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GENEVA, SWITZERLAND-Patients with melanoma receiving proton pump inhibitors (PPIs) for co-morbidities derived approximately half the clinical benefit from immunotherapy consisting of nivolumab plus ipilimumab as patients receiving the same combination but not on PPI medication, according to findings presented at the 2018 ESMO Immuno-Oncology Congress (Abstract LBA2).

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This analysis of data from the CheckMate 069 trial did not show the same negative impact with ipilimumab monotherapy in patients on PPIs.


Krisztian Homicsko, MD, MSc, PhD, in the Service of Immune Oncology, CHUV in Lausanne, Switzerland, and colleagues conducted this retrospective analysis of data from 140 participants in the Checkmate 069 (NCT019274199) phase II 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 extraordinary results across multiple tumor types in CheckMate and other clinical trials, there is a paucity of data explaining the effect of medications taken for co-morbidities on the efficacy of immunotherapy, which prompted this analysis.


Checkmate 069 Details

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 co-medications. They also compared variables such as disease stage, LDH levels, BRAF status, sex, age, and body mass index. In 135 patients with available pre-treatment serum samples, a protein array was also performed for 440 analytes.


Response rates with combined nivolumab and ipilimumab nearly halved in patients on PPIs.


PPIs are considered to be the most effective drugs for inhibiting gastric acid secretion and are also sometimes prescribed in asthma.


The investigators conducted univariate analysis, which showed that PPI 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 PPI users both of which are expressed on neutrophil granulocytes. In accordance with the serum protein analysis, PPI users had significantly increased neutrophil levels at baseline.


The impact of proton pump inhibitors was confirmed in an independent cohort of 93 first-line melanoma patients who were treated with nivolumab or pembrolizumab monotherapy.



The authors pointed out that PPIs could negatively affect the benefit from PD1-based therapies for melanoma both for monotherapy and also for ipilimumab and nivolumab combination therapy.


They suggested that PPIs might produce a unique inflammatory immune status prior to initiating immune therapy that interferes with treatment efficacy.


These results suggest that PPIs should be avoided when possible in patients diagnosed with melanoma and recommended for PD1-based immunotherapies. It remains unclear if PPI initiation during PD1-based therapy will have a similar impact. Further studies are required to precisely define the exact mechanism of PPIs impact on systemic immunity.


In addition, these findings have implications for the design of future immunotherapy clinical trials.