By Turna Ray
Amgen this week presented new data that not only provides further evidence that Vectibix is not efficacious in metastatic colorectal cancer patients with certain KRAS mutations, but also suggests that the company may attempt to expand the indication for the drug.
The company this week presented results from two Phase III studies investigating the safety and efficacy of Vectibix in combination with chemotherapy in patients with non-mutated KRAS tumors in the first-line and second-line settings at the American Society of Clinical Oncology's Gastrointestinal Cancers Symposium in Orlando, Fla.
The results suggest that Vectibix in addition to chemotherapy improves the progression-free survival for patients with wild-type KRAS in the first-line setting, as well as PFS, overall survival, and response rate in this subset of patients as a second-line treatment.
"Our data reinforce the importance of the KRAS mutation as a predictive biomarker for responsiveness to Vectibix therapy," Roger Perlmutter, Amgen's executive vice president of research and development, said in a statement. "We believe that KRAS testing should be conducted in all patients with colorectal cancer soon after diagnosis, to allow physicians to choose the most appropriate treatment strategies for their patients."
The US Food and Drug Administration informed healthcare providers last year that before treating metastatic colorectal cancer patients with EGFR-inhibiting monoclonal antibody treatments, such as Amgen's Vectibix or Bristol-Myers Squibb/ImClone's Erbitux, patients should be tested to ensure they carry non-mutated KRAS genes and thus will respond to such treatments [see PGx Reporter 07-22-2009].
Vectibix is currently approved in the US as a single agent for the treatment of EGFR-expressing, metastatic colorectal cancer in patients with disease progression who have received treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.
The two Phase III prospective, randomized studies discussed this week not only provide further evidence that mCRC patients with certain KRAS mutations will not respond to the drug, but also suggest that Amgen will likely attempt to expand the indication for Vectibix in combination with chemotherapy in the first and second-line setting.
In the so-called "203" trial, researchers from various academic centers sponsored by Amgen investigated the anti-EGFR inhibiting monoclonal antibody Vectibix plus FOLFOX4 as a first-line treatment in metastatic colorectal cancer in more than 1,180 patients.
Patients were randomized to receive Vectibix and FOLFOX4 or FOLFOX4 alone. In the trial, patients with wild-type KRAS mutations experienced a median PFS with the Vectibix/chemo combination compared to a median PFS of 8 months in the chemotherapy arm. For those with mutated KRAS tumors, median PFS was 7.3 months in the combination arm versus 8.8 months in the chemotherapy group.
In this study, in which all patients had their tumor tissue genetically analyzed to establish KRAS status, 60 percent had wild-type tumors and 40 percent had mutated KRAS. Adverse event rates were similar in both arms, except the Vectibix-related rate of grade 3/4 infusion reactions was reported in less than 1 percent of patients in the combination arm, according to the abstract.
Based on these results, researchers concluded that Vectibix "significantly improves PFS and is well tolerated when added to FOLFOX4 for first-line treatment of patients with wild-type KRAS in mCRC" and that "PFS was inferior in patients with mutated tumors who received" the drug.
"This study, designed to prospectively analyze KRAS mutation status, confirms the importance of KRAS as a predictive biomarker in the setting of first-line mCRC treatment with an anti-EGFR mAb in combination with chemotherapy," the researchers stated. Overall survival was not reported as part of this study.
In study '181, researchers compared the safety and effectiveness of Vectibix in combination with FOLFIRI to FOLFIRI alone as a second-line treatment of metastatic colorectal cancer. For this multi-center, randomized Phase III trial, more than 1,180 patients who had received treatment with one other chemotherapy regimen had their tumor tissue genetically tested to establish KRAS status.
For patients with wild-type KRAS, representing around 55 percent of study participants, median PFS was 5.9 months for the combination treatment and 3.9 months for the chemotherapy arm. Median overall survival was 14.5 months for the combination arm and 12.5 months for chemotherapy alone. Response rate in the Vectibix/FOLFIRI group was 35 percent and 10 percent among chemo-only treated patients.
Among patients with mutated KRAS, there was no difference in median PFS, overall survival, or response rates between the two arms. Furthermore, there was no difference in adverse reactions between the two arms, in general. But incidences of Vectibix-related toxicities, rash, diarrhea, and hypomagnesemia were higher in the combination arm.
The results of this study led researchers to conclude that Vectibix "significantly improves PFS and is well tolerated when added to FOLFIRI for second-line treatment in patients with wild-type KRAS in mCRC."
The diagnostics firm DxS has separate deals with Amgen and BMS to develop companion KRAS diagnostics for Vectibix and Erbitux. DxS' tests are already available in European countries as a companion to these drugs. In the US, DxS' test awaits FDA approval and is currently available for use in the research setting.