Novel immunotherapy combination showed high efficacy among patients with microsatellite stable metastatic colorectal cancer

March 2023 – Results from a phase I study presented at the American Society for Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium showed promising clinical activity with long-lasting responses for a novel combination immunotherapy regimen among heavily pretreated patients with microsatellite stable metastatic colorectal cancer (mCRC). The combination therapy consisted of two immunotherapies – botensilimab (Agenus) and balstilimab (Agenus).

What is microsatellite stable metastatic colorectal cancer?

When a colorectal tumour undergoes biomarker testing or molecular profiling, microsatellite status will be assessed. Molecular profiling examines a tumour for the presence of specific biomarkers that can help guide a patient’s treatment. A colorectal tumour will either be microsatellite instability high (MSI-H)/mismatch repair deficient (dMMR) or microsatellite stable (MSS) / mismatch repair proficient (pMMR). Microsatellite instability is found most often in colorectal cancer, gastric cancer, and endometrial cancer, but it may also be found in many other types of cancer. Knowing whether cancer is microsatellite instability-high may help plan the best treatment.

Mismatch repair refers to the repair pathway that exists in our cells to repair mistakes that have occurred when our DNA (genetic material) is replicated (copied), or during normal DNA repair that occurs when our DNA gets damaged. MSS/pMMR represents the normal state of the cell with a properly functioning (“proficient”) mismatch repair pathway. The majority of colorectal cancer patients have MSS tumours – about 85% of all-stage CRC and about 96% of stage IV mCRC are MSS.

MSS tumours have been referred to as “cold” tumours because they generally do not respond to treatment with immunotherapy. MSI-H or deficient mismatch repair (dMMR) is the mutated state where the mismatch repair pathway is not functioning normally. Colorectal tumours that are positive for the MSI-H/dMMR biomarker – about 15% of all CRC and 4% of stage IV mCRC – are more likely to experience benefit from treatment with immunotherapy.

The study

In this study, the researchers treated a small group (70) of heavily pretreated (patients who had received several previous therapies) MSS mCRC patients with the combination of botensilimab and balstilimab. Typically, immunotherapies (also referred to as checkpoint inhibitors) do not work in MSS colorectal cancer tumours. The combination treatment, however, showed impressive efficacy, with over 70% disease control rate, which indicates the percentage of patients that achieved stable disease that does not shrink or grow significantly over a certain period of time. Over 20% of patients had objective response rates, some of which were near complete responses (the disappearance of all signs of cancer in the body) and many of which were long-lasting effects. The 12-month overall survival rate was 63%. It is important to note that the patients who experienced the greatest benefit from the combination were those that did not have any active metastasis in their liver. The combination treatment was also well tolerated by patients in terms of toxicities.

Interpretation of study results

These results are meaningful because they show very promising activity in heavily pretreated patients with MSS mCRC that otherwise would have few treatment options available to them. After not responding to multiple lines of previous treatment, these patients would only be candidates for weakly effective treatments like trifluridine/tipiracil (Lonsurf) or regorafenib (Stivarga).

Phase 2 of this study has already been launched with various trial sites opening. The second phase of the study is a randomized trial (patients will be randomly assigned to receive the various treatment arms under investigation) that will examine two different doses of the combination treatment and compare them to the standard of care, which consists of either regorafenib or Lonsurf. “It’s a very effective combination, a very safe combination when management of toxicity is done carefully, and it really is so much better – in a non-comparative sense- than Lonsurf or regorafenib. We will see in the randomized phase 2 if that will come to fruition, but as someone who has given a lot of Lonsurf, a lot of regorafenib and a lot of this drug – it’s just in a different league”, says lead study author Benjamin L. Schlecter, MD, of the Dana-Farber Cancer Institute.