Survival Comparable With Bevacizumab, Cetuximab in mCRC

Frontline therapy with bevacizumab (Avastin) or cetuximab (Erbitux) combined with either FOLFOX or FOLFIRI yielded a comparable survival benefit of approximately 29 months in patients with KRAS wild-type metastatic colorectal cancer

Alan P. Venook, MD

Frontline therapy with bevacizumab (Avastin) or cetuximab (Erbitux) combined with either FOLFOX or FOLFIRI yielded a comparable survival benefit of approximately 29 months in patients with KRAS wild-type metastatic colorectal cancer (mCRC), according to results from the phase III CALGB/SWOG 80405 trial.

“Either bevacizumab or cetuximab with either FOLFIRI or FOLFOX are perfectly reasonable options for first-line therapy in this population of patients,” lead author Alan P. Venook, MD, the Madden Family Distinguished professor of Medical Oncology and Translational Research at the University of California in San Francisco, said in a press briefing at the 2014 ASCO Meeting.

Historically, the combination of bevacizumab and FOLFOX has been widely used in treating patients with mCRC in the United States, while European physicians more frequently prescribe cetuximab-based regimens.

At last year’s ASCO annual meeting, results from the phase III FIRE-3 study showed a survival benefit with cetuximab over bevacizumab in KRAS wild-type patients but did not demonstrate an improvement in progression-free survival or overall response. It has been hypothesized that downstream treatments may have impacted the trial outcome. The results from 80405 may offer further clarity in the first-line mCRC space.

In the final 80405 trial design, 1137 patients with treatment-naïve KRAS wild-type (codons 12 and 13) mCRC (performance status 0-1) were randomized in a 1:1 ratio to cetuximab (n = 578) or bevacizumab (n = 559) plus physician’s choice of FOLFOX or FOLFIRI. Cetuximab was administered at an induction dose of 400 mg/m2 followed by 250 mg/m2 weekly, and patients received bevacizumab at 5 mg/kg every 2 weeks. Among all patients, 26.6% were treated with FOLFIRI and 73.4% received FOLFOX. Treatment was continued until curative surgery, disease progression, or unacceptable toxicity.

Median patient age in the study was 59 years and 61% of patients were male. Overall survival (OS) was the primary endpoint.

At a median follow-up of 24 months, OS was 29 months (95% CI, 25.7-31.2) in the bevacizumab arm and 29.9 months (95% CI 27.0-32.9) in the cetuximab arm (HR = 0.925; 95% CI, 0.78-1.09; P = .34).

“The overall survival exceeding 29 months in both arms really establishes a new benchmark for the treatment of patients with colorectal cancer,” Venook said.

With the secondary endpoint of progression-free survival, disease progression was delayed by a median of 10.8 months (95% CI, 9.7-11.4) in patients receiving bevacizumab compared with 10.4 months (95% CI, 9.6-11.3) in the cetuximab group (HR = 1.04; 95% CI, 0.91-1.17; P = .55).

The treatment side effects in the trial were comparable to those reported with these agents in previous clinical research. Common toxicities associated with bevacizumab include high blood pressure, headache, mouth sores, nosebleed, diarrhea, bleeding from the rectum, loss of appetite, fatigue, and weakness. With cetuximab therapy, the most frequently reported side effects include acne-like rash, itching, changes in fingernails and toenails, infections, fatigue, and low blood electrolyte levels.

The toxicities associated with FOLFOX and FOLFIRI also vary. FOLFOX can cause neuropathy that results in treatment discontinuation, while FOLFIRI is associated with higher rates of alopecia and diarrhea.

With the comparable efficacy established in the 80405 study, and the similar costs of cetuximab and bevacizumab therapy, Venook said,“[The choice of] first line therapy should reflect the patient’s preference or concern for potential side effects.”

Regarding the next steps with 80405, Venook said, “There are a lot of data still pending. There are information gaps that we will fill in as we go along over the next 6 months to a year.” Additional analyses underway include FOLFOX versus FOLFIRI, expanded RAS, response rate, duration of therapy, dose intensity, specifics of surgery, and subsequent therapies. The researchers hope the additional data may help identify optimal treatment choices for patient subsets.

Another targeted therapy, panitumumab (Vectibix), was recently approved in combination with chemotherapy as a frontline treatment for patients with KRAS wild-type mCRC. One of the studies on which the FDA based its approval was the phase III ASPECCT trial, in which single-agent panitumumab was shown to be noninferior to cetuximab in patients with previously treated KRAS wild-type mCRC.

In an interview with OncLive, Venook said it is likely that the 80405 results could be extrapolated to panitumumab, and that the three targeted agents are all valid frontline options in treating KRAS wild-type mCRC. “This is an evolving field, but I would assume [these results] apply to panitumumab, as well.”

Venook AP, Niedzwiecki D, Lenz HJ, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol. 2014;32:5s (suppl; abstr LBA3).

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