In the international phase lll trial, researchers randomly assigned 1,581 patients with unresectable advanced or metastatic GC, GEJC, or EAC to receive nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone. Chemotherapy was either oxaliplatin plus capecitabine (51.5%) or leucovorin, 5-flurouracil, and oxaliplatin (48.5%).
The coprimary endpoints were OS and PFS among patients with PD-L1 tumor expression of combined positive score (CPS) of 5 or higher. Secondary endpoints included objective response rate (ORR), OS, and PFS in all randomized patients. The median patient age at baseline was 63 years, and 71% of patients were male. Almost one-quarter of patients were Asian. Most tumors were GC (70%), followed by GEJC (18%) and EAC (13%). The majority of patients had metastatic disease (96%), and a few patients had tumors with high microsatellite instability (4%). The present interim evaluation was for the nivolumab-plus-chemotherapy and chemotherapy-alone groups.
Among trial patients with a PD-L1 CPS of 5 or higher, the ORR was considerably greater in the nivolumab-plus-chemotherapy group at 60% compared with 45% with chemotherapy, with a duration of response of 9.5 and 7.0 months, respectively. Additionally, nivolumab plus chemotherapy substantially prolonged survival, with a median OS of 14.4 months compared with 11.1 months with chemotherapy alone (hazard ratio [HR], 0.71; 98.4% CI, 0.59-0.86; P <.0001) among patients with a PD-L1 CPS of 5 or more. This benefit was consistent among patients with a PD-L1 CPS of 1 or higher (HR, 0.77; 99.3% CI, 0.64-0.92; P =.0001) and all randomized patients (HR, 0.80; 99.3% CI, 0.68-0.94; P =.0002).
Nivolumab plus chemotherapy also enhanced PFS, with an average of 7.7 months compared with 6 months with chemotherapy alone (HR, 0.68; 98.0% CI, 0.56-0.81; P <.0001) among patients with a PD-L1 CPS of at least 5. Nivolumab-plus-chemotherapy treatment also improved PFS among patients with a PD-L1 CPS of 1 or higher (HR, 0.74; 95% CI, 0.65-0.85) and all randomized patients (HR, 0.77; 95% CI, 0.68-0.87). Additionally, OS supported nivolumab plus chemotherapy over chemotherapy alone across all subgroups.
Grade 3 to 4 treatment-related adverse events occurred in 59% of patients in the nivolumab-plus-chemotherapy arm and 44% of patients in the chemotherapy arm, which led to treatment terminations among 36% and 24% of patients, respectively. The researchers concluded that nivolumab is the first PD-1 inhibitor to demonstrate superior OS and PFS with a manageable safety profile in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced GC, GEJC, or EAC.
Nivolumab plus chemotherapy represents a potential new standard first-line treatment option for this patient population.
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