Genetic makeup predicts colorectal cancer response to panitumumab


Patients can be tested to see if they have a gene that responds to a drug for colorectal cancer.

The new data-reported by lead author Rafael Amado, M.D., an Amgen scientist, in an oral session at the recent 2008 Gastrointestinal Cancers Symposium in Orlando – were generated from an analysis of an earlier Phase III randomized, controlled clinical trial that first defined the treatment effect of panitumumab in patients with metastatic colorectal cancer (mCRC).

In September 2006, findings from that pivotal trial ("408") led the Food & Drug Administration to approve panitumumab later that year as second- or third-line therapy for RC in patients who did not respond to standard chemotherapy and had exhausted all other treatment options.

Interestingly, in 2006 the corresponding European regulatory body-the European Committee for Medicinal Products for Human Use (CHMP)-did not approve the drug at first. It was only during several heated sessions later that CHMP members changed their minds and conditionally approved panitumumab in the European Union for patients with refractory mCRC-but only those patients whose tumors lack a KRAS mutation. Similar marketing applications have been filed with Health Canada, Australia, and Switzerland.

"Our study yet again confirms that patients with advanced colorectal cancer will benefit from Vectibix, but only if they are among the 60% with a normal form [wild-type] of the KRAS gene present in their tumors-not a mutation," emphasized Amado. "KRAS gene mutations occur in some 40% of advanced colorectal cancer patients," he said.

From the clinical perspective, Amado had a positive outlook: "By testing for KRAS mutations, physicians may now be able to identify which patients will most likely benefit from panitumumab treatment and potentially avoid the unnecessary side effects and expense in those who are unlikely to respond...Understanding cancer mutation status can help identify optimal drug therapy for a patient."

No effect of Vectibix therapy was observed in patients who had tumors with KRAS mutations, he added. "The mutated KRAS gene is clearly associated with drug resistance." The pivotal Phase III study on which the current analysis was based involved 427 patients whose KRAS status was known; 43% of them had a mutated KRAS gene. All the patients had metastatic colorectal cancer and had experienced the entire range of standard treatment options to no avail. They were now randomized to receive either best supportive care (palliative care with no anti-cancer drugs) or best supportive care plus panitumumab every two weeks.

For the latter group, median progression-free survival was 12.3 weeks for those with a normal KRAS gene versus 7.4 weeks for those with a mutated gene. For the best supportive care group, median progression-free survival was 7.3 weeks regardless of KRAS status.

Amado emphasized the following data: Among patients with normal KRAS who received panitumumab, 17% responded (i.e., their tumors shrank) and 34% had stable disease (i.e., their tumors did not grow). In the group with a mutated KRAS gene who received panitumumab, tumors did not respond (i.e., did not shrink) in a single patient -"Not one," he reiterated- and only 12% of those patients had stable disease.

Most of the side effects from panitumumab were skin rashes, Amado noted. They are "the most common and reversible side effect of all EGFR (epidermal growth factor receptor) inhibitors." The anti-EGFR class of drugs includes such widely known biologically targeted cancer treatments as cetuximab (Erbitux, ImClone/Merck/BMS), erlotinib (Tarceva, OSI/Genentech), and now panitumumab.

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