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PDCD1 Polymorphisms May Predict Response to Anti-PD-1 Blockade in Patients With Metastatic Melanoma

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posted on 2021-08-03, 03:04 authored by Sagun ParakhSagun Parakh, A Musafer, S Paessler, T Witkowski, CSNLW Suen, CSA Tutuka, MS Carlino, AM Menzies, RA Scolyer, Jonathan CebonJonathan Cebon, Alexander DobrovicAlexander Dobrovic, GV Long, O Klein, Andreas BehrenAndreas Behren
A significant number of patients (pts) with metastatic melanoma do not respond to anti-programmed cell death 1 (PD1) therapies. Identifying predictive biomarkers therefore remains an urgent need. We retrospectively analyzed plasma DNA of pts with advanced melanoma treated with PD-1 antibodies, nivolumab or pembrolizumab, for five PD-1 genotype single nucleotide polymorphisms (SNPs): PD1.1 (rs36084323, G>A), PD1.3 (rs11568821, G>A), PD1.5 (rs2227981, C>T) PD1.6 (rs10204225, G>A) and PD1.9 (rs2227982, C>T). Clinico-pathological and treatment parameters were collected, and presence of SNPs correlated with response, progression free survival (PFS) and overall survival (OS). 115 patients were identified with a median follow up of 18.7 months (range 0.26 – 52.0 months). All were Caucasian; 27% BRAF V600 mutation positive. At PD-1 antibody commencement, 36% were treatment-naïve and 52% had prior ipilimumab. The overall response rate was 43%, 19% achieving a complete response. Overall median PFS was 11.0 months (95% CI 5.4 - 17.3) and median OS was 31.1 months (95% CI 23.2 - NA). Patients with the G/G genotype had more complete responses than with A/G genotype (16.5% vs. 2.6% respectively) and the G allele of PD1.3 rs11568821 was significantly associated with a longer median PFS than the AG allele, 14.1 vs. 7.0 months compared to the A allele (p=0.04; 95% CI 0.14 – 0.94). No significant association between the remaining SNPs and responses, PFS or OS were observed. Despite limitations in sample size, this is the first study to demonstrate an association of a germline PD-1 polymorphism and PFS in response to anti-PD-1 therapy in pts with metastatic melanoma. Extrinsic factors like host germline polymorphisms should be considered with tumor intrinsic factors as predictive biomarkers for immune checkpoint regulators.


This work was supported by funds from the Operational Infrastructure Support Program provided by the Victorian Government, Australia and Melanoma Research Victoria (MRV). AMM is supported by a Cancer Institute NSW Fellowship. A. Behren is the recipient of a Fellowship from the Victorian Government Department of Health and Human Services acting through the Victorian Cancer Agency. We would like to thank Sudheer Veduruparthi for his assistance in SNP genotyping. RS is supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1093017) and Practitioner Fellowship (APP1141295).


Publication Date



Frontiers in Immunology



Article Number

ARTN 672521







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