Association of a Mediterranean Diet With Outcomes for Patients Treated With Immune Checkpoint Blockade for Advanced Melanoma

Question  Is a habitual diet associated with tumor response to immune checkpoint blockade (ICB) in advanced melanoma?

Findings  In this cohort study of 91 patients with advanced melanoma in the UK and the Netherlands, higher adherence to the principles of a Mediterranean diet was associated with a higher probability of response to treatment with ICB.

Meaning  The results of this study suggest that while further studies across different countries will be needed to confirm the findings and offer patient-specific advice, habitual diet may have a role in improving responses to ICB.

Importance  Immune checkpoint blockade (ICB) has improved the survival of patients with advanced melanoma. Durable responses are observed for 40% to 60% of patients, depending on treatment regimens. However, there is still large variability in the response to treatment with ICB, and patients experience a range of immune-related adverse events of differing severity. Nutrition, through its association with the immune system and gut microbiome, is a poorly explored but appealing target with potential to improve the efficacy and tolerability of ICB.

Objective  To investigate the association between habitual diet and response to treatment with ICB.

Design, Setting, and Participants  This multicenter cohort study (the PRIMM study) was conducted in cancer centers in the Netherlands and UK and included 91 ICB-naive patients with advanced melanoma who were receiving ICB between 2018 and 2021.

Exposures  Patients were treated with anti–programmed cell death 1 and anti–cytotoxic T lymphocyte–associated antigen 4 monotherapy or combination therapy. Dietary intake was assessed through food frequency questionnaires before treatment.

Main Outcomes and Measures  Clinical end points were defined as overall response rate (ORR), progression-free survival at 12 months (PFS-12), and immune-related adverse events that were grade 2 or higher.

Results  There were a total of 44 Dutch participants (mean age, 59.43 [12.74] years; 22 women [50%]) and 47 British participants (mean age, 66.21 [16.63] years; 15 women [32%]). Dietary and clinical data were prospectively collected from 91 patients receiving ICB between 2018 and 2021 for advanced melanoma in the UK and the Netherlands. Logistic generalized additive models revealed positive linear associations between a Mediterranean dietary pattern that was high in whole grains, fish, nuts, fruit, and vegetables and the probability of ORR and PFS-12 (probability of 0.77 for ORR; P = .02; false discovery rate, 0.032; effective degrees of freedom, 0.83; probability of 0.74 for PFS-12; P = .01; false discovery rate, 0.021; effective degrees of freedom, 1.54).

Conclusions and RelevanceThis cohort study found a positive association between a Mediterranean diet, a widely recommended model of healthy eating, and response to treatment with ICB. Large prospective studies from different geographies are needed to confirm the findings and further elucidate the role of diet in the context of ICB.

In this cohort study, we examined dietary patterns in association with response to treatment with ICB across patients from the UK and the Netherlands. The results suggested that a Mediterranean-style diet that is enriched in whole grains, fish, nuts, fruit, legumes and vegetables is associated with a higher probability of response in ICB-treated patients with advanced melanoma.

The traditional principles of the Mediterranean diet (ie, high in plant-derived foods and low in processed foods and meat) remain the most widely used dietary recommendations of public health institutions globally. A potential mechanism underlying the association between diet and immunotherapy response is the gut microbiome. Preclinical studies have shown immunomodulatory and antitumor activities of several nutrients, including fiber, polyphenols, and antioxidants, that are mediated via the gut microbiome (eTable 10 in Supplement 1).^12-15 The Mediterranean diet has been associated with an increased abundance of bacteria producing SCFAs³ that have been shown to be predictive of immunotherapy response in several studies.^2,4-6 Within a published cohort of 52 patients treated with ICB for different solid tumors, high fecal SCFA concentrations were shown to be associated with longer PFS.⁶

There are 2 reports that describe an association between specific nutrients (fiber^5,12 and omega-3 fatty acids¹²) and ICB response in patients. In a cohort of 128 patients with melanoma, patients reporting a high fiber intake were more likely to respond, which was confirmed in conventionally housed specific pathogen–free mice, but not in germ-free mice, suggesting the gut microbiome as a mediator. A study in patients with stage 3 melanoma found omega-3 fatty acids to be associated with response and butyrate-producing microbial pathways. The Mediterranean diet is characterized by a high content of fiber from plant-derived foods and unsaturated fats from fish and nuts; as such, these studies support our findings.^5,6,12

Collecting extensive dietary data from patients with advanced cancer is challenging, and the primary strengths of this study are the prospective dietary assessment and depth of data collected from a real-world population of patients across 2 European countries. Limitations included sample size and the difference between UK and Dutch food frequency questionnaires. To overcome these limitations, we have (1) accounted for differences in the statistical models used and (2) chosen to complement the analysis of foods and nutrients by diet scores that are comparable across countries. Specific food preferences and nutrient sources vary across geographies,^5,6,12 suggesting a need for multinational cohort studies paired with more resolution on food compositions.

The results of this cohort study suggest that the Mediterranean dietary pattern is associated with a higher probability of PFS and ORR in patients receiving ICB for advanced melanoma. These findings suggest a potential role for diet in improving responses to ICB treatment outcomes.

Accepted for Publication: November 29, 2022.

Published Online: February 16, 2023. doi:10.1001/jamaoncol.2022.7753

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2023 Bolte LA et al. JAMA Oncology.

Corresponding Author: Rinse Weersma, MD, PhD, Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, PO Box 30.001, Groningen 9700 RB, the Netherlands (r.k.weersma@umcg.nl).

Author Contributions: Ms Bolte and Dr Björk had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Ms Bolte and Drs Lee, Björk, Spector, Hospers and Weersma contributed equally.

Concept and design: Bolte, Lee, Björk, Campmans-Kuijpers, Bataille, Spector, Hospers, Weersma.

Acquisition, analysis, or interpretation of data: Bolte, Lee, Björk, Leeming, Campmans-Kuijpers, de Haan, Vich Vila, Maltez-Thomas, Segata, Board, Harries, Lorigan, de Vries, Nathan, Fehrmann, Hospers, Weersma.

Drafting of the manuscript: Bolte, Lee, Björk, Campmans-Kuijpers, Fehrmann, Hospers.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Bolte, Björk, Campmans-Kuijpers, Vich Vila, Segata, Lorigan.

Obtained funding: Bolte, Fehrmann, Bataille, Hospers, Weersma.

Administrative, technical, or material support: Bolte, Lee, Leeming, Segata, Fehrmann, Bataille, Hospers, Weersma.

Supervision: Björk, Segata, Nathan, Bataille, Spector, Hospers, Weersma.

Conflict of Interest Disclosures: Drs Bolte, Björk, and de Haan reported grants from the Seerave Foundation during the conduct of the study. Dr Leeming reported personal fees from Zoe Ltd outside the submitted work. Dr Campmans-Kuijpers reported grants from Seerave Foundation during the conduct of the study as well as personal fees from Takeda and Janssen outside the submitted work. Dr Segata reported grants from the Seerave Foundation during the conduct of the study as well as personal fees from Zoe outside the submitted work. Dr Board reported funding for conferences and paid speaker fees from BMS, MSD, and Novartis. Dr Lorigan reported personal fees from BMS, Merck, Novartis, GSK, Amgen, Chugai, PierreFabre, NeraCare, Roche, and OncologyEducationCanada outside the submitted work. Dr de Vries reported institutional financial support from NSABP, Daiichi Sankyo, and Crescendo Biologics; grants from Amgen, Genentech, Roche, CytomX, G1 Therapeutics, Bayer, Synthon, Regeneron, Crescendo Biologics, GE Healthcare, and AstraZeneca; and service as a member of the ESMO-MCBS working party, chair of the ESMO Cancer Medicines Working Group, cochair of the RECIST committee, and member of expert panel for selection of the Essential Medicine List for the World Health Organization outside the submitted work. Dr Spector reported being a founder of and shareholder in Zoe Ltd outside the submitted work. Dr Hospers reported grants from the Seerave Foundation during the conduct of the study as well as personal fees from Amgen, Bristol-Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi, and Pierre Fabre and grants from Bristol Myers Squibb. Dr Weersma reported personal fees from Takeda Pharmaceuticals outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by the Seerave Foundation. This work was also supported by the Dutch Cancer Society grant 10034 POINTING to EGEdV.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We acknowledge the funding of the Seerave Foundation. We thank all participants of the study for their contribution and the research nurses at the University Medical Center Groningen and Kings College London for logistical support and collection of questionnaires. We thank the EPIC-Norfolk study for the development of the EPIC-Norfolk food frequency questionnaire. These individuals were not compensated for their contributions.

Data Sharing Statement: See Supplement 2.