High Tumor Mutational Burden Associated With Improved Progression-Free Survival Among Patients With NSCLC

A cohort study found high tumor mutational burden (TMB) to be associated with improved local-regional control and progression-free survival (PFS) among patients with non-small cell lung cancer (NSCLC) treated with chemoradiation and durvalumab.

“The addition of consolidative durvalumab to chemoradiation has improved disease control and survival in locally advanced [NSCLC]. However, there remains a need to identify biomarkers for response to this therapy to allow for risk adaptation and personalization," explained Emily S. Lebow, MD, Memorial Sloan Kettering Cancer Center, New York, NY, and colleagues.

The study enrolled 81 consecutive patients with unresectable locally advanced NSCLC who had prospective comprehensive genomic profiling and had been treated with chemoradiation and adjuvant durvalumab between November 2013 and March 2020. The patients were separated into either the TMB-high (≥10 mutations/megabase [mt/Mb], n = 36) group or the TMB-low (<10 mt/Mb, n = 45) group. The primary outcomes were 24-month local-regional failure (LRF) and progression-free survival (PFS). Patients were also evaluated by the presence of somatic alterations associated with radiation resistance (KEAP1/NFE2L2) or radiation sensitivity (DNA damage repair pathway).

The median follow-up time was 26 months. Patients with TMB-high tumors had a significantly lower 24-month LRF rate (9%) vs patients with TMB-low tumors (51%; P = .001), and 24-month PFS was improved in patients with TMB-high tumors (66%) compared with patients with TMB-low tumors (27%; P = .003).

Additionally, patients with KEAP1/NFE2L2-altered tumors experienced a 24-month LRF of 52% vs 27% among patients with KEAP1/NFE2L2-wildtype tumors (P = .05). Cox analysis revealed only TMB status was associated with LRF (hazard ratio [HR] 0.17, 95% confidence interval [CI], 0.03 to 0.64; P = .02) and PFS (HR 0.45, 95% CI, 0.21 to 0.9; P = .03. Other factors such as DNA damage repair pathway alterations, PD-L1 expression, histology, and disease state did not exhibit any significant association with LRF or PFS.

“These findings suggest that patients with unresectable locally advanced NSCLC with high TMB have a reduced risk of local-regional failure and improved progression-free survival after treatment with definitive chemoradiation and consolidative durvalumab,” Dr Lebow et al concluded.

Source:

Lebow ES, Shepherd A, Eichholz JE, et al. 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. JAMA Netw Open. 2023;6(1):e2249591. doi:10.1001/jamanetworkopen.2022.49591