Cetuximab, Bevacizumab Equivalent as First-Line Therapy in KRAS Wild-Type mCRC

Alan P. Venook, MD

A head-to-head comparison of cetuximab (Erbitux) and bevacizumab (Avastin) in a phase III trial that was nearly 10 years in the making showed equivalence for chemotherapy plus either agent in terms of overall survival (OS), progression-free survival (PFS), and response rates for patients with certain previously untreated metastatic colorectal cancers (mCRC). However, variations were seen when different chemotherapy regimens were combined with either agent.

Alan Venook, MD, the Madden Family Distinguished Professor of Medical Oncology and Translational Research at the University of California, San Francisco presented findings on behalf of investigators from CALGB (Cancer and Leukemia Group) investigators June 28 at the ESMO 16^th Annual World Congress on Gastrointestinal Cancer.

Trial 80405 enrolled patients with previously untreated KRAS (codons 12, 13) wild-type metastatic adenocarcinoma of the colon or rectum, who had an ECOG performance status of 0 or 1 and tumor blocks available for EGFR analysis. Patients were randomized to receive either chemotherapy/cetuximab or chemotherapy/bevacizumab. They were assigned to chemotherapy with either irinotecan/5FU/leucovorin (FOLFIRI) or oxaliplatin/5FU/leucovorin (FOLFOX) by investigator decision. A third arm not detailed during the presentation gave patients chemotherapy in addition to both bevacizumab and cetuximab, according to a summary at ClinicalTrials.gov.

“The CALGB/SWOG 80405 trial was designed and formulated in 2005, and the rationale was simple: We had new drugs, bevacizumab and cetuximab, and the study was designed to determine if one was better than the other in first-line for patients with colon cancer,” remarked Venook.

The agents target different pathways that are involved in mCRC; cetuximab, an IgG1 monoclonal antibody, targets the epidermal growth factor receptor (EGFR) and bevacizumab targets the vascular endothelial growth factor (VEGF).

The primary endpoint of the study was OS, and secondary endpoints included PFS and response.

A total of 1137 patients were enrolled. Following randomization, patients received chemotherapy plus either bevacizumab (n=559) or cetuximab (n=578) until progression or unacceptable toxicity. The bevacizumab dose was 5 mg/kg every other week; the cetuximab dose was a 400 mg/m² loading dose, then 250 mg/m² every week.

OS rates were similar between treatment arms; median OS was 29.9 months with chemotherapy plus cetuximab compared with 29.0 months with chemotherapy plus bevacizumab (hazard ratio [HR] = 0.92; P = .34). Median PFS was 10.8 months with bevacizumab compared with 10.4 months with cetuximab (HR = 1.04; P = .55).

“There was no meaningful difference in outcome between treatment arms,” commented Venook. “In both arms, patients lived close to 30 months. About 10% of patients lived more than 5 years. Overall, patients did much better than anticipated, and this result was indifferent to the type of treatment.”

OS and PFS evaluated by chemotherapy backbone showed some variations in outcomes.

For instance, OS in the FOLFOX group was improved with cetuximab more than with bevacizumab; median OS in the FOLFOX arm was 30.1 months with cetuximab versus 26.9 months with bevacizumab (HR = 0.9; P = .09).

In the FOLFIRI group, median PFS with cetuximab was 10.3 months versus 11.6 months with bevacizumab (HR 1.0; P = .89).

Venook presented freshly analyzed data from his statistician that is documented but not yet audited, showing that objective response rate (ORR) among patients treated with chemotherapy/cetuximab was higher than for those in the chemotherapy/bevacizumab arm (66% versus 57%, respectively).

Further analysis showed that ORR was 67% versus 56% with FOLFOX plus cetuximab and bevacizumab, respectively. With FOLFIRI, the ORR was 62% versus 61% with cetuximab and bevacizumab, respectively.

Complete response was achieved by 7.4% and 3.0% of patients receiving cetuximab and bevacizumab, and partial response was 58% versus 54%, in the respective groups.

No significant differences in grade 3 or 4 diarrhea or any other grade 3 or 4 toxicities were observed.

In the respective cetuximab and bevacizumab arms, treatment was discontinued due to disease progression by 31.8% versus 27.2%, due to adverse event/change in therapy by 54.6% and 56.3%, or due to death on study by 2.1% versus 2.7% of patients.

“Overall survival on chemotherapy plus cetuximab is not different from chemotherapy plus bevacizumab; FOLFIRI or FOLFOX with either cetuximab or bevacizumab can be considered for first-line therapy of patients with KRAS (codons 12, 13) wild-type metastatic colorectal cancer,” Venook commented.

“This was a long-awaited phase 3 trial with a head-to-head comparison of two different molecular approaches.” He continued: “We now know that using any monoclonal antibody with any standard chemotherapy in first-line treatment may give the patient the likelihood of surviving about 30 months,” said Dirk Arnold, MD, director of the Department of Medical Oncology at the Tumour Biology Centre in Freiburg, Germany.

“The only issue raising some questions is the fact that patients who bear any mutations may be at risk of a detrimental effect,” Arnold said. “So genetic testing is not only a prerequisite to ensure the maximum benefit, it is also needed to ensure that we do not harm patients by treating them.”

The study was sponsored by CALGB and the Southwest Oncology Group (SWOG).

Reference

Venook A, Neidzwiecki D, Lenz H-J. 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. Presented at: the ESMO 16^th Annual World Congress on Gastrointestinal Cancer; June 25-28, 2014; Barcelona, Spain. Abstract O-0119.

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