Cetuximab and Panitumumab Equally Effective in Colorectal Cancer

October 6, 2010 — Now that the results from large phase 3 trials with panitumumab (Vectibix) in advanced colorectal cancer have been published and scrutinized alongside earlier results with cetuximab (Erbitux), it appears that both drugs are equally effective in patients with wild-type KRAS colorectal cancer.

"It now seems safe to say that panitumumab and cetuximab [are] equally effective and interchangeable in clinical practice, either as monotherapy or in combination with cytotoxic chemotherapy," writes Alex Grothey, MD, professor of oncology at the Mayo Clinic in Rochester, Minnesota, in an editorial published online October 4 in the Journal of Clinical Oncology.

The editorial accompanies the final results from 2 manufacturer-sponsored trials (designated PRIME 203 and 181) in which panitumumab was added to chemotherapy regimens.

The new data "add substantially to the body of evidence" for these drugs in the treatment of advanced colorectal cancer, Dr. Grothey reports.

Publication of New Panitumumab Data

One trial looked at first-line treatment with panitumumab added to fluorouracil, leucovorin, and oxaliplatin (FOLFOX); the other looked at second-line therapy with panitumumab added to fluorouracil, leucovorin, and irinotecan (FOLFORI). Both treatments showed a statistically significant improvement in progression-free survival in patients with wild-type KRAS metastatic colorectal cancer.

Dr. Grothey notes that, as far as he knows, these 2 studies were the first in which "the primary end point was prospectively adjusted to focus on KRAS wild-type colorectal cancer."

In earlier trials, the results were reanalyzed retrospectively to determine the KRAS status of the patients' tumors. Nevertheless, most of the results so far point in the same direction (with the exception of the Continuous Chemotherapy Plus Cetuximab or Intermittent Chemotherapy [COIN] trial): these drugs work only in patients with wild-type KRAS colorectal.

This has led to the testing of all colorectal cancer for KRAS status and the use of the results to select patients for therapy. This move rapidly made its way into guidelines, regulatory approval, and clinical practice, writes Dr. Grothey, so "one might think that we should have convincingly defined the role of EGRF antibodies in the management of colorectal cancer by now."

But a number of questions remain, he cautions. Perhaps the most important one facing oncologists, from a practical point of view, is how these drugs fit into the treatment algorithm with another targeted drug — bevacizumab (Avastin).

Where Do They Fit Alongside Bevacizumab?

At this point in time, EGRF antibodies should not be combined with bevacizumab, Dr. Grothey notes, because there have been reports of an antagonistic effects when both were combined with fluoropyrimidine-containing chemotherapy regimens. There have been hints of "intriguing activity," but these data have not been confirmed, he adds.

Hence, EGRF antibodies and bevacizumab have to be used sequentially — but which should be tried first?

Answers to this question should be forthcoming from 2 ongoing phase 3 head-to-head comparisons of cetuximab and bevacizumab added to chemotherapy (first-line in the CALGB 80405 trial, and second line in the SWOG S0600 trial).

Until definite data from these trials are reported, oncologists have to rely on an analysis of the available data, Dr. Grothey notes. He reviews the data available so far, and makes a few recommendations.

"In a purely palliative setting, where the goal of therapy is to extend patient's lives and maintain their quality of life for as long as possible, EGRF antibodies should be reserved for later lines of therapy," he suggests.

He explains this recommendation by pointing out that "the antitumor activity of these agents appears to be independent of the line of therapy. . . . In fact, their benefit, as measured by the hazard ratio of [progression-free survival], is greater when the antibodies have been used as salvage treatment or even as single agents, compared with earlier lines of therapy."

However, there are situations in which the EGRF antibodies should be considered in front-line therapy, Dr. Grothey continues.

EGRF antibodies used with chemotherapy have consistently resulted in improved objective response rates in KRAS wild-type colorectal cancer. This would be useful in patients "in whom substantial tumor shrinkage might allow for surgical resection of metastases, and for patients who require a rapid response to alleviate threatening symptoms from bulky tumor burden." It would also be useful in patients who have contradictions to bevacizumab, he adds.

Clarification of where the 2 approaches fit with one another should come once results from the ongoing head-to-head trials are reported, Dr. Grothey concludes.

Approached for comment, John Marshall, MD, chief of hematology/oncology at Georgetown University, in Washington, DC, who writes the Marshall on Oncology videoblog on Medscape Medical News, said he broadly agrees with the these suggestions.

"Our aversion to using EGFR antibodies in earlier lines of therapy is primarily due to the well-documented rash that patients experience. As we learn to better manage this toxicity, we may begin to see earlier use of the compounds," he told Medscape Medical News.

We have assumed that we can mix and match as we choose, but this in fact may not be so.

The ongoing head-to-head trials "will be critical in our decision making," he continued. "Our trial data to date with both bevacizumab and panitumumab combined with FOLFOX have not been overwhelmingly positive, and our enthusiasm for the addition of these agents to standard chemotherapy needs further support."

"We must also consider which chemotherapy agents to add to which biologics. To date, we have assumed that we can mix and match as we choose, but this in fact may not be so," Dr. Marshall said. "In the absence of new agents on the horizon for colon cancer, we must spend this time optimizing the agents we do have."

Dr. Grothey reports receiving research funding from Genentech and Bayer Pharmaceuticals. Dr. Marshall reports serving as an advisor or consultant and as a speaker for Amgen, Genentech, and Roche.

J Clin Oncol. Published online October 4, 2010. Abstract, Abstract, Abstract

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