Prospective study of programmed death 1 (PD-1) single-nucleotide polymorphisms in patients with metastatic lung adenocarcinoma treated with Pembrolizumab

Background Pembrolizumab (P) is a humanized monoclonal antibody targeting PD-1 with demonstrated antitumor activity in patients (pts) with metastatic lung adenocarcinoma (MLA). Its efficacy is enhanced in tumors expressing programmed death ligand 1 (PD-L1). However, functional single-nucleotide polymorphisms (SNPs) in the PD-1 gene may impair the activity of P, potentially leading to suboptimal clinical outcomes. We investigated whether 5 functional PD-1 SNPs (rs11568821 C>T, rs10204525 C>T, rs7421861 A>G, rs2227981 A>G, and rs41386349 A>G) are associated with progression-free survival (PFS) in MLA pts treated with P. Methods Consecutive MLA pts receiving P therapy were prospectively enrolled across five institutions in Central Italy. An accrual target of 120 was established. Assuming a risk allele frequency >10%, the study was powered to detect an association with a PFS hazard ratio (HR) >2.5 after 80 events. Associations between the SNPs and PFS (primary endpoint) were assessed using univariate and multivariate models. An exploratory analysis was also performed to evaluate the relationship between inferred haplotypes and early progression (<6 months). Results Fifty-seven pts were treated with P (PD-L1 expression >50%) and 63 pts with P plus chemotherapy (PD-L1 expression <50%). There were 83 males and 37 females, with an overall median age of 68. KRAS mutations occurred in 34 pts (28%). Median PFS in carriers of the rs7421861 A/A, A/G and G/G genotypes was 26.8 months, 19.5 months and 6,3 months, respectively (univariate p= 0.001). Median PFS in carriers of the rs2227981 A/A, A/G, and G/G genotypes was 34 months, 20 months, and 19,5 months, respectively (univariate p=0.04). The rs7421861-rs2227981 G-G haplotype was significantly associated with early progression with a 2.51 HR and 95% confidence interval (CI 1.16-5.43; p=0.01). The detrimental effect of the homozygous rs7421861 G/G genotype on PFS was retained in the multivariate model with a 2.71 HR and 1.14-6.45 95% CI; p=0.02. Conclusions The rs7421861 SNP, in its minor homozygous genotype, was associated with poorer PFS in MLA pts treated with P. This findingsuggests a potential host-related factor contributing to resistance to anti-PD-1 therapy and warrants further investigation.