Abstract 1060P
Background
Patients (pts) with cutaneous melanoma (CM) have higher rates of response to immune checkpoint inhibitors (ICI) than pts with mucosal and uveal melanoma (MM/UM). Response to ICI is influenced by multiple factors, including the circulating levels of immunomodulatory metabolites. Accordingly, we sought to interrogate the serum metabolome of pts with CM, MM and UM to identify differences that could potentially influence this differential response to ICI.
Methods
This is an exploratory, retrospective observational study of pts with advanced melanoma treated with ICI. Metabolites were analyzed in serum samples collected before ICI therapy, and using a liquid chromatography mass spectrometry platform. Differences in metabolomics profiles were compared using Random Forest (RF), Multidimensional scaling (MDS), and Kruskal-Wallis test. Overall survival (OS) was assessed using Kaplan-Meier, Log-Rank, and Cox regression models. Statistical significance was set to 0.05.
Results
Serum levels of 115 metabolites in 13 CM, 12 MM and 11 UM pts were analyzed. MDS analysis indicated distinct metabolomic profiles amongst the three melanoma subtypes. Using RF analysis, high levels of Hydroxykynurenine (HKyn) distinguished MM and UM from CM. Further interrogation revealed CM had lower HKyn (p<0.001) and higher Kynurenic Acid (p<0.028) compared to MM and UM. UM, the most ICI-resistant melanoma subtype, was associated with higher levels of the polyamine spermine (SPM) compared to CM and MM (p=0.029). This finding suggests that high SPM may correlate with resistance to ICI, potentially across melanoma subtypes. Indeed, in our CM cohort of patients, lower SPM had a trend toward longer median OS (12.8 vs 6.1 months, p=0.258) on treatment with ICI. This was validated in external published cohort, including 78 patients with advanced CM melanoma treated with ICI, as lower plasma SPM was associated with increased mOS, 24.9 vs 11.1 months (p=0.020).
Conclusions
These data indicate altered polyamine metabolism and high circulating levels of SPM identified as a feature of the UM, and distinct kynurenine metabolism in all three melanoma subtypes which may influence their response to ICI. Validation of these data in larger cohorts is still required.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Canadian Institutes Health Research.
Disclosure
A. Rose: Financial Interests, Personal, Advisory Board: Pfizer. R. Laister: Financial Interests, Personal, Advisory Board: Protocol Intelligence; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Jazz Pharmaceuticals; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Servier; Financial Interests, Personal, Other, honoraria: AstraZeneca; Financial Interests, Personal, Other, honoraria: Celgene; Financial Interests, Personal, Other, honoraria: Janssen; Financial Interests, Personal, Other, honoraria: Merck; Financial Interests, Personal, Other, honoraria: Jazz Pharmaceuticals; Financial Interests, Personal, Other, honoraria: Seattle Genetics. A. Spreafico: Financial Interests, Personal, Advisory Board, Compensated: Merck; Financial Interests, Personal, Advisory Board, Compensated: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board, Compensated: Oncorus; Financial Interests, Personal, Advisory Board, Compensated: Janssen; Financial Interests, Institutional, Research Grant, Funding paid to Dr. Spreafico Institution to support clinical trials: Novartis; Financial Interests, Institutional, Research Grant, Funding paid to Dr. Spreafico Institution to support clinical trials: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant, Funding paid to Dr. Spreafico Institution to support clinical trials: Symphogen AstraZeneca/Medimmune; Financial Interests, Institutional, Research Grant, Funding paid to Dr. Spreafico Institution to support clinical trials: Merck; Financial Interests, Institutional, Research Grant, Funding paid to Dr. Spreafico Institution to support clinical trials: Bayer; Financial Interests, Institutional, Research Grant, Funding paid to Dr. Spreafico Institution to support clinical trials: Surface Oncology; Financial Interests, Institutional, Research Grant, Funding paid to Dr. Spreafico Institution to support clinical trials: Northern Biologics; Financial Interests, Institutional, Research Grant, Funding paid to Dr. Spreafico Institution to support clinical trials: Janssen Oncology/Johnson & Johnson; Financial Interests, Institutional, Research Grant, Funding paid to Dr. Spreafico Institution to support clinical trials: Roche; Financial Interests, Institutional, Research Grant, Funding paid to Dr. Spreafico Institution to support clinical trials: Regeneron; Financial Interests, Institutional, Research Grant, Funding paid to Dr. Spreafico Institution to support clinical trials: Alkermes; Financial Interests, Institutional, Research Grant, Funding paid to Dr. Spreafico Institution to support clinical trials: Array Biopharma/Pfizer; Financial Interests, Institutional, Research Grant, Funding paid to Dr. Spreafico Institution to support clinical trials: GSK; Financial Interests, Institutional, Research Grant, Funding paid to Dr. Spreafico Institution to support clinical trials: Treadwell. D. Hogg: Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb ; Financial Interests, Institutional, Research Grant: Merck Serono; Financial Interests, Personal, Advisory Board: Merck Serono; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Roche. M.O. Butler: Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: GlaxoSmithKline; Financial Interests, Personal, Advisory Board: IOVANCE; Financial Interests, Personal, Advisory Board: Instil Bio; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Adaptimmune; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: Immunocore; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Advisory Board: Sun Pharma; Financial Interests, Personal, Advisory Board: Immunovaccine; Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Takara Bio. S. Saibil: Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Sanofi genzyme. All other authors have declared no conflicts of interest.