Healthcare Industry News: fluoropyrimidine
News Release - June 1, 2008
Updated Data from Ongoing Phase 3 Trials Support the Continued Study of Vectibix(R) (panitumumab) in Combination with Standard ChemotherapyPhase 2 Data Corroborate the Role of the KRAS Biomarker in Advanced Colorectal Cancer
Abstract Numbers 4064, 4034, 4127
CHICAGO--(HSMN NewsFeed)--Amgen (NASDAQ:AMGN ) today announced updated interim pooled, blinded, safety results from two Phase 3 trials evaluating Vectibix® (panitumumab) in combination with standard chemotherapy in earlier lines of metastatic colorectal cancer (mCRC). Updated data from these trials, as well as the first prospective trial evaluating the impact of the clinical biomarker KRAS on Vectibix efficacy in combination with chemotherapy, were presented at the 2008 American Society of Clinical Oncology’s (ASCO) Annual Meeting in Chicago.
“The data being generated from a number of our ongoing trials in various settings of colorectal cancer continue to inform us about the safety of Vectibix in combination with standard chemotherapy,” said Roger M. Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. “Our data regarding the importance of KRAS mutation status emphasize the significance of this biomarker in developing individualized therapy for colorectal cancer.”
PRIME (203) Study
The “PRIME” or 20050203 study is a global, Phase 3 trial investigating Vectibix in combination with FOLFOX chemotherapy as first-line treatment for mCRC among wild-type KRAS and all randomized patients. Final enrollment was completed in February 2008 with a total of 1,183 patients.
Pooled safety data from a planned interim analysis, conducted by an independent Data Monitoring Committee (DMC), of 903 patients (455 Vectibix plus FOLFOX; 448 FOLFOX only), of which 99 percent received at least one cycle of therapy, showed the following pooled grade 3/4 adverse events: neutropenia (28 percent), diarrhea (11 percent), fatigue (4 percent), nausea (3 percent), dehydration (3 percent) and hypomagnesaemia, pulmonary embolism, febrile neutropenia and deep vein thrombosis (2 percent, respectively). Fifty-six percent of the pooled patient population had skin and subcutaneous tissue system organ class (SOC) events of any grade; 10 percent grade 3 and less than one percent grade 4. Based upon this interim safety analysis, the DMC recommended that the PRIME study continue per protocol.
Patients enrolled in this study were randomized to receive either 6.0 mg/kg of Vectibix and FOLFOX once every two weeks (Q2W) or FOLFOX alone Q2W. The primary endpoint is progression-free survival (PFS). Other endpoints include overall survival, objective response rate, time to progression, duration of response and safety.
All study endpoints will be investigated by patients’ KRAS mutational status in both treatment arms as a biomarker for Vectibix activity in combination with FOLFOX chemotherapy as first-line treatment for mCRC.
The 20050181 (“181”) study is a global, Phase 3 trial investigating Vectibix in combination with FOLFIRI chemotherapy as second-line treatment for patients with mCRC assessed according to KRAS mutational status. The 181 study final enrollment was completed in March 2008 with a total of 1,187 patients.
Pooled safety data from a planned interim analysis, conducted by the independent DMC, of 1,097 patients (548 Vectibix plus FOLFIRI; 549 FOLFIRI only), of which 99.6 percent received at least one cycle of therapy, showed the following pooled grade 3/4 adverse events: neutropenia (17 percent), diarrhea (10 percent), fatigue (5 percent), nausea, dehydration, pulmonary embolism, febrile neutropenia (2 percent, respectively), and hypomagnaesemia and deep vein thrombosis (1 percent, respectively). Sixty-three percent of the pooled patient population had skin and subcutaneous tissue SOC events of any grade; 15 percent grade 3 and less than one percent grade four. Based upon this interim safety analysis, the DMC recommended that the 181 study continue per protocol.
Patients were randomized to receive either 6.0 mg/kg of Vectibix and FOLFIRI Q2W or FOLFIRI Q2W alone. The co-primary endpoints are progression-free survival and overall survival. Other endpoints include objective response rate, time to progression, duration of response and safety.
All study endpoints will be investigated by patients’ KRAS mutational status in both treatment arms as a biomarker for Vectibix activity in combination with FOLFIRI chemotherapy as second-line treatment for mCRC.
The single-arm PRECEPT study (n=109) was designed to prospectively evaluate the efficacy of Vectibix when combined with the chemotherapy regimen FOLFIRI, according to KRAS status, in patients with metastatic disease which had progressed following first-line treatment with an oxaliplatin-based chemotherapy regimen plus bevacizumab.
Data from this interim efficacy analysis (n=64 wild-type KRAS, n=45 mutant KRAS) showed that patients with wild-type KRAS had longer PFS (median: 26 weeks wild-type versus 16 weeks mutant KRAS) and time to treatment failure (median: 20 weeks wild-type versus 15 weeks mutant KRAS). Overall response rates were similar in this interim analysis. In line with other EGFr-inhibitor class data in combination with chemotherapy, the addition of Vectibix to FOLFIRI was tolerable. Vectibix-related serious adverse events (grade 3 or higher) were observed in 15 patients, or 13 percent of the 115 patients included in the safety analysis. The most frequently reported serious adverse events were neutropenia (23 percent), skin-related toxicity (19 percent) and diarrhea (13 percent).
“These data are the first to measure the potential impact of KRAS status in combination treatment with Vectibix and chemotherapy, and add to the growing body of evidence that help validate KRAS as a potential patient selection biomarker for anti-EGFr therapy,” said Allen Cohn, M.D., Rocky Mountain Cancer Center, U.S. Oncology, Denver, Colorado. “KRAS mutational status ranks among one of the most important scientific advances in colorectal cancer and has the potential to redefine how these patients are currently treated.”
Vectibix is the EGFr-inhibitor of choice in the treatment of advanced colorectal cancer patients who have failed standard chemotherapy due to its demonstrated efficacy, safety and convenient Q2W dosing schedule.
In the United States (U.S.), Vectibix is indicated for the treatment of patients with EGFr-expressing mCRC after disease progression on, or following fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens. The effectiveness of Vectibix for the treatment of EGFr-expressing, metastatic colorectal carcinoma is based on progression-free survival. Currently no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Vectibix.
In the European Union (EU), Vectibix is approved as monotherapy for the treatment of patients with EGFr-expressing mCRC with non-mutated (wild-type) KRAS genes after failure of standard chemotherapy regimens.
Important Product Safety Information
Dermatologic toxicities, related to Vectibix blockade of EGF binding and subsequent inhibition of EGF receptor-mediated signaling pathways, included but were not limited to dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Dermatologic toxicities were reported in 89 percent of patients treated with Vectibix and were severe in 12 percent of patients. Severe dermatologic toxicities were complicated by infection, including sepsis, septic death, and abscesses requiring incisions and drainage. Vectibix may need to be withheld or discontinued for severe dermatologic toxicities.
Severe infusion reactions occurred with Vectibix in approximately one percent of patients. Severe infusion reactions were identified as anaphylactic reactions, bronchospasm, fever, chills and hypotension. Although fatal infusion reactions have not been reported with Vectibix, they have occurred with other monoclonal antibody products. Severe infusion reactions require stopping the infusion and possibly permanently discontinuing Vectibix, depending on the severity and/or persistence of the reaction.
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