AstraZeneca – Selumetinib and AZD8330 – MEK Program
In December 2003, we entered into an out-licensing and collaboration agreement with AstraZeneca to develop our MEK program. Under the agreement, AstraZeneca acquired exclusive worldwide rights to our clinical development candidate, selumetinib (previously known as AZD6244, or ARRY-142886), together with two other compounds for oncology indications, including AZD8330, which we invented during the collaboration. We retained the rights to all therapeutic indications for MEK compounds not selected by AstraZeneca for development, subject to the parties’ agreement to work exclusively together. In April 2009, the exclusivity of the parties’ relationship ended, and both companies are now free to independently research, develop and commercialize small molecule MEK inhibitors in the field of oncology. To date, we have earned $21.5 million in up-front and milestone payments. The agreement also provided for research funding, which is now complete, and provides potential additional development milestone payments of approximately $75 million and royalties on product sales. Under this collaboration, we were responsible for Phase 1 clinical testing, which we completed in 2004, and AstraZeneca is responsible for all future development and commercialization of the compounds under the collaboration.
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MEK is a key protein kinase in the RAS/RAF/MEK/ERK pathway, which signals cancer cell proliferation and survival. MEK has been shown to be frequently activated in cancer, in particular in tumors that have mutations, including BRAF and NRAS, in the RAS and RAF pathways. Selumetinib is a small molecule MEK inhibitor that targets a key position in this pathway.
Development Status: Selumentinib is currently in Phase 2 development in a range of solid tumors. There were two presentations of significant data for selumetinib during fiscal 2012, which are summarized below.
Phase 2 trial in patients with KRAS non-small cell lung cancer (NSCLC) – Data was presented in June 2012 at the American Society of Clinical Oncology (ASCO) Annual Meeting from a double blind, randomized Phase 2 study conducted by AstraZeneca comparing the efficacy of selumetinib in combination with docetaxel versus docetaxel alone in second-line therapy in 87 patients with KRAS-mutation positive locally advanced or metastatic NSCLC (Stage IIIB — IV). This study showed statistically significant improvement in progression-free survival, objective response rate, and alive and progression-free at six months as well as a trend for improvement in median overall survival in favor of selumetinib in combination with docetaxel versus docetaxel alone (9.4 mo vs 5.2 mo; 56 events, median follow-up 219 days) but did not reach statistical significance. Hazards were non-proportional (HR 0.80; 80% CI 0.56, 1.14; 1-sided p=0.2069). All secondary endpoints, including response rate (selumetinib/docetaxel 37%, docetaxel 0%; p<0.0001) and progression free survival (selumetinib/docetaxel 5.3 mo, docetaxel 2.1 mo; 71 events; HR = 0.58; 80% CI 0.42, 0.79; 1-sided p=0.0138), were significantly improved for selumetinib in combination with docetaxel versus docetaxel alone.
The tolerability profile of selumetinib in combination with docetaxel was consistent with previously conducted studies. There was an increased incidence of Grade 3 or 4 neutropenia and febrile neutropenia and of Grade 1 or 2 diarrhea in patients receiving the selumetinib combination versus docetaxel alone.
This study was the first completed randomized combination trial with a MEK inhibitor in KRAS mutant advanced NSCLC and Array believes was the first prospective study to demonstrate clinical benefit as defined by response rate and progression free survival of a targeted therapy for patients with KRAS mutant cancer of any type. Approximately 20 to 25 percent of the NSCLC patient population has the KRAS mutation which amounts to approximately 160,000 patients globally. Currently, patients with KRAS NSCLC have a poor prognosis with limited treatment options. Targeting MEK dependent tumors with selumetinib demonstrates the potential of a personalized approach to medicine in the treatment of cancer and suggests that further clinical evaluation of selumetinib in KRAS mutation positive NSCLC patients is warranted.
Phase 2 trial in patients with recurrent low-grade serous ovarian or peritoneal cancer – In April 2012, the Gynecologic Oncology Group presented results of a Phase 2 trial with selumetinib in women with recurrent low-grade serous ovarian or peritoneal cancer at the American Association for Cancer Research Annual Meeting. This trial was funded by the National Cancer Institute and run by the Gynecologic Oncology Group.
In the reported trial, 52 women each received 100-mg doses of selumetinib orally twice daily in four-week cycles until disease progression or toxicity. The median number of cycles received was 4.5; 33% received 12 or more cycles. Prior to the trial, 58% of the patients in the trial had received three or more rounds of chemotherapy. The disease control rate, defined as either complete or partial response or progression-free survival or progression-free survival of greater than 6 months, was 81% of patients. Eight patients had complete (1) or partial (7) responses, and 34 (63%) had progression-free survival of greater than 6 months. The median survival rate without cancer progression was 11 months. Only three patients experienced grade 4 adverse events.
There are 38 on-going trials with selumetinib, including trials in NSCLC, thyroid cancer, melanoma, ocular melanoma, hepatocellular cancer, rectal cancer, colorectal cancer, pancreatic cancer and breast cancer.