Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers

Molecular Cancer Therapeutics - Tập 16 Số 11 - Trang 2598-2608 - 2017
Aaron M. Goodman1,2,3, Shumei Kato1,2, Lyudmila Bazhenova1, Sandip Pravin Patel1, Garrett M. Frampton4, Vincent A. Miller4, Philip J. Stephens4, Gregory A. Daniels1, Razelle Kurzrock1,2
11Division of Hematology/Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, California.
22Center for Personalized Cancer Therapy, University of California San Diego, Moores Cancer Center, La Jolla, California.
33Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, California.
44Foundation Medicine, Cambridge, Massachusetts.

Tóm tắt

Abstract Immunotherapy induces durable responses in a subset of patients with cancer. High tumor mutational burden (TMB) may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non–small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free survival (PFS), and overall survival (OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥20 mutations/mb) versus low to intermediate TMB was 22/38 (58%) versus 23/113 (20%; P = 0.0001); median PFS, 12.8 months vs. 3.3 months (P ≤ 0.0001); median OS, not reached versus 16.3 months (P = 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders versus nonresponders treated with anti-PD-1/PD-L1 monotherapy was 18.0 versus 5.0 mutations/mb (P < 0.0001). Interestingly, anti-CTLA4/anti-PD-1/PD-L1 combinations versus anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%; P = 0.004) and PFS (P = 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. Mol Cancer Ther; 16(11); 2598–608. ©2017 AACR.

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Molecular Cancer Therapeutics

Tập 16 Số 11

2598-2608

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