Immunotherapy with either nivolumab (Opdivo®, Bristol-Myers Squibb) or the combination of nivolumab plus ipilimumab (Yervoy®, Bristol-Myers Squibb) in patients with chemotherapy-refractory esophagogastric cancer leads to durable responses and encouraging long-term overall survival (OS) with a manageable safety profile, concluded the investigators of the Phase I/II CheckMate 032 (NCT01928394) study.

Previously, the Japan Pharmaceuticals and Medical Devices Agency (PMDA) approved nivolumab for the treatment of patients with chemotherapy-refractory gastric and gastroesophageal junction (GEJ) cancers regardless of the programmed death-ligand 1 (PD-L1) expression. The PMDA approval was based on the Phase III, randomised, placebo-controlled ATTRACTION-2 (ONO-4538-12) trial, which showed superior survival with the programmed death 1 (PD-1) inhibitor (12-month OS rate: 26·2%) vs placebo (12-month OS rate: 10·9%).

The pathogenesis of esophagogastric adenocarcinoma has been linked to chronic inflammation, DNA damage that results in high microsatellite instability (MSI), high mutational burden, and overexpression of immune checkpoint proteins.

The CheckMate 032 study randomised 160 Western patients with locally advanced or metastatic chemotherapy-refractory gastric, esophageal, or GEJ cancer 1:1:1 to receive nivolumab 3 mg/kg (N3, N=59), nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3, N=49), or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1, N=52). The primary efficacy endpoint was the objective response rate (ORR). A translational component of the study was the association between tumour PD-L1 status with survival and response.

The investigator-assessed ORR were 12% (95% CI, 5%-23%) in patients treated with N3 alone, 24% (95% CI, 13%-39%) in patients receiving the N1I3 combination, and 8% (95% CI, 2%-19%) in patients treated with N3I1. The responses were irrespective of tumour PD-L1 status. The respective median follow-up in the three groups was 28, 24, and 22 months. The 12-month progression-free survival (PFS) rate was 8% in the N3 group, 17% in the N1I3 group, and 10% in the N3I1 group. The 12-month OS rates were 39%, 35%, and 24%, respectively.

Treatment-related adverse events (TRAEs) in ≥ 15% of patients across all treatment groups included fatigue, pruritus, rash, diarrhoea, decreased appetite, and increased ALT and AST levels. Grade 3/4 TRAEs were most commonly seen in patients of the N1I3 group (47%). In the N3 and N3I1 groups, Grade 3/4 TRAEs occurred in 17% and 27% of patients, respectively. The investigators reported one possible treatment-related death due to tumour lysis syndrome in the N3I1 group.

References

Janjigian YY, et al. J Clin Oncol. 2018; DOI: 10.1200/JCO.2017.76.6212
Kang YK, et al. Lancet. 2017: DOI: 10.1016/S0140-6736(17)31827-5