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 rs7421861G-allele is associated with poorer outcomes in pembrolizumab-treated MLA patients and warrants further validation.