Proton Pump Inhibitor Use and Efficacy of Nivolumab and Ipilimumab in Advanced Melanoma

Simple Summary Immune checkpoint inhibitors have been shown to improve survival in patients with advanced melanoma; however, a proportion of patients do not experience durable clinical benefit with these agents. Findings from a previous study suggested that the use of proton pump inhibitors while receiving immune checkpoint inhibitors may lead to worse clinical outcomes. To validate those results, we performed this retrospective analysis using data from three clinical trials involving patients with advanced melanoma treated with immune checkpoint inhibitors. We found that there is not enough evidence to conclude that proton pump inhibitors influence the efficacy of immune checkpoint inhibitors. Prospective studies are needed to conclusively determine if the use of proton pump inhibitors has any meaningful impact on the efficacy of immune checkpoint inhibitors in patients with advanced melanoma. The impact of proton pump inhibitors (PPIs) on clinical outcomes with first-line immune checkpoint inhibitors (ICIs) in patients with metastatic melanoma was previously analyzed in the phase II study, CheckMate 069. This retrospective analysis utilized data from three phase II/III studies of first-line ICI therapy in untreated advanced melanoma: CheckMate 066, 067, and 069. All randomized patients with PPI use <= 30 days before initiating study treatment were included in the PPI-use subgroup. Possible associations between baseline PPI use and efficacy were evaluated within each treatment arm of each study using multivariable modeling. Approximately 20% of 1505 randomized patients across the studies reported baseline PPI use. The median follow-up was 52.6-58.5 months. Objective response rate (ORR), progression-free survival (PFS), and overall survival analyses provided insufficient evidence of a meaningful association between PPI use and efficacy outcomes with nivolumab-plus-ipilimumab, nivolumab, or ipilimumab therapy. In five of the six ICI treatment arms, 95% confidence intervals for odds ratios or hazard ratios traversed 1. Significant associations were observed in the CheckMate 069 combination arm between PPI use and poorer ORR and PFS. This multivariable analysis found insufficient evidence to support meaningful associations between PPI use and ICI efficacy in patients with advanced melanoma.