AstraZeneca – Selumetinib – MEK Program
In December 2003, we entered into Collaboration and License 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 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. Our research obligations ended in 2004 and AstraZeneca is responsible for all future development and commercialization of the compounds under the collaboration. 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.
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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: There are 45 on-going trials with selumetinib, including trials in non-small cell lung cancer, or NSCLC, thyroid cancer, melanoma, ocular melanoma, hepatocellular cancer, colorectal cancer, pancreatic cancer and breast cancer. AstraZeneca began a pivotal trial called ASTRA with selumetinib in thyroid cancer in May 2013 and expects to begin a Phase 3 trial in non-small cell lung cancer in 2013. Recent presentations of significant data for selumetinib are summarized below.
Phase 2 trial in patients with uveal melanoma – Promising data on selumetinib in an ongoing Phase 2 trial of patients with uveal melanoma were presented at the 2013 ASCO Annual Meeting. At the meeting, Memorial Sloan-Kettering Cancer Center presented data on selumetinib that showed it to be the first targeted therapy to demonstrate significant clinical benefit of more than doubling of progression-free survival for patients with metastatic uveal melanoma. These results suggest that selumetinib has the potential as a new standard of care for patients with very few treatment options. Survival for these patients with advanced disease has held steady at only nine months to a year for decades.
Memorial Sloan-Kettering researchers found that progression-free survival in patients receiving selumetinib was nearly 16 weeks and 50% of these patients experienced some tumor shrinkage, with 15% achieving major shrinkage. Patients receiving temozolomide, the current standard of care, achieved progression-free survival of seven weeks and no tumor shrinkage. Despite the study's cross-over design - the patients whose tumors progressed on temozolomide began taking selumetinib - there was a trend towards improved survival with selumetinib. Selumetinib was generally tolerable, with most side effects manageable with conservative supportive care or dose modification.
Phase 2 trial in patients with radioiodine refractory thyroid cancer – In February 2013, a pilot study was published in the New England Journal of Medicine reporting the results of a Phase 2 trial in which selumetinib demonstrated positive therapeutic activity in patients with RAI-refractory disease. In that study, selumetinib produced clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine. Based on these results, AstraZeneca has initiated a pivotal trial called ASTRA combining selumetinib with radioactive iodine in the treatment of differentiated thyroid cancer.
Phase 2 trial in patients with KRAS-mutant NSCLC – AstraZeneca presented data at the 2012 ASCO Annual Meeting from its double-blind, randomized Phase 2 study 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 versus 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.
Phase 2 trial in patients with recurrent LGSOC or peritoneal cancer – 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 2012 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 six months, was 81% of patients. Eight patients had complete (1) or partial (7) responses, and 34 (63%) had progression-free survival of greater than six months. The median survival rate without cancer progression was 11 months. Only three patients experienced grade 4 adverse events.