Christopher Lieu, MD

A study presented at the 2017 ASCO Gastrointestinal Cancers Symposium in San Francisco, CA shows promising results for the addition of vemurafenib to treatment with cetuximab and irinotecan in patients with metastatic colorectal cancer that have a BRAF V600E mutation. In the randomized trial, patients who received vemurafenib, a BRAF inhibitor, in combination with cetuximab and irinotecan showed increased progression-free survival and disease control compared with their counterparts who did not receive the drug. The strategy implies that inhibiting BRAF (with vemurafenib) along with EGFR (with cetuximab) may be more potent than either of these targeted treatments used alone.

“Patients with metastatic colorectal cancer that have a BRAF V600E mutation (about 5-10% of all patients that have metastatic colorectal cancer) tend to have a significantly worse prognosis than patients who do not have this mutation,” explains Chris Lieu, MD, director of the CU Cancer Center colorectal medical oncology program.  “This is a group of patients that clearly need better treatment options, and this study is a very positive step in the right direction.”

The discovery takes place in a mutational landscape that can be seen as a musical mixing board. Alone, vemurafenib turns down BRAF but at the expense of turning up the gene EGFR, which is involved in controlling the rate of cell replication (a hallmark of cancer). The unfortunate up-regulation of EGFR may be one reason that BRAF inhibitors alone have not been especially successful in treating colorectal tumors.

“The bench research that investigated the resistance mechanisms of colorectal cancer to this class of targeted therapy led to the development of this trial,” says Lieu. “This is truly a success of what we consider bench to bedside research.”

In the study 106 patients were given a combination of the common colorectal cancer chemotherapy irinotecan with cetuximab, adding or not adding vemurafenib. Patients who were given the combination of the three drugs had better progression-free survival than patients on cetuximab and irinotecan alone (4.4 months versus 2 months) and an increased disease control rate (67 percent versus 22 percent). This study allowed crossover, where patients who were not randomized to receive the BRAF inhibitor (vemurafenib) were allowed to receive the combination of all three drugs at the time that their tumor grew.  Fifty percent of patients who were enrolled onto the trial crossed over and receive the three-drug study regimen. 

“These results and others demonstrate that recent successes in genetically targeted therapies may be only a first step toward the best clinical use of these therapies,” Lieu says. “Now, the challenge is to combine, sequence and prescribe these therapies with the most rational strategies to the patient populations most likely to benefit.”