ESMO Immuno-Oncology 2018: Does Proton Pump Inhibitor Therapy Impact the Efficacy of Nivolumab Plus Ipilimumab?
Patients with melanoma receiving proton pump inhibitors for comorbidities derived approximately half the clinical benefit from immunotherapy consisting of nivolumab (Opdivo) plus ipilimumab (Yervoy) as patients receiving the same combination but not treated with proton pump inhibitors, according to findings presented by Homicsko et al at the European Society for Medical Oncology (ESMO) Immuno-Oncology Congress 2018 in Geneva, Switzerland (Abstract LBA2).
This analysis of data from the CheckMate 069 trial did not show the same negative impact with ipilimumab monotherapy in patients on proton pump inhibitors.
Analysis of CheckMate 069
Krisztian Homicsko, MD, PhD, of CHUV, and colleagues conducted this retrospective analysis of data from 140 participants in the phase II CheckMate 069 clinical trial. In CheckMate 069, patients with previously untreated, unresectable, or metastatic melanoma received immunotherapy consisting of ipilimumab monotherapy or ipilimumab combined with nivolumab.
Although immunotherapy has demonstrated activity across multiple tumor types in CheckMate and other clinical trials, there is a paucity of data explaining the effect of medications taken for comorbidities on the efficacy of immunotherapy, which prompted this analysis.
The investigators compared response rates, progression-free survival (PFS), and overall survival (OS) in patients receiving one or more concomitant treatments with 11 different classes of comedications. They also compared variables such as disease stage, LDH levels, BRAF status, sex, age, and body mass index. In 135 patients with available pretreatment serum samples, a protein array was also performed for 440 analytes.
Proton pump inhibitors are considered to be the most effective drugs for inhibiting gastric acid secretion, and are also sometimes prescribed in asthma.
Findings
The investigators conducted univariate analysis, which showed that proton pump inhibitor treatment received by patients that was detected at baseline decreased the objective response rates almost by half, and also reduced the length of PFS and OS in patients treated with ipilimumab and nivolumab—but not with ipilimumab alone.
This effect remained consistent across multiple comparisons and in multivariate analysis.
Evaluation of the pretreatment serum samples showed changes in NCAM1/CD56 and CSF3R levels in patients treated with proton pump inhibitors, both of which are expressed on neutrophil granulocytes. In accordance with the serum protein analysis, patients treated with proton pump inhibitors had significantly increased neutrophil levels at baseline.
The impact of proton pump inhibitors was confirmed in an independent cohort of 93 patients with melanoma who were treated with first-line nivolumab or pembrolizumab monotherapy.
The researchers concluded, “Our analysis shows that proton pump inhibitors could negatively impact on the benefit from [programmed cell death protein 1 (PD-1)]–based therapies both for monotherapy and also for ipilimumab and nivolumab combination therapy. Proton pump inhibitors might establish a unique inflammatory immune status prior to immune therapy initiation that interferes with treatment efficacy. These results suggest that if possible, proton pump inhibitors should be avoided in patients [treated with] PD-1–based immun[o]therapies. Also, the results will have important implication for design of future clinical trials.”
Disclosure: The study authors’ full disclosures can be found at academic.oup.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
