Promising results from Exelixis' cabozantinib phase 2 trial against metastatic ovarian cancer

Exelixis, Inc. (NASDAQ:EXEL) reported longer follow-up data from a fully enrolled cohort of patients with advanced epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube carcinoma treated with cabozantinib (XL184) in an ongoing phase 2 adaptive randomized discontinuation trial. Cabozantinib shows promising activity in these patients independent of prior response to platinum-based therapies.

Ronald J. Buckanovich, M.D., Ph.D., Assistant Professor, Department of Internal Medicine and Assistant Professor, Department of Obstetrics and Gynecology, University of Michigan, presented the data today in an oral session at the American Society of Clinical Oncology's 2011 Annual Meeting (Abstract #5008) in Chicago.

As of the February 11, 2011 cut-off date, accrual in this cohort was complete at 70 patients. Randomization was halted, and randomized patients were un-blinded based on an observed high rate of clinical activity.

Patient Population and Overall Response Rate

All 70 patients enrolled into the ovarian cancer cohort had minimum follow-up of at least 12 weeks and were thus evaluable for safety and the primary efficacy endpoint of response per RECIST. Approximately half of the 70 patients enrolled in the cohort were considered platinum refractory/resistant (49%), defined as a platinum-free interval of 6 months or less, and the remainder of patients (51%) had platinum-sensitive disease based on a platinum-free interval greater than 6 months. More than half the patients (57%) had received 2 or more prior lines of platinum therapy. Some patients also had additional prior lines of therapy with agents such as pegylated liposomal doxorubicin or topotecan (32%), gemcitabine (29%), and VEGF pathway inhibitors (10%). Evidence of objective tumor regression was observed in 73% of patients with at least 1 post-baseline scan. The best overall response rate per RECIST criteria was 24% (16 partial responses [PRs] and 1 complete response). The overall Week-12 disease control rate (DCR) was 53%.

"These latest results in metastatic ovarian cancer demonstrate the potential broad utility of cabozantinib beyond bone-predominant types of cancers such as castration-resistant prostate cancer. The high rates of durable response with our dual inhibitor of MET and VEGFR2 compare favorably to those of other single-agent targeted therapies and cytotoxic agents in development," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "These results underscore the potential of cabozantinib in metastatic ovarian cancer, and we are in discussions with leading cooperative groups to plan further evaluation of cabozantinib in randomized trials for this indication."

Activity in Platinum-Sensitive, -Refractory, and -Resistant Disease

Two of 11 patients (18%) with platinum refractory disease, defined as a platinum-free interval of <1 month, achieved a confirmed response (1 complete response and 1 PR). In the subset of patients with platinum-resistant disease, defined as a platinum-free interval of 1-6 months, 5 of 23 (22%) achieved a PR. Ten of 36 patients (28%) with platinum sensitive disease achieved a PR. The median duration of response has not yet been reached with 36 weeks of median follow-up. The Week-12 DCR in the platinum-refractory, -resistant, and -sensitive groups was 36%, 39%, and 67%, respectively. A total of 37 patients experienced reductions in the ovarian cancer tumor marker CA125, including 8 with decreases greater than 50%. There is no consistent concordance between CA125 changes and tumor regression.

"The continued activity of cabozantinib in a larger population of ovarian cancer patients is very encouraging, especially with respect to the clinical benefit observed in both platinum-sensitive and platinum-resistant/refractory disease. This activity profile has not been observed with other single-agent TKIs, and cabozantinib has the potential to be an important new treatment for ovarian cancer," said Ignace Vergote, M.D., Ph.D., senior author of the presentation and Chairman of the Leuven Cancer Institute at the University of Leuven, European Union. "The high rate of disease control in platinum-resistant and platinum-refractory disease suggests that cabozantinib may help to address the substantial unmet medical need faced by patients who have sub-optimal responses to platinum-based therapies. I believe that further evaluation will help to define the potential role of cabozantinib in the treatment of ovarian cancer."

Safety and Tolerability

Safety data are available for the 70 patients in the Lead-In phase of the study. The most common grade 3 or 4 adverse events (AEs), regardless of causality, were diarrhea (10%), fatigue (9%), PPE syndrome (7%), vomiting (4%), abdominal pain (3%), hypomagnesemia (3%), and nausea, constipation, rash, increased transaminase, and hypertension (each 1%). Two cabozantinib-related grade 5 AEs, one enterocutaneous fistula and one intestinal perforation, were reported after the Lead-In phase. At least one dose reduction was reported in 37% of patients. Less frequent important medical events, regardless of causality, were hemorrhage (11% all grades, 0% grade 3 or 4), venous thrombosis (6%, 4%), and gastrointestinal perforation (6%, 0%).