Tumor Mutational Burden Identifies Cancer Responsive to Immunotherapy

MedMaven

by Dr. C.H. Weaver M.D. 7/2020

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

About 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. (1) 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. (2-6)

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. (9)

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

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. 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. (6-11)

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.

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.

References:

  1. FDA approves pembrolizumab for adults and children with TMB-H solid tumors
  2. Schrock AB, et al. Ann Oncol. 2019; doi:10.1093/annonc/mdz134.
  3. Alexandrov LB et al. Nature. 2013; 500: 415-421.
  4. Yuan J et al. J lmmunother Cancer. 2016; 4:3.
  5. Schumacher TN, Schreiber RD. Science. 2015;348(6230):69-74.
  6. Gibney GT et al. Lancet Oncol. 2016; 6;17: e542-e551.
  7. Mandal R, Samstein RM, Lee KW, et al. Genetic diversity of tumors with mismatch repair deficiency influences anti–PD-1 immunotheray response. Science. 2019;364(6439):485-491.
  8. 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.
  9. Le DT, Uram JN, Wang H. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520.
  10. Janjigian YY, Sanchez-Vega F, Jonsson P, et al. Genetic predictors of response to systemic therapy in esophagogastric cancer. Cancer Discov. 2018;8(1):49-58.
  11. 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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