Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Proton Pump Inhibitor Therapy Negatively Impacts the Efficacy of Nivolumab Plus Ipilimumab Combination Treatment in Melanoma

Reduced efficacy not apparent with patients on PPIs receiving ipilimumab monotherapy
15 Dec 2018
Melanoma and other skin tumours;  Cancer Immunology and Immunotherapy

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 ESMO Immuno-Oncology Congress 2018 in Geneva, Switzerland.

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, 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 tumour 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.

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 ipilimumabnearly 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.


LBA2 – Homicsko K, Richtig G, Tuchmann F, et al. Proton pump inhibitors negatively impact survival of PD-1 inhibitor based therapies in metastatic melanoma patients.

Last update: 15 Dec 2018

No external funding was reported.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.