LAKE FOREST, Calif., April 03, 2007 /PRNewswire/ -- Amgen's recent discontinuation of treatment with Vectibix (panitumumab), the first fully human IgG2 monoclonal antibody (MAb) targeting the epidermal growth factor receptor (EGFr), in the phase IIIb Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) trial is a disappointing setback. PACCE was evaluating the addition of Vectibix to a regimen of standard oxaliplatin- or irinotecan-based chemotherapy and bevacizumab (Avastin; Genentech), an antiangiogenic vascular endothelial growth factor (VEGF) inhibitor, for first line treatment of metastatic colorectal cancer (CRC). The trial was halted after preliminary review of data from a pre-planned interim efficacy analysis, scheduled after the first 231 events (death or disease progression), revealed a statistically significant difference in progression-free survival (PFS) and overall survival in favor of the control arm and higher toxicity in the Vectibix arm. Total enrollment of this trial had reached 1,054. Amgen is continuing phase III trials of Vectibix as a single biologic combined with chemotherapy as a first- or second-line treatment. No other clinical trials are being modified at this time, however, Amgen is evaluating data across all trials. Vectibix is approved as a third line treatment for metastatic, refractory CRC expressing EGFr.
EGFr has been efficaciously targeted by approved monoclonal antibodies (MAb), which prevent ligands from binding to the extracellular segment of the receptor, and tyrosine kinase inhibitors (TKI), which inhibit the intracellular segment of EGFr and initiation of intracellular signal transduction pathways. The application of EGFr-targeted therapy in CRC is based on the overexpression of EGFr in tumor cells in a high percentage (up to 77%) of patients with CRC. VEGF expression is also increased in patients with CRC. The combination of two drugs targeting different molecular pathways known to contribute to malignancy is attractive because multiple redundant pathways are evident in many types of cancer. Combining molecularly targeted therapies with cytotoxic chemotherapy agents is the standard approach, and will remain so in the near to medium term, because of the proven efficacy of the latter drug class.
Higher toxicities, lower survival rates.
Higher toxicities may have been anticipated by PACCE investigators. There was an increased incidence of Grade 3 severe events of diarrhea, dehydration and infections in the Vectibix-treated patients. In addition, an increased incidence of pulmonary embolism was observed in patients who were treated with Vectibix compared with those who were not (4% and 2%, respectively). There was 1 (<1%) fatality from pulmonary embolism of a patient treated with Vectibix. However, the lower PFS and overall survival in the Vectibix arm would not haven been anticipated. Increased survival rates were the goal, to be gained possibly at the expense of higher toxicity. The causes of reduced survival rates have not yet been explained.
AMG 706 trial may shed light.
Findings from another Amgen clinical trial with Vectibix, this one in combination with the developmental VEGF inhibitor, AMG 706, with or without cytotoxic chemotherapy, may provide insight into underlying mechanisms. AMG 706 is a potent, oral, small molecule angiogenesis inhibitor that selectively targets multiple kinases, including VEGFr, platelet-derived growth factor receptor beta (PDGFrB, PDGFr), Kit, and Ret. It is currently in a phase I/II trial in combination with Vectibix and carboplatin/paclitaxel (CP), versus Vectibix and CP, in patients with advanced (Stage IIIb/IV) non-small cell lung cancer (nsclc). The Vectibix plus AMG 706 arm will provide information about the effects of EGFr inhibition plus VEGFr inhibition. The triple therapy arm of this trial is directly analogous to the triple therapy arm of the PACCE trial (i.e., EGFr inhibition plus VEGF inhibition plus cytotoxic chemotherapy). Results of this trial are eagerly awaited.
Vectibix is priced lower than Erbitux.
Amgen's commercialization strategy for Vectibix includes a pricing strategy that undercuts the price of Erbitux (cetuximab; ImClone), which suggests that price pressure on biologics used to treat cancer may now become a factor when new agents of the same drug class are introduced. Vectibix therapy is priced at about $8,000 a month (five 100 mg vials at about $4,000, every 2 weeks), compared to about $10,000 per month for Erbitux. The high cost of biologic cancer therapies has drawn public criticism and increased scrutiny of pricing policies, insurance coverage, and cost/benefit analysis.
Role of EGFr testing.
Although EGFr testing is employed in many clinical trials to select patients for EGFr-targeted therapies (e.g., MAb, TKI), and it is required by the FDA for selection of patients for treatment with Erbitux, its utility as a predictor of medication response is not yet clear. Testing for gene amplification or overexpression of HEr2, an EGFr family receptor, is well established, required by FDA, and offers theragnostic value for treatment of women with breast cancer with Herceptin (trastuzumab; Genentech). Most EGFr studies to date, however, do not supply data that indicates which subsets of patients may derive the most benefit from EGFr-targeted agents. EGFr is overexpressed in varying degrees in a wide variety of malignancies. Many new tests of EGFr expression and mutations are in development and a large number of clinical trials is underway to elucidate their roles in determining patient selection for EGFr-targeted therapies.
About Future Oncology
Currently in its 10th year, Future Oncology has covered every aspect of the oncology field, and represents a powerful resource for professionals involved in the development or marketing of products in this sector. The recent issue of Future Oncology (Volume 8, Number 11/12, March 28, 2007) begins a four-part series on the EGFr Pathway in cancer. Part I reviews ligands, receptors, downstream effectors, and EGFr tests on the market and in development. Part II assesses the role of the EGFr pathway to clinical cancer indications. Part III delineates the clinical and market performance of commercialized agents targeting the EGFr pathway. Part IV describes over 50 novel EGFr-targeted drugs in development. A sample issue of Future Oncology, as well as indices and tables of contents of previous issues may be found at http://newmedinc.com.
About New Medicine's Oncology KnowledgeBASE (nm|OK)
New Medicine's Oncology KnowledgeBASE (nm|OK), residing at http://www.nmok.net, is an edited, inclusive analysis of all aspects of oncology drug development globally, including technologies, targets, companies, business affiliations, medical and clinical developments, including protocols and results of thousands of clinical trials, and global markets, among others. Currently, nm/OK profiles over 3,000 anticancer agents/technologies, over 1,500 targets implicated in malignancy, and over 2,000 companies developing/marketing products in the oncology sector.
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