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. 2023 May 1;6(5):e2311181.
doi: 10.1001/jamanetworkopen.2023.11181.

Assessment of Tumor Mutational Burden and Outcomes in Patients With Diverse Advanced Cancers Treated With Immunotherapy

Charu Aggarwal  1   2 , Rotem Ben-Shachar  3 , Yinjie Gao  3 , Seung Won Hyun  3 , Zachary Rivers  3 , Carrie Epstein  3 , Kristiyana Kaneva  3 , Chithra Sangli  3 , Halla Nimeiri  3 , Jyoti Patel  4
Affiliations

Assessment of Tumor Mutational Burden and Outcomes in Patients With Diverse Advanced Cancers Treated With Immunotherapy

Charu Aggarwal et al. JAMA Netw Open. .

Abstract

Importance: There are few studies assessing the association of tumor mutational burden (TMB) and clinical outcomes in a large cohort of patients with diverse advanced cancers.

Objective: To clinically validate a TMB biomarker from a next-generation sequencing targeted gene panel assay.

Design, setting, and participants: A prespecified cohort study using the deidentified clinicogenomic Tempus database of patients sequenced between 2018 and 2022, which contained retrospective, observational data originating from 300 cancer sites including 199 community sites and 101 academic sites. Patients with advanced solid tumors across 8 cancer types and more than 20 histologies, sequenced with Tempus xT who were treated with immune checkpoint inhibitors (ICIs) in the first-line or second-line setting were included. Data were analyzed from September 2018 to August 2022.

Exposure: Treatment with US Food and Drug Administration (FDA)-approved antiprogrammed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) ICI and/or in combination with a cytotoxic T-lymphocyte-associated protein-4 ICI.

Main outcomes and measures: The primary outcome was the association of tumor mutational burden (TMB) binary category (high [≥10 mut/mb] vs low) with overall survival (OS) in patients treated with ICIs. Secondary outcomes were progression-free survival (PFS), and time to progression (TTP).

Results: In the evaluable cohort of 674 patients, the median (IQR) age was 69.4 (28.6-89.8) years, 271 patients (40.2%) were female, and 435 patients (64.5%) were White. The most common advanced cancers were non-small cell lung cancer (330 patients [49.0%]), followed by bladder cancer (148 patients [22.0%]), and head and neck squamous cell carcinoma (96 patients [14.8%]). Median (IQR) follow-up was 7.2 (3.2-14.1) months. High TMB (TMB-H) cancers (206 patients [30.6%]) were significantly associated with longer OS than low TMB (TMB-L) cancers (hazard ratio [HR], 0.72; upper confidence bound [UCB], 0.91; P = .01). In a prospective subset of 403 patients treated with ICIs after TMB testing, TMB-H cancers (135 patients [33.5%]) were significantly associated with longer OS (HR, 0.61; UCB, 0.84; P = .005), PFS (HR, 0.62; UCB, 0.82; P = .003), and TTP (HR, 0.67; UCB, 0.92; P = .02) than TMB-L cancers. An overall survival benefit was seen regardless of the type of ICI used (pembrolizumab, 339 patients; HR, 0.67; UCB, 0.94; P = .03), other ICIs (64 patients; HR, 0.37; UCB, 0.85; P = .03), and after adjusting for PD-L1 and microsatellite stability status (403 patients; HR = 0.67; UCB, 0.92; P = .02).

Conclusions and relevance: In this cohort study of patients with advanced solid tumors treated with ICIs in diverse clinics, TMB-H cancers were significantly associated with improved clinical outcomes compared with TMB-L cancers.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Aggarwal reported receiving grants from Genentech/Roche, Merck Sharp & Dohme, AstraZeneca/MedImmune, Blueprint Genetics, Shionogi, Incyte, and Macrogenics; personal fees from Genentech, Celgene, AstraZeneca/Daiichi Sankyo, Turning Point, Pfizer, Janssen, Lilly, Merck, Regeneron/Sanofi, Eisai, BeiGene, and Boehringer Ingelheim outside the submitted work. Dr Ben-Shachar reported being an employee and shareholder of Tempus Labs outside the submitted work. Ms Gao reported being an employee of Tempus Labs outside the submitted work. Dr Hyun reported being an employee of Tempus Labs outside the submitted work. Dr Rivers reported being an employee of Tempus Labs and receiving personal fees from Bayer Pharmaceuticals outside the submitted work. Ms Epstein reported being an employee of Tempus Labs outside the submitted work. Dr Kaneva reported being an employee at Tempus Labs outside the submitted work. Ms Sangli reported being an employee and shareholder of Tempus Labs outside the submitted work. Dr Nimeiri reported being an employee and shareholder of Tempus Labs and being a shareholder of AbbVie outside the submitted work. Dr Patel reported being an advisor for AnHeart, Astra Zenenca, AbbVie, BMS, Takeda, Genentech, and Lilly outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flow Diagram Showing Cohort Selection
The final evaluable 674 patient cohort was further stratified into prospective (immune checkpoint inhibitors [ICIs] received after tumor mutational burden testing) and retrospective patients (ICIs received before tumor mutational burden testing; see Methods section). CGP indicates comprehensive genomic profiling.
Figure 2.
Figure 2.. Kaplan-Meier Analysis of Clinical End Points by TMB Status
Panel A, Kaplan-Meier plot of overall survival (OS) in evaluable patients treated with immune checkpoint inhibitors. The No. at risk only includes patients with corrected study entry to account for immortal time bias (see Methods section). Panel B, Kaplan-Meier plot of OS in prospective patients treated with immune checkpoint inhibitors. Panel C, Kaplan-Meier plot of progression-free survival (PFS) in prospective patients treated with immune checkpoint inhibitors. Panel D, Kaplan-Meier plot of time to progression (TTP) in prospective patients treated with immune checkpoint inhibitors. OS indicates overall survival; PFS, progression-free survival; TTP, time to progression
Figure 3.
Figure 3.. Assessment of Overall Survival by Tumor Mutational Burden (TMB)-Status in Each Cancer Indication
One-year survival probability in individual cancer types by TMB status estimated from Kaplan-Meier analysis. HNSCC indicates head and neck squamous cell cancer; NSCLC, non–small cell lung cancer.
See this image and copyright information in PMC

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