Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4)

Abstract

Background: Nivolumab is approved as an option for third- or later-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) cancer in several countries after ATTRACTION-2. To further improve the therapeutic efficacy of first-line therapy, exploration of a nivolumab-chemotherapy combination is warranted. In part 1 (phase II) of ATTRACTION-4, the safety and efficacy of nivolumab combined with S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (CapeOX) as first-line therapy for unresectable advanced or recurrent human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer were evaluated.

Patients and methods: Patients were randomized (1 : 1) to receive nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) or CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal.

Results: Of 40 randomized patients, 39 (nivolumab plus SOX, 21; nivolumab plus CapeOX, 18) and 38 (21 and 17, respectively) comprised the safety and efficacy populations, respectively. Most frequent (>10%) grade 3/4 treatment-related adverse events were neutropenia (14.3%) in the nivolumab plus SOX group, and neutropenia (16.7%), anemia, peripheral sensory neuropathy, decreased appetite, type 1 diabetes mellitus, and nausea (11.1% each) in the nivolumab plus CapeOX group. No treatment-related death occurred. Objective response rate was 57.1% (95% confidence interval 34.0-78.2) with nivolumab plus SOX and 76.5% (50.1-93.2) with nivolumab plus CapeOX. Median overall survival was not reached (NR) in both groups. Median progression-free survival was 9.7 months (5.8-NR) and 10.6 months (5.6-12.5), respectively.

Conclusion: Nivolumab combined with SOX/CapeOX was well tolerated and demonstrated encouraging efficacy for unresectable advanced or recurrent HER2-negative G/GEJ cancer. ATTRACTION-4 has proceeded to part 2 (phase III) to compare nivolumab plus SOX/CapeOX versus placebo plus SOX/CapeOX.

Clinicaltrials.gov id: NCT02746796.

Keywords: S-1; capecitabine; gastric/gastroesophageal cancer; nivolumab; oxaliplatin; programmed death-1.

Figure 1.

Kaplan–Meier curves for (A) overall survival and (B) progression-free survival (central assessment) (FAS population) CapeOX, capecitabine plus oxaliplatin; FAS, full analysis set; SOX, S-1 (tegafur–gimeracil–oteracil potassium) plus oxaliplatin.

Figure 2.

(A) Best change from baseline in the sum of longest target lesion diameters in each patient receiving nivolumab plus SOX. (B) Best change from baseline in the sum of longest target lesion diameters in each patient receiving nivolumab plus CapeOX. (C) Percent change in sum of longest diameters of target lesion from baseline in each patient receiving nivolumab plus SOX. (D) Percent change in sum of longest diameters of target lesion from baseline in each patient receiving nivolumab plus CapeOX (central assessment) (FAS population). CapeOX, capecitabine plus oxaliplatin; FAS, full analysis set; PD-L1, programmed death-ligand 1; SOX, S-1 (tegafur–gimeracil–oteracil potassium) plus oxaliplatin.