Experts Emphasize Therapy Options, Expanded Mutation Testing in mCRC

Lauren Zoeller
Published: Tuesday, Nov 18, 2014
Dr. Johanna C. Bendell

Johanna C. Bendell, MD

Confusion persists about the best choice of frontline therapy for patients with metastatic colorectal cancer (mCRC) after a landmark clinical trial that was conceived a decade ago to answer that question concluded without a superiority finding, according to a panel of internationally recognized experts in gastrointestinal oncology.

The take-home message from a recent OncLive Peer Exchange roundtable entitled “Optimizing the Treatment of mCRC” is that physicians can choose which treatment strategy would work best for each patient: either cetuximab (Erbitux) or bevacizumab (Avastin) with either FOLFOX or FOLFIRI.

Both agents are FDA-approved for frontline therapy in combination with chemotherapy.

The phase III CALGB/SWOG 80405 study demonstrated that combining either of the targeted agents with chemotherapy resulted in a comparable survival benefit of approximately 29 months among patients with KRAS wild-type mCRC.1

“The 30,000-foot view is that we have overall survival of 29 months in both arms of a study that was done across the US and Canada in many sites,” said Alan P. Venook, MD, during the panel discussion. “The survivorship is much better than what we’ve seen before. That’s exciting. Now, the devil is in the details in figuring out how we can improve on it.” Venook presented the results of 80405 during a plenary session at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting in June. It was the first ASCO plenary session to focus on CRC in years, noted Johanna C. Bendell, MD, who served as moderator for the Peer Exchange discussion.

How the Study Design Evolved

The 80405 study was designed to evaluate the overall survival (OS) of patients with advanced CRC who were treated with either FOLFOX or FOLFIRI and then randomized to cetuximab, bevacizumab, or both. Since the trial was initiated, the cetuximab/bevacizumab arm was dropped based on worse outcomes with dual-targeted therapy.

As the trial design incorporated the investigator’s choice of the frontline chemotherapy regimen, the ultimate question asked by the study was a biologic one: What’s better—anti-EGFR therapy or an anti- VEGF therapy? Cetuximab targets EGFR, while bevacizumab targets VEGF.

Originally, KRAS mutations were not considered and the protocol was amended to look specifically at KRAS wild-type patients. Overall, 80405 was an enormous undertaking, incorporating a number of correlative studies.

“New Benchmark” Established

In the final trial, 1137 patients with treatment-naïve mCRC, KRAS wild-type status at exon 2 codons 12 and 13, and performance status 0-1, were randomized 1:1 to cetuximab (n = 578) or bevacizumab (n = 559). At a median follow-up of 24 months, OS was equivalent in both arms—29 months for bevacizumab and 29.9 months for cetuximab (HR, 0.925; P = .34). “Overall survival exceeding 29 months in both arms really establishes a new benchmark for the treatment of patients with CRC,” Venook said. Median progression-free survival (PFS) was also equivalent for both antibodies at 10.8 months in patients receiving bevacizumab compared with 10.4 months in the cetuximab group (HR, 1.04; P = .55). Toxicities with both agents were in line with those previously reported.

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