High Tumor Mutation Burden Associated With Improved Clinical Outcomes of Immune Checkpoint Inhibitors in NSCLC

A study identified that tumor mutation burden (TMB) levels are associated with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) among patients who received programmed cell death–1 (PD-1)/ programmed death ligand–1 (PD-L1) blockade as treatment for advanced non-small cell lung cancer (NSCLC).

“Although [TMB] has been explored as a potential biomarker of immunotherapy efficacy in solid tumors, there still is a lack of consensus about the optimal TMB threshold that best discriminates improved outcomes of immune checkpoint inhibitor therapy among patients with [NSCLC]," explained Biagio Ricciuti, MD, Dana-Farber Cancer Institute, MA, and colleagues.

This multicenter cohort study included 1552 patients with advanced NSCLC who received PD-1/PD-L1 inhibition at Memorial Sloak Kettering Cancer Center, Dana-Farber Cancer Institute, and in the Stand UP To Cancer/Mark Foundation database between September 2013 and September 2020. Patients were grouped into either low (≤19.0 mutations per megabase [muts/Mb]) or high (>19.0 muts/Mb) TMB, with a median TMB of 9.8 muts/Mb.

Those patients with a TMB >19.0 muts/Mb had a significantly higher ORR to immune checkpoint inhibitors (42.5% vs 18.0%; difference = 24.5%; 95% confidence interval [CI], 12.7% to 36.2%; P  <  .001), a longer PFS (hazard ratio [HR] 0.38; 95% CI, 0.28 to 0.52; P < .001), and a longer OS (HR 0.46; 95% CI, 0.32 to 0.65; P < .001) when compared to those patients with a TMB ≤19 muts/Mb. In a multivariable analysis of the 3 independent locations, high TMB was still had a significant association with improved ORR, PFS, and OS.

Patients with high tumor mutation burden levels also experienced improved outcomes with immunotherapy in every PD-L1 tumor subgroup (<1%, 1% to 49%, and ≥50%). Patients with high TMB and PD-L1 expression ≥50 had an ORR as high as 57% to PD-1/PD-L1 inhibition, whereas patients with low TMB and PD-L1 expression <1% had an ORR as low as 8.7% to PD-1/PD-L1 inhibition. Dr Ricciuti and coauthors also noted, "high TMB levels were associated with increased CD8-positive, PD-L1–positive T-cell infiltration, increased PD-L1 expression on tumor and immune cells, and upregulation of innate and adaptive immune response signatures.”

Dr Ricciuti et all concluded, “These findings suggest that increasing TMB levels are associated with immune cell infiltration and an inflammatory T-cell–mediated response, resulting in increased sensitivity to PD-1/PD-L1 blockade in NSCLC across PD-L1 expression subgroups.”

Source:

Ricciuti B, Wang X, Alessi JV, et al. Association of high tumor mutation burden in non-small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels. JAMA Oncol. 2022;8(8):1160-1168. doi:10.1001/jamaoncol.2022.1981