Dostarlimab in msi-h/dmmr colorectal cancer

The results of a study recently published in the New England Journal of Medicine, PD-1 blockade in locally advanced rectal cancer with mismatch repair deficiency, stunned the world. A complete response to therapy was achieved in all patients treated with the PD-1 blocker dostarlimab in the study.

Even during the follow-up period (between 6 and 25 months), it was not possible to detect any recurrence or progression using magnetic resonance imaging (MRI) and endoscopic examinations [1]

Study objective and implementation

The aim of the study is to investigate the overall response to treatment with the PD-1 inhibitor dostarlimab alone or in combination with chemotherapy and radiotherapy. The assessment is divided into the categories "complete remission", "partial remission" and "stable disease". According to the design of the study, categorization as complete remission requires endoscopic control and MRI of the rectal area.

A total of 30 participants with stage I and II dMMR colorectal cancer are to be treated with dostarlimab in the current phase II study. With the exception of one patient, the lymph nodes are already affected in all participants. Of the 18 patients enrolled in the study so far, with an average age of 54, 78% already have tumor stage T3 or T4. All patients had wild-type dMMR and BRAF V600E tumors; the average tumor mutation burden was 67 mutations per million bases. In addition, most of the participants suffered from large extensive tumors. Standard treatment for most would be a combination of surgery, chemotherapy and radiation.

Study participants will receive intravenous treatment with 500 mg of the antibody dostarlimab every three weeks for six months. The current state of the disease is continuously monitored by imaging and endoscopic examinations. If complete remission is not observed in study participants, chemotherapy or radiation therapy and, if the disease progresses, surgery should be performed. However, this case did not occur in previous participants, as complete remission was observed in all cases with dostarlimab administration. ^[1]

study evaluation

With 60,000 new cases and 25,000 deaths in Germany each year, colorectal cancer is one of the most common types of cancer. ^[2] A diagnosis of colorectal cancer affects more than 1.9 million people worldwide. But only 12 to 15% of these rectal cancers are classified as dMMR by biomarker status. Defective DNA mismatch repair is referred to as dMMR (deficient MMR), which causes the accumulation of mismatch errors. As a result, microsatellites begin to have different lengths. Statistically, this particular form of colorectal cancer is more likely to affect patients with poorly differentiated and/or mucinous right-sided adenocarcinoma. ^[3] The rate of patients with MSI-H is also very low, 2%. have patients with MSI-H/dMMR status. According to current studies, the prognosis is good in the early stages, but if metastases have already formed, the prognosis is rather poor. ^[4] However, in this small target group with MSI-H/dMMR, checkpoint inhibition can be considered very effective.

Whether PD-1 inhibition can replace chemotherapy or a combination of chemotherapy and radiotherapy in future and targeted therapies cannot yet be said with certainty. Here, further studies are absolutely necessary, especially with follow-up over a longer period. Nevertheless, the results published so far are very impressive and show that cancer patients can greatly benefit from personalized and targeted therapy.