Certain cases of advanced colorectal cancer respond better to three-drug regimen

Patients with a form of advanced colorectal cancer driven by a mutated version of the BRAF gene have limited treatment options. However, results from a multicenter clinical trial suggest that this cancer may respond to a combination of three targeted drugs.

These results were presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, by Professor Josep Tabernero, MD, PhD, head of the medical oncology department at Vall d'Hebron University Hospital and director of the Vall d'Hebron Institute of Oncology, Barcelona, Spain.

The study is investigating the BRAF inhibitor encorafenib combined with cetuximab, which inhibits the epidermal growth factor receptor (EGFR), with or without a third drug, alpelisib, which inhibits the PI3K, another cancer-causing pathway, in a phase I clinical trial in patients with advanced BRAF-mutated colorectal cancer.

"Among the 54 patients enrolled in the dose-finding part of the trial, we found that tumors shrank in 23% of the patients receiving encorafenib and cetuximab, and in 32% of patients receiving a combination of all three drugs," he said.

"The median length of time that patients survived without their disease worsening ranged from 16 weeks for patients receiving the dual therapy to 19 weeks for those receiving all three drugs. While we were not comparing patients on these therapies with patients receiving the normal standard of care, these progression-free survival times are nearly double those for patients who have been treated in the past with standard of care therapies."

Tabernero continued by explaining that patients with advanced colorectal cancer whose tumors have BRAF mutations invariably fail to meaningfully respond to standard treatments, which leads to a dismal prognosis. Recent attempts to inhibit BRAF in colorectal tumors with a single agent have been largely disappointing. So, this trial used a trio of existing therapies in these patients.

"While it is still early days and these are preliminary data, this combinatorial strategy is showing improved efficacy, extended progression-free survival, with manageable side effects in patients. This study, therefore, represents a significant step forward in providing metastatic colorectal cancer patients with fresh hope and a new therapeutic avenue," said Tabernero.

Patients on the trial were treated with encorafenib, taken orally once a day, together with a standard intravenous dose of cetuximab (400 mg/m2 for the initial loading dose, followed by 250 mg/m2 weekly). In addition, 28 of the patients also received an oral dose of alpelisib once a day.

The researchers found that the combination of drugs was generally well tolerated by the patients. Adverse side effects for the dual therapy included fatigue, reactions to the infusion, and low phosphate levels in the blood. The addition of alpelisib also caused nausea, diarrhea, skin rashes, high blood sugar levels, and increased levels of lipase.

The trial is continuing to enroll patients.

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