KRAS Mutation Status Predicts Responsiveness to Panitumumab (2007)

BARCELONA—Scientists showed earlier this year that colorectal cancer patients whose tumors carry a mutated KRAS gene do not respond to cetuximab, an antibody that blocks the epidermal growth factor receptor (EGFR). Now researchers find that the same is true for treatment with panitumumab, another anti-EGFR antibody, according to data presented here at ECCO-14, the European Cancer Congress. Based on these data, the European Agency for the Evaluation of Medicinal Products (EMEA) is expected to approve panitumumab therapy only for those colorectal cancer patients whose tumors have non-mutated KRAS genes, said a spokesperson from Amgen, which makes the antibody. The company is in discussion with the US Food and Drug Administration regarding these new data, but do not yet know how the agency will handle the information. Colorectal cancer specialists, however, appear ready to accept this limitation. “In the very near future, I think it will be standard of care to only give these drugs to patients with wild-type KRAS,” said GI cancer specialist Leonard Saltz, MD, Attending Physician at Memorial Sloan-Kettering Cancer Center in New York. The importance of KRAS mutations is not limited to colorectal cancer, however. Such mutations also confer resistance to erlotinib, a small molecule inhibitor of EGFR, in lung cancer. “I think it will turn out to be consistent across the board for all EGFR inhibitors,” said Jordan Berlin, MD, Clinical Director of GI Oncology at Vanderbilt-Ingram Cancer Center, who was a coauthor on the panitumumab study. “It has held true in the two disease sites where EGFR inhibitors are used most. And it is important to know which patients should not get these moderately effective drugs.” Dr. Saltz said the consistency across disease types was to be expected because KRAS works downstream in the EGFR signaling pathway, relative to the receptor itself. In normal cells, KRAS is turned on when EGFR is activated. However, when mutated the KRAS protein becomes perpetually active, regardless of the status of EGFR. Thus, blocking EGFR activation with an antibody or small molecule has no effect, he explained. “If KRAS is mutated, it becomes a downstream driver [of the tumor], and upstream inhibitors don't have an effect.” Although not all patients with wild-type KRAS respond to EGFR inhibitors, identifying patients a priori who will not respond saves them toxicity and expense. Both of which are important, experts agree. Panitumumab & KRAS In the current analysis, Rafael Amado, MD, Executive Director of Global Development at Amgen, and colleagues correlated KRAS mutational status with clinical outcomes in patients who had been treated in a registration trial comparing panitumumab with best supportive care. Of the 463 patients in the trial, tissue was unavailable for KRAS testing in 18 patients and the test failed in another 18. Of the 427 completed tests, 184 tumors (43%) carried a mutant KRAS gene. Although this characteristic was not used during stratification of patients, the frequency of the mutation in the two trial arms was similar, with 40% of patients in the active drug arm and 46% of patients in the control arm having KRAS mutations. The overall progression-free survival time in the trial was 8.0 weeks in the panitumumab arm and 7.3 weeks in the best supportive care arm, with most patients having disease progression before the first assessment at eight weeks. Looking at just those patients whose tumors harbor a KRAS mutation, progression-free survival was 7.4 weeks in the panitumumab arm and 7.3 weeks in the control arm. In patients whose tumors had the wild-type gene, progression-free survival was 12.3 weeks in the panitumumab arm and 7.3 in the best supportive care arm. Only patients with wild-type KRAS genes responded to the drug. Of 124 patients with wild-type KRAS and treated with panitumumab, 21 (17%) responded. None of the 84 patients with mutant KRAS responded to panitumumab therapy. Stable disease also favored the wild type group. Of those with the mutation, 12% in the panitumumab arm had stable disease, compared with 8% in the control arm. In contrast, of the patients with wild-type KRAS, 34% of the patients treated in the panitumumab arm had stable disease, versus 12% in the control arm. Patients were allowed to cross over to the panitumumab arm after their disease progressed on best supportive care, and 77% of those patients chose to do so. Given that trial design, overall survival analysis is complicated, yet when the team compared survival by mutation status, there was a substantial difference. Median overall survival was higher for patients with wild-type KRAS, 8.1 months in the panitumumab arm and 7.6 months in those initially assigned to best supportive care. Of those with the KRAS mutation, survival was 4.9 and 4.4 months for those in the active drug and control arms, respectively. “The efficacy of panitumumab in patients with metastatic colon cancer seems to be confined to patients whose tumors harbor wild KRAS,” Dr. Amado concluded. “The treatment effect on that group was significant with a reduction in disease progression or death of about 55 percent. Therefore KRAS genotyping of tumors should be strongly considered and performed if a test is available in patients with metastatic colorectal cancer patients being considered for treatment with panitumumab monotherapy.” What impact these data have on panitumumab combination therapy remains an open question, Dr. Amado noted. Although the KRAS study was performed after the clinical outcomes were recorded in this trial, the analysis was done in a blinded fashion, Dr. Amado said. That methodology was sufficient for Dr. Saltz, who has not been involved in the work. “This is a definitive study,” he said, and no prospective trial is necessary to bring the data into the clinic. “Going forward, ongoing studies should be retooled to limit them to only patients with wild-type KRAS.” Into the Clinic Thus far, no such test has been approved for sale in the US, but Dr. Saltz said he expects that one will be available “very quickly.” Currently, Amgen recommends that physicians interested in testing patient tumors for KRAS mutation contact their local laboratory to see what is available. Amgen itself has no plans to develop a test at this time. The test used for the current analysis is marketed by DxS, Ltd. in Manchester, UK. That said, some clinicians, including the lung cancer group at Memorial Sloan-Kettering Cancer Center, already test their patients for KRAS mutation status before prescribing EGFR inhibitors. Researchers have been looking for a marker that can identify patients who will respond to EGFR inhibitors. While wild-type KRAS status doesn't mean that a patient will respond for sure, “it means they are in the game,” Dr. Saltz said. And that puts clinicians one step closer to identifying the patients who will benefit from the drug.