CHICAGO - Exelixis Inc.'s investigational cancer drug cabozantinib demonstrated activity in patients with nine kinds of cancer as part of a single Phase II trial that employs a novel adaptive randomized discontinuation design. The company presented updated data from the trial in three sessions at the American Society of Clinical Oncology meeting June 3-7 in Chicago.

In the randomized discontinuation trial, patients who had complete or partial responses stayed on the drug; those with stable disease were randomized to cabozantinib or placebo; and patients with progressive disease were removed.

Using the RDT design, 490 patients with active, advanced disease received open-label cabozantinib during a 12-week lead-in phase. The endpoint, a combination of complete and partial response and stable disease rates, called the disease control rate, was at least 40% in the melanoma (47%), hipatocellular cancer (73%), breast (45%), prostate (68%), ovarian (53%) and non-small cell lung cancer (40%) cohorts.

Based on those results, the castration-resistant prostate cancer and ovarian cancer cohorts were advanced to a non-randomized extension, and the company expects to start a Phase III study in prostate cancer by the end of the year.

"We have a study oversight committee with members of the company and principal investigators evaluating the data on an ongoing basis, so you can make decisions very quickly based on the activity you see for the individual cohorts," Exelixis Chief Medical Officer Gisela Schwab explained in an interview.

The company also is discussing further evaluation of the drug in a randomized Phase II/III trial in ovarian cancer, Schwab said. Those studies are in addition to the open-label cohorts already ongoing "to give us more information in consistently heavily pretreated patients."

Cabozantinib (XL 184) is an oral inhibitor of both MET and VEGF2 kinases. The dual activity allows the agent to thwart both angiogenesis in existing tumors and tumor cell invasion and metastasis. In addition, cabozantinib studies so far have shown reductions in markers of bone resorption similar to bone-targeting agents, as well as a reduction in markers of bone formation. That translates into patients with bone metastasis experiencing reduced pain and a reduction in narcotic use.

Updated interim data from the fully enrolled cohort of 171 CRPC patients in the randomized portion of the study released June 6 showed significant improvement in PFS in cabozantinib patients.

A total of 31 patients with stable disease at week 12 were randomized to either placebo or cabozantinib. From week 12 on, the investigator-assessed median PFS is 6 weeks for the placebo group (n=17) and 21 weeks for the cabozantinib group (n=14). The hazard ratio corresponds to an 87% reduction in risk of progression for the cabozantinib group.

Excluding the placebo group, the median PFS was 29 weeks overall, while the median PFS in docetaxel-naive and -pretreated patients was 24 weeks and 29 weeks, respectively, indicating that cabozantinib treatment produces durable disease control in both docetaxel-naive and pretreated populations.

Among patients with bone metastases, partial or complete resolution of bone scan was observed in 82 (76%) of patients; 23 patients (21%) had stable disease on bone scan, and only three (3%) had progressive disease in bone. Safety and tolerability were the same as would be expected with other kinase inhibitors.

-Shirley Haley (s.haley@elsevier.com)

Exelixis' Lead-In Trial Design Evaluates Cabozantinib Disease Activity Against Multiple Cancers At 12 Weeks

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