ANTI-EGFR ANTIBODIES IN COLORECTAL CANCER

January 26, 2010 (Orlando, Florida) — Further analyses of major trials of the 2 monoclonal antibodies against the epidermal growth-factor receptor (EGFR) — panitumumab (Vectibix, Amgen) and cetuximab (Erbitux, Bristol-Myers Squibb) — support their benefit as first-line treatment for metastatic colorectal cancer in patients with wild-type (normal) KRAS gene status, but found them futile in the small subset with BRAF mutations.

The updates were reported here at the 2010 Gastrointestinal Cancers Symposium (GICS), which is sponsored by the American Gastroenterological Association, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

In the primary survival analysis of the phase 3 PRIME trial, first-line treatment with panitumumab, given with 5-flurorouracil, leucovorin, and oxaliplatin (FOLFOX4), delayed progression by 1.6 months and extended overall survival to approximately 2 years in patients with wild-type KRAS, according to Salvatore Siena, MD, from the Ospedale Niguarda Ca' Granda in Milan, Italy.

In the PRIME trial of 1183 metastatic colorectal cancer patients, 60% had the wild-type KRAS gene, whereas 40% had mutated KRAS and therefore did not benefit from the addition of the drug. Patients were randomized to receive standard FOLFOX4 chemotherapy alone (control group) or FOLFOX4 chemotherapy plus panitumumab 6.0 mg/kg every 2 weeks.

The primary end point, median progression-free survival, was 9.6 months in wild-type KRAS patients in the panitumumab group and 8.0 months in the control group, for a 20% reduction in risk with panitumumab (P = .02). The secondary end point, median overall survival, was 23.9 months in the panitumumab group and 19.7 months in the control group.

"There was a 4.2-month advantage with panitumumab that was almost statistically significant (hazard ratio [HR], 0.83; P = .07)," Dr. Siena told Medscape Oncology. "It did not reach significance, probably because of our rigorous statistical design, which was a hierarchical sequential analysis," he explained.

"We had a very good control arm," he added. "In my opinion, this 4.2-month difference is clinically meaningful, although not statistically significant."

Response rates in wild-type patients were numerically higher: 55% in the panitumumab group and 48% in the control group (P = .07).

As expected, patients with mutated KRAS did not benefit from panitumumab. Progression-free survival in those patients was actually more favorable with FOLFOX4 alone than with FOLFOX4 plus panitumumab (8.8 months vs 7.3 months; P = .02).

In updated data from the OPUS trial, Carsten Bokemeyer, MD, from the University Hospital Hamburg-Eppendorf in Germany, reported that in KRAS wild-type patients (n = 82), cetuximab plus FOLFOX4 led to a median overall survival of 22.8 months, compared with 18.5 months for FOLFOX4 alone, although the 15% reduction in risk was not statistically significant. Disease progression, however, was significantly lower, by 43.3% (P = .0064), and tumor response rates were significantly higher (57.3% vs 34.0%; P = .0027) with the combination, Dr. Bokemeyer reported.

BRAF Mutations Associated With Poor Prognosis

In an update of the phase 3 CRYSTAL trial, principal investigator Eric Van Cutsem, MD, from University Hospital Gasthuisberg, in Leuven, Belgium, provided more evidence that BRAF mutations are prognostic indicators of worse outcomes in KRAS wild-type patients.

The BRAF mutation was present in 9% of the 666 patients with KRAS wild-type tumors in CRYSTAL, and these patients derived no benefit from treatment with cetuximab, he reported.

The main results of CRYSTAL (n = 1198), reported at the 2009 European Society for Medical Oncology/European CanCer Organization meeting in Berlin by Dr. Van Cutsem, showed that treatment with cetuximab plus folinic acid, fluorouracil, and irinotecan (FOLFIRI) was associated with a 30% reduction in progression (P = .0012) and a 20% reduction in mortality (P = .0093), compared with FOLFIRI alone, in the KRAS wild-type population.

In the analysis of FOLFIRI plus cetuximab in KRAS wild-type patients, median overall survival was 23.5 months overall and 25.1 months for patients with both KRAS and BRAF wild-type status, but just 14.1 months for KRAS wild-type patients who had BRAF mutations. Progression-free survival was, respectively, 9.9, 10.9, and 8.0 months.

"The findings suggest that BRAF tumor mutations are associated with poor prognosis in first-line metastatic colorectal cancer," Dr. Van Cutsem said.

CALBG 80405 May Determine Optimal Agent

In a lecture on metastatic treatment options for KRAS wild-type tumors, Cornelius J. Punt, MD, from Radboud University Nijmegen Medical Center in the Netherlands, said that because superiority has not been shown for anti-EGFR antibodies over bevacizumab in the first-line setting, panitumumab and cetuximab should not be chosen over bevacizumab unless they are proven to be preferable.

A head-to-head comparison of these agents is being conducted in the CALGB 80405 trial. The study will randomize patients to FOLFOX or to FOLFIRI plus bevacizumab, cetuximab, or bevacizumab and cetuximab, and the findings can be extrapolated to panitumumab, said Jordon Berlin, MD, clinical director of gastrointestinal oncology at Vanderbilt's Ingram Cancer Center in Nashville, Tennessee.

Dr. Berlin told Medscape Oncology that CALGB 80405 will be critically important in determining which first-line approach is optimal. "This head-to-head comparison will answer this question," he said. "Until these agents are compared head to head, bevacizumab has more momentum."

"There is a huge cosmetic factor with the EGFR inhibitors," he pointed out, notably skin toxicity, which the majority of responders develop. "While the side effects of bevacizumab are scary — stroke, bowel perforation, bleeding — they are very rare. If a patient is at high risk for these, they should not get bevacizumab; perhaps I would use an EGFR inhibitor. Clearly, for KRAS mutant tumors, there is no role for the EGFR inhibitors, so that is an easy answer for 40% of patients. However, for the 60% with KRAS wild-type tumors, we need the CALGB trial."

The PRIME trial was funded by Amgen. At least 1 author of this study reports employment, consultancy, stock ownership, honoraria, and research funding from Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co, ImClone Systems, Merck & Co, Merck Serono, Roche, Sanofi-Aventis, Pfizer, and Sanofi-Synthelabo.

2010 Gastrointestinal Cancers Symposium (GICS): Abstract 283. Presented January 22-24, 2010.