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Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers
Aaron M Goodman1,2,3, Shumei Kato4,2, Lyudmila Bazhenova4
1Division of Hematology/Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, California. a1goodman@ucsd.edu.
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.
Insights
High tumor mutational burden (TMB) is a strong predictor of positive outcomes for cancer patients receiving PD-1/PD-L1 blockade immunotherapy. This biomarker is associated with improved response rates, progression-free survival, and overall survival across various cancer types.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Immunotherapy has shown durable responses in a subset of cancer patients.
- High tumor mutational burden (TMB) is a potential biomarker for PD-1/PD-L1 blockade efficacy in melanoma and non-small cell lung cancer (NSCLC).
- The predictive value of TMB in diverse cancers treated with various immunotherapies requires examination.
Purpose of the Study:
- To investigate the association between tumor mutational burden (TMB) and patient outcomes.
- To analyze response rate (RR), progression-free survival (PFS), and overall survival (OS) in patients treated with immunotherapy.
- To evaluate TMB as a predictive biomarker for immunotherapy response across different cancer types.
Main Methods:
- Retrospective analysis of data from 1,638 patients with comprehensive genomic profiling and TMB assessment.
- Analysis of 151 immunotherapy-treated patients for RR, PFS, and OS.
- Multivariable analysis to assess the independent association of TMB with outcomes.
Main Results:
- Higher TMB (≥20 mutations/mb) was significantly associated with improved RR (58% vs. 20%), median PFS (12.8 vs. 3.3 months), and median OS (not reached vs. 16.3 months) compared to low to intermediate TMB.
- Similar positive correlations between TMB and favorable outcomes were observed in patients treated with anti-PD-1/PD-L1 monotherapy (median TMB 18.0 vs. 5.0 mutations/mb for responders vs. nonresponders).
- Combination anti-CTLA4/anti-PD-1/PD-L1 therapy predicted better RR and PFS independently of TMB, suggesting a different predictive mechanism for dual checkpoint blockade.
Conclusions:
- Elevated TMB is a robust predictor of favorable outcomes for patients receiving PD-1/PD-L1 blockade immunotherapy across diverse tumor types.
- The predictive power of TMB for immunotherapy response is particularly evident with PD-1/PD-L1 blockade.
- Dual checkpoint blockade (anti-CTLA4/anti-PD-1/PD-L1) offers significant clinical benefit, but its efficacy appears less dependent on TMB compared to anti-PD-1/PD-L1 monotherapy.
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