CHICAGO – Choose one from column A – FOLFOX or FOLFIRI – and one from column B – cetuximab or bevacizumab – and the outcomes will be virtually identical, say investigators reporting on a phase III trial.
Patients with untreated KRAS wild-type metastatic adenocarcinoma of the colon or rectum who were assigned to either the FOLFOX or FOLFIRI chemotherapy regimens at their doctors’ discretion and were then randomized to receive either cetuximab (Erbitux) or bevacizumab (Avastin) had statistically indistinguishable overall survival rates out to 84 months of follow-up, said Dr. Alan Venook at the annual meeting of the American Society of Clinical Oncology, who is a professor of medical oncology, University of California, San Francisco.
Dr. Alan P. Venook
Median overall survival (OS) was 29.0 months in the bevacizumab plus chemotherapy group, and 29.9 months in the cetuximab plus chemotherapy group. Median progression-free survival was 10.8 months and 10.4 months, respectively, Dr. Venook reported in a plenary session at the annual meeting of the American Society of Clinical Oncology.
The findings of the CALGB/SWOG 80450 study suggest that any combination of one of the two chemotherapy regimens and one of the two angiogenesis inhibitors can be considered as equally efficacious options for first-line therapy of patients with KRAS wild-type metastatic colorectal cancer.
"Overall survival exceeding 29 months in both arms establishes a new benchmark for treatment of these patients. This was accomplished across a broad clinical trials network and suggests that the results apply in a variety of practice settings," he said.
Dr. Venook noted that a 1992 meta-analysis based on clinical trials conducted in the 1980s showed a median overall survival of 8 months, highlighting the significant progress made in the field over the last 2 decades.
Take your pick
The investigators enrolled patients with KRAS wild-type metastatic CRC (codons 12 and 13) and Eastern Cooperative Oncology Group performance status of 0 or 1 to, at the treating physician’s discretion, either FOLFOX (oxaliplatin, 5-fluoauracil [5-FU] and leucovorin, the mFOLOX6 modification), or to FOLFIRI (irinotecan, 5-FU, and leucovorin). Treatment could be either for palliative intent or as part of a strategy to resect all metastases. Approximately 75% of the patients received FOLFOX, Dr. Venook said.
The patients were then randomized to receive either bevacizumab or cetuximab. The study, which initially enrolled patients without regard to mutational status and included an arm in which patients received both antiangiogenic agents, was amended following accrual of the first 1420 patients to include only patients with wild-type KRAS, and the combination bevacizumab-cetuximab arm was dropped.
For the current, 11th interim analysis, the investigators compared outcomes for 578 patients treated with cetuximab, and 559 treated with bevacizumab.
As noted before, overall survival (OS) in an intention-to-treat population, the primary endpoint was virtually identical when comparing chemotherapy plus cetuximab or bevacizumab. The hazard ratio (HR) for bevacizumab was 0.925 (P = .34).
Similarly, although PFS was .4 months longer in bevacizumab-treated patients, the difference was not significant (HR, 1.04; P = .55).
Likewise, there were no differences looking at either of the antiangiogenics plus FOLFOX (median OS was 30.1 months with cetuximab vs. 26.9 with bevacizumab, HR , .9; P = .09), or FOLFIRI (28.9 months with cetuximab vs. 33.4 months with bevacizumab, HR, 1.2; P = .28).
Median overall survival among patients determined to be disease free after therapy was 66.3 months.
The only marked differences between the combinations came in grade 3 or 4 toxicities, with grade 3 rash seen with cetuximab but not with bevacizumab, and grade 3 or 4 hypertension and gastrointestinal events occurring more frequently with bevacizumab.
There were similar numbers of study withdrawals and deaths on study.
Dr. Venook noted that data on response rates, duration of therapy by dose intensity, and other parameters are pending and will be reported at a later date.
The results show that "for the time being, the cetuximab added to standard chemotherapy, mainly FOLFOX is not superior to bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. Expanded RAS analysis may change this statement in the near future," commented Dr. Josep Tabernero, head of medical oncology at Vall d’Hebron University Hospital in Barcelona, the invited discussant.
"The treatment choice for each patient should consider efficacy, safety, cost, drug availability and some other important parameters," he said.
Dr. Clifford Hudis, president of ASCO and chief of the breast cancer service at Memorial Sloan–Kettering Cancer Center in New York, commented that the study may give clinicians the confidence to expand treatment options for patients with metastatic CRC.