Tumor Mutational Burden Predicts Progression-Free Survival and Local-Regional Control in Locally Advanced Non-Small Cell Lung Cancer Patients Treated with Chemoradiation and Durvalumab

Abstract

<h3>Purpose/Objective(s)</h3> The impact of tumor genomics on disease outcomes in locally advanced non-small cell lung cancers (NSCLC) treated with concurrent chemoradiation (cCRT) and durvalumab remains unclear. We assessed if tumor mutational burden (TMB) and mutations in genes associated with radiation sensitivity can predict for disease control. <h3>Materials/Methods</h3> Consecutive patients treated with cCRT and durvalumab who underwent tumor genomic profiling were included. Genomic characteristics including TMB and 26 genes from three radio-sensitizing DNA damage and repair (DDR) pathways (DNA checkpoints, Fanconi Anemia and homologous recombination) and genes associated with radiation resistance (KEAP1, NFE2L2, STK11, PIK3CA) were examined. Cox modeling was used to assess associations between clinical features, TMB, and pathogenic mutations in DDR or radiation resistance genes with disease outcomes. Kaplan-Meier analysis was used to estimate overall survival (OS), progression-free survival (PFS) and local-regional failure (LRF) and compare PFS and LRF between patients with high-TMB (≥ 10 mt/Mb) and low-TMB. A p-value <0.05 was considered significant. <h3>Results</h3> Eighty-one patients with median follow-up of 26 months were assessed. Median age was 67 years, 71% (n=57) had stage IIIB/IIIC disease and PD-L1 expression was available for 67 (83%) patients, of whom 42 (63%) had PD-L1 ≥1%. Median TMB was 8.8 mt/Mb. In total, 17% (n=14) and 35% (n=28) of patients had pathogenic mutations in DDR and radiation resistance genes, respectively (Table 1). Among all patients, the 24-month OS, PFS and LRF estimates were 72% (95% CI: 62-82), 45% (34-56%) and 31% (1-43%), respectively. On Cox analysis, only TMB associated with PFS [HR: 0.95 (0.92-0.98), p=0.009] and LRF [HR: 0.89 (0.83-0.97, p=0.009]. Neither PDL1 expression, DDR or radiation resistance mutations, histology, stage nor ECOG associated with PFS or LRF. Compared to patients with low-TMB, patients with high-TMB had improved PFS and less LRF: 24-month PFS: 66% vs 27% (p=0.003) and 24-month LRF: 9% vs 52% (p=0.001). <h3>Conclusion</h3> In patients with locally advanced NSCLC treated with cCRT and durvalumab, high-TMB predicts for improved progression-free survival and local-regional control. Potential underlying mechanisms include increased genomic instability and tumor immunogenicity enhancing sensitivity to this multimodal treatment.