PMID- 37129893
OWN - NLM
STAT- MEDLINE
DCOM- 20230504
LR  - 20230510
IS  - 2574-3805 (Electronic)
IS  - 2574-3805 (Linking)
VI  - 6
IP  - 5
DP  - 2023 May 1
TI  - Assessment of Tumor Mutational Burden and Outcomes in Patients With Diverse 
      Advanced Cancers Treated With Immunotherapy.
PG  - e2311181
LID - 10.1001/jamanetworkopen.2023.11181 [doi]
LID - e2311181
AB  - 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.
FAU - Aggarwal, Charu
AU  - Aggarwal C
AD  - Division of Hematology-Oncology, Department of Medicine, University of 
      Pennsylvania, Philadelphia.
AD  - Abramson Cancer Center, Philadelphia, Pennsylvania.
FAU - Ben-Shachar, Rotem
AU  - Ben-Shachar R
AD  - Tempus Labs, Chicago, Illinois.
FAU - Gao, Yinjie
AU  - Gao Y
AD  - Tempus Labs, Chicago, Illinois.
FAU - Hyun, Seung Won
AU  - Hyun SW
AD  - Tempus Labs, Chicago, Illinois.
FAU - Rivers, Zachary
AU  - Rivers Z
AD  - Tempus Labs, Chicago, Illinois.
FAU - Epstein, Carrie
AU  - Epstein C
AD  - Tempus Labs, Chicago, Illinois.
FAU - Kaneva, Kristiyana
AU  - Kaneva K
AD  - Tempus Labs, Chicago, Illinois.
FAU - Sangli, Chithra
AU  - Sangli C
AD  - Tempus Labs, Chicago, Illinois.
FAU - Nimeiri, Halla
AU  - Nimeiri H
AD  - Tempus Labs, Chicago, Illinois.
FAU - Patel, Jyoti
AU  - Patel J
AD  - Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, 
      Illinois.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230501
PL  - United States
TA  - JAMA Netw Open
JT  - JAMA network open
JID - 101729235
RN  - 0 (B7-H1 Antigen)
RN  - 0 (Antineoplastic Agents, Immunological)
RN  - 0 (Biomarkers, Tumor)
SB  - IM
MH  - United States/epidemiology
MH  - Humans
MH  - Female
MH  - Aged
MH  - Aged, 80 and over
MH  - Male
MH  - *Carcinoma, Non-Small-Cell Lung/drug therapy
MH  - *Lung Neoplasms/pathology
MH  - B7-H1 Antigen
MH  - Retrospective Studies
MH  - Cohort Studies
MH  - Prospective Studies
MH  - Mutation
MH  - *Antineoplastic Agents, Immunological/therapeutic use/pharmacology
MH  - Immunotherapy
MH  - Biomarkers, Tumor/genetics
PMC - PMC10155064
COIS- 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.
EDAT- 2023/05/02 12:43
MHDA- 2023/05/04 12:42
PMCR- 2023/05/02
CRDT- 2023/05/02 11:33
PHST- 2023/05/04 12:42 [medline]
PHST- 2023/05/02 12:43 [pubmed]
PHST- 2023/05/02 11:33 [entrez]
PHST- 2023/05/02 00:00 [pmc-release]
AID - 2804390 [pii]
AID - zoi230353 [pii]
AID - 10.1001/jamanetworkopen.2023.11181 [doi]
PST - epublish
SO  - JAMA Netw Open. 2023 May 1;6(5):e2311181. doi: 
      10.1001/jamanetworkopen.2023.11181.