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Tumor mutational load predicts survival after immunotherapy across multiple cancer types.

ABSTRACT: Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.

SUBMITTER: Samstein RM

PROVIDER: S-EPMC6365097 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Tumor mutational load predicts survival after immunotherapy across multiple cancer types.

Samstein Robert M RM Lee Chung-Han CH Shoushtari Alexander N AN Hellmann Matthew D MD Shen Ronglai R Janjigian Yelena Y YY Barron David A DA Zehir Ahmet A Jordan Emmet J EJ Omuro Antonio A Kaley Thomas J TJ Kendall Sviatoslav M SM Motzer Robert J RJ Hakimi A Ari AA Voss Martin H MH Russo Paul P Rosenberg Jonathan J Iyer Gopa G Bochner Bernard H BH Bajorin Dean F DF Al-Ahmadie Hikmat A HA Chaft Jamie E JE Rudin Charles M CM Riely Gregory J GJ Baxi Shrujal S Ho Alan L AL Wong Richard J RJ Pfister David G DG Wolchok Jedd D JD Barker Christopher A CA Gutin Philip H PH Brennan Cameron W CW Tabar Viviane V Mellinghoff Ingo K IK DeAngelis Lisa M LM Ariyan Charlotte E CE Lee Nancy N Tap William D WD Gounder Mrinal M MM D'Angelo Sandra P SP Saltz Leonard L Stadler Zsofia K ZK Scher Howard I HI Baselga Jose J Razavi Pedram P Klebanoff Christopher A CA Yaeger Rona R Segal Neil H NH Ku Geoffrey Y GY DeMatteo Ronald P RP Ladanyi Marc M Rizvi Naiyer A NA Berger Michael F MF Riaz Nadeem N Solit David B DB Chan Timothy A TA Morris Luc G T LGT

Nature genetics 20190114 2

Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all ...[more]

PMID: 30643254

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Project description:Objective: Panel-based sequencing is widely used to measure tumor mutational burden (TMB) in clinical trials and is ready to enter routine diagnostics. However, cut-off points to distinguish "TMB-high" from "TMB-low" tumors are not consistent and the clinical implications of TMB in predicting responses to immune checkpoint blockade (ICB) in gastric cancer are not clearly defined. We aimed to assess whether TMB is associated with the response to immunotherapy and to examine its relation with other biomarkers of immunotherapy response in advanced gastric cancer. Design: In total, 63 patients with advanced gastric cancer treated with ICB were included in the study. Panel-based TMB in gastric tumor samples, treatment responses to ICB, clinicopathological data, and time to progression were retrospectively analyzed. Microsatellite instability (MSI) status, Epstein-Barr virus (EBV) positivity, and programmed death-ligand 1 (PD-L1) combined positive score (CPS) were also analyzed. Results: TMB ranged from 0 to 446 mutations/megabase (mt/mb) and was significantly associated with MSI (P < 0.001), PD-L1 CPS (P = 0.022), response to ICB (P = 0.04), chemotherapy (P = 0.02) and older patient age (?65 years; P = 0.0014). The cut-off point of 14.31 mt/mb determined by log-rank statistics for progression-free survival divided the tumors into eight (12.7%) TMB-high and 55 (87.3%) TMB-low tumors. The median TMB of the chemo-refractory group was significantly higher (8.43 mt/mb) compared to that of chemo-naïve group (3.42 mt/mb) (P = 0.02). Patients with TMB-high tumors showed prolonged progression-free survival in univariate [HR, 0.32; 95% confidence interval (CI), 0.12-0.90] and multivariate (HR, 0.21; 95% CI, 0.07-0.69) analyses. In area under the receiver operating curve (AUC) analysis of TMB, PD-L1, EBV, MSI, and their combination, the AUC value was the highest for EBV (0.97), followed by MSI (0.96), PD-L1 (0.81), the combination (0.78), and TMB (0.56). Conclusion: In addition to EBV, MSI, and PD-L1 CPS, TMB could be used as a predictive biomarker in patients with advanced gastric cancer treated with ICB and may aid clinical decision making.

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Tumor mutational load predicts survival after immunotherapy across multiple cancer types.

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Tumor mutational load predicts survival after immunotherapy across multiple cancer types.

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