Tissue Tumor Mutational Burden Predictive of Response to Immunotherapy
Previous studies evaluating the efficacy of atezolizumab have suggested that tTMB-H may be predictive of a good checkpoint immunotherapy response.
CHICAGO — High tissue tumor mutational burden (tTMB-H) may be associated with improved immunotherapy efficacy among patients with various cancers and across lines of therapy, according to findings to be presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting.
Data from previous studies evaluating the efficacy of atezolizumab have suggested that tTMB-H may be predictive of a good response to checkpoint immunotherapy and identify a distinct patient population not yet distinguished by PD-L1 immunohistochemistry or immune gene expression signatures.
For this retrospective analysis, researchers assessed the tTMB of patients previously enrolled in 7 atezolizumab monotherapy studies (ClinicalTrials.gov Identifier: NCT02008227, NCT01903993, NCT02031458, NCT01846416, NCT02951767, NCT02302807, NCT01375842), which included patients with non-small-cell lung cancer (NSCLC), metastatic urothelial carcinoma (mUC), and other solid tumors. The FoundationOne (F1) assay was used to evaluate tTMB. Of the 987 patients in the biomarker evaluable population (BEP), 175 (17.7%) had a high tTMB which was defined as ≥ 16 mutations per megabase (mut/Mb).
Results showed that tTMB was associated with efficacy across the various study tumor types and lines of therapy.
The overall response rate (ORR) to atezolizumab therapy was 16.4% (95% CI, 14.2-18.9) among the BEP, and was 29.7% (95% CI, 23.1-37.1) versus 13.5% (95% CI, 11.3-16.1) among patients with tTMB-H and low tTMB (tTMB-L), respectively. Patients with tTMB-H also had a longer median duration of response (DoR) with 29.0 months (95% CI, 18.6-not evaluable) compared with the BEP overall (16.6 months; 95% CI, 13.8-23.1) and patients with tTMB-L (13.8 months; 95% CI, 12.5-17.4).
The median DoR (6.2 months) and ORR (14%-15%) were similar among all patients treated with chemotherapy regardless of tTMB measurements.
tTMB-H, however, was not associated with increased efficacy in some of the control cohorts; the pooled ORR was 14.9%, 14.4%, and 15.1% in BEP, tTMB-H, and tTMB-L, respectively in the OAK, POPLAR, and IMVigor211 studies.
A further analysis revealed that patients with both PD-L1 status of IC2/3 or TC2/3 — a measure indicated by 5% or higher PD-L1 expression — and tTMB-H had enriched responses to atezolizumab therapy. A subset of patients with NSCLC and mUC had ORRs of 38% and 50%, respectively.
A positive correlation was observed between tTMB and whole-exome sequencing-based neoantigen load (NAL) in mUC and NSCLC; NAL was associated with atezolizumab ORR in mUC.
Survival analyses based on tTMB are still under investigation.
The authors concluded that "tTMB-H by F1 may serve as a surrogate biomarker for NAL and may complement PD-L1 expression in providing predictive value. Ongoing studies are prospectively evaluating both tissue-based TMB and blood-based TMB and their association with cancer immunotherapy efficacy.”
Legrand FA, Gandara DR, Mariathasan S, et al. Association of high tissue TMB and atezolizumab efficacy across multiple tumor types. Oral presentation at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL.