Validation of cancer-type-dependent benefit from immune checkpoint blockade in TMB-H tumors identified by the FoundationOne CDx assay

Abstract

The pan-cancer approval of immune checkpoint blockade (ICB) with pembrolizumab for any patient with a high tumor mutation burden (TMB-H) solid tumor has been met with mixed responses. 1 Prasad V. Addeo A. The FDA approval of pembrolizumab for patients with TMB >10 mut/Mb: was it a wise decision? No. Ann Oncol. 2020; 31: 1112-1114 Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar In a meta-analysis of data from over 3000 patients with cancer, 2 McGrail D.J. Pilié P.G. Rashid N.U. et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann Oncol. 2021; 32: 661-672 Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar we previously observed that the benefit from ICB in TMB-H tumors was restricted to cancers where neoantigen load was positively correlated with immune cell infiltration, termed ‘category I’ cancers, including melanoma and bladder cancer. In contrast, in breast, kidney, brain, and other ‘category II’ cancers, where neoantigen load was not associated with increased immune infiltration, no benefit from ICB in TMB-H tumors was detected. A key limitation of this study was that the majority of samples were not profiled by the approved FoundationOne CDx (Foundation Medicine, Cambridge, MA) companion diagnostic, a targeted sequencing panel which profiles 324 cancer-related genes, potentially resulting in the misclassification of TMB-H tumors. 3 Fabrizio D. Cristescu R. Albacker L. et al. Real-world prevalence across 159 872 patients with cancer supports the clinical utility of TMB-H to define metastatic solid tumors for treatment with pembrolizumab. Ann Oncol. 2021; 32: 1193-1194 Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar While we found no evidence of improved response to ICB at any TMB threshold, 2 McGrail D.J. Pilié P.G. Rashid N.U. et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann Oncol. 2021; 32: 661-672 Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar ,4 McGrail D.J. Pilié P.G. Rashid N.U. et al. Reply to: ‘Real-world prevalence across 159 872 patients with cancer supports the clinical utility of TMB-H to define metastatic solid tumors for treatment with pembrolizumab.’ by D. Fabrizio et al. Ann Oncol. 2021; 32: 1194-1197 Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar prospective validation of ICB response rates in TMB-H category I and II cancers as determined by FoundationOne CDx assay remained to be carried out.