Call it a draw: Cetuximab (Erbitux), an EGFR inhibitor, and bevacizumab (Avastin), a VEGF inhibitor, confer comparable benefits as first-line treatment with chemotherapy for metastatic colorectal cancer, according to the phase III Cancer and Leukemia Group B (CALGB)/Southwest Oncology Group (SWOG) 80405 trial presented at the 2014 ASCO Annual Meeting Plenary Session.1
“We did not show a meaningful difference between the arms. These two distinctly different biological treatments did not impart differences in outcomes. Either is appropriate in the first-line metastatic setting,” said Alan P. Venook, MD, the Madden Family Distinguished Professor of Medical Oncology and Translational Research at the University of California, San Francisco.
The high median overall survival—29-plus months—along with the finding that 10% of patients were alive past 5 years, confirms the progress that has been made in metastatic colorectal cancer over the years, Dr. Venook emphasized. Approximately 25 years ago, the median overall survival for these patients was about 8 months, he noted.
Clifford A. Hudis, MD, FACP, Immediate Past President of ASCO, who moderated the press briefing, commented, “This study sets a new standard and a new high bar for clinical trials in advanced colorectal cancer.”
Rationale for the Federally Funded Trial
CALGB/SWOG 80405, designed in 2004, was a Herculean effort, involving 14 amendments and 11 interim analyses as the field of colorectal cancer treatment evolved over 10 years. At the time it was designed, bevacizumab and cetuximab had been only recently approved.
“The drugs were new at the time, and they had very different toxicity profiles. The question was, which was the optimal first-line treatment?” Dr. Venook said at a press briefing. “The assumption at the start was that maybe one was better.”
The results of the trial were highly anticipated, since the previous FIRE-3 trial, reported at the 2013 ASCO Annual Meeting, found that cetuximab improved overall survival but not progression-free survival.2 The findings puzzled many experts, who looked forward to the results of this nonindustry, federally funded trial that compared the two monoclonal antibodies.
“Some of our results appear contrary to findings in other studies. We await complete data to place these in perspective,” Dr. Venook said.
Survival High in Both Arms
The study involved 1,137 previously untreated KRAS wild-type (codons 12, 13) metastatic colorectal cancer patients. The study had a superiority design for the cetuximab combination, with overall survival the primary endpoint.
Patients were randomly assigned to chemotherapy plus either bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 initial dose, then 250 mg/m2 weekly). The selection of chemotherapy was based on physician preference: 73.4% received FOLFOX (fluorouracil [5-FU], leucovorin,
oxaliplatin) and 26.6% received FOLFIRI (5-FU, leucovorin, irinotecan). Four-week treatment holidays were permitted.
At a median follow-up of 24 months, no significant differences were observed in either overall survival or progression-free survival between the treatment groups, which was 29 months and 10.8 months, respectively, with bevacizumab/chemotherapy and 29.9 months and 10.4 months, respectively, with cetuximab/chemotherapy. In the FOLFOX arm, median overall survival was 30.1 months with cetuximab and 26.9 months with bevacizumab (P = .09).
Since three-quarters of the physicians chose FOLFOX as the chemotherapy backbone, the small subset receiving FOLFIRI limits any comparison of the chemotherapy backbone. The results suggest that either is “a perfectly reasonable first-line option,” Dr. Venook said.
No Surprises in Toxicity
No new toxicities emerged in this study. With bevacizumab, common side effects were hypertension, headache, mucositis, nosebleed, diarrhea, rectal bleeding, loss of appetite, fatigue, and weakness, while cetuximab patients were more likely to have acneiform rash, pruritus, changes in fingernails and toenails, infections, fatigue, and low serum electrolyte levels. FOLFOX was associated with more neuropathy, whereas FOLFIRI caused more alopecia and diarrhea.
The overall quality of life for patients on either drug was similar, though, as expected, cetuximab-treated patients reported less “skin satisfaction” with that drug.
CALGB/SWOG 80405 and FIRE-3
In an interview with The ASCO Post, Dr. Venook discussed his findings vis-à-vis those of FIRE-3. He attributed differences in the findings as a reflection of the “different patterns of care” in Germany vs North America, especially the near-universal use of FOLFIRI in the former, the greater and “less biased” use of effective second- and third-line treatments in CALGB/SWOG 80405 (88% vs 67%), and the 15% rate of liver metastasis resection in the current study.
He acknowledged that the CALGB/SWOG data “still need to be vetted and validated,” but he emphasized, “our patients’ 29-plus months of median overall survival is unprecedented, and is longer than the 27 months shown in FIRE-3.”
He added, “These patients are doing a little better, and I believe this represents a less biased approach. This is what cooperative groups do: treat patients in studies for which companies are not paying the bill.”
Future Analyses
“The clinical information and biospecimens from the patients in this study represent a rich resource and unique opportunity to gain a deeper understanding of colorectal cancer,” Dr. Venook said.
Yet to come are the clinical subset analyses and molecular studies. The investigators will evaluate outcomes by site of primary tumor and patient gender; outcomes in patients with intact primary tumors; pharmacoeconomics and disparities; effect of vitamin D, lifestyle, and diet; and outcomes in the preamendment cohorts, which included patients with KRAS-mutant disease and those receiving two biologics.
The focus for the next few months will be on analyzing the tumor specimens for what is called “expanded” RAS. The exclusion of patients with RAS mutations other than codons 12 and 13, and including mutations in NRAS, has been shown to enrich populations likelier to benefit from the EGFR antibodies. This might result in a subset of patients being identified who would best be treated by the EGFR antibodies. ■
Disclosure: Dr. Venook is a consultant or advisor for Bristol-Myers Squibb, Chugai Pharma, Mirna, Pharmacyclics, Roche/Genentech, and Sanofi, and has received research funding from Bayer, Genomic Health, GlaxoSmithKline, Onyx, and Roche/Genentech. For full disclosures of the study authors visit abstracts.asco.org.
References
1. Venook AP, Niedzwiecki D, Lenz H-J, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum. ASCO Annual Meeting. LBA3. Presented June 1, 2014.
2. Heinemann V, von Weikersthal LF, Decker T, et al: Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). ASCO Annual Meeting. Abstract LBA3506. Presented June 1, 2013.
