Proton Pump Inhibitor Use and Efficacy of Nivolumab and Ipilimumab in Advanced Melanoma
by
, , ,
Krisztian Homicsko
1,*
,
Reinhard Dummer
2
,
Christoph Hoeller
3,
Jedd D. Wolchok
4,5,6,
F. Stephen Hodi
7,
James Larkin
8,
Paolo A. Ascierto
9,
Victoria Atkinson
10,11,
Caroline Robert
12,13, 
Michael A. Postow
5,14,
Sandra Re
15,
David Paulucci
15,
Darin Dobler
15 and
Olivier Michielin
16 1
Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland
2
Department of Dermatology, Universitäts Spital, 8091 Zurich, Switzerland
3
Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria
4
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
5
Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA
6
Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA
7
Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
8
Medical Oncology, Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK
9
Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori IRCCS Fondazione Pascale, 80131 Naples, Italy
10
Division of Cancer Services, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia
11
Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD 4120, Australia
12
Dermatology Service, Gustave Roussy, 94805 Villejuif, France
13
Melanoma Research Unit, Paris-Saclay University, 91400 Orsay, France
14
Melanoma Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
15
Bristol Myers Squibb, Princeton, NJ 08543, USA
16
Precision Oncology Center, Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland
*
Author to whom correspondence should be addressed.
Cancers 2022, 14(9), 2300; https://doi.org/10.3390/cancers14092300
Submission received: 2 April 2022
/
Revised: 22 April 2022
/
Accepted: 25 April 2022
/
Published: 5 May 2022
(This article belongs to the Special Issue Systemic Therapies in 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.
Abstract
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.
