A B Schrock1, C Ouyang2, J Sandhu3, E Sokol1, D Jin1, J S Ross4, V A Miller1, D Lim3, I Amanam3, J Chao3, D Catenacci5, M Cho6, F Braiteh7, S J Klempner8, S M Ali1, M Fakih9. 1. Foundation Medicine, Inc., Cambridge. 2. Center for Informatics, City of Hope National Medical Center, Duarte; Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte. 3. Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte. 4. Foundation Medicine, Inc., Cambridge; Department of Pathology, SUNY Upstate Medical University, Syracuse. 5. Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center and Biological Sciences, Chicago. 6. Division of Hematology and Oncology, Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento. 7. Department of Hematology/Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas. 8. The Angeles Clinic and Research Institute, Los Angeles, USA. 9. Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte. Electronic address: mfakih@coh.org.
Abstract
BACKGROUND: Microsatellite instability (MSI) is a biomarker for response to immune checkpoint inhibitors (ICPIs). PD-1 inhibitors in metastatic colorectal carcinoma (mCRC) with MSI-high (MSI-H) have demonstrated a high disease control rate and favorable progression-free survival (PFS); however, reported response rates to pembrolizumab and nivolumab are variable and often <50%, suggesting that additional predictive biomarkers are needed. METHODS: Clinicopathologic data were collected from patients with MSI-H mCRC confirmed by hybrid capture-based next-generation sequencing (NGS) treated with PD-1/L1 inhibitors at five institutes. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mb of sequenced DNA and reported as mutations/Mb. Potential biomarkers of response and time to progression were analyzed by univariate and multivariate analyses. Once TMB was confirmed as a predictive biomarker, a larger dataset of 18 140 unique CRC patients was analyzed to define the relevance of the identified TMB cut-point. RESULTS: A total of 22 patients were treated with PD-1/L1 inhibitors including 19 with pembrolizumab monotherapy. Among tested variables, TMB showed the strongest association with objective response (OR; P < 0.001) and PFS, by univariate (P < 0.001) and multivariate analysis (P < 0.01). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37 and 41 mutations/Mb. All 13 TMBhigh cases responded, while 6/9 TMBlow cases had progressive disease. The median PFS for TMBhigh has not been reached (median follow-up >18 months) while the median PFS for TMBlow was 2 months. A TMB of 37.4 mutations/Mb in a large MSI-H mCRC population (821/18, 140 cases; 4.5%) evaluated by NGS corresponded to the 35th percentile cut-point. CONCLUSIONS: TMB appears to be an important independent biomarker within MSI-H mCRC to stratify patients for likelihood of response to ICPIs. If validated in prospective studies, TMB may play an important role in guiding the sequencing and/or combinations of ICPIs in MSI-H mCRC.
BACKGROUND: Microsatellite instability (MSI) is a biomarker for response to immune checkpoint inhibitors (ICPIs). PD-1 inhibitors in metastatic colorectal carcinoma (mCRC) with MSI-high (MSI-H) have demonstrated a high disease control rate and favorable progression-free survival (PFS); however, reported response rates to pembrolizumab and nivolumab are variable and often <50%, suggesting that additional predictive biomarkers are needed. METHODS: Clinicopathologic data were collected from patients with MSI-H mCRC confirmed by hybrid capture-based next-generation sequencing (NGS) treated with PD-1/L1 inhibitors at five institutes. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mb of sequenced DNA and reported as mutations/Mb. Potential biomarkers of response and time to progression were analyzed by univariate and multivariate analyses. Once TMB was confirmed as a predictive biomarker, a larger dataset of 18 140 unique CRCpatients was analyzed to define the relevance of the identified TMB cut-point. RESULTS: A total of 22 patients were treated with PD-1/L1 inhibitors including 19 with pembrolizumab monotherapy. Among tested variables, TMB showed the strongest association with objective response (OR; P < 0.001) and PFS, by univariate (P < 0.001) and multivariate analysis (P < 0.01). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37 and 41 mutations/Mb. All 13 TMBhigh cases responded, while 6/9 TMBlow cases had progressive disease. The median PFS for TMBhigh has not been reached (median follow-up >18 months) while the median PFS for TMBlow was 2 months. A TMB of 37.4 mutations/Mb in a large MSI-H mCRC population (821/18, 140 cases; 4.5%) evaluated by NGS corresponded to the 35th percentile cut-point. CONCLUSIONS:TMB appears to be an important independent biomarker within MSI-H mCRC to stratify patients for likelihood of response to ICPIs. If validated in prospective studies, TMB may play an important role in guiding the sequencing and/or combinations of ICPIs in MSI-H mCRC.
Authors: S Derks; L K de Klerk; X Xu; T Fleitas; K X Liu; Y Liu; F Dietlein; C Margolis; A M Chiaravalli; A C Da Silva; S Ogino; F G Akarca; G J Freeman; S J Rodig; J L Hornick; E van Allen; B Li; S X Liu; V Thorsson; A J Bass Journal: Ann Oncol Date: 2020-05-06 Impact factor: 32.976
Authors: Katherine I Zhou; Bryan Peterson; Anthony Serritella; Joseph Thomas; Natalie Reizine; Stephanie Moya; Carol Tan; Yan Wang; Daniel V T Catenacci Journal: Clin Cancer Res Date: 2020-08-20 Impact factor: 12.531