These data were generated from a biomarker analysis of a Phase 3, randomized, controlled clinical trial (the "408" study) that investigated the treatment effect of Vectibix monotherapy plus BSC versus BSC alone in patients with mCRC. The data showed the relative effect of Vectibix versus BSC was significantly greater in patients with non-mutated versus mutated KRAS (HR = 0.45 vs. HR = 0.99). Median PFS in patients without the mutation treated with Vectibix plus BSC was 12.3 weeks versus 7.3 weeks, respectively. When the analysis standardized the time to tumor assessment, the median PFS was 16 weeks versus 8 weeks, respectively (HR= 0.49 vs. 1.07). Some of these data were presented for the first time at the European Cancer Conference (ECCO) in September 2007.
"These data have substantially advanced our thinking about individualized treatment of colorectal cancers," said Roger M. Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. "We are hopeful that the use of biomarkers like KRAS will enable improved treatment outcomes for colorectal cancer patients."
Additional endpoints of this analysis examined overall survival by KRAS status and treatment. When the treatment arms were combined (non-mutated vs. mutated) overall survival was longer in patients with non-mutated compared with mutated KRAS (HR = 0.67). No differences in overall survival were observed between Vectibix and BSC in either KRAS subgroup, potentially due to a high rate of crossover from BSC to Vectibix after progression, and similar efficacy of Vectibix in these patients.
In exploratory analyses, colorectal cancer symptoms and health-related quality of life (HRQoL) outcomes were compared between Vectibix and BSC treated patients using a validated instrument such as the Functional Assessment of Cancer Therapy-colorectal symptom index and HRQoL using the EQ-5D index, and the EORTC-QLQ-C30 Global Health Status. In patients with tumors carrying non-mutated KRAS genes, the analysis demonstrated that in Vectibix treated patients clinically meaningful inferior symptom control and QoL scores could be excluded compared to BSC, and that in fact, a clinically meaningful difference in favor of Vectibix was observed at most time points. In contrast, a clinically significant worsening of symptom control and QoL scores could not be excluded in patients with mutated KRAS tumors treated with Vectibix compared to BSC. The United States (U.S.) prescribing information states that the effectiveness of Vectibix as a single agent is based on progression-free survival; currently no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Vectibix.
Over twenty years of study have shown that KRAS plays an important role in cell growth regulation and oncogenesis. Anti-epidermal growth factor receptor (EGFr) therapies work by blocking the activation of EGFr, thereby inhibiting downstream events that lead to cancer cell signaling. However, in patients with tumors harboring a mutated or activated KRAS, the KRAS protein is always turned "on" regardless of whether EGFr has been activated or therapeutically inhibited. Thus, in patients with mutated KRAS, signaling continues despite anti-EGFr therapy. Mutated KRAS is detected in approximately 40 percent of CRC tumors.
In the Vectibix-treated group, patients with non-mutated KRAS had on average double the number of Vectibix infusions as patients with mutated KRAS (10.0 vs. 4.9). Additionally, 20 percent of the KRAS evaluable patients had a treatment-related grade 3 adverse event (12 percent mutated vs. 25 percent non-mutated).
About the Analysis
Of the 463 randomized patients in the "408" trial, 427 had available KRAS data and 57 percent had tumors with normal, non-mutated KRAS. In the group of patients with non-mutated KRAS that received Vectibix, 17 percent responded to treatment and 34 percent reported stable disease. There were no responders in the group of patients treated with Vectibix that had mutated KRAS and stable disease was only reported in 12 percent of patients.
Vectibix was approved in the U.S. in September 2006 as a monotherapy for the treatment of patients with EGFr expressing mCRC after disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. In the U.S., Vectibix is not approved for use based on KRAS status. In December 2007, the European Medicines Agency (EMEA) granted a conditional marketing authorization for Vectibix as monotherapy for the treatment of patients with EGFr expressing mCRC with non-mutated (wild-type) KRAS genes after failure of standard chemotherapy regimens. Regulatory applications in the rest of the world are still pending.
KRAS and other biomarker analyses have and will continue to be integrated into the ongoing clinical program studying Vectibix in earlier lines of mCRC therapy in combination with chemotherapy, as well as in other tumor types. Emerging data from our ongoing Phase 3 trials examining Vectibix in combination with chemotherapy in the first- and second-line of mCRC (181 and 203) will be presented later at this meeting.
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 1 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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Christine Regan, 805-447-5476 (media)
Arvind Sood, 805-447-1060 (investors)