Immuno-cancer drugs have been proven to be therapeutic in various types of cancers such as malignant melanoma, lung cancer, and bladder cancer, while only 5% of metastatic colorectal cancer patients receive help from immuno-cancer treatments. More than 95% of colorectal cancer patients are known to be microsatellite stable (MSS), while immuno-cancer drug monotherapy has been proven to be effective in colon cancer accompanied by a gene abnormality called microsatellite instability (MSI-High), which does not respond to conventional immuno-cancer treatments.
 

In September 2022, the European Society of Oncology (ESMO) in Paris published the results of a Phase 1 clinical study of combination therapy of botensilimab (anti-CTLA-4 antibody) and valstilimab (anti-PD-1 antibody) in 41 patients with MSS metastatic colorectal cancer.
 

The average age of the 41 MSS colon cancer patients in the study was 57 years old, female patients accounted for 59%, and physical performance was good at 1. Previously, on average, they were treated with four types of drugs, and 34% of patients had previous experience with immuno-cancer drugs. 51% of patients had tumors containing RAS mutations, and 5% of patients had tumors containing BRAF mutations.
 

In this study, 1 mg/kg (n=7) or 2 mg/kg of botensilimab was administered every 6 weeks, and 3 mg/kg of valstilimab was administered every 2 times.
 

During the average 5.8-month follow-up period, we showed good results, reporting a total of 73% disease control rates, including 24% objective response rate and 49% stable disease maintenance. Patients with no active liver metastasis showed more positive responses with an objective response rate of 42% and a disease control rate of 96%. At the time of data analysis, 80% of patients were continuing treatment, and 30% of patients were being treated for more than a year. The response of treatment was not related to the presence of RAS mutations, and PD-L1 positive was reported in one of the patients who had a treatment response. All patients who responded to treatment were patients with no high tumor mutation burden, and two patients who had no previous effect on combination therapy with immuno-cancer drugs and TKI were also reported to have a treatment response.
 

Although 76% of patients had all levels of treatment-related side effects, the most common treatment-related side effects were diarrhea or enteritis (10%), fatigue (2%), fever (2%), increased liver levels (2%), and joint pain (2%), and severe pneumonia and other side effects were rare.
 

Immunization-related adverse events were reported in 46% of patients, of which 17% reported immune-related adverse events of Grade 3 or higher, which resulted in botensilimab discontinuation in 10% of patients and both drugs in 10% of patients.

Colorectal cancer is the second leading cause of cancer-related death worldwide, and about 95% are MSS-type colorectal cancer, making it difficult to prove the therapeutic effect of immuno-cancer drugs, but the results of effective and durable immuno-cancer combination therapy have been introduced and are expected. A large phase 2 randomized comparative clinical trial of MSS colon cancer patients will begin within this year.