Chemotherapy or Immunotherapy? TMB May Help Predict Best Treatment Choice for Some Metastatic Colorectal Cancer Patients

Pan-tumor biomarkers are key to some of today’s most remarkable cancer breakthroughs. One such biomarker is microsatellite instability (MSI), which plays an important role in immunotherapy treatment for advanced colorectal cancer patients. In the last four years, for example, the FDA approved two immunotherapies–Keytruda (pembrolizumab)1 and Opdivo (nivolumab)2–as second line treatment for patients with metastatic colorectal cancer who have high MSI (MSI-H).

These regulatory approvals were a significant advancement for patients, yet patients with advanced colorectal cancer with MSI-H have variable responses to immunotherapy.3,4,5 In fact, some appear to fare better on chemotherapy. How does an oncologist know which treatment to choose first? The role of additional biomarkers may help.

Our recent study, published April 30, 2019 in Annals of Oncology, shows that tumor mutational burden (TMB), an emerging pan-tumor biomarker that provides an assessment of the overall number of mutations within a tumor or cancer, may help inform treatment decisions for MSI-H metastatic colorectal cancer patients. In the study, researchers found that TMB appears to be an important biomarker within this subset of patients and may be a predictor for whether these patients will respond to immunotherapy. The study supports the idea that further stratifying MSI-H metastatic colorectal cancer patients based on the level of TMB present could be an important part of treatment planning. If this stratification proves effective in future studies, it could one day help physicians determine if immunotherapy or chemotherapy is best even within this subset of patients with MSI-H disease.

This study found that TMB is predictive as a continuous variable, suggesting that patients with very high levels of TMB may respond particularly well to immunotherapy, further informing treatment choices. In this study, all patients who had high TMB (13/13) responded to immunotherapy, compared to only 2/9 patients with low TMB (< 37 mutations/Mb).

Additionally, two cases in this study had been previously determined to be DNA mismatch repair (MMR) proficient using an immunohistochemistry test (a way of evaluating protein levels within a tumor or cancer) and therefore would not have been candidates for immunotherapies, which are approved for MMR deficient or MSI-H disease. This underscores the importance of the depth and breadth of comprehensive genomic profiling to help provide broad insights into the genomic makeup of each patient’s tumor.

The study used genomic insights from Foundation Medicine’s comprehensive genomic profiling (CGP) assays (FoundationOne® and FoundationOne®CDx), as well as real-world outcome data from 22 patients with advanced colorectal cancer from five oncology institutions throughout the U.S., including City of Hope (Duarte, CA), The Angeles Clinic (Los Angeles, CA), Comprehensive Cancer Centers of Nevada, UC Davis, and University of Chicago.

This study adds to the evidence supporting the use of TMB to identify patients most likely to benefit from immunotherapy across a wide range of tumor types. Our hope is that this study will lead to additional research that will provide a clearer picture of TMB’s utility as a biomarker of response in metastatic colorectal cancer, helping to inform more personalized treatment planning for each patient.