Abstract 1128P
Background
Interaction of the programmed cell death-1 (PD-1) receptor with its ligands leads to downregulation of the T cell effector function and impairs antitumor immunity. Immune checkpoint inhibitors (ICIs) targeting PD-1 have proven efficacy in patients with several malignancies. Single nucleotide polymorphisms (SNPs) in genes related to the PD-1 axis likely affect T cell response upon anti-PD treatment. In fact, specific SNPs in the PDCD1 gene downregulate expression of PD-1 by T cells and are associated with decreased susceptibility to cancer. In this study, we investigated whether SNPs in genes related to the PD-1 axis are predictive of survival in metastatic melanoma patients treated with anti-PD-1 monotherapy.
Methods
Consecutive patients with metastatic melanoma who were treated either with nivolumab or pembrolizumab were included. Prospectively collected samples were genotyped for SNPs in HLAA (rs60131261), GZMB (rs8192917), IL-10 (rs3024493), IL2RA (rs2104286), IL-2RB (rs3218253), IFNG (rs2430561; rs2069705; rs2069718), PDCD1 (rs2227981), PTPN11 (rs2301756), and ZAP70 (rs13420683). Associations between SNPs and overall survival (OS) or progression free survival (PFS) were tested using Cox regression analysis. Associations with p ≤ 0.10 were tested multivariably and internally validated by bootstrapping.
Results
In total, 119 patients were included. The median follow-up was 2.6 years. Variation of PDCD1 (rs2227981) and GZMB (rs8192917) showed a trend towards OS (HR 2.03; 95%CI: 0.10-4.12; p 0.051 and HR 1.81; 95%CI: 0.95-3.36; p 0.060, respectively) and PFS (GZMB: HR 1.63; 95%CI: 1.00-2.67; p 0.051). After correction for prognostic factors (i.e. age, ECOG performance status and LDH), only variation of PDCD1 remained significantly associated with poorer OS (HR 2.37; 95%CI: 1.11-5.04; p 0.026), which was internally validated (Bias-corrected 95%CI: 1.04-6.25).
Conclusions
Patients with metastatic melanoma who have germline variation of PDCD1 have a significant poorer overall survival after anti-PD-1 monotherapy. These findings suggest that germline variations in immune-related genes are relevant for response and resistance to ICIs, which could be further explored in genome wide association studies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Erasmus University Medical Center.
Funding
Has not received any funding.
Disclosure
J.G. Aerts: Honoraria (self): MSD; Honoraria (self): BMS; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Licensing/Royalties: Amphera; Honoraria (self): Eli-Lilly; Honoraria (self): Takeda; Honoraria (self): Bayer; Honoraria (self): Roche; Honoraria (self): AstraZeneca. R.H. Mathijssen: Research grant/Funding (self): Astellas; Research grant/Funding (self): Bayer; Research grant/Funding (self): Boehringer-Ingelheim; Research grant/Funding (self): Cristal Therapeutics; Research grant/Funding (self), Licensing/Royalties: Pamgene; Research grant/Funding (self): Pfizer; Speaker Bureau/Expert testimony, Research grant/Funding (self): Novartis; Research grant/Funding (self): Roche; Advisory/Consultancy, Research grant/Funding (self): Servier. A.A.M. Van der Veldt: Advisory/Consultancy: BMS; Advisory/Consultancy: MSD; Advisory/Consultancy: Eisai; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Novartis; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Merck. All other authors have declared no conflicts of interest.