{"entity":{"id":"tmb-high","kind":"biomarker","name":"TMB-high (tumour mutational burden >= 10 mutations per megabase)","aka":["TMB-H","TMB-high","TMB high","tumor mutational burden","tumour mutational burden","TMB >= 10 mut/Mb","TMB ≥10","TMB-H solid tumors","bTMB","blood TMB"],"tldr":"TMB counts how many mutations a tumour carries per million DNA letters. Ten or more, measured by FoundationOne CDx, allows pembrolizumab for almost any solid tumour after other treatment has failed.","summary":"Tumour mutational burden is the number of somatic non-synonymous (and, on some panels, synonymous) mutations per megabase of sequenced coding DNA, estimated from a large targeted panel and calibrated to whole-exome values. Pembrolizumab's US label (June 2020, KEYNOTE-158) covers unresectable or metastatic TMB-H solid tumours defined as >= 10 mutations per megabase by an FDA-authorised test, after prior treatment and with no satisfactory alternative; FoundationOne CDx is the listed companion diagnostic. Because panels differ in gene content and algorithms, a TMB of 10 on one assay is not the same as 10 on another; the label's limitation of use notes the benefit was not established in patients with central nervous system cancers. TMB is a genome-wide readout with no parent gene, so it sits under no target here.","asOf":"2026-09-23","links":[{"label":"KEYTRUDA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287"}],"tags":["biomarker","genome-wide"],"related":["msi-high","dmmr-ihc"],"cancers":["metastatic-cancer","nsclc","melanoma","urothelial","tnbc","tnbc-metastatic","pancreatic","colorectal","gallbladder"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab","foundationone-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["tmb","ngs","tumour-agnostic","neoantigen"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-barroso-sousa-breast-tmb-prevalence-ann-oncol-2020","paper-barroso-sousa-tmb-pten-ici-mtnbc-ccr-2020","paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019","paper-philip-kras-wild-type-pancreatic-ccr-2022","paper-domingo-somatic-pole-proofreading-colorectal-lancet-gastro-2016","paper-le-mmr-deficiency-pd1-nejm-2015","paper-nepal-gallbladder-microenvironment-subtypes-j-hepatol-2021","paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025","paper-giraldo-gallbladder-msk-impact-ccr-2022","paper-rizvi-mutational-landscape-pd1-science-2015","paper-rizvi-targeted-ngs-immunotherapy-determinants-jco-2018","paper-ricciuti-tmb-pd-l1-levels-jama-oncol-2022","paper-keynote-042-tmb-mutations-ann-oncol-2023","paper-keynote-189-407-tmb-jtocrr-2023","paper-checkmate-026-first-line-nivolumab-nejm-2017"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: 10 or more mutations per megabase in about 5% of breast cancers, more often HR-negative/HER2-negative and metastatic (8.4% versus 2.9%; Barroso-Sousa 2020), 4.1% of 123 TCGA triple-negative exomes (cBioPortal) and 18% of 62 pretreated metastatic TNBC patients on immunotherapy trials, where it went with progression-free survival of 12.5 versus 3.7 months (Barroso-Sousa 2020, Clin Cancer Res). The tumour-agnostic pembrolizumab indication applies on a FoundationOne CDx value; APOBEC rather than mismatch repair drives most hypermutated TNBC.","Pancreatic ductal adenocarcinoma: 10 or more mutations per megabase in 1 to 2% of panel-tested tumours (35 of 2,336 MSK-IMPACT samples, median 3.46; cBioPortal), and TMB-high at the stricter 20 threshold together with MSI-high in 0.5% of samples (Singhi 2019); 4.5% of KRAS wild-type against 1% of mutant tumours (Philip 2022). Exome medians are about 1 per megabase, so the panel figure is a convention rather than a biological rate.","Colorectal cancer: 10 or more mutations per megabase in 15 to 19% of panel-tested tumours (1,340 of 7,237 in crc_msk_2026, median 6.05; cBioPortal), but almost all of that group is the MSI-high group (median 56.9) plus the POLE-hotspot group (median 172.1), against 5.7 in microsatellite-stable disease. A TMB-high result in a microsatellite-stable tumour with no POLE exonuclease mutation therefore deserves scrutiny before it is used to justify a checkpoint inhibitor under the tumour-agnostic approval, for which there is no colorectal-specific evidence.","Gallbladder cancer: median 4.1 non-synonymous mutations per megabase on the 505-gene MSK-IMPACT panel with 28 of 244 samples (11.5%) at 10 or more (cBioPortal gbc_mskcc_2022), against a median of 0.82 per megabase by whole-exome sequencing (Nepal 2021) and TMB-high in 1.3% (1 of 79) of Indian patients on mixed panels (Suryavanshi 2025). The pembrolizumab threshold applies only to the FoundationOne CDx value.","Lung cancer: this is where mutational burden was discovered as a predictor and where it failed as a selector. It is a real correlate: burden tracks response, progression-free survival and overall survival for single-agent PD-(L)1 blockade within every PD-L1 stratum in 1,552 patients, with response 57% where burden and PD-L1 are both high and 8.7% where neither is (Ricciuti 2022), and tissue burden of 175 or more mutations per exome selected benefit from pembrolizumab monotherapy in KEYNOTE-042 (overall survival hazard ratio 0.62 against 1.09 below the cut) (Mok 2023). But the threshold moves with the assay and the unit, the data-derived cut in the largest cohort was more than 19 mutations per megabase rather than 10, and in the trials of pembrolizumab with chemotherapy, the regimen most patients receive, continuous burden predicted nothing in either histology (Garassino 2023). The tumour-agnostic approval at 10 or more mutations per megabase rests on a basket trial with no lung cohort."],"measurement":"tmb-threshold","scoringRule":{"text":"Somatic mutations per megabase of coding sequence counted on a validated panel; 10 or more is TMB-high for the pembrolizumab indication.","quote":"tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-authorized test","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","sourceLabel":"KEYTRUDA prescribing information"},"thresholds":[{"value":"TMB >= 10 mutations per megabase","drugId":"pembrolizumab","cancerId":"metastatic-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-authorized test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.","status":"current"}],"tests":["foundationone-cdx","foundationone-liquid-cdx","caris-mi-cancer-seek","tempus-xt","trusight-oncology-500","stratangs","omniseq-insight","altera","oncoextra","bostongene-tumor-portrait","tempus-xe"],"assays":["tmb-panel","foundationone-cdx-panel"],"companionDiagnostics":[{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["pembrolizumab"],"indication":"Solid Tumors - Tissue","pma":"P170019/S016 (06/16/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"If a FoundationOne CDx report gives a TMB of 10 or more mutations per megabase, pembrolizumab is on label for your cancer once other treatments have been tried, whatever the organ it started in. A TMB from a different test may use a different scale; ask whether the number was measured on an FDA-authorised assay before treating it as the same threshold."},"route":"/biomarkers/tmb-high/","neighbours":{"biomarker":[{"id":"ctdna-mrd-positive","kind":"biomarker","name":"ctDNA MRD positivity (molecular residual disease after curative treatment)","route":"/biomarkers/ctdna-mrd-positive/"},{"id":"dmmr-ihc","kind":"biomarker","name":"dMMR (mismatch repair deficiency by IHC)","route":"/biomarkers/dmmr-ihc/"},{"id":"msi-high","kind":"biomarker","name":"MSI-high (microsatellite instability by PCR or sequencing)","route":"/biomarkers/msi-high/"}],"cancer":[{"id":"urothelial","kind":"cancer","name":"Bladder & urothelial cancer","route":"/cancers/urothelial/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","route":"/cancers/gallbladder/"},{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"},{"id":"metastatic-cancer","kind":"cancer","name":"Metastatic cancer (cancer that has spread)","route":"/cancers/metastatic-cancer/"},{"id":"tnbc-metastatic","kind":"cancer","name":"Metastatic triple-negative breast cancer","route":"/cancers/tnbc-metastatic/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"drug":[{"id":"foundationone-cdx","kind":"drug","name":"FoundationOne CDx / Liquid CDx","route":"/drugs/foundationone-cdx/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"}],"term":[{"id":"neoantigen","kind":"term","name":"Neoantigen","route":"/terms/neoantigen/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"},{"id":"tumour-agnostic","kind":"term","name":"Tumour-agnostic (tissue-agnostic) approval","route":"/terms/tumour-agnostic/"}],"paper":[{"id":"paper-ricciuti-tmb-pd-l1-levels-jama-oncol-2022","kind":"paper","name":"Association of high tumor mutation burden in non-small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels","route":"/key-papers/paper-ricciuti-tmb-pd-l1-levels-jama-oncol-2022/"},{"id":"paper-keynote-042-tmb-mutations-ann-oncol-2023","kind":"paper","name":"Associations of tissue tumour mutational burden and mutational status with clinical outcomes in KEYNOTE-042","route":"/key-papers/paper-keynote-042-tmb-mutations-ann-oncol-2023/"},{"id":"paper-keynote-189-407-tmb-jtocrr-2023","kind":"paper","name":"Associations of tissue tumour mutational burden and mutational status with clinical outcomes with pembrolizumab plus chemotherapy versus chemotherapy for metastatic non-small-cell lung cancer","route":"/key-papers/paper-keynote-189-407-tmb-jtocrr-2023/"},{"id":"paper-herbst-impower110-atezolizumab-pd-l1-nejm-2020","kind":"paper","name":"Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC","route":"/key-papers/paper-herbst-impower110-atezolizumab-pd-l1-nejm-2020/"},{"id":"paper-gandara-blood-tmb-atezolizumab-nat-med-2018","kind":"paper","name":"Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab","route":"/key-papers/paper-gandara-blood-tmb-atezolizumab-nat-med-2018/"},{"id":"paper-checkmate-026-first-line-nivolumab-nejm-2017","kind":"paper","name":"CheckMate 026: first-line nivolumab in stage IV or recurrent non-small-cell lung cancer","route":"/key-papers/paper-checkmate-026-first-line-nivolumab-nejm-2017/"},{"id":"paper-giraldo-gallbladder-msk-impact-ccr-2022","kind":"paper","name":"Comprehensive molecular characterization of gallbladder carcinoma and potential targets for intervention","route":"/key-papers/paper-giraldo-gallbladder-msk-impact-ccr-2022/"},{"id":"paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025","kind":"paper","name":"Genomic profiling of Indian gallbladder carcinoma: mutational insights in a high-incidence population","route":"/key-papers/paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025/"},{"id":"paper-nepal-gallbladder-microenvironment-subtypes-j-hepatol-2021","kind":"paper","name":"Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes","route":"/key-papers/paper-nepal-gallbladder-microenvironment-subtypes-j-hepatol-2021/"},{"id":"paper-le-mmr-deficiency-pd1-nejm-2015","kind":"paper","name":"Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ","route":"/key-papers/paper-le-mmr-deficiency-pd1-nejm-2015/"},{"id":"paper-philip-kras-wild-type-pancreatic-ccr-2022","kind":"paper","name":"Molecular characterization of KRAS wild-type tumors in patients with pancreatic adenocarcinoma","route":"/key-papers/paper-philip-kras-wild-type-pancreatic-ccr-2022/"},{"id":"paper-rizvi-targeted-ngs-immunotherapy-determinants-jco-2018","kind":"paper","name":"Molecular determinants of response to anti-PD-1 and anti-PD-L1 blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing","route":"/key-papers/paper-rizvi-targeted-ngs-immunotherapy-determinants-jco-2018/"},{"id":"paper-checkmate-227-n-engl-j-med-2018","kind":"paper","name":"Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden","route":"/key-papers/paper-checkmate-227-n-engl-j-med-2018/"},{"id":"paper-barroso-sousa-breast-tmb-prevalence-ann-oncol-2020","kind":"paper","name":"Prevalence and mutational determinants of high tumor mutation burden in breast cancer","route":"/key-papers/paper-barroso-sousa-breast-tmb-prevalence-ann-oncol-2020/"},{"id":"paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019","kind":"paper","name":"Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers","route":"/key-papers/paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019/"},{"id":"paper-rizvi-mutational-landscape-pd1-science-2015","kind":"paper","name":"Rizvi 2015: the mutational landscape determines who responds to PD-1 blockade in lung cancer","route":"/key-papers/paper-rizvi-mutational-landscape-pd1-science-2015/"},{"id":"paper-domingo-somatic-pole-proofreading-colorectal-lancet-gastro-2016","kind":"paper","name":"Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer","route":"/key-papers/paper-domingo-somatic-pole-proofreading-colorectal-lancet-gastro-2016/"},{"id":"paper-barroso-sousa-tmb-pten-ici-mtnbc-ccr-2020","kind":"paper","name":"Tumor mutational burden and PTEN alterations as molecular correlates of response to PD-1/L1 blockade in metastatic triple-negative breast cancer","route":"/key-papers/paper-barroso-sousa-tmb-pten-ici-mtnbc-ccr-2020/"}]}}