Targeted therapy a possibility in KRAS-mutated metastatic colorectal cancer

The authors evaluated the use of sorafenib and irinotecan-based combination chemotherapy in patients with KRAS-mutated metastatic colorectal cancer who had progressive disease despite prior treatment.

KRAS-mutated metastatic colorectal cancer is a cancer that has a mutated KRAS gene (an important gene in various signaling pathways) and that has spread beyond the colon or the rectum. Metastatic colorectal cancers are often treated with both chemotherapy and targeted biological agents. However, KRAS mutations often render the cancers unresponsive to many targeted drugs known to be useful in the treatment of colorectal cancer. Thus, the search for new drug targets or chemotherapy combination treatments remains a high priority.

Sorafenib is an oral targeted biological agent which inhibits cell growth and prevents the development of new blood vessels. It is typically used in the treatment of kidney and liver cancers, and has been shown to work even in the presence of a KRAS mutation. The authors of this early phase trial evaluated the possibility of combining sorafenib with the standard irinotecan chemotherapy regimen in treating KRAS-mutated colorectal cancer patients.

54 patients were recruited for this trial. 72% had liver metastases and nearly half had lung metastases. Surgical removal of the primary tumor had occurred in 87% of patients, while removal of distant metastases had occurred in 31% of patients. All patients had previously received combined fluorouracil and irinotecan chemotherapy. Patients were treated with oral sorafenib twice daily and irinotecan chemotherapy every 2 weeks. On average, patients underwent 4 treatment cycles, and the average follow up was 7 months.

Most adverse events were mild or moderate. Severe adverse events included diarrhea (37%), weakness or lack of energy (22%), neutropenia (dangerously low levels of white blood cells; 18%) and hand-foot syndrome (redness, swelling or pain in the hands or feet; 13%). Life-threatening or disabling neutropenia was observed in 16.7% of patients.

Of the 54 patients enrolled, 64.9% of patients demonstrated some response to treatment. Only 17% of patients received sorafenib at the full dose for the entire treatment schedule. Of the 9 patients treated with full-dose sorafenib for the entire schedule, 66.7% of patients achieved stable disease (cancer that is neither decreasing nor increasing in extent or severity). The average time following treatment before disease progression was 3.7 months, and on average, overall survival was 8 months.

The authors concluded that combining sorafenib and irinotecan in extensively pretreated patients with KRAS-mutated metastatic colorectal cancer is feasible and may hold significant benefit for selected patients.

The high percentage of patients who were unable to tolerate the full-dose of sorafenib used in this trial suggests new dosage limits should be considered.