Survival Comparable With Bevacizumab, Cetuximab in mCRC

Alan P. Venook, MD

Frontline therapy with bevacizumab or cetuximab 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. (Abstract LBA3)

“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 announcing the findings 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, whereas 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.

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.

“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 progressionfree 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.

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 which results in treatment discontinuation, whereas 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.”

Another targeted therapy, panitumumab, 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 wildtype mCRC.

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.”

Nurse Perspective

Laura Metcalfe, MSN, RN, APN,C, AOCNS

John Theurer Cancer Center

Hackensack, NJ

The results from CALGB/SWOG 80405 served to confirm what oncology clinicians have known for a few years now. I have attended several conferences where it has even been described as “dealer’s choice,” when it comes to deciding on the best sequencing of these regimens. As stated in the article, FOLFOX/bevacizumab is the most common frontline therapy in the United States, while in Europe cetuximab-based regimens are more common.

In our practice, FOLFOX/bevacizumab is our frontline therapy unless there is some contraindication. For example, if a patient already has neuropathy, be it from diabetes or some other cause, we would likely not want to use oxaliplatin. Also, if the patient uses his/her hands in their profession, eg, a surgeon or a musician, we also might choose to avoid oxaliplatin. Coronary artery disease might preclude the use of bevacizumab.

In the absence of any contraindication, FOLFOX and bevacizumab has a much better side effect profile and remains our preferred regimen. No hair loss and no skin rash and minimal nausea and diarrhea make it a very well tolerated regimen. We try to reserve the cetuximab/irinotecan or panitumumab/irinotecan regimens for later progressions. Many of our FOLFOX/bevacizumab patients are working and are able to continue working while receiving treatment. In general, they look and feel well. The hair loss and skin rash associated with cetuximab/ irinotecan or panitumumab/irinotecan regimens leave patients with altered body image and often reluctance to see people who now can see that they are “sick.” Also, the irinotecan-induced diarrhea often makes leaving the house difficult due to concerns of “not making it” to the bathroom on time.

Obviously, when treating mCRC extending the patient’s life while maintaining as much quality of life as possible is our primary endpoint. Given that both of the regimens show comparable survival rates, FOLFOX/bevacizumab remains our first-line regimen of choice assuming no contraindications.