CETUXIMAB MAY WORK FOR CODON-13 KRAS MUTATED COLORECTAL CANCER

NEW YORK (Reuters Health) Oct 26 - Counter to prevailing opinion, not all advanced colorectal cancers with KRAS mutations are insensitive to cetuximab (Erbitux). Tumors with a KRAS mutation on codon-13 seem to respond to treatment with the EGFR-blocker, according to an international research team.

"Hopefully this report will raise the awareness of the clinical community on the possibility that it may not only be necessary to assess the mutational status of a given cancer gene (wild-type or mutant) but also to precisely ascertain which residue is mutated," senior author Dr. Sabine Tejpar said. "This is the first work indicating that individual mutations (for example in KRAS or PIK3CA) impact differently the response to therapy. This can be described as mutation-targeted rather than gene-targeted therapies."

In 2009, the US Food and Drug Administration updated the labels of cetuximab and panitumumab, another antibody directed against epidermal growth factor receptor (EGFR), to exclude treatment of metastatic colorectal cancer with KRAS mutations.

Based on preclinical data and anecdotal reports, Dr. Tejpar, from University Hospital Gasthuisberg, Leuven, Belgium, and colleagues suspected that KRAS codon 13 mutations, as opposed to codon 12 mutations, can respond to anti-EGFR treatment.

They pooled data from several clinical trials for more than 700 patients with chemotherapy-refractory metastatic colorectal cancer. Among 579 patients treated with cetuximab, with or without other chemotherapy, 40% had KRAS mutations, of which 14.5% were the glycine-to-aspartate transition mutation on codon 13 (p.G13D). A separate group of 195 patients received best supportive care only.

Analysis showed that cetuximab-based therapy led to significantly longer overall survival among patients who were KRAS wild-type or who had p.G13D mutations (p < 0.001 for both), but not among those with other KRAS mutations.

Among patients not receiving cetuximab, 13 with p.G13D-mutated tumors had shorter median overall survival (3.6 months) than those with other KRAS-mutated tumors (4.7 months) or wild-type KRAS tumors (5.0 months). However, multivariate analysis showed no significant difference among groups in overall or progression-free survival.

During cetuximab treatment, median overall survival was 7.6 months in the p.G13D group vs. 5.7 months in the other KRAS-mutation group (multivariate hazard ratio 0.50, p = 0.005). The authors saw a similar pattern for progression-free survival: 4.0 vs. 1.9 months (multivariate HR 0.50, p = 0.004).

But overall and progression-free survival for KRAS wild-type tumors (median 10.1 and 4.2 months) didn't differ significantly from patients with p.G13D-mutated tumors on univariate or multivariate analysis.

Dr. Tejpar's group also looked at the association between treatment response and KRAS mutation status in cell lines and in tumors grown as xenografts in immunocompromised mice.

Cetuximab administration reduced cellular proliferation in vitro and "prominently inhibited the growth" of both wild-type and p.G13D tumors, they report, but didn't affect cells or tumors with KRAS p.G12V mutations.

"These results provide a cell-based molecular explanation to our clinical observation that patients with p.G13D-mutated tumors benefit from cetuximab treatment, while those with other KRAS-mutated tumors do not," the authors write.

Still, they note several limitations to their research, including its reliance on nonrandomized or cross-trial comparisons, with the likelihood of inadequate controlling for unknown confounders.

"A prospective trial is now needed to confirm our evidence," Dr. Tejpar told Reuters Health via email. "In the meantime current FDA and EMEA regulations (stating that cetuximab and panitumumab should be given only to KRAS wild type CRC patients) should be followed. I am sure, however, that upon publication of our work, oncologists and pathologists will be faced with practical issues regarding the use of these drugs in G13D mutated patients."

Another priority, the researcher added, is that "virtually all patients who initially respond to cetuximab and panitumumab eventually relapse within a relatively short period of time, but the reasons for this are completely unknown. Our next goal is to understand the molecular basis of secondary (acquired) resistance to EGFR-targeted therapies in CRCs as this is an unmet and urgent clinical need."

Cetuximab is manufactured and distributed in North America by ImClone and Bristol-Myers Squibb, while in the rest of the world distribution is by Merck KGaA. In the U.S., each weekly dose of cetuximab costs roughly $500.

Seven authors disclose relationships with Bristol-Myers Squibb or Merck Serono.

JAMA. Posted October 11, 2010. Abstract