Multicenter prospective study of programmed death 1 (PD-1) single-nucleotide polymorphisms (SNPs) in patients with metastatic lung adenocarcinoma (MLA) treated with pembrolizumab (P)

Background P is a humanized monoclonal antibody against PD-1 that has antitumor activity in MLA patients (pts), with increased activity in tumors that express programmed death ligand 1 (PD-L1). Functional PD-1 SNPs may impair P activity leading to unfavorable clinical outcomes. We investigated whether five functional PD-1 SNPs (rs11568821 C>T, rs10204525 C>T, rs7421861 A>G, rs2227981 A>G, rs41386349 A>G) may impact on the progression-free survival (PFS) of MLA pts treated with P. Methods Consecutive pts with MLA undergoing P therapy were prospectively enrolled at five participating institutions in Central Italy. A target accrual of 120 pts was planned. Assuming a risk allele frequency > 10%, an association with PFS hazard ratio (HR) > 2.5 could be detected after 80 events. Univariate analyses and multivariate models were adopted for association analysis between SNPs and PFS (primary end-point). An exploratory analysis was conducted to examine the association between inferred haplotypes and early progression <6 months. Results One hundred twenty non-oncogene-addicted MLA pts were enrolled. 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 hazard ratio (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 SNPs in the minor homogenous genotype showed an association with unfavorable PFS in MLA pts treated with P. This finding warrants further investigation as an unfavorable host-related feature in pts treated with anti-PD-1.