Exelixis, Inc. reported top-line results from the ongoing phase III clinical trial of cabozantinib in patients with advanced medullary thyroid cancer (MTC), known as the EXAM trial.

The trial met its primary endpoint of improving progression-free survival (PFS) compared with placebo and substantially exceeded the threshold of a 75 per cent increase in PFS originally assumed when the trial was designed.

Cabozantinib significantly improved median PFS by 7.2 months compared with placebo. The median PFS on the cabozantinib arm was 11.2 months versus 4.0 months on the placebo arm; hazard ratio (HR) 0.28, (95% CI 0.19, 0.40), p < 0.0001. Exelixis intends to report the EXAM data at an upcoming medical conference.

“The success of the EXAM trial is an important advance for MTC patients and for Exelixis,” said Michael M Morrissey, PhD, president and chief executive officer of Exelixis. “These data demonstrate cabozantinib's profound anti-tumour activity in an indication that has seen little clinical progress over the past few decades. They also highlight Exelixis' late-stage clinical development capabilities that will continue to be of critical importance as cabozantinib advances through late-stage development in other indications. Potential approval of cabozantinib in MTC would be a first step to achieve our goal of improving the lives of cancer patients, and would set a solid foundation on which to build a cabozantinib franchise that includes large indications such as prostate cancer.”

Exelixis will consult with the US FDA to determine whether the trial conduct should be changed as a result of these data in conjunction with the SPA. The company is requesting permission to begin a rolling submission of the New Drug Application (NDA) for cabozantinib in this indication to the US Food and Drug Administration (US FDA). It is anticipated that the filing will be completed in the first half of 2012.

“The prospect of a new highly effective therapy for MTC gives patients and physicians a reason for great optimism,” said Steven I Sherman, MD, Chair and Naguib Samaan Distinguished Professor in Endocrinology and Medical Director, Endocrine Multidisciplinary Centre at MD Anderson Cancer Centre, who was also an investigator in the study. “Personally, as a clinician who treats many patients with advanced MTC, it is particularly gratifying to see Exelixis' commitment to the thorough evaluation of cabozantinib in this indication in a large phase III study, and the resultant positive outcome of the trial. This represents important progress in the treatment of MTC, an indication that has long been underserved and still has a significant unmet medical need. I believe that cabozantinib has great potential to improve the care and outcomes of MTC patients.”

EXAM is an international, randomized, placebo-controlled, double-blinded study of cabozantinib in patients with progressive, unresectable, locally advanced, or metastatic MTC. Patients were randomized in a 2:1 ratio to receive cabozantinib or placebo administered at a daily dose of 175 mg. The study did not allow for cross-over from the placebo arm to cabozantinib. With an enrollment target of 315 patients and a planned event-driven analysis, the trial provides 90 per cent power to detect a 75 per cent increase in progression-free survival, the primary endpoint of the study. Additionally the study is designed to assess overall survival at a later time point once those events have been achieved, and is powered to detect a 50 per cent improvement in survival compared with placebo. Exelixis is conducting this trial under a SPA from the US FDA, which allows for full approval on the basis of PFS if the data are supportive. EXAM completed enrollment in the first quarter of 2011.

As previously announced, Exelixis is pursuing a SPA with the US FDA for the first of three planned pivotal trials of cabozantinib in patients with prostate cancer. This trial, XL184-306, is expected to begin by the end of 2011. Exelixis is also working to finalize the design of the XL184-307 and XL184-308 pivotal trials in prostate cancer, which will have endpoints of overall survival and bone metastasis-free survival, respectively. Both trials are expected to begin in 2012. Enrollment is also ongoing in the non-randomized extension (NRE) cohorts in metastatic castration-resistant prostate cancer and ovarian cancer of the company's randomized discontinuation trial (RDT). The RDT and the NRE cohorts are designed to identify additional indications for late-stage clinical evaluation.

Cabozantinib is a potent inhibitor of MET, RET and VEGFR2 that inhibits tumour growth, metastasis and angiogenesis in preclinical models. MET is up-regulated in many tumour types, and promotes tumour cell survival, invasion and metastasis. Further up-regulation of MET occurs under hypoxic conditions, which are often exacerbated by VEGF-pathway inhibitors, promoting increased tumour cell invasion and metastases. Activation of RET is a frequent occurrence in both medullary and papillary thyroid cancers. The therapeutic role of cabozantinib is currently being investigated across multiple tumour types.

Exelixis, Inc. is a biotechnology company committed to developing small molecule therapeutics for the treatment of cancer.