A multicenter prospective study of single nucleotide polymorphisms in the PDCD1 (programmed cell death 1) gene in patients with metastatic lung adenocarcinoma treated with pembrolizumab

Introduction Pembrolizumab, a monoclonal antibody targeting programmed death-1 (PD-1), improves outcomes in metastatic lung adenocarcinoma (MLA) expressing programmed death ligand-1 (PD-L1). Single-nucleotide polymorphisms (SNPs) in the PDCD1 gene may impair PD-1 signaling and reduce the efficacy of pembrolizumab. We evaluated the impact of rs11568821 C > T, rs10204525 C > T, rs7421861 A > G, rs2227981 G > A, and rs41386349 G > A on progression-free survival (PFS) in non-oncogene-addicted MLA patients treated with pembrolizumab-based regimens. Materials and methods Patients were prospectively enrolled: those expressing PD-L1 ≥ 50% received pembrolizumab monotherapy, whereas those expressing PD-L1 < 50% received pembrolizumab plus platinum-pemetrexed chemotherapy. Associations between SNPs and PFS (primary endpoint) were assessed using univariate and multivariable Cox models. Secondary endpoints included response rate and overall survival (OS). Results Among 141 evaluable patients, 71 received pembrolizumab and 70 received combination therapy. Median PFS was 20 months (95% confidence interval [CI], 13-27) overall, 25 months (95% CI, 16–34) with pembrolizumab, and 13 months (95% CI, 8–23) with combination therapy. Rs7421861 was significantly associated with PFS: 23 months (95% CI, 13–40) in A/A, 20 months (95% CI, 12–29) in A/G, and 6 months (95% CI, 3–11) in G/G patients. In multivariable analysis, G/G genotype showed the strongest effect (HR 2.85; 95% CI, 1.53–5.29; p = 0.001). Most G/G carriers (12/13) had stable or progressive disease, and OS was also inferior. Discussion The rs7421861-G allele is associated with poorer outcomes in pembrolizumab-treated MLA patients and warrants further validation.