Abstract
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.
Highlights
Programmed cell death-1 (PD-1) is a member of the CD28 family of co-stimulatory molecules and is expressed on activated CD4+ and CD8+ T cells [1]
The overall response rate (ORR) in our patient cohort was similar to those reported in clinical trials of anti-PD1 therapies in metastatic melanoma [14, 15]
We identified that the G allele of PD1.3 rs11568821 was significantly associated with longer progression free survival (PFS) in anti-PD-1 treated patients
Summary
Programmed cell death-1 (PD-1) is a member of the CD28 family of co-stimulatory molecules and is expressed on activated CD4+ and CD8+ T cells [1]. Constitutive high level expression of PD-1 on tumor specific T lymphocytes is a major factor restraining an effective anti-tumor immune response in patients with advanced malignancies [3]. Despite the success of these agents, a significant proportion of patients do not respond to anti-PD-1 therapy; identifying biomarkers that predict therapeutic efficacy remains an urgent need [4]. A number of single nucleotide polymorphisms (SNPs) in PDCD1 have been identified and shown to be associated with the development of autoimmune conditions, including Crohn’s disease, systemic lupus erythematosus, type I diabetes, rheumatoid arthritis, and multiple sclerosis [6]. The effect of PD-1 polymorphism in cancer remains unclear, with some studies reporting an increase in the risk of developing some cancer types while others have reported a reduced risk [8,9,10]. Despite the crucial role that the PD-1/PD-L1 pathway plays in limiting anti-tumor immune responses, there are no data exploring the potential influence of PD-1 polymorphisms on the treatment response to anti-PD-1 blockade
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