Tumor Mutational Burden Identifies Cancer Responsive to Immunotherapy

MedMaven

by Dr. C.H. Weaver M.D. 10/2020

On June 16th 2020 The Food and Drug Administration (FDA) granted accelerated approval to the immune checkpoint inhibitor (ICI) Keytruda® (pembrolizumab) for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) cancers, that have progressed following prior treatment and who have no satisfactory alternative treatment options. (1) This was the first FDA approval for the treatment of cancer based on TMB.

What is TMB?

Tumor mutational burden is a measurement of the mutations carried by tumor cells and is a predictive biomarker being studied to evaluate its association with response to immunotherapy.
It is hypothesized that these tumor mutations can result in proteins expressed by tumor cells that are recognized by the immune system, called neoantigens. A greater number of mutations can theoretically result in a greater number of neoantigens, and therefore more immune system activation.

Why is TMB important?

Taken together, a tumor harboring a high number of mutations — or a tumor with a high TMB may be more likely to respond to immune checkpoint inhibitor therapies because ICIs work by enhancing the immune response to tumor cells. Retrospective studies found that response to ICI treatment and subsequent survival were associated with high TMB in certain cancers. (5-7)

How is TMB measured?

TMB is measured using DNA sequencing, such as Whole Exome Sequencing (WES) to determine the number of acquired mutations in the tumor. Tumor cells with high TMB may have more novel antigens (targets) which are associated with an increase in cancer-fighting T cells to direct an anti-cancer response. (7-11)

What is a “high” TMB?

Researchers are still working to determine how best to define a "high" TMB but have currently defined it as 10 or more mutations/Mb. (12)

What cancer types are likely to have a high TMB?

A study of more than 100,000 human cancer genomes found that the level of TMB varies widely across cancer types. Focusing on 167 different cancer types that had larger sample sizes, adults with cancer carried a higher TMB than children with cancer. TMB was highest in skin cancers, including squamous cell carcinoma and melanoma, and cancers of the lung, bladder, cervix, and kidney. The lowest levels of TMB were found in myelodysplastic or myeloproliferative disorders and cancers of the bone or soft tissue, adrenal gland, and thymus. However, there was wide variability in TMB for each cancer type, meaning that some patients harbored very high or very low TMBs regardless of their specific disease type. (13)

What is the relationship between MSI and TMB?

Microsatellite instability (MSI) is the condition of genetic hypermutability or a predisposition to mutations in cells that results from impaired DNA mismatch repair (MMR). DNA MMR corrects errors that spontaneously occur during DNA replication such as single base mismatches or short insertions and deletions. The proteins involved in MMR correct polymerase errors by forming a complex that binds to the mismatched section of DNA, excises the error, and inserts the correct sequence in its place. (2) Cells with abnormally functioning MMR are unable to correct errors that occur during DNA replication and consequently accumulate errors. This causes the creation of novel microsatellite fragments. The presence of MSI represents phenotypic evidence that MMR is not functioning normally, and specific tests can be used to detect for the presence of MSI. (3-7)

High levels of microsatellite instability (MSI-high) occur in about 10% to 15% of colorectal cancers as well as non-colorectal cancers, and research has demonstrated that ~ 50% of MSI-high patients with advanced colon cancer respond to treatment with immune checkpoint inhibitor medications like Keytruda and this improves survival compared to chemotherapy. (14)

Not all patients with MSI-high cancers however respond to treatment. Research suggests that the TMB may help further predict which patients with MSI-high disease can be optimally treated with immune checkpoint inhibitors.

The presence of MSI-high is associated with higher TMB, however TMB does not guarantee the presence of MSI-high. Testing for MSI-high is recommended for colorectal and other cancers and it may be beneficial to measure most patients for MSI-high using a next-generation sequencing test because of the potential implications on treatment response.

TMB in Colon Cancer

Doctors have evaluated TMB in colon cancer patients and found a very strong association between TMB and response to treatment. The researchers estimated the optimal predictive cut point for TMB to be between 37 mutations/megabyte and 41 mutations/megabyte. They then used the Foundation Medicine database to analyze a larger group of patients to confirm the optimal TMB cut point of 37 mutations/megabyte they identified.

Patients who fall outside the cut-point range may be less likely to benefit from checkpoint inhibitor immunotherapy therapy but the best approach to these patients is still being determined. These data appear to support the integration of a tumor mutational burden score as a potential decision tool in the sequencing of checkpoint inhibition and chemotherapy.

The accelerated approval of Keytruda was based on data from an analysis of patients with various previously treated unresectable or metastatic cancers with TMB-H who were treated with Keytruda on the Keynote 158 clinical trial. Patients received Keytruda intravenously every 3 weeks until unacceptable toxicity or documented disease progression.

The main outcome measures were overall response rate and duration of response in patients who had received at least 1 dose of Keytruda. Among the 102 patients who had tumors identified as TMB-H, the overall response rate was 29% and 4% of patients achieved a complete response while 25% had a partial response. (15)

Challenges With TMB

Although the use of TMB to select ICI's like Keytruda for a patient has been approved by the FDA, some experts have raised concerns about using TMB as a biomarker. (1,10)

  • TMB is measured differently between studies, using different assays — for example, some enriching for certain mutations (and others not), the number of genes included in the assay, the type of mutations included — and different thresholds for defining “high” compared with “low” mutation burden.1 These differences can lead to variations in the scoring of TMB.
  • The turnaround time for TMB is currently approximately 2 to 3 weeks, which could delay the start of treatment. (10)
  • There are mixed results from trials about the utility of TMB and additional research is required.

Through its recent approval, the FDA acknowledged the characterization of “high TMB” as a way to identify patients who may benefit from Keytruda treatment. Although there have been multiple studies that have associated high TMB with response and clinical benefit to ICI therapies, many challenges and questions remain regarding the optimal use of TMB as a biomarker.

References

  1. FDA approves pembrolizumab for adults and children with TMB-H solid tumors
  2. Sholl LM, Hirsch FR, Hwang D, et al. [The promises and challenges of tumor mutation burden as an immunotherapy biomarker: a perspective from the International Association for the Study of Lung Cancer Pathology Committee](https://www.jto.org/article/S1556-0864(20%2930424-X/abstract). J Thorac Oncol. Published online June 6, 2020. doi:10.1016/j.jtho.2020.05.019
  3. US Food and Drug Administration. FDA approves pembrolizumab for adults and children with TMB-H solid tumors [press release]. Published June 17, 2020. Accessed August 13, 2020.
  4. 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(1):34. doi:10.1186/s13073-017-0424-2.
  5. 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(6230):124–128. doi:10.1126/science.aaa1348
  6. Samstein RM, Lee C-H, 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
  7. Gandara DR, Paul SM, Kowanetz M, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018;24(9):1441-1448. doi:10.1038/s41591-018-0134-3
  8. Hellmann MD, Ciuleanu T-E, 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
  9. US Food and Drug Administration. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%) [press release]. Published May 15, 2020. Accessed August 13, 2020.
  10. Marabelle A, Fakih MG, Lopez J, et al. [Association of tumor mutational burden with outcomes of select advanced solid tumors treated with pembrolizumab in KEYNOTE-158](https://www.annalsofoncology.org/article/S0923-7534(19%2959404-2/pdf). Ann Oncol. 2019;30(suppl 5; abstr 4445):v475-v532. doi:10.1093/annonc/mdz253.018
  11. Addeo A. Tumor mutation burden—from hopes to doubts. JAMA Oncol. 2019;5(7):934-935. doi:10.1001/jamaoncol.2019.0626
  12. Schrock AB, et al. Ann Oncol. 2019; doi:10.1093/annonc/mdz134.
  13. Alexandrov LB et al. Nature. 2013; 500: 415-421.
  14. Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51(2):202-206.
  15. Yaeger R, Chatila WK, Lipsyc MD, et al. [Clinical sequencing defines the genomic landscape of metastatic colorectal cancer](https://www.cell.com/cancer-cell/fulltext/S1535-6108(17%2930556-1). Cancer Cell. 2018;33(1):125-136.
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