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KRAS Status Predicts Benefit for Cetuximab in Met Colon Ca

KRAS Status Predicts Benefit for Cetuximab in Met Colon Ca

ABSTRACT: Ongoing studies of cetuximab in metastatic colorectal cancer patients are being amended to include KRAS mutation testing.

CHICAGO—Newly diagnosed patients with metastatic colorectal cancer are most likely to benefit from cetuximab (Erbitux) when their tumors contain the normal version of the KRAS gene, compared to patients with KRAS mutations, according to a conclusive analysis from the phase III CRYSTAL trial presented at the ASCO 2008 plenary session (abstract 2).

 

“For the first time, in a large population, we are able to show that we can predict which patients will be helped with new biologicals.”

                                — Dr. Eric Van Cutsem

CRYSTAL compared chemotherapy alone to chemotherapy plus cetuximab for the first-line treatment of metastatic disease. Eric Van Cutsem, MD, PhD, of the University Hospital Gasthuisberg, Leuven, Belgium, presented the findings.

“For the first time, with a study in a large patient population, we are able to show that we can predict which patients will be helped with new biologicals,” Dr. Van Cutsem said at an ASCO press conference.

The relative benefit, based on KRAS status, has been suggested for some time, and has also been observed with panitumumab (Vectibix), the other EGFR monoclonal antibody studied in colorectal cancer. The ASCO presentation essentially makes the picture complete. European guidelines already restrict these agents to wild type KRAS patients, which occur in approximately 65% of colorectal cancer patients.

Investigators examined tumor samples from 587 of the 1,198 patients in the trial for the presence of mutations in codon 12/13 of KRAS, which they found in 36%. Patients with KRAS mutations derived no additional benefit from cetuximab, with response rates of approximately 40% in either arm. In contrast, response rates in patients with wild-type KRAS were 59% with the combination vs 43% with FOLFIRI alone (P = .0025).

Additionally, wild-type KRAS patients treated with cetuximab had a 32% reduced risk of disease progression, while no risk reduction was observed in the mutated population.

For patients with KRAS mutations, overall responses and progression-free survival were similar whether they received cetuximab or not.

The addition of cetuximab in wild-type KRAS patients increased median disease-free survival to 9.9 months, from 8.7 months with FOLFIRI alone (P = .017). One-year progression-free survival was 43% vs 25%, respectively. The grade 3-4 adverse event profile was similar between the KRAS wild-type and mutant populations.

“When we enriched the population, we showed a much greater benefit with cetuximab,” Dr. Van Cutsem noted.

At the press conference, Julie Gralow, MD, University of Washington, said, “The presence of EGFR has not really predicted for benefit with targeted therapy, so it is exciting to see the predictive value of KRAS. It reveals the two-thirds of patients who may benefit with cetuximab, and we do not need to give the drug to the other one-third. Better selection is one means of affording these new agents.”

 

Vantage Point

‘The first consistent signal that we can select our patients for EGFR-targeted antibodies. . .’

—S. Gail Eckhardt, MD

All patients with metastatic colorectal cancer should be tested for the mutational status of KRAS prior to utilization of EGFR-based antibody therapy, said discussant Dr. Eckhardt, professor and division head of medical oncology, and Stapp Harlow Chair in Cancer Research, University of Colorado, Denver.

 

‘The first consistent signal that we can select our patients for EGFR-targeted antibodies. . .’

                                      — S. Gail Eckhardt, MD

While CRYSTAL was a retrospective study conducted on subsets of patients, the subsets were similar to the intent-to-treat population in terms of demographics and disease characteristics. The findings are consistent with other smaller studies and are “robust,” she said.

“These data clearly raise concerns about ongoing and future studies that incorporate cetuximab or panitumumab in the metastatic setting,” she maintained.

The C80405 trial (FOLFIRI or FOLFOX plus cetuximab, bevacizumab, or both) is being amended for KRAS mutation testing, and mutated patients will not be eligible. S0600 (irinotecan plus cetuximab with or without bevacizumab) is under amendment as well, as is the adjuvant N0147 trial (FOLFOX with or without cetuximab).

Academic groups, industry, the NCI and the FDA will need to move quickly to develop validated assays for KRAS testing that are sensitive, reproducible, and feasible, she added.

“These results (and others) represent the first consistent signal that we can select our patients for EGFR-targeted antibodies, thus enhancing their benefit,” Dr. Eckhardt concluded. “Although robust, these results were obtained retrospectively. In the future, we should make greater efforts to develop biomarkers in concert with earlier trials so that prospective validation becomes the norm in large randomized phase III trials. Hopefully, this is only the beginning of the era of individualized therapy for patients with colorectal cancer.”

 
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