Nivolumab as the first immunotherapy gained FDA accelerated approval for patients with previously untreated advanced gastric cancers

Accounted for 3.8% of all new cancer cases, gastric cancer (GC) was the sixth commonest cancer in Hong Kong in 2018.1 While chemotherapy remains as the standard of care for advance GC or gastroesophageal junction cancer (GEJC), most chemotherapy regimens fail to provide substantial survival benefits, resulting in poor prognosis and median overall survival (OS) of around 1 year in patients with newly diagnosed metastatic GC or GEJC.2 This poor prognosis catalyzed the recent Food and Drug Administration (FDA) accelerated approval of nivolumab, in combination with fluoropyrimidine- and platinum-containing chemotherapy, for advanced or metastatic GC, GEJC and esophageal adenocarcinoma (EAC).3

GC and GEJC are associated with immune system evasion and the overexpression of immune checkpoint proteins, providing the rationale for immunotherapy with anti-programmed cell death protein-1 (PD-1) or programmed death-ligand 1 (PD-L1).2 However, instead of frontline treatment, immune checkpoint inhibitors are mostly approved for the third or later line of therapy for advanced GC or GEJC.2,4

Apart from other immune checkpoint inhibitors, nivolumab, a human immunoglobulin (Ig) G4 monoclonal antibody inhibitor of PD-L1, as third or later line of treatment improved OS over placebo in phase 3 Asian trial published in 2017, resulting in the subsequent approval of nivolumab in Japan, Taiwan and South Korea for the treatment of unresectable advanced or recurrent GC progressing after chemotherapy.4 Following these results, the benefit of nivolumab as a first-line treatment for advanced GC was evaluated in a study published in September 2020 which led to its accelerated FDA approval in April 2021.3,5

This accelerated approval was based on the efficacy and safety of nivolumab evaluated in CHECKMATE-649, a randomized, open-label, global phase 3 trial that enrolled 1,581 patients with previously untreated advanced or metastatic GC, GEJC or EAC.3 In the study, 789 patients received nivolumab (360mg every 3 weeks [Q3W] or 240mg every 2 weeks [Q2W]) in combination with chemotherapy (XELOX [capecitabine plus oxaliplatin] Q3W or FOLFOX [fluorouracil, leucovorin, and oxaliplatin] Q2W), and 792 patients received chemotherapy alone.5 The dual primary endpoints were OS and progression-free survival (PFS) assessed by blinded independent central review among patients whose tumors expressed a PD-L1 combined positive score (CPS) of 5 or above (n=955).5

With a minimum follow-up of 12 months, the combination of nivolumab and chemotherapy demonstrated a statistically significant improved OS and PFS versus chemotherapy alone in patients with PD-L1 CPS ≥5.5 Median OS was 14.4 months in the nivolumab plus chemotherapy arm versus 11.1 months in the chemotherapy arm (HR=0.71; 95% CI: 0.61-0.83; p<0.0001).3,5 Median PFS was 7.7 months among those treated with the combination therapy versus 6.0 months among those treated with chemotherapy only (HR=0.68; 95% CI: 0.58-0.79; p<0.0001).3,5 Statistically significant OS benefit was also observed in all-randomized population (n=1,581) regardless of the PD-L1 CPS, with a median OS of 13.8 months in the combination group versus 11.6 months in the chemotherapy group (HR=0.80; 95% CI: 0.71-0.90; p=0.0002).3,5

No new safety signals were identified with the combination involving nivolumab, and the incidence rates of treatment-related events across both arms were similar.5 According to the FDA, the most common adverse reactions (incidence of 20% or above) observed in patients receiving nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.3

Overall, CHECKMATE-649 demonstrated the superiority of nivolumab plus chemotherapy over chemotherapy alone in previously untreated patients with advanced GC, GEJC or EAC irrespective of PD-L1 CPS level.5 With the promising efficacy and manageable safety profile, this newly approved frontline combination treatment may represent a paradigm shift in the management of advanced disease.5

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