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Tumor Mutational Burden as a Marker of Response to Immunotherapy in MSI-High Metastatic Colorectal Cancer

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Key Points

  • The patients whose tumor cells had a mutation score less than a cut-off point of 37 were less likely to respond to immunotherapy and more likely to have their disease quickly worsen.
  • Those who had a tumor mutation score above the cut-off point of 41 were more likely to respond to pembrolizumab or nivolumab.
  • Patients who responded to immunotherapy appeared to have durable responses, with the majority experiencing ongoing major shrinkage beyond 1.5 years (the time of study analysis), while the median progression-free survival for patients with a low tumor mutational burden was 2 months.

Foundational research recently published by Schrock et al in Annals of Oncology may help patients with microsatellite instability (MSI)-high metastatic colorectal cancer decide whether to choose immunotherapy or chemotherapy as their first treatment option.

“Immunotherapy is the new, hot thing, but sometimes traditional chemotherapy can be a better choice,” said senior study author Marwan Fakih, MD, Co-Director of the Gastrointestinal Cancer Program at City of Hope. “Our study suggests tumor genomics could help doctors decide what kind of treatment will benefit each patient most. Taking this kind of personalized medicine approach, we will be able to provide patients with options that yield better outcomes and are more cost-effective.”

At the moment, doctors rely only on MSI status to determine which patients with metastatic colorectal cancer receive immunotherapy, Dr. Fakih said.

“Finding methods to identify the right, personalized treatment for a patient is top-of-mind, especially in today’s precision medicine landscape,” Dr. Fakih said.

Study Methods

Dr. Fakih and his colleagues retrospectively analyzed the data of 22 patients—all of whom had high MSI, a biomarker that indicates they’re a good candidate to receive immune checkpoint inhibitor treatment. The patients then received treatment with either pembrolizumab or nivolumab.

The scientists looked at tumor characteristics, tumor genomics, and outcome data and compared those analyses to a database containing 18,140 metastatic colorectal cancer patients.

Findings

The study found that the degree of tumor mutation a patient with metastatic colorectal cancer had was associated with varying responses to immunotherapy when considered in combination with the established biomarker MSI.

The patients whose tumor cells had a mutation score less than a cutoff point of 37 were less likely to respond to immunotherapy and more likely to have their disease quickly worsen. Those who had a tumor mutation score above the cutoff point of 41 were more likely to respond to pembrolizumab or nivolumab. Notably, the patients who responded to immunotherapy appeared to have durable responses, with the majority experiencing ongoing major shrinkage beyond 1.5 years (the time of study analysis), while the median progression-free survival for patients with a low tumor mutational burden was 2 months.

The implication is that patients with MSI and a high tumor mutation score should consider receiving immunotherapy as their first treatment, Dr. Fakih said. Those with MSI and a low tumor mutation score (less than 37) should be considered for chemotherapy rather than immunotherapy as their first treatment option, he added.

“Comprehensive genomic profiling is critical to assess the underlying genomic drivers of a tumor, as well as important biomarkers that require broad DNA interrogation like tumor mutational burden and MSI,” said first study author Alexa Schrock, PhD, Associate Director of Clinical Development at Foundation Medicine. “In this study, we’ve seen the importance of evaluating both tumor mutational burden and MSI when making treatment decisions for [patients with] metastatic colorectal cancer.”

Disclosure: For full disclosures of the study authors, visit academic.oup.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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