What Is Tumor Mutational Burden (TMB)? What Does a TMB-High (TMB-H) Report Signify for Immunotherapy?
In this article
From Mutation Count to Treatment Decision: A Comprehensive Guide to Reading Your TMB Report Correctly
More and more genomic test reports now include a line such as "Tumor mutational burden (TMB): 15 mut/Mb · High." Tumor mutational burden shows how many mutations are found in each megabase of tumor DNA, that is, in every 1 million DNA letters. The more mutations there are, the more likely the immune system is to recognize the tumor as "foreign"; for this reason, immunotherapy is, on average, more likely to work in TMB-high tumors. The US Food and Drug Administration (FDA) granted pembrolizumab accelerated approval for advanced TMB-high solid tumors in 2020; in October 2026, when it converted this to traditional (full) approval, it raised the threshold from ≥10 to ≥13 mutations per megabase. However, TMB does not mean the same thing in every cancer type, it can vary from laboratory to laboratory, and on its own it is not enough to make a treatment decision. In this guide, we explain step by step what TMB is, how it is measured, when it can guide treatment and how to read your report. We have covered the FDA's October 2026 decision, how pembrolizumab works and next-generation sequencing (NGS) in separate articles.
- What is TMB? It is the number of tumor-specific mutations found in each megabase of tumor DNA (mutations/Mb). A value of 10 or more is usually considered "high"; the FDA's current threshold for pembrolizumab is ≥13.
- Why does it matter? As mutations increase, so do the new proteins (neoantigens) that the immune system can recognize. In KEYNOTE-158, among 220 patients with TMB ≥13, tumors shrank with pembrolizumab in 36%; in 58% of responders, the response lasted at least 1 year.
- What are its limits? A TMB-high result predicts response in melanoma, lung cancer and bladder cancer, but not in breast cancer, prostate cancer or brain tumors. The result can vary with the type of test, the tumor content of the sample and the laboratory. There are no comparative survival data.
- If your report says TMB-high: First consider the standard treatments for your cancer type and your MSI and PD-L1 results. In Türkiye, the TMB-high indication is not reimbursed by SGK (the Social Security Institution); off-label use approval or clinical trial options can be discussed.
Why does this matter?
Immune checkpoint inhibitors (such as pembrolizumab, nivolumab and atezolizumab) have transformed cancer treatment over the past decade; in some patients they produce responses that last for years. But these drugs do not work in every patient, can cause serious side effects and are expensive. That is why there is a great need for markers (biomarkers) that can help answer the question "who will benefit?" Alongside PD-L1 and microsatellite instability (MSI), TMB became one of the first numerical genomic markers that can be used regardless of cancer type.
Today, broad genomic panels are performed routinely at many centers, and TMB appears on almost every report. This leads patients and physicians to ask, "My TMB is high; should I receive immunotherapy?" The right answer depends on the cancer type, how TMB was measured, other markers and the treatment options available. A misinterpreted TMB result can lead either to missing a treatment that could work or to choosing a treatment that is unlikely to help (ESCAT, the scale for evaluating genetic test reports).
What is tumor mutational burden (TMB)?
Tumor mutational burden (TMB) is a number obtained by dividing the mutations found in the DNA of tumor cells, but not in normal cells, by the length of DNA examined; it is written as "mutations per megabase (mut/Mb)." A value of 10 or more is usually considered high. On average, TMB-high tumors are more likely to respond to immunotherapy, but this is not true for every cancer type.
A simple comparison: Think of the tumor's DNA as a long book. A megabase is a 1-million-letter section of that book. TMB counts how many "typos" there are in that section. As the typos increase, so do the changes in the proteins the cell makes that are not normally found in the body; the immune system can recognize these changes as foreign.
Figure 1 · Tumor mutational burden: how many mutations in 1 megabase?
A visual comparison of low, high and very high TMB
| Term | Meaning |
|---|---|
| Mutations per megabase (mut/Mb) | Number of mutations in every 1 million DNA letters |
| TMB-low | Usually below 10 mut/Mb |
| TMB-high (TMB-H) | Usually ≥10 mut/Mb; the FDA's current threshold for pembrolizumab is ≥13 mut/Mb |
| Hypermutation, ultramutation | Very high values (e.g., >20, >100 mut/Mb); mostly due to MSI, POLE alterations or certain drugs |
| Neoantigen | A new protein fragment produced by a mutation that the immune system can recognize as foreign |
| Level of evidence | TMB is rated at different levels by tumor type on ESMO's ESCAT scale (comparison of advanced genomic tests) |
How does a mutation turn into an immune response?
A mutation in a gene can change the protein that gene makes. The cell displays small fragments of the proteins it makes on its surface using molecules called HLA; T cells scan these fragments like an "ID check." A mutated protein fragment, that is, a neoantigen, can be recognized as foreign by a T cell. Tumors, however, stop T cells with "brake" molecules such as PD-L1. Immune checkpoint inhibitors release this brake, allowing T cells to attack the tumor (immunotherapies and cancer vaccines).
Figure 2 · From mutation to immune response
Neoantigen, T cell, the PD-1/PD-L1 brake and pembrolizumab
For this reason, TMB is really a "proxy" for the neoantigen load, which we cannot measure directly. Not all mutations are equal: mutations present in all tumor cells (clonal) trigger a stronger immune response than those present in only some cells (subclonal). Loss of HLA molecules by the tumor, or a microenvironment that keeps immune cells out, can block a response despite high TMB (why the location of mutations matters).
Which tumors have high TMB?
TMB can vary more than a hundredfold between cancer types. The highest values are seen in cancers exposed to external factors that damage DNA directly: melanoma and cutaneous squamous cell carcinoma, linked to the sun's ultraviolet rays, and lung, head and neck, and bladder cancers, linked to tobacco. In childhood cancers, prostate, breast and pancreatic cancers, sarcomas and brain tumors, TMB is usually low.
Figure 3 · Tumor mutational burden by cancer type
Usually high, intermediate and low; important exceptions
Biological causes of high TMB
| Cause | What happens? | Where is it seen? |
|---|---|---|
| Tobacco | Chemicals in tobacco smoke leave a characteristic mutation signature in DNA | Lung, head and neck, bladder (smoking and cancer) |
| Ultraviolet (UV) light | Sunlight causes characteristic mutations | Melanoma, skin cancers (melanoma) |
| Mismatch repair deficiency (dMMR/MSI-high) | DNA copying errors cannot be corrected, so mutations accumulate | Colorectal, endometrial, stomach; Lynch syndrome (hereditary cancers) |
| POLE / POLD1 alterations | The proofreading function of the enzyme that copies DNA is impaired; more than 100 mut/Mb can be seen | Endometrial, colorectal |
| APOBEC enzymes | The cell's own enzymes cause changes in DNA | Bladder, breast, head and neck |
| Treatment-related | Some drugs (e.g., temozolomide) can leave many new mutations in the tumor | Brain tumors; this type of TMB-high usually does not increase response to immunotherapy |
Are TMB and MSI the same thing?
No, but they are related. Most MSI-high (or dMMR) tumors are also TMB-high; yet only a small share of TMB-high tumors are MSI-high. Response to immunotherapy is much stronger in MSI-high tumors, which have had a tissue-agnostic approval since 2017; important results have been achieved even in early-stage colon and rectal cancer (dostarlimab in dMMR rectal cancer, atezolizumab after surgery in dMMR colon cancer). So if your report includes both TMB and MSI, the MSI result is usually more decisive.
How is TMB measured?
TMB is calculated by reading DNA extracted from tumor tissue with next-generation sequencing. The gold standard is whole-exome sequencing, which reads all protein-coding genes (about 30 megabases); but because it is expensive and slow, in practice broad panels that read 300–500 genes (about 0.8–1.5 megabases) are used. FoundationOne CDx, which the FDA approved as the first companion diagnostic for pembrolizumab, is one such panel (tumor test panels).
Figure 4 · How is TMB measured?
From tissue to number, and why the amount of DNA read matters
- Panel size: The less DNA that is read, the greater the effect of each single mutation and the less certain the result. At least about 1 megabase is usually recommended.
- Tumor cell content: If the sample contains few tumor cells, some mutations can be missed and TMB can come out falsely low.
- Which mutations are counted: Laboratories include or exclude certain types of mutations (e.g., those that do not change protein structure); methods for filtering out inherited variants also differ (inherited variant analysis).
- Harmonization: The same sample can give results that differ by a few units on different panels; this is why international projects focus on harmonizing panels. It matters which test the threshold was set with.
- Blood TMB: Blood TMB, calculated from circulating tumor DNA, is under investigation; but a large prospective study in lung cancer did not confirm its value for choosing treatment, and it has no place in routine use (ctDNA tests).
The evidence: how well does immunotherapy work in TMB-high tumors?
KEYNOTE-158 and FDA approval
The FDA approval is based on KEYNOTE-158, a trial without a comparison group in which pembrolizumab alone was given to previously treated patients with advanced solid tumors. In the first analysis in 2020, tumors shrank in 29% of 102 patients with TMB ≥10, compared with 6% of 688 patients with lower TMB. In the updated 2026 analysis, the response rate was 36% among 220 patients with TMB ≥13, and in 58% of responders the response lasted at least 12 months. Because benefit could not be confirmed in tumors with TMB between 10 and 13, the FDA raised the threshold to ≥13.
KEYNOTE-158: pembrolizumab response by TMB level
Previously treated advanced solid tumors; share of patients whose tumors shrank, %.
Single-arm trial; no comparison group. The 2026 analysis includes the prespecified TMB-high cohort (145 patients) and 75 patients evaluated retrospectively. The failure to confirm benefit in tumors with TMB between 10 and 13 led to the higher threshold. There are no comparative survival data.
| FDA approval (October 2026) | Details |
|---|---|
| Drug | Pembrolizumab (Keytruda) and its subcutaneous form (Keytruda Qlex) |
| Patients | Adults and children; unresectable or metastatic solid tumors |
| Condition | TMB ≥13 mut/Mb by an FDA-approved test; progression after prior treatment and no satisfactory alternative options |
| Dose | In adults, 200 mg every 3 weeks or 400 mg every 6 weeks; up to 24 months |
| Nature of the evidence | Single-arm trial; no comparative progression-free or overall survival data |
Source: ASCO Post report on the FDA decision (October 2026). The European Medicines Agency (EMA) has not granted a tissue-agnostic approval for TMB-high.
Not the same in every cancer type
A study of 31 cancer types published in Annals of Oncology in 2021 showed that the meaning of TMB varies by tumor type. In melanoma, lung cancer and bladder cancer, where the amount of T cells in the tumor rises along with mutational burden, TMB-high tumors responded to immunotherapy at a rate of 39.8%, and the odds of response were 4 times higher than in TMB-low tumors. In breast cancer, prostate cancer and brain tumors, however, the response rate of TMB-high tumors was only 15.3%, no better than that of TMB-low tumors. This is why some experts advocate cancer-type-specific thresholds rather than a single universal one (immunotherapy in hormone receptor-positive breast cancer).
TMB-high does not mean the same thing in every cancer
Response rate to immune checkpoint inhibitors in TMB-high tumors, % (McGrail, Annals of Oncology 2021).
In Group 1, that is, in cancers where the amount of T cells in the tumor rises with mutational burden, TMB-high tumors had 4.1 times higher odds of response than TMB-low tumors. In Group 2, being TMB-high did not increase response; the odds ratio was 0.46. This is a retrospective analysis.
The lesson from lung cancer
In non-small cell lung cancer, the CheckMate 227 trial showed that nivolumab + ipilimumab prolonged progression-free survival compared with chemotherapy in patients with TMB ≥10. With longer follow-up, however, the overall survival benefit was similar whether TMB was high or low. For this reason, treatment choice in lung cancer today is based on PD-L1 level and driver mutations, not TMB (dual immunotherapy in lung cancer).
TMB in lung cancer: progression-free survival improved, overall survival did not separate
CheckMate 227, non-small cell lung cancer with TMB ≥10; median progression-free survival, months.
In patients with TMB ≥10, dual immunotherapy delayed disease progression (hazard ratio 0.58) and raised the response rate from 26.9% to 45.3%. However, later analyses found a similar overall survival benefit whether TMB was high or low; for this reason, TMB is not used to choose treatment in lung cancer.
How should you read your report?
Although genomic tumor profiling reports look different from one laboratory to another, alongside TMB they usually include MSI status, sometimes PD-L1, the test used and the proportion of tumor cells in the sample. The representative report below shows how to interpret each line.
Figure 5 · Reading your report: a representative example
TMB, MSI, PD-L1, test type and tumor content
Figure 6 · Decision path when a TMB-high report arrives
Evaluation in four steps
Figure 7 · Six questions when interpreting a TMB result
Test, sample, threshold, cancer type, other markers and options
Which markers matter besides TMB?
| Marker | What does it show? | Where is it used? |
|---|---|---|
| PD-L1 (TPS, CPS) | Level of the brake molecule on tumor and immune cells | Treatment choice in many cancers, such as lung, stomach, head and neck, breast and cervical cancer |
| MSI-high / dMMR | DNA repair deficiency; very high neoantigen load | Tissue-agnostic; colorectal, endometrial, stomach (tissue-agnostic treatments) |
| POLE alterations | Ultramutation; high likelihood of response to immunotherapy | Endometrial, colorectal; mostly research |
| Gene expression signatures | Whether the tumor is "hot," that is, full of immune cells | Research; better prediction together with TMB (RNA sequencing) |
| Artificial intelligence models | Combine clinical, imaging and laboratory data | Research (artificial intelligence in lung cancer) |
| Clinical factors | Performance status, disease burden, steroid and antibiotic use, liver metastases | Can affect response in all cancers |
Side effects
Being TMB-high does not change the risk of side effects; the side effects of pembrolizumab are the same as in its other indications. Besides the tumor, the immune system can also turn against healthy tissues: skin rash, diarrhea and colitis, thyroid and other hormone gland disorders, and inflammation of the lungs, liver and kidneys can occur. Most are easily treated if recognized early; report any new symptom to your care team right away (immunotherapy side effects, side effects involving hormone glands).
Questions to ask your doctor
- Which test was my TMB measured with, and how many megabases did the panel cover? Was the tumor cell content of the sample adequate?
- What threshold does the report use? Is my result ≥13, or between 10 and 13?
- Has TMB been shown to predict response to immunotherapy in my cancer type?
- What are my MSI and PD-L1 results? Is there already an approved immunotherapy for my cancer type?
- Which standard treatments are recommended first? Is off-label use approval or a clinical trial an option for pembrolizumab?
- If treatment starts, which side effects should I watch for, and how will response be assessed?
- "TMB-high means immunotherapy will definitely work." No. Tumors shrank in about one third of patients with TMB ≥13; in most they did not. TMB is an indicator of probability.
- "If TMB is low, immunotherapy is of no use at all." Wrong. Immunotherapy is effective in cancers with low TMB, such as kidney cancer and Hodgkin lymphoma, and in many tumors with high PD-L1.
- "Every laboratory gives the same TMB result." No. Panel size, the calculation method and tumor content can change the result by a few units; results close to the threshold should be interpreted with care.
- "The higher the TMB, the better." Although this is the trend in most cancers, high TMB does not increase response in hypermutated brain tumors that develop after temozolomide.
- "If TMB-high is found, immunotherapy should be the first option." The FDA approval is for patients who have been treated before and have no satisfactory options left; proven treatments for your cancer type are considered first.
- "TMB indicates an inherited risk." No. TMB counts mutations that arise later in the tumor; however, a very high TMB can point to an inherited DNA repair disorder such as Lynch syndrome and may call for genetic counseling.
- Pembrolizumab is licensed in Türkiye; however, the TMB-high solid tumor indication is not reimbursed by SGK (immunotherapy reimbursement conditions).
- Use in this indication requires off-label use approval from TİTCK (the Turkish Medicines and Medical Devices Agency); the legal routes available for non-reimbursed drugs are the subject of a separate article.
- Broad genomic panels can be performed in Türkiye at many centers and through laboratories abroad; check your report for which panel was used and how many megabases it covered.
- For how long it takes new approvals to reach Türkiye, see our access map.
Frequently Asked Questions
- What is tumor mutational burden (TMB)?
- TMB is the number of mutations found in each megabase (1 million letters) of tumor DNA that are not present in normal cells; it is written as "mutations per megabase." A value of 10 or more is usually considered high. The more mutations there are, the more likely the immune system is to recognize the tumor.
- What does TMB-high (TMB-H) mean, and can I receive immunotherapy?
- TMB-high means that your tumor carries a large number of mutations. The FDA has approved pembrolizumab for patients with advanced solid tumors with TMB ≥13 who have been treated before and have no other good options left. The decision depends on your cancer type, your MSI and PD-L1 results and the treatments available.
- Why did the FDA raise the TMB threshold from 10 to 13?
- In the updated analysis performed for the traditional approval in October 2026, the response rate was 36% among 220 patients with TMB ≥13; benefit could not be confirmed in tumors with TMB between 10 and 13. For this reason, the FDA updated the definition of TMB-high to ≥13 mutations per megabase.
- Is the TMB result the same in every laboratory?
- No. Panel size, which mutations are counted, how inherited variants are filtered out and the proportion of tumor cells in the sample can change the result by a few units. This is why results close to the threshold in particular should be interpreted together with the type of test.
Glossary
- Tumor mutational burden (TMB)
- The number of tumor-specific mutations found in each megabase of tumor DNA.
- Megabase (Mb)
- 1 million DNA letters (bases).
- Neoantigen
- A new protein fragment produced by a mutation that the immune system can recognize as foreign.
- HLA
- Surface molecules that display the cell's protein fragments to immune cells.
- Immune checkpoint inhibitors
- Drugs that release brakes such as PD-1, PD-L1 or CTLA-4, allowing the immune system to attack the tumor.
- MSI-high / dMMR
- A breakdown of the system that corrects copying errors in DNA; it leads to the accumulation of many mutations.
- Whole-exome sequencing
- Reading all protein-coding genes (about 30 megabases).
- Gene panel
- A targeted sequencing test that reads hundreds of cancer-related genes together.
- Companion diagnostic
- A test approved together with a drug to determine who should receive that drug.
- Tissue-agnostic approval
- Approval of a drug based on a biological feature of the tumor rather than the organ where it started.
DROZDOGAN Academy Commentary
TMB is an important marker that turns the idea "the more mutations, the better the immune system can see the tumor" into a number in the era of immunotherapy. But the 2026 threshold change also shows that a single number cannot fully capture a complex immune relationship.
⚡ Why it matters
In some patients with high TMB who have exhausted standard treatments, pembrolizumab can produce long-lasting responses. Identifying the right patient is critical, both to avoid missing this opportunity and to avoid treatment that is unlikely to help.
✅ Strengths
TMB is numerical, is reported at no extra cost on many genomic panels, and is consistently associated with response in cancers such as melanoma, lung cancer and bladder cancer. The 2026 analysis is based on a large, prespecified cohort.
⚠️ Limitations
The approval rests on a single-arm trial; there are no comparative survival data. The predictive power of TMB varies by cancer type; differences between panels and results close to the threshold create uncertainty.
🩺 In practice
We review a TMB-high report at the tumor board together with the cancer type, MSI, PD-L1, test quality and treatment history. When standard options are exhausted and TMB is ≥13, we discuss pembrolizumab, access conditions in Türkiye and clinical trial options with our patients (clinical trials).
❓ Open questions
Should cancer-type-specific thresholds be used? Can clonal TMB, neoantigen quality and gene expression signatures improve the predictive power of TMB? Will blood-based TMB measurement be able to replace tissue testing?
Bottom line: TMB is an indicator of how "visible" a tumor may be to the immune system. TMB ≥13 opens an important door to pembrolizumab, especially for patients who have exhausted standard options; but it does not guarantee a response. Review your result with your doctor together with your cancer type, MSI, PD-L1 and the features of the test.
- This article was prepared in October 2026.
- Information on the FDA decision is based on the ASCO Post report; KEYNOTE-158 data are based on the 2020 publication and the 2026 approval announcement; and differences by cancer type are based on the 2021 study by McGrail and colleagues. Detailed results for patients with TMB between 10 and 13 have not been reported in publicly available sources.
- TMB levels by cancer type reflect general trends, and numerical median values are not given. The report in Figure 5 is fictional; it does not represent a real laboratory.
- Comparisons in the charts come from different analyses and cannot be compared directly. The illustrations are simplified. The Academy commentary is our own.
- This article is not medical advice; treatment decisions should be made by the team that knows the patient.
References
- The ASCO Post. FDA grants traditional approval to pembrolizumab for TMB-H solid tumors. October 2026. ascopost.com
- Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 2020;21:1353-1365. doi:10.1016/S1470-2045(20)30445-9
- McGrail DJ, Pilié PG, Rashid NU, et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann Oncol 2021;32:661-672. doi:10.1016/j.annonc.2021.02.006
- Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet 2019;51:202-206. doi:10.1038/s41588-018-0312-8
- Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 2017;9:34. doi:10.1186/s13073-017-0424-2
- Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 2017;377:2500-2501. doi:10.1056/NEJMc1713444
- Rizvi NA, Hellmann MD, Snyder A, et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348:124-128. doi:10.1126/science.aaa1348
- Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018;378:2093-2104. doi:10.1056/NEJMoa1801946
- Merino DM, McShane LM, Fabrizio D, et al. Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms. J Immunother Cancer 2020;8:e000147. doi:10.1136/jitc-2019-000147
- Touat M, Li YY, Boynton AN, et al. Mechanisms and therapeutic implications of hypermutation in gliomas. Nature 2020;580:517-523. doi:10.1038/s41586-020-2209-9
- Cristescu R, Mogg R, Ayers M, et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 2018;362:eaar3593. doi:10.1126/science.aar3593
Was this article helpful?
Your feedback helps us improve our content.
Reader comments
Share your comment
Your name and comment are published only after administrator approval. Your email address is never shown to visitors.
Be the first to comment.