Predictive Impact of Tumor Mutational Burden on Real-World Outcomes of First-Line Immune Checkpoint Inhibition in Metastatic Melanoma.

Abstract

The choice of threshold and reliability of high tumor mutational burden (TMB) to predict outcomes and guide treatment choice for patients with metastatic melanoma receiving first-line immune checkpoint inhibitor (ICI) therapy in the real world is not well known. Using a deidentified nationwide (US-based) melanoma clinicogenomic database, we identified a real-world cohort of patients with metastatic melanoma (N = 497) who received first-line monotherapy anti-PD-1 (n = 240) or dual anti-PD-1 and anti-CTLA-4 ICI (n = 257) and had a tissue-based comprehensive genomic profiling test TMB score. TMB-high (TMB-H; ≥10 mutations per megabase [muts/Mb], n = 352, 71%) was independently predictive of superior real-world progression-free survival and overall survival versus TMB-low (<10 mut/Mb, n = 145, 29%) in both mono ICI (hazard ratio [HR], 0.45 [95% CI, 0.32 to 0.63]; <i>P</i> < .001; HR, 0.61 [95% CI, 0.41 to 0.90]; <i>P</i> = .01, respectively) and dual ICI (HR, 0.67 [95% CI, 0.49 to 0.90]; <i>P</i> = .009; HR, 0.61 [95% CI, 0.42 to 0.88]; <i>P</i> = .007, respectively) patients. Dual ICI offered no significant advantage in <i>BRAF</i>wt patients and unexpectedly demonstrated greatest benefit in the TMB 10-19 mut/Mb group, identifying a TMB-very high (≥20 mut/Mb, n = 247, 50%) <i>BRAF</i>mut patient subgroup for whom mono ICI may be preferable. TMB-H predicts superior outcomes on ICI while coassessment of <i>BRAF</i> status and TMB may inform first-line regimen choice.