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

Abstract

ImportanceThe addition of consolidative durvalumab to chemoradiation has improved disease control and survival in locally advanced non–small cell lung cancer (NSCLC). However, there remains a need to identify biomarkers for response to this therapy to allow for risk adaptation and personalization.ObjectivesTo evaluate whether TMB or other variants associated with radiation response are also associated with outcomes following definitive chemoradiation and adjuvant durvalumab among patients with locally advanced unresectable NSCLC.Design, Setting, and ParticipantsThis cohort study included consecutive patients with unresectable locally advanced NSCLC treated with chemoradiation and adjuvant durvalumab between November 2013 and March 2020 who had prospective comprehensive genomic profiling. This study was completed at a multisite tertiary cancer center. The median (IQR) follow-up time was 26 (21-36) months. Statistical analysis was conducted from April to October 2022.ExposuresPatients were grouped into TMB-high (≥10 mutations/megabase [mt/Mb]) and TMB-low (<10 mt/Mb) groups and were additionally evaluated by the presence of somatic alterations associated with radiation resistance (KEAP1/NFE2L2) or radiation sensitivity (DNA damage repair pathway).Main Outcomes and MeasuresThe primary outcomes were 24-month local-regional failure (LRF) and progression-free survival (PFS).ResultsIn this cohort study of 81 patients (46 [57%] male patients; median [range] age, 67 [45-85] years), 36 patients (44%) had TMB-high tumors (≥10 mt/Mb). Patients with TMB-high vs TMB-low tumors had markedly lower 24-month LRF (9% [95% CI, 0%-46%] vs 51% [95% CI, 36%-71%]; P = .001) and improved 24-month PFS (66% [95% CI, 54%-84%] vs 27% [95% CI, 13%-40%]; P = .003). The 24-month LRF was 52% (95% CI, 25%-84%) among patients with KEAP1/NFE2L2-altered tumors compared with 27% (95% CI, 17%-42%) among patients with KEAP1/NFE2L2-wildtype tumors (P = .05). On Cox analysis, only TMB status was associated with LRF (hazard ratio [HR], 0.17; 95% CI, 0.03-0.64; P = .02) and PFS (HR, 0.45; 95% CI, 0.21-0.90; P = .03). Histology, disease stage, Eastern Cooperative Oncology Group status, programmed cell death ligand 1 expression, and pathogenic KEAP1/NFE2L2, KRAS, and DNA damage repair pathway alterations were not significantly associated with LRF or PFS.Conclusions and RelevanceIn this cohort study, TMB-high status was associated with improved local-regional control and PFS after definitive chemoradiation and adjuvant durvalumab. TMB status may facilitate risk-adaptive radiation strategies in unresectable locally advanced NSCLC.

Multi-institutional analysis of aneuploidy and outcomes to chemoradiation and durvalumab in stage III non-small cell lung cancer

“…We have recently identified tumor mutational burden (TMB) and very-high PD-L1 (programmed death ligand 1) expression levels to independently predict for disease control. 2 3 Aneuploidy may be a biomarker with special relevance in this patient population that may be informative beyond TMB and PD-L1.…”

Predictive value of 18F‐FDG PET/CT and serum tumor markers for tumor mutational burden in patients with non‐small cell lung cancer

“…Currently, there is no generally accepted cutoff value to define TMB‐high. In this study, TMB‐high was defined as ≥10 mutations/Mb as this category is consistent with those used in several randomized trials in lung cancer 3,14,15 and adopted by the Food and Drug Administration for refractory solid tumor approval of anti–PD‐1 therapy 16 . In addition, it is also the minimum threshold developed by a multistakeholder group convened by the Friends of Cancer Research to coordinate a standard cutoff across clinical trials 17,18 …”

Predicting of overall survival in non-small cell lung cancer patients receiving concurrent radiochemotherapy and adjuvant durvalumab – a Polish real-world single-center experience

“…Tumor PD-L1 expression has been shown to be a predictive factor in some studies, although its role remains controversial due to variations in testing methods and interpretation [5]. Other biomarkers, such as tumor mutational burden [6] and immune gene signatures [7], are also being investigated and may provide valuable insights into patient selection and treatment response. Additionally, emerging research suggests that genetic alterations, such as KRAS mutations, may hold promise for identifying patients who are less likely to benefit from durvalumab therapy [8].…”