Just in time for the American Society of Clinical Oncology (ASCO) meeting in Chicago, Exelixis Inc. completed the filing of its rolling new drug application (NDA) with the FDA for cabozantinib (XL184) in the lead indication of progressive, unresectable, locally advanced or metastatic medullary thyroid cancer (MTC).

Cabo is an inhibitor of tumor growth, metastasis and angiogenesis that simultaneously targets MET, VEGFR2 and RET.

The South San Francisco-based company submitted its NDA under the fast-track designation and requested priority review, which, if granted, would generate a six-month PDUFA date and a likely product launch at the end of 2012, according to Gisela Schwab, the company's executive vice president and chief medical officer.

In addition, Exelixis initiated COMET-1, a pivotal Phase III trial of cabo in the much larger indication of metastatic castration-resistant prostate cancer (mCRPC). The study's primary endpoint is overall survival (OS) in mCRPC patients with disease progression following treatment with docetaxel and Zytiga (abiraterone acetate, Johnson & Johnson) and/or MDV3100 (enzalutamide, Medivation Inc.).

Exelixis expects to complete enrollment within a year and release top-line data in the first half of 2014, Schwab told BioWorld Today.

The NDA filing is based on data from the EXAM trial, a pivotal Phase III in advanced MTC that was conducted under a special protocol assessment (SPA), with progression-free survival (PFS) as the primary endpoint.

In October 2011, Exelixis announced top-line results from EXAM demonstrating that, compared with placebo, cabo improved median PFS by 7.2 months. The median PFS on the cabo arm was 11.2 months vs. four months on the placebo arm (a hazard ratio of 0.28, [95 percent CI 0. 19, 0.40], p < 0.0001 .) (See BioWorld Today, Oct. 25, 2011.)

However, Piper Jaffray & Co. analyst Edward Tenthoff said in a research note that only 5 percent to 10 percent of thyroid cancer patients have MTC, and only 30 percent of those cases recur. "We forecast cabo will achieve MTC sales of $64 million in 2013 with peak sales of $175 million by 2018," he wrote.

The big play for cabo, at least in the early going, is mCRPC. Early results of XL184 in prostate cancer suggested unprecedented activity, particularly in men with bone metastases, according to Matthew R. Smith, director of the Genitourinary Malignancies Program at Massachusetts General Hospital Cancer Center and a lead investigator in the XL184 program. Improvements were observed not only in bone scans, but also in pain relief. (See BioWorld Today, Nov. 19, 2010.)

The question is whether COMET-1 can confirm the early findings and – of importance to the FDA – demonstrate improved OS in mCRPC. The double-blind, placebo-controlled study will include up to 240 international sites and enroll 960 patients with bone metastases, with no limit to the number or type of prior treatments. Patients will be randomized 2-to-1 to receive cabo (60 mg daily, N = 640) or prednisone (5 mg twice daily, N = 320). Each arm also will receive placebo to account for the once-daily vs. twice-daily dosing regimens of cabo and prednisone.

Despite increasing density in the prostate cancer space, Exelixis has confidence in cabo. Most prostate cancer patients suffer from bone metastases, which lead to complications that result in the majority of deaths, Schwab explained.

With cabo, "we've seen a profile characterized by tumor shrinkage of soft tissue and visceral lesions as well as a very remarkable effect on bone metastases as they're visualized on bone scans," she said.

The company plans to conduct a single interim analysis after 387 events. The secondary endpoint is bone scan response as assessed by an independent radiology facility.

Cabo also is being evaluated for its ability to reduce pain associated with bone metastases in the COMET-2 Phase III in men with mCRPC. The endpoint was selected when Exelixis was unable to agree with the FDA on a SPA using composite endpoints of pain reduction and bone scan response. (See BioWorld Today, Nov. 2, 2011.)

"With the two studies, we hope to achieve a potential label that speaks to the drug's ability to prolong the life of patients and also to improve the quality of life," Schwab said, noting that a label encompassing the ability to control mCRPC-related pain would distinguish cabo from the crowd.

Earlier this month, Exelixis also revealed a broad expansion of the cabo clinical development program under a Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute's Cancer Therapy Evaluation Program (CTEP). The CRADA covers the lion's share of funding for up to 20 active clinical trials per year over five years, with Exelixis providing $20,000 per trial per year.

CTEP already has approved the first tranche of 13 trials. Ultimately, the program is designed to evaluate additional indications for cabo in randomized Phase II studies, conduct signal search studies and examine the effect of cabo in combination with other agents.

"We can build on the data emerging from these trials and potentially launch Phase III studies," Schwab said.

Exelixis, which has focused its resources exclusively on cabo, likely will remain in the spotlight at ASCO. The company is scheduled to present five posters on cabo and provide updates on the Phase III EXAM and Phase II randomized discontinuation trials in CRPC, liver and renal cell carcinoma.

The company conducted a major pruning of its pipeline last year to focus on cabo's development, and nearly a dozen compounds in its portfolio have been out-licensed to partners, including GlaxoSmithKline plc, of London, Sanofi-Aventis SA, of Paris, and Bristol-Myers Squibb Co., of New York. (See BioWorld Today, Dec. 17, 2007, Dec. 15, 2008, May 29, 2009, Oct. 12, 2010, and Dec. 27, 2011.)

On Wednesday, shares of Exelixis (NASDAQ:EXEL) lost 3 cents during a broad market swoon, closing at $4.59.