Amgen posted results of a biomarker analysis which indicated that in metastatic colorectal cancer (mCRC) patients who have failed all other chemotherapeutic regimens, the efficacy of Vectibix (panitumumab) monotherapy is confined to patients with non-mutated (wild-type) KRAS tumours.
Specifically, in patients with non-mutated KRAS tumours, Vectibix significantly increased progression-free survival (PFS) and had an impact on quality of life (QoL) and disease-related symptoms, compared to best supportive care (BSC) alone.
These data were generated from a biomarker analysis of a phase III, randomised, 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 tumour 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, Research and Development, 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 tumours 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 favour 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 tumours treated with Vectibix compared to BSC. The United States (US) 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 signalling. However, in patients with tumours harbouring 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, signalling continues despite anti-EGFr therapy. Mutated KRAS is detected in approximately 40 percent of CRC tumours.
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 per cent non-mutated).
Of the 463 randomised patients in the "408" trial, 427 had available KRAS data and 57 per cent had tumours with normal, non-mutated KRAS. In the group of patients with non-mutated KRAS that received Vectibix, 17 per cent responded to treatment and 34 per cent 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 per cent of patients.
Vectibix was approved in the US 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 US, 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 tumour types. Emerging data from our ongoing phase III trials examining Vectibix in combination with chemotherapy in the first- and second-line of mCRC.