Defining Immunotherapy Response with MSI-H and dMMR

Keytruda® (pembrolizumab), an immunotherapy, was approved by the FDA for patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors in May 2017. This was the first time a drug has been approved based on the results of a biomarker test for a genetic trait and not on the anatomical site of the tumor. It represents a paradigm shift, as the biomarker solely defines the treatment rather than the organ defining the treatment.

Our comprehensive genomic profiling plus approach with Caris Molecular Intelligence® includes testing for MSI as a standard part of every profile, along with MMR status in select lineages. MSI/MMR status, along with total mutational load (TML) and analysis of PD-L1 by IHC, provide an optimized pathway for physicians to explore opportunities for immunotherapy. As demonstrated in the studies below, pembrolizumab has the potential to produce durable responses in a high percentage of cases with MSI-H tumors, and should be included as part of the patient work up when considering immunotherapy opportunities.

What are MSI-H and dMMR and how do they play a role in immunotherapy treatment? With many ongoing clinical trials further exploring other immunotherapy drugs, it will be imperative to understand these biomarkers and their theranostic value as new drug options for these patients will expand in the months ahead.


Defining Microsatellite Instability-High and Mismatch Repair Deficient (dMMR)


Microsatellites are short repeating sequences of 2-5 nucleotides of DNA. The number of repetitions varies between individuals. These microsatellite sequences are particularly vulnerable to DNA repair errors because of slippage during replication and, therefore, microsatellite sequences rely more heavily on the mismatch repair system for repairs.2 As such, microsatellites provide an excellent tool to measure if a tumor has mismatch repair defects. When a tumor has a high rate of mutations in its microsatellite repeats, it likely has one or more mutations in a key mismatch repair protein involved in repairing these errors. The most prominent mismatch repair proteins are MLH1, MSH2, MSH6, and PMS2. The presence of altered or mutated versions of these proteins in the tumor can be detected by immunohistochemistry (IHC) assays. When one or more of the MMR proteins is mutated or missing, the tumor is considered dMMR. When MSI is detected by measuring the number of mutations in microsatellites, the patient is considered MSI-H. The majority of tumors that are dMMR are also MSI-H.2

While most microsatellites are located in noncoding areas of the genome, other areas can also be affected. Mismatch repair defects lead to a hypermutated phenotype and can lead to mutations in proteins necessary for DNA repair, apoptosis, cell growth, and epigenetics. The cumulative effects of these mutations can lead to cancer.

Germline mutations in the MMR pathway result in Lynch syndrome, which is a heritable condition of dMMR that is associated with an increased risk of cancer in several tumor types. However, dMMR status can also arise from somatic mutations or from epigenetic silencing of MMR genes. Additionally, MSI-H tumors are not always associated with dMMR; MSI-H status may arise from proteins that are currently unknown.2

As described above, tumors that are MSI-H or dMMR have a higher mutational load, meaning an increased frequency of mutations across the genome. When these mutations occur within coding sequences, they can lead to the production of new proteins that act as neoantigens. Neoantigens are abnormal peptides that the body recognizes as foreign. When neoantigens are presented to cytotoxic T-lymphocytes, they trigger a recruitment of tumor-infiltrating lymphocytes (TILs) within the tumor. This suggests that MSI-H tumors are particularly capable of activating an immune response due to their high number of neoantigens.2

Despite the influx of tumor-fighting T-cells, the tumor can counter the attack by producing molecules that turn off or reduce the fighting ability of the T-cells. Examples of these molecules include CTLA-4, PD-1, PD-L1, and LAG-3. To rejuvenate the ability of the immune system to attack the tumor, drugs have been developed that block these molecules from binding to their targets: nivolumab (anti-PD-1), ipilimumab (anti-CTLA-4), and pembrolizumab (anti-PD-1). Since MSI-H tumors express the genes that encode many of these molecules at significantly higher levels than MSS tumors, it was hypothesized that MSI-H tumors would be particularly good candidates for this class of therapies.2

 

Role of MSI-H in immunotherapy treatment


Two studies have tested the hypothesis that MSI-H or dMMR status is a predictor of response to pembrolizumab.3,4 The hypothesis considered that, while the average tumor has dozens of somatic mutations, MSI-H tumors have thousands.5 Further, tumors that are MSI-H/dMMR are infiltrated with T cells due to the neoantigens that result from their lack of mismatch repair and/or high level of microsatellite instability. So, researchers felt that augmenting the immune system with a PD-1 blockade may be highly effective in dMMR tumors. Indeed, both studies found that dMMR status predicted response to pembrolizumab, which is an immune checkpoint inhibitor that targets PD-1.

The first study, published in the New England Journal of Medicine, enrolled 3 cohorts: 11 patients with dMMR colorectal cancer (CRC), 21 patients with mismatch repair-proficient CRC, and 9 patients with other types of cancer that were dMMR.3 Immune-related objective response rates were 40% among the patients with dMMR CRC, 0% among patients with mismatch repair-proficient CRC, and 71% among patients with other types of dMMR tumors. Likewise, the immune-related progression-free survival at 20 weeks was 78% for dMMR CRC, 11% for mismatch repair-proficient CRC, and 67% for other types of dMMR tumors. Median progression-free and overall survival was not reached for patients with dMMR CRC after a median of 36 weeks of follow-up and for patients with other tumors that were dMMR after a median of 21 weeks of follow-up. Among patients with mismatch repair-proficient CRC, median progression-free survival was 2.2 months and median overall survival was 5.0 months.

The second study, published in Science, examined response to pembrolizumab among 86 patients with dMMR tumors across 12 tumor types.4 These patients had all received at least 1 prior therapy. Objective radiographic responses occurred in 53% (46 of 86 patients), and 21% of the patients had a complete radiographic response. A total of 77% (66 of the 86 patients) had their disease controlled, which was defined as partial response + complete response + stable disease. Both median progression-free survival and median overall survival were not reached after a median of 12.5 months of follow-up.

Given the high and durable responses among patients who had progressive disease when they enrolled, the authors of the pan-tumor study sought to estimate the fraction of cancer patients for whom these study results might be applicable. Across 12,019 tumors, Caris Life Sciences® performed next generation sequencing (NGS) to identify MSI-H cases. Cases that were MSI-H were found in 24 of 32 tumor types examined. This represents about 40,000 stage I-III and 20,000 stage IV cancers in the United States annually. In other words, over 5% of all tumors are MSI-H. MSI was seen at relatively high levels in endometrial, stomach, small intestinal and colorectal cancers, but was also seen at low levels in uterine sarcomas and cervical, prostate, bile duct, liver, neuroendocrine and ovarian cancers.4

The novel Caris MSI NGS assay was compared with PCR fragment analysis, which is considered the gold standard method to detect MSI. Using ~2100 matched cases analyzed by both PCR fragment analysis and MSI NGS, the Caris NGS technique had 95.8% sensitivity, 99.4% specificity, 94.5% positive predictive value, and 99.2% negative predictive value.4 Unlike many other MSI assays on the market, the Caris MSI assay does not require normal tissue, making analysis of MSI-H possible even for patients with limited tissue available.

 

Pembrolizumab approval


Keytruda (pembrolizumab) was approved by the FDA in May 2017 for the “treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). This indication covers patients with solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options and patients with colorectal cancer that has progressed following treatment with certain chemotherapy drugs.”6

Data supporting this FDA approval included responses in 15 cancer types: colorectal cancer, endometrial cancer, biliary cancer, gastric or gastroesophageal junction cancer, pancreatic cancer, small intestinal cancer, breast cancer, prostate cancer, bladder cancer, esophageal cancer, sarcoma, thyroid cancer, retroperitoneal adenocarcinoma, small cell lung cancer, and renal cell cancer.1

 

The Caris Approach


Comprehensive Genomic Profiling PLUS (CGP+) with Caris Molecular Intelligence can help you make more informed therapy decisions when considering immunotherapies. Our approach to assess DNA, RNA and proteins reveals a molecular blueprint to guide more precise and individualized treatment decisions for immunotherapies, as well as targeted therapies and chemotherapeutic agents. Learn how we help oncologists illuminate better treatment plans that are proven to extend overall survival and improve clinical outcomes.

 

References

  1. Lemery S. Regulatory considerations regarding tissue agnostic development. ASCO Annual Meeting; June 6, 2017; Chicago, IL.
  2. Lee V, Murphy A, Le DT, Diaz LA, Jr. Mismatch repair deficiency and response to immune checkpoint blockade. Oncologist. 2016;21(10):1200-1211.
  3. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520.
  4. Le DT, Durham JN, Smith KN, et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017.
  5. Le DT. Approach to the development of drugs for patients with MSI-H cancers. ASCO Annual Meeting; June 6, 2017; Chicago, IL.
  6. U.S. Food & Drug Administration. FDA approves first cancer treatment for any solid tumor with a specific genetic feature. May 23, 2017; https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm560167.htm. Accessed July 8, 2017.