1119P - Genomic and transcriptomic predictors of resistance to anti-PD1 monotherapy in patients with advanced melanoma

Background

Anti-PD1 therapy has improved survival of patients with advanced melanoma. However, a substantial number of patients does not benefit due to tumor resistance. To understand failure of anti-PD1 therapy in advanced melanoma, the primary objective of this study was to identify genomic and transcriptomic characteristics associated with resistance to anti-PD1.

Methods

In this prospective multicenter study (NCT01855477), tumor biopsies and matched whole-blood samples were collected from 279 patients with advanced melanoma prior to the start of first-line systemic therapy. Whole genome sequencing (WGS) and high-quality RNA sequencing (RNA-Seq) were performed. To identify immune-predictive biomarkers, the cohort was split into two independent cohorts, a training cohort with in-depth clinical data (N=76) and a testing cohort (N=203). After tumor biopsy, 114 previously untreated patients were treated with anti-PD1 monotherapy. Based on their tumor response after anti-PD1 therapy, patients were categorized as good or poor responders.

Results

Overall, the two cohorts were similar based on clinical, genomic, and transcriptomic features. Unsupervised hierarchical clustering of the RNA-seq data revealed two distinct immunogenic gene expression patterns in the advanced melanoma transcriptome, reflecting low and high expression of immune cell-related genes. Patients with a poor tumor response after anti-PD1 generally had a lower number of specific immunogenic signatures and were categorized into a cluster with low expression of different immune cell-related genes, including signatures of IFN-gamma, effector T-cells and antigen presentation pathways. The cluster of patients with the low immunogenic gene expression score was also associated with a poor overall survival compared to the cluster with high immunogenic gene expression scores.

Conclusions

Based on different immune signatures, a cluster with low immune-related expression patterns was found in patients with a poor response after anti-PD1 monotherapy. This specific cluster may contribute to better understand resistance to anti-PD1 and identify patients with melanoma who need alternative treatment strategies.

Clinical trial identification

NCT01855477.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Erasmus Medical Center research fellowship.

Disclosure

M. Jalving: Financial Interests, Institutional, Advisory Board, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board, Advisory board: Merck; Financial Interests, Institutional, Advisory Board: Pierre Fabre. J.W. de Groot: Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb, Pierre Fabre. H.M. Westgeest: Financial Interests, Personal and Institutional, Advisory Board: Merck. K. Suijkerbuijk: Financial Interests, Institutional, Advisory Board: Novartis, BMS, AbbVie, Pierre Fabre, MSD; Financial Interests, Institutional, Other, honoraria for Safety Review Committee: sairopa; Financial Interests, Institutional, Research Grant: Novartis, TigaTx, Bristol Myers Squibb, Philips. J.B.A.G. Haanen: Financial Interests, Institutional, Advisory Board: Bristol Myers Squipp, Achilles Therapeutics, Ipsen, Merck Sharpe & Dohme, Merck Serono, Pfizer, Molecular Partners, Novartis, Roche, Sanofi, Iovance Biotherapeutics, AstraZeneca; Financial Interests, Institutional, Advisory Board, SAB member: BioNTech, Immunocore, Gadeta, Instil Bio, PokeAcel, T-Knife; Financial Interests, Personal, Advisory Board, SAB member: Neogene Therapeutics, Scenic; Financial Interests, Personal, Advisory Board: Third Rock Venture, CureVac, Imcyse; Financial Interests, Personal, Stocks/Shares: Neogene Therapeutics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, BioNTech US, Merck Sharpe & Dohme, Amgen, Novartis, Asher Bio, Sastra Cell Therapy; Non-Financial Interests, Member: ASCO, AACR, SITC; Other, Other, Editor-in-Chief IOTECH: ESMO; Other, Other, Editorial Board ESMO Open: ESMO; Other, Other, Editorial Board: Kidney Cancer. A.A.M. Van der Veldt: Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb, Eisai, Ipsen, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi. All other authors have declared no conflicts of interest.