ASCO 2014: Patients With Metastatic Colon Cancer Respond to New Combination Therapy, Phase IB Study Shows
In a new study presented at the 2014 ASCO Annual Meeting in Chicago (Abstract 3516), researchers from The University of Texas MD Anderson Cancer Center found patients with advanced colorectal cancer responded well to a combination therapy of the drugs vemurafenib (Zelboraf), cetuximab (Erbitux), and irinotecan. The phase IB trial examined the BRAF V600 mutation, which is present in 5% to 10% of patients with colorectal cancer.
Previous research identified this mutation as a target for therapy, but response rates with single-agent vemurafenib were poor. In vitro data in colorectal cancer cell lines have shown that blockade of mutated BRAF by vemurafenib triggers EGFR activation, and, preclinical models demonstrated that EGFR inhibition combined with vemurafenib results in synergistic toxicity, which is further augmented by irinotecan.
"Patients with a BRAF mutation in colorectal cancer are recognized for having aggressive disease that doesn't typically respond to standard chemotherapy," said lead author David Hong, MD, Associate Professor, Investigational Cancer Therapeutics at MD Anderson. "So when BRAF inhibitors initially started, there was excitement this could become the new standard of care; however, we found they didn't work very well."
Study Details
In this trial, researchers combined escalating doses of vemurafenib, along with cetuximab and irinotecan, two drugs previously used in the treatment of metastatic colorectal cancer. Twelve patients were enrolled at two dose levels including seven at dose level 1 (vemurafenib 480 mg, cetuximab 250 mg, and irinotecan 180 mg) and five at dose level 2 with vemurafenib increased to 720 mg.
Radiographic images were evaluated every four cycles over the course of a 14-day cycle of treatment. Patients were assessed for adverse events with the most common including rash, diarrhea, and nausea.
Improved Responses
Of the nine evaluable patients, partial responses or stable disease was seen in all eight patients with colorectal cancer who underwent restaging scans following the beginning of their treatment. The response rate for the eight colorectal patients was 50%, whereas response rates with single-agent vemurafenib are less than 10%.
“What's promising is the fact that we're seeing these high response rates in early studies …There's clearly some kind of synergistic activity with the combination,” Dr. Hong said.
A U.S. cooperative randomized phase II trial of this combination in BRAF-mutated colorectal cancer will begin later this summer led by Scott Kopetz, MD, PhD, Associate Profressor in the Department Gastrointestinal Medical Oncology and senior author of the phase I study.
“While early, the exciting aspect is that we're seeing substantial response rates,” Dr. Kopetz said, noting that “questions remain about the duration of these responses and what the mechanisms of resistance are.”
Dr. Hong, Dr. Kopetz, and Funda Meric-Bernstam, MD, receive research support from Genentech. Michael Overman, MD, receives research support from Genentech and Roche.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
