Negative Cabozantinib Prostate Study Triggers Massive Exelixis Restructuring

Michael M. Morrissey, PhD

Cabozantinib (Cometriq) failed to significantly extend overall survival (OS) compared with prednisone as a treatment for men with metastatic castration-resistant prostate cancer (mCRPC), according to initial results from the phase III COMET-1 trial released by Exelixis, the company developing the drug.

Based on these top-line findings, Exelixis announced that it plans to cut 160 employees (70%) from its workforce. Additionally, all company-sponsored studies investigating cabozantinib as a treatment for men with prostate cancer have been stopped, including a phase II trial exploring the drug in combination with abiraterone acetate. The phase III COMET-2 study comparing cabozantinib to mitoxantrone plus prednisone, which was expected to report results later this year, was deprioritized by the company.

The restructuring of the company is expected to take place by the end of 2014 and will cost in $6-8 million. According to Exelixis, this reconfiguration of the company should enable it to maintain several ongoing phase III studies, specifically those focused on hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). In response to the news, Exelixis' shares fell by more than 50% in early morning trading.

“We are very disappointed that COMET-1 did not meet its primary endpoint of extending overall survival in men with mCRPC,” Michael M. Morrissey, PhD, president and chief executive officer at Exelixis, said in a statement. “We remain focused on the development program for cabozantinib beyond mCRPC, including the ongoing METEOR and CELESTIAL phase III pivotal trials, from which we expect top-line data in 2015 and 2017, respectively.”

The COMET-1 study enrolled 960 patients with bone metastatic CRPC following progression on docetaxel, abiraterone, and/or enzalutamide. Patients were randomized in a 2:1 ratio to cabozantinib at 60 mg daily or prednisone at 5 mg twice daily. A statistically significant advantage in OS was defined as a 25% reduction in the risk of death.

The median OS with cabozantinib was 11.0 months compared with 9.8 months with prednisone (HR = 0.90; 95% CI, 0.76 — 1.06; P = .212). The median progression-free survival (PFS) was 5.5 versus 2.8 months, for cabozantinib and prednisone, respectively (HR = 0.50; 95% CI, 0.42 — 0.60; P <.0001).

Exelixis announced early results from the study. A full analysis of available data will be submitted for presentation at an upcoming conference.

Cabozantinib initially generated excitement through the demonstration of dramatic bone scan activity in patients with CRPC in phase II data presented at the 2011 ASCO Annual Meeting. In the 9-arm study, complete or partial bone scan resolution was seen in 86% of patients with CRPC. The highest objective response rates (ORR) were seen in patients with ovarian cancer (24%), HCC (14%), breast cancer (10%), and non-small cell lung cancer (10%).

The most commonly reported adverse events with cabozantinib included fatigue (13%), PPE syndrome (7%), diarrhea (5%), and hypertension (5%). Additionally, 6 deaths were reported in the study. Cabozantinib-associated side effects in the COMET-1 study were reportedly similar to earlier studies of the drug.

The FDA approved cabozantinib for the treatment of patients with metastatic medullary thyroid cancer in November 2012. This approval was based on the phase III EXAM trial that demonstrated a dramatic improvement in PFS with cabozantinib compared with placebo.

Cabozantinib will continue to be explored across a number of other tumor types, including non-small cell lung cancer, colorectal cancer, multiple myeloma, and pancreatic cancer.

The phase III METEOR study is comparing cabozantinib to everolimus in patients with advanced RCC following frontline treatment with a VEGFR TKI. PFS is the primary endpoint of the study, with secondary outcome measures focused on OS and ORR. The phase III CELESTIAL trial is comparing cabozantinib to placebo for patients with HCC following treatment with sorafenib.

“We have thoughtfully prepared for this scenario and the resulting very difficult decisions. The workforce reduction we have announced today is necessary to significantly reduce our corporate operating expenses," Morrissey said