Genes Linked to Cetuximab/Panitumumab Resistance

December 3, 2008

Genetic factors have been found to affect the response of patients with metastatic colorectal cancer (CRC) to the epidermal growth factor receptor (EGFR) inhibitors cetuximab (Erbitux) and panitumumab (Vectibix).

Genetic factors have been found to affect the response of patients with metastatic colorectal cancer (CRC) to the epidermal growth factor receptor (EGFR) inhibitors cetuximab (Erbitux) and panitumumab (Vectibix). Two recent studies shed additional light on how BRAF and KRAS genetic status influences response to these medications.

A poster presentation* at the Second Annual Molecular Markers in Cancer Meeting and pooled data from 4 clinical trials confirm that only patients with the wild-type KRAS gene respond to panitumumab treatment. “We knew from the start that not everyone was responding to panitumumab,” explained Daniel Freeman, PhD, principle scientist in oncology research for Amgen Inc and lead author of the poster. He described the researchers’ goal as trying to “deliver on the promise of personalized medicine and give medications only to those who would benefit.”

A total of 795 patients with metastatic CRC were included in the studies; all had received panitumumab monotherapy. Researchers located tumor samples for 90% of the patients, which they analyzed for KRAS status. The found that the overall response rate was 13.7% among patients who had the wild-type gene, but there was no response in those with KRAS mutations.

Dr. Freeman noted that the ability to identify KRAS status in 90% of the patients decreased the chances of introducing bias. “The high rate of ascertainment gives a high degree of confidence that these results really did predict what was occurring in the entire population.”

Compared with patients who had KRAS mutations, patients with wild-type KRAS tumors had longer median overall survival (5.7 mo vs 8.3 mo, respectively) and progression-free survival (1.7 mo vs 3.3 mo, respectively). They also had a higher rate of adverse events. This was likely because patients with wild-type KRAS tumors received 7 infusions versus 4 for patients with mutant KRAS.

“KRAS, according to our results, turns out to be a very nice biomarker,” said Dr. Freeman. He added that the improved rates of response and disease control indicate that patients with wild-type KRAS who are treated with panitumumab derive a survival benefit. “At the end of the day, stratifying patients based on KRAS status will potentially increase the response to this medication,” he concluded.

The second study retrospectively examined responses to panitumumab and its sister medication cetuximab in patients with metastatic CRC who have the BRAF mutation. The European Medications Agency recommends cetuximab and panitumumab only for patients with metastatic CRC who have wild-type KRAS tumors.

Lead author of the study, Federica Di Nicolantonio, PharmD, PhD, The Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Italy, said that “despite being highly specific, KRAS mutations are poorly sensitive.” Dr. Di Nicolantonio noted that only 30% to 40% of patients who do not respond to treatment with either cetuximab or panitumumab have KRAS mutations.

Researchers wanted to determine whether BRAFmutations might have a prognostic value in the treatment of patients with CRC. They examined records from 113 patients with advanced CRC who had undergone treatment with cetuximab or panitumumab. Investigators measured each patient’s objective response, time to progression, overall survival, and KRAS or BRAF mutational status. They also assessed the effect of the BRAF V600E mutation on the tumor’s response to medication.

KRAS mutations were identified in 30% of patients, and researchers associated the mutations with resistance to the medication. In total, 79 patients had wild-type KRAS tumors, and investigators detected the BRAF V600E mutation in 11 of these patients. None of the V600E patients responded to cetuximab or panitumumab, and none of the patients who did respond to either of the 2 medications carried a BRAF mutation. Patients with a BRAF mutation demonstrated significantly shorter periods of progression-free survival and overall survival than those who only had wild-type KRAS.

Investigators observed that introducing BRAF V600E allele to cellular models of colorectal cancer impaired the efficacy of cetuximab and panitumumab. In cells that carried the mutation, treatment with sorafenib, a BRAF inhibitor, restored sensitivity to both medications.

Dr. Di Nicolantonio said that because KRAS and BRAF mutations are mutually exclusive to CRC, considering the BRAF mutations allowed the researchers to “explain another fraction [10%-12%] of nonresponding patients.” She added that independent studies involving other cohorts must first verify these findings, but that “if BRAF mutations are confirmed to be another adverse predictive molecular marker, then oncologists and pathologists should certainly consider testing BRAF alongside KRAS before starting treatment with EGFR-targeted monoclonal antibodies.”

The results, however, still fail to complete the picture of patients’ resistance to EGFR inhibitors: 46 out of 114 (41%) of nonresponsive patients in this study did not carry mutations in either gene. “This means further molecular markers are needed to better define patients who are unlikely to benefit from EGFR-targeted treatments,” Dr. Di Nicolantonio said.

J Clin Oncol

Di Nicolantonio F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. . 10.1200/JCO.2008.18.0786 [E-pub ahead of print]

Freeman D, et al. Efficacy of panitumumab monotherapy in relation to KRAS mutational status for treating metastatic colorectal cancer (mCRC) from four clinical studies. Second Annual Meeting on Molecular Markers Highlights in Advances in Personalized Cancer Medicine. Hollywood, FL. October 30-November 1, 2008. Abstract.

*This study was paid for by Amgen Inc, the maker of panitumumab, and Dr. Freeman is an Amgen Inc employee.

Kurt Ullman is a freelance medical and health writer based out of Indianapolis.