Anti-EGFR Agents Detrimental in Colorectal Cancer Patients With KRAS Mutation

Nick Mulcahy

October 09, 2009

October 9, 2009 (Philadelphia, Pennsylvania) — For the second time in a major clinical study, patients with colorectal cancer whose tumors contain the mutant form of the KRAS gene have shown negative outcomes when treated with an antiepidermal growth factor receptor (EGFR).

It is already well established that only patients with wild-type KRAS tumors benefit from treatment with an anti-EGFR agent and that patients with KRAS mutations do not.

In both Europe and the United States, labeling for the anti-EGFR agents now calls for use only in patients with wild-type tumors, as reported by Medscape Oncology.

However, the finding that these drugs produce a negative outcome in patients with mutated KRAS is relatively novel. This finding has now been reported with both of the anti-EGRF inhibitors, panitumumab (Vectibix) and cetuximab (Erbitux).

The negative finding with panitumumab comes from the PRIME study, and has just been reported — initially at the recent European Society of Medical Oncology (ESMO) meeting in Berlin, Germany, and last week here at the annual meeting of the International Society of Gastrointestinal Oncology (ISGIO).

In the PRIME study, panitumumab was used with the FOLFOX regimen as first-line treatment for colorectal cancer; results showed worse outcomes in patients with KRAS mutations receiving panitumumab plus FOLFOX than in those receiving FOLFOX alone.

The negative finding with cetuximab was reported in 2008, and comes from the Dutch CAIRO2 study. In that study, when cetuximab was added to a regimen of chemotherapy and bevacizumab for the first-line treatment of colorectal cancer, outcomes in patients with KRAS mutations were worse.

At the ISGIO meeting, PRIME investigator Salvatore Siena, MD, said that the reason for the detrimental effect of panitimumab in patients with mutated KRAS "remains unknown." Dr. Siena is from Ospedale Niguarda Ca'Granda, in Milan, Italy.

Going forward, the right thing to do is to get the information on all patients.

These varied treatment outcomes in colorectal cancer patients serve as a reminder of the importance in determining the molecular biology of their tumors, said a member of a panel discussion on metastatic colorectal cancer at ISGIO. "Going forward, the right thing to do is to get the information on all patients," said Howard Hochster, MD, from the New York University Cancer Institute in New York City.

Currently in the United States, only stage IV patients are all profiled for their tumor status, noted panel member Leonard Saltz, MD, from Memorial Sloan-Kettering Cancer Center in New York City.

"Whether we can justify profiling all colorectal cancer patients from an insurance point of view is another question," he added

Coke and Pepsi

Both panitumumab and cetuximab are anti-EGFR monoclonal antibodies. Both panitumumab and cetuximab are approved in the United States for metastatic colorectal cancer, but as second-line agents. Panitumumab is approved as a monotherapy, whereas cetuximab is approved both as a monotherapy and in combination with irinotecan.

"Cetuximab and panitumumab are like Coke and Pepsi," said Dr. Saltz told Medscape Oncology at ISGIO. "They are 2 brands of a very similar drug."

Two new trials with panitumumab were presented at both ESMO and ISGIO. In both studies, the agent was used in combination with chemotherapy for metastatic colorectal cancer — with FOLFOX as a first-line treatment (the PRIME study) and with FOLFIRI as a second-line treatment.

These are marketing studies.

"These are marketing studies," said Dr. Saltz. "Panitumumab is not a meaningful new treatment."

However, Dr. Saltz highlighted a number of ways in which panitumumab has value for clinicians and patients.

"Panitumumab is about 20% cheaper than cetuximab. And in the Southern United States, allergic reactions to cetuximab are much higher than in other regions for some reason. Panitumumab can be a treatment option," he said.

However, another attendee at ISGIO approached by Medscape Oncology was enthusiastic about panitumumab and its possible use in combination with chemotherapy for metastatic colorectal cancer.

These are 2 very important trials.

"Current practice is to use bevacizumab as the targeted therapy in metastatic colorectal cancer," said Bert O'Neil, MD, from the University of North Carolina in Chapel Hill.

The new studies with panitumumab are valuable, said Dr. O'Neil. "These are 2 very important trials because potentially they will give [American] clinicians an earlier opportunity to use an anti-EGFR agent in combination with chemotherapy," he said.

Results With Panitumumab in Combination with Chemotherapy: 2 Studies

In the PRIME trial, a phase 3 multicenter European study, patients were randomized to receive either panitumumab plus FOLFOX or FOLFOX alone as first-line therapy for metastatic adenocarcinoma of the colon or rectum. The patients had received no previous chemotherapy for metastatic disease and no previous oxaliplatin therapy. The primary end point was progression-free survival.

In patients with wild-type KRAS tumors, panitumumab statistically significantly improved progression-free survival when added to FOLFOX (n = 325), compared with FOLFOX alone (n = 331) (median, 9.6 vs 8.0 months; hazard ratio [HR], 0.80; P = .02).

In patients with mutant KRAS tumors, panitumumab statistically significantly decreased progression-free survival when added to FOLFOX (n = 219), compared with FOLFOX alone (n = 221) (median, 7.3 vs 8.8 months; HR, 1.29; P = .02).

The adverse event profile was "as expected" with an anti-EGFR antibody, said investigator Dr. Siena.

In the other phase 3 study, also conducted in Europe, patients were randomized to receive either panitumumab plus FOLFIRI or FOLFIRI alone as a second-line treatment. Patients had metastatic adenocarcinoma of the colon or rectum and only 1 previous chemotherapy regimen for their metastatic disease. The coprimary end points were progression-free survival and overall survival.

In patients with wild-type KRAS tumors, panitumumab statistically significantly improved progression-free survival when added to FOLFIRI (n = 303), compared with FOLFOX alone (n = 294) (median, 5.9 vs 3.9 months; HR, 0.73; P = .004).

Overall survival was also better in patients with wild-type tumors receiving panitumumab plus FOLFIRI, compared with FOLFIRI alone, but not significantly (median, 14.5 vs 12.5 months; HR, 0.85; P = .12).

There was no evidence of benefit in patients with mutated KRAS tumors, said lead investigator Michel Ducreux, MD, from Institut Gustave Roussy in Villejuif, France. However, notably, in this study, these patients did not do worse on panitumumab, as they did in the PRIME trial.

Combination Therapy Approach: Modest Benefit

In a recent essay published in the March/April 2009 issue of the official publication of ISGIO, Gastrointestinal Cancer Research, Dr. Saltz described the current strategy in colorectal cancer of combining, with standard chemotherapy, various new drugs, such as an anti-EGFR agent or the anti-vascular endothelial growth factor bevacizumab, as a case of "if you can't beat 'em, join 'em."

He explained that none of a variety of new agents have met the hope that they would replace standard chemotherapy as the new first-line standard, and described the overall benefit of combination therapy as "modest."

Dr. Saltz has also been an outspoken critic of the cost of targeted therapies, as reported by Medscape Oncology.

Given the performance of various would-be alternatives to chemotherapy for colorectal cancer, it is likely that new agents will be accompanied by specific diagnostic criteria, such as KRAS status, for the selection of appropriate patients for treatment, he writes. The approach will protect patients with "little or no likelihood of success from the expense and toxicity of treatment."

Both studies of panitumumab were funded by Amgen. Dr. Saltz is a consultant to Delcath, Novartis, Genomic Health, Genzyme, Roche, Genentech, Bristol-Myers Squibb, ImClone, Merck, Biorhera, and Pfizer. He also reports research funding from Roche, Genentech, Bristol-Myers Squibb, ImClone, Merck, Biorhera, Pfizer, Amgen, Taiho, and CureTech. Dr. O'Neil is a consultant to Sanofi-Aventis and Bristol-Myers Squibb. He is a member of the speaker's bureau for Sanofi-Aventis, Bristol-Myers Squibb, and Amgen, the makers of panitumumab. Dr. Ducreux is a consultant to Roche Pharma, Amgen, and Pfizer, and has received honoraria from these companies and from Bayer.

International Society of Gastrointestinal Oncology annual meeting: Abstracts 0925 and 0926. Presented October 3, 2009.

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