Tissue-specific thresholds of mutation burden associated with anti-PD-1/L1 therapy benefit and prognosis in microsatellite-stable cancers

Authors:

Maishara Muquith 1, Magdalena Espinoza 2, Andrew Elliott 3, Joanne Xiu 3, Andreas Seeber 4, Wafik El-Deiry 5, Emmanuel S Antonarakis 6, Stephanie L Graff 7, Michael J Hall 8, Hossein Borghaei 9, Dave S B Hoon 10, Stephen V Liu 11, Patrick C Ma 12, Rana R McKay 13, Trisha Wise-Draper 14, John Marshall 15, George W Sledge 3, David Spetzler 3, Hao Zhu 1 16, David Hsiehchen 17 18

Abstract

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers.

External Link