Tumor mutational burden and survival on immune checkpoint inhibition in >8000 patients across 24 cancer types
Background There is uncertainty around clinical applicability of tumor mutational burden (TMB) across cancer types, in part because of inconsistency between TMB measurements from different platforms. The KEYNOTE 158 trial supported United States Food and Drug Administration (FDA) approval of the Fou...
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BMJ Publishing Group
2025-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/2/e010311.full |
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| author | Vivek Subbiah Samuel J Klempner Neeraj Agarwal David P Carbone Amit Mahipal Shilpa Gupta David Fabrizio Jeffrey S Ross Gerald Li David R Gandara Miles C Andrews Jonathan W Riess Ramez N Eskander Ryon P Graf Geoffrey R Oxnard Sarah Sammons Jeremy Snider Lilia Bouzit Cheryl Cho-Phan Megan Price Julia C F Quintanilha Richard Sheng Poe Huang |
| author_facet | Vivek Subbiah Samuel J Klempner Neeraj Agarwal David P Carbone Amit Mahipal Shilpa Gupta David Fabrizio Jeffrey S Ross Gerald Li David R Gandara Miles C Andrews Jonathan W Riess Ramez N Eskander Ryon P Graf Geoffrey R Oxnard Sarah Sammons Jeremy Snider Lilia Bouzit Cheryl Cho-Phan Megan Price Julia C F Quintanilha Richard Sheng Poe Huang |
| author_sort | Vivek Subbiah |
| collection | DOAJ |
| description | Background There is uncertainty around clinical applicability of tumor mutational burden (TMB) across cancer types, in part because of inconsistency between TMB measurements from different platforms. The KEYNOTE 158 trial supported United States Food and Drug Administration (FDA) approval of the Foundation Medicine test (FoundationOneCDx) at TMB≥10 mut/Mb as a companion diagnostic (CDx) for single-agent pembrolizumab in second+line. Using a large real-world dataset with validated survival endpoint data, we evaluated clinical validity of TMB measurement by the test in over 8000 patients across 24 cancer types who received single-agent immune checkpoint inhibitor (ICI).Methods Patients with advanced-stage cancers from 24 cancer types treated with single-agent anti-PD(L)1 therapy in standard-of-care settings were included. Deidentified data from electronic health records from approximately 280 cancer treatment facilities were captured into a clinico-genomic database. This study used the TMB algorithm from the FDA-approved test supporting solid tumor CDx and composite mortality variable validated against the national death index: real-world overall survival (rwOS). Following a prespecified analysis plan, rwOS by TMB level was assessed using Cox PH models adjusted for Eastern Cooperative Oncology Group performance status, prior treatment, microsatellite instability, sex, age, opioid rx pretherapy, and socioeconomic assessment.Results 8440 patients met inclusion criteria. Adjusting for aforementioned factors, increasing TMB was significantly associated with rwOS across tumor types; HRs (95% CIs) relative to TMB<5: TMB 5 to <10: 0.95 (0.89 to 1.02), TMB 10 to <20: 0.79 (0.73 to 0.85), TMB≥20: 0.52 (0.47 to 0.58). For individual cancer types with prespecified statistical power, adjusted rwOS comparing TMB≥10 vs TMB<10 significantly favored TMB≥10 in 9 of 10 cancer types. In microsatellite stable subcohorts (except colorectal cancer), TMB≥10 remained associated with enriched ICI benefit. Exploratory assessments of patients receiving ICI+chemotherapy (n=4369) observed more favorable rwOS only in TMB≥20.Conclusions Across >8000 patients treated with single-agent ICI, and within individual cancer types with sufficient power, elevated TMB based on the FDA-approved CDx was associated with more favorable rwOS compared with similar patients with lower TMB levels. This biomarker deserves further clinical investigation to potentially guide the use of immunotherapy in expanded clinical contexts. |
| format | Article |
| id | doaj-art-c6cfaa552c1142baa3b5d85097213d74 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-c6cfaa552c1142baa3b5d85097213d742025-02-07T07:50:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-02-0113210.1136/jitc-2024-010311Tumor mutational burden and survival on immune checkpoint inhibition in >8000 patients across 24 cancer typesVivek Subbiah0Samuel J Klempner1Neeraj Agarwal2David P Carbone3Amit Mahipal4Shilpa Gupta5David Fabrizio6Jeffrey S Ross7Gerald Li8David R Gandara9Miles C Andrews10Jonathan W Riess11Ramez N Eskander12Ryon P Graf13Geoffrey R Oxnard14Sarah Sammons15Jeremy Snider16Lilia Bouzit17Cheryl Cho-Phan18Megan Price19Julia C F Quintanilha20Richard Sheng Poe Huang21Sarah Cannon Research Institute, Nashville, Tennessee, USAMassachusetts General Hospital Cancer Center, Boston, Massachusetts, USADepartment of Medical Oncology, University of Utah Health Huntsman Cancer Institute, Salt Lake City, Utah, USAThe Ohio State University Medical Center, Columbus, Ohio, USALake Health University Hospitals Seidman Cancer Center, Cleveland, Ohio, USADepartment of Hematology and Oncology, Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio, USAFoundation Medicine Inc, Boston, Massachusetts, USAFoundation Medicine Inc, Boston, Massachusetts, USAFoundation Medicine Inc, Boston, Massachusetts, USADepartment of Medicine, Cancer Ctr So./Division of Hematologic & Oncology, UC Davis, Sacramento, California, USADepartment of Medicine, Monash University Central Clinical School, Melbourne, Victoria, AustraliaUC Davis Comprehensive Cancer Center, Sacramento, California, USADepartment of Obstetrics, Gynecology and Reproductive Sciences, UC San Diego Health Moores Cancer Center, La Jolla, California, USAFoundation Medicine Inc, San Diego, California, USABoston Medical Center, Boston, Massachusetts, USABreast Oncology Program, Dana-Farber Cancer Institute, Boston, Massachusetts, USAFlatiron Health Inc, New York, New York, USAFlatiron Health Inc, New York, New York, USAFlatiron Health Inc, New York, New York, USAFlatiron Health Inc, New York, New York, USAFoundation Medicine Inc, Boston, Massachusetts, USAFoundation Medicine Inc, Boston, Massachusetts, USABackground There is uncertainty around clinical applicability of tumor mutational burden (TMB) across cancer types, in part because of inconsistency between TMB measurements from different platforms. The KEYNOTE 158 trial supported United States Food and Drug Administration (FDA) approval of the Foundation Medicine test (FoundationOneCDx) at TMB≥10 mut/Mb as a companion diagnostic (CDx) for single-agent pembrolizumab in second+line. Using a large real-world dataset with validated survival endpoint data, we evaluated clinical validity of TMB measurement by the test in over 8000 patients across 24 cancer types who received single-agent immune checkpoint inhibitor (ICI).Methods Patients with advanced-stage cancers from 24 cancer types treated with single-agent anti-PD(L)1 therapy in standard-of-care settings were included. Deidentified data from electronic health records from approximately 280 cancer treatment facilities were captured into a clinico-genomic database. This study used the TMB algorithm from the FDA-approved test supporting solid tumor CDx and composite mortality variable validated against the national death index: real-world overall survival (rwOS). Following a prespecified analysis plan, rwOS by TMB level was assessed using Cox PH models adjusted for Eastern Cooperative Oncology Group performance status, prior treatment, microsatellite instability, sex, age, opioid rx pretherapy, and socioeconomic assessment.Results 8440 patients met inclusion criteria. Adjusting for aforementioned factors, increasing TMB was significantly associated with rwOS across tumor types; HRs (95% CIs) relative to TMB<5: TMB 5 to <10: 0.95 (0.89 to 1.02), TMB 10 to <20: 0.79 (0.73 to 0.85), TMB≥20: 0.52 (0.47 to 0.58). For individual cancer types with prespecified statistical power, adjusted rwOS comparing TMB≥10 vs TMB<10 significantly favored TMB≥10 in 9 of 10 cancer types. In microsatellite stable subcohorts (except colorectal cancer), TMB≥10 remained associated with enriched ICI benefit. Exploratory assessments of patients receiving ICI+chemotherapy (n=4369) observed more favorable rwOS only in TMB≥20.Conclusions Across >8000 patients treated with single-agent ICI, and within individual cancer types with sufficient power, elevated TMB based on the FDA-approved CDx was associated with more favorable rwOS compared with similar patients with lower TMB levels. This biomarker deserves further clinical investigation to potentially guide the use of immunotherapy in expanded clinical contexts.https://jitc.bmj.com/content/13/2/e010311.full |
| spellingShingle | Vivek Subbiah Samuel J Klempner Neeraj Agarwal David P Carbone Amit Mahipal Shilpa Gupta David Fabrizio Jeffrey S Ross Gerald Li David R Gandara Miles C Andrews Jonathan W Riess Ramez N Eskander Ryon P Graf Geoffrey R Oxnard Sarah Sammons Jeremy Snider Lilia Bouzit Cheryl Cho-Phan Megan Price Julia C F Quintanilha Richard Sheng Poe Huang Tumor mutational burden and survival on immune checkpoint inhibition in >8000 patients across 24 cancer types Journal for ImmunoTherapy of Cancer |
| title | Tumor mutational burden and survival on immune checkpoint inhibition in >8000 patients across 24 cancer types |
| title_full | Tumor mutational burden and survival on immune checkpoint inhibition in >8000 patients across 24 cancer types |
| title_fullStr | Tumor mutational burden and survival on immune checkpoint inhibition in >8000 patients across 24 cancer types |
| title_full_unstemmed | Tumor mutational burden and survival on immune checkpoint inhibition in >8000 patients across 24 cancer types |
| title_short | Tumor mutational burden and survival on immune checkpoint inhibition in >8000 patients across 24 cancer types |
| title_sort | tumor mutational burden and survival on immune checkpoint inhibition in 8000 patients across 24 cancer types |
| url | https://jitc.bmj.com/content/13/2/e010311.full |
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