Universal cutoff for tumor mutational burden in predicting the efficacy of anti-PD-(L)1 therapy for advanced cancers

• Published in: Frontiers in cell and developmental biology Vol. 11; p. 1209243
• Main Authors: Mo, Shu-Fen, Cai, Zeng-Zhi, Kuai, Wen-Hao, Li, Xuexin, Chen, Yu-Tong
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 2023
• Subjects: advanced solid tumors; anti-PD-(L)1 therapy; biomarker; Cell and Developmental Biology; Medicin och hälsovetenskap; tumor mutational burden (TMB); universal cutoff; advanced solid tumors; tumor mutational burden (TMB); biomarker; anti-PD-(L)1 therapy; universal cutoff
• ISSN: 2296-634X; 2296-634X
• DOI: 10.3389/fcell.2023.1209243

The US Food and Drug Administration (FDA)'s tumor-agnostic approval of pembrolizumab in high tumor mutational burden (TMB-high, i.e., TMB≥10 mut/Mb) cases, based on the data from KEYNOTE-158, has raised considerable concerns among the immuno-oncology community. This study aims to statistically infer the optimal universal cutoff in defining TMB-high that is predictive of the efficacy of anti-PD-(L) 1 therapy in advanced solid tumors. We integrated MSK-IMPACT TMB data from a public cohort and the objective response rate (ORR) for anti-PD-(L) 1 monotherapy across diverse cancer types in published trials. The optimal TMB cutoff was determined by varying the universal cutoff to define TMB-high across cancer types and examining the cancer-level correlation between objective response rate and the proportion of TMB-high cases. The utility of this cutoff in predicting overall survival (OS) benefits from anti-PD-(L) 1 therapy was then evaluated in a validation cohort of advanced cancers with coupled MSK-IMPACT TMB and OS data. In silico analysis of whole-exome sequencing data from The Cancer Genome Atlas was further employed to assess the generalizability of the identified cutoff among panels comprising several hundred genes. The cancer type-level analysis identified 10 mut/Mb as the optimal cutoff for MSK-IMPACT in defining TMB-high, with the corresponding TMB-high (TMB≥10 mut/Mb) percentage strongly correlated with ORR for PD-(L) 1 blockade across cancer types [correlation coefficient, 0.72 (95% CI, 0.45-0.88)]. This cutoff was also the optimum in defining TMB-high (via MSK-IMPACT) when predicting OS benefits from anti-PD-(L) 1 therapy in the validation cohort. In this cohort, TMB≥10 mut/Mb was associated with significantly improved OS (hazard ratio, 0.58 [95% CI, 0.48-0.71]; < 0.001). Moreover, analyses revealed excellent agreement of TMB≥10 mut/Mb cases between MSK-IMPACT and the FDA-approved panels and between MSK-IMPACT and various randomly sampled panels. Our study demonstrates that 10 mut/Mb is the optimal, universal cutoff for TMB-high that guides the clinical application of anti-PD-(L) 1 therapy for advanced solid tumors. It also provides rigorous evidence beyond KEYNOTE-158 for the utility of TMB≥10 mut/Mb in predicting the efficacy of PD-(L) 1 blockade in broader settings, which could help to mitigate the challenges in embracing the tumor-agnostic approval of pembrolizumab in TMB-high cases.