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 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. 

MEK Pathway in Cancer Animation

To learn more about MEK's role in cancer and our clinical compound, ARRY-142886, please watch the Macromedia® Flash® animation.
© 2004 AstraZeneca Pharmaceuticals LP

View MEK Flash

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.

The Phase 1 trial Array conducted in 2004 evaluated tolerability and pharmacokinetics of selumetinib following oral administration to patients with advanced cancer. In addition, the trial examined patients for indications of biological activity as well as pharmacodynamic and tumor biomarkers. Selumetinib inhibited the MEK pathway in tumor tissue at the dose that was later selected for Phase 2 studies and provided prolonged disease stabilization in a number of cancer patients who had previously received numerous other cancer therapies.

In June 2006, AstraZeneca initiated a Phase 2 study for selumetinib in patients with malignant melanoma, resulting in a $3 million milestone payment to us. The trial was a randomized Phase 2 study that compared selumetinib to Temodar® (temozolomide) in the treatment of patients with stage III/IV melanoma. AstraZeneca enrolled approximately 180 patients at 40 centers worldwide in this study. AstraZeneca also initiated additional Phase 2 studies for selumetinib in colorectal, pancreatic and non-small cell lung cancer during 2006.

In 2008, AstraZeneca presented Phase 1 clinical trial results at the annual meeting of the American Society of Clinical Oncology, or ASCO, of a new selumetinib capsule formulation that replaces the mix/drink formulation used in all prior trials to that time. AstraZeneca reported that the new capsule's maximum tolerated dose was 25% lower yet provided, on average, higher exposure than historical values for the mix/drink formulation. AstraZeneca also reported a complete response in one of the patients. AstraZeneca also presented at ASCO the following Phase 2 clinical trial results of selumetinib using the prior formulation:

• Selumetinib compared to Alimta® (pemetrexed) in 84 non-small cell lung cancer, or NSCLC, patients: neither of these drugs demonstrated superior efficacy.
• Selumetinib compared to Temodar in patients with advanced melanoma: there was no difference between the two treatment arms in the overall population comparing the safety and tolerability profile for selumetinib and these results were consistent with the results reported from the Phase 1 trial.
• Selumetinib compared to Xeloda® (capecitabine) in patients with metastatic colorectal cancer: results showed that selumetinib was generally well tolerated, with neither of these drugs demonstrating superior efficacy.

AstraZeneca also reported that, in patients suffering from melanomas with RAF mutations in clinical trials, selumetinib provided partial responses in two out of 14 patients using the Phase 2 mix/drink formulation and a complete response in one out of eight patients using the Phase 1 new capsule formulation.

AstraZeneca presented at the 2009 American Association for Cancer Research annual meeting results on a Phase 2 trial of selumetinib that showed a 12% overall response rate among patients with biliary cancer.

In 2010, AstraZeneca presented at the ASCO annual meeting results of a Phase 1 clinical trial using the selumetinib capsule formulation in melanoma patients. This study evaluated two doses of selumetinib (50 mg twice daily and 75 mg twice daily) in combination with four different chemotherapies: DTIC® (dacarbazine) (1000 mg/m2), Taxotere (75 mg/m2), Tarceva® (erlotinib) (100 mg daily) or Torisel® (temsirolimus) (25 mg weekly). The study enrolled 25 melanoma patients, 18 of whom had evaluable tumors. Fourteen out of the 18 patients were treated with selumetinib plus DTIC, three with selumetinib plus Taxotere and one with selumetinib plus Torisel. Sixty seven percent of these patients had previously failed at least one prior systemic treatment. Of the 18 patients, nine had BRAF mutations. Of those patients with BRAF mutations, five had a partial response, four had stable disease with a median time-to-progression of 31 weeks. The other nine patients had wild-type BRAF, five of whom had stable disease and four of whom had progressive disease with a median time-to-progression of eight weeks. The median time to progression difference between BRAF mutant and wild type BRAF was statistically significant (p=0.01, Wilcoxon rank-sum test). Selumetinib plus chemotherapy had a 56% response rate in patients with BRAF mutations, whereas no responses were observed in patients with wild-type BRAF. While the number of patients analyzed is small, the trend toward clinical benefit in patients with BRAF mutation is inferred. This is the first disclosed efficacy data with the new formulation of selumetinib, which provides twice the drug exposure at the preferred dose.

During 2010, AstraZeneca completed enrollment in two Phase 2 trials with selumetinib, which are the first two randomized Phase 2 combination trials with a MEK inhibitor:

• Selumetinib in combination with DTIC compared with DTIC alone in first-line melanoma patients with BRAF- mutation. The trial completed enrollment of 91 patients in March 2010 with the primary end-point of overall survival.
• Selumetinib in combination with Taxotere compared with Taxotere alone in second-line non-small cell lung cancer patients with KRAS-mutation. The trial completed enrollment of approximately 80 patients in July 2010 with the primary end-point of overall survival.

Selumetinib is currently the subject of the following select additional Phase 2 trials:

• Selumetinib or Temodar in patients with uveal melanoma. One hundred fifty nine patients are anticipated to enroll in this trial.
• Selumetinib in combination with irinotecan in second-line patients with KRAS or BRAF mutation positive advanced or metastatic colorectal cancer. Fifty seven patients are anticipated to enroll in this trial.
• Selumetinib in combination with Tarceva in non-small cell lung cancer patients with KRAS or KRAS wild-type mutations. One hundred patients are anticipated to enroll in this trial.
• Selumetinib in combination with Nexavar® (sorafenib) in patients with advanced hepatocellular cancer. One hundred patients are anticipated to enroll in this trial.
• Selumetinib in combination with MK-2206 in patients with advanced colorectal cancer. Thirty eight patients are anticipated to enroll in this trial.

In addition to the selumetinib trials described above, AstraZeneca has an ongoing Phase 1 clinical trial with ASD8330 in patients with solid tumors.