Colorectal Cancer KRAS Mutation: Combining with Cetuximab Increases Treatment Efficacy

KRAS inhibitors are gaining attention as a new breakthrough in the treatment of colorectal cancer. KRAS inhibitors (KRAS G12C targeted therapies), which first achieved success in lung cancer, are expanding their scope into the field of colorectal cancer by proving excellent therapeutic effects through combination therapy.

According to a video from the medical channel After the Rain, Professor Kim Han-sang of the Department of Medical Oncology at Yonsei Cancer Center explained that approximately 40–45% of colorectal cancer patients possess KRAS mutations. KRAS is an important protein involved in the growth of cancer cells; when a mutation occurs, unlike normal cells, the switch remains in the 'ON' state, inducing the proliferation of cancer cells. Recently, not only technologies to inhibit this 'KRAS ON' state but also the development of drugs that induce a 'KRAS OFF' state are actively underway.

Characteristics of Colorectal Cancer KRAS Mutations and the Importance of the G12C Mutation

KRAS mutations are very diverse. Various forms exist, such as G12D, G12C, G13D, and G12V, among which the G12C mutation has accumulated the most research and evidence to date. G12C accounts for approximately 3–4% of all colorectal cancer patients, appearing in about one out of every 33 patients.

Professor Kim Han-sang explained, "When a G12C mutation occurs, the amino acid position that should originally be glycine changes to cysteine, creating a site where a drug can attach." Due to the amino acid structure, glycine is a very flat position, making it difficult to create drugs, but with advancements in biotechnology, drugs such as Sotorasib and Adagrasib targeting G12C have been developed. Recently, drugs targeting G12D or G12V are in the clinical trial stage, which is expected to provide new opportunities for patients.

A Treatment Strategy Unique to Colorectal Cancer, Different from Lung Cancer: Combination with EGFR Antibody

An important point in colorectal cancer treatment is that the treatment method differs from lung cancer. In lung cancer, efficacy can be seen even with the use of a KRAS inhibitor alone, but colorectal cancer is characterized by cancer cells growing through other bypass routes. Therefore, it is difficult to see sufficient effects with only a KRAS inhibitor.

To overcome this, a combination therapy using a KRAS inhibitor along with the EGFR antibody Cetuximab is required in colorectal cancer. Citing results from past Phase 3 trials, the video emphasized that while the effect was only 2 months when using existing drugs in third-line or later therapies, the responsiveness significantly improved to 5.7 months when KRAS inhibitors were combined with Cetuximab. Currently, such combination therapies are being used in some countries like the United States, and in Korea, treatment opportunities are being prepared through clinical trials and other means. However, there is volatility based on clinical results, such as the recent cancellation of approval for certain drugs in the United States.

Evaluation of Anticancer Treatment Response and Patient Response

During anticancer treatment, the patient's condition and response must be continuously evaluated. Answering patient questions, Professor Kim Han-sang mentioned 'organ-specific diversity,' where the response to anticancer drugs can appear differently depending on the organ. For example, even if there are no changes in the lungs or bones, if the response is good in the liver, the overall situation can be evaluated as being well-controlled. In this way, the response to anticancer drugs varies by cancer type, person, and organ.

The timing for considering a change in anticancer drugs is when new lesions appear or when the tumor size increases noticeably on a CT scan. However, drugs are not changed immediately just because tumor markers in a blood test have risen; decisions are made in conjunction with CT results. Even if tumor markers rise, if there is no significant change on the CT, anticancer treatment can be maintained.

Furthermore, in cases where liver metastasis has progressed multifocally, it may be important for prognosis management to quickly start treatment through combination cytotoxic anticancer therapy rather than waiting for genetic testing results. This is because as liver metastasis worsens, symptoms such as leg edema, ascites, weight loss, and jaundice may appear sequentially over time. Patients should establish treatment strategies by consulting closely with their primary physician.