-Youn Oh et al. J Clin Oncol. 2026;44(16):4006.
