The introduction of immune-checkpoint inhibitors (ICIs) has revolutionized the treatment paradigm for advanced melanoma, leading to substantial benefit in overall survival (OS). However, several patients still do not benefit from ICIs and to date there are no predictive biomarkers for PD-1 inhibitors. PD-1 axis single nucleotide variants (SNVs) may affect receptor/ligand interactions in the tumor microenvironment and consequently the immune response and efficacy of ICIs. Based on this rationale, their predictive and prognostic role was investigated.
We analyzed, in metastatic melanoma patients treated with nivolumab or pembrolizumab, five PD-1 SNVs, namely PD1.3G>A (rs11568821), PD1.5 C>T (rs2227981), PD1.6 G>A (rs10204525), PD1.7 T>C(rs7421861), PD1.10 C>G (rs5582977) and three PD-L1 SNVs:+8293 C>A (rs2890658), PD-L1 C>T (rs2297136) and PD-L1 G>C (rs4143815) by pyrosequencing methods. Association of SNV genotypic frequencies with best overall response (BOR) to PD-1 inhibitors and development of immune-related adverse events (irAEs) were estimated through a modified Poisson regression. A Cox regression modelling approach was applied to evaluate the SNV association with OS. All regression analyses were adjusted for individual confounding factors.
A total of 125 patients with advanced melanoma were included in the analysis. In patients carrying the PD-L1 C>T variant, a trend towards a lower relative risk (RR) of having progressive disease was observed in the C/T genotype (RR=0.60; 95%CI 0.25-1.41). In addition, a trend for a reduction in irAEs occurrence was observed in patients with PD1.7 C/C and PD-L1 +8293 C/A genotypes (RR = 0.35 [95%CI 0.09-1.31] and RR=0.45 [95%CI 0.22-0.93], respectively). Finally, a trend for a survival benefit was observed in PD1.7 C/C (HR=0.41 [95%CI 0.16-1.00]) and PD-L1 C/T (HR=0.53 [95%CI 0.24-1.18]) SNV genotypes.
Our study showed that SNV of PD-1 and PD-L1 may play a role as a predictive biomarker of response and development of irAEs to PD-1 inhibitor therapy. Some of the investigated SNVs were also associated with a reduction of the risk of death, although a larger group of patients is needed to confirm these results.
The authors.
Italian Ministry of Health RF-2016-02362288 and Ricerca Corrente 2019-2021.
F. Spagnolo: Financial Interests, Personal, Invited Speaker: Sanofi Genzyme, Roche, BMS, Novartis, Merck, Sunpharma, MSD, Pierre Fabre; Financial Interests, Personal, Advisory Board: Novartis, Philogen, Sunpharma, MSD. P. Queirolo: Financial Interests, Personal, Advisory Board: Roche/Genentech, Novartis, MSD, BMS, Pierre Fabre, Sanofi, Sun Pharma, Merck Serono; Financial Interests, Personal, Sponsor/Funding: MSD Oncology, Sanofi/Regeneron. All other authors have declared no conflicts of interest.