Exelixis, Inc. (NASDAQ:EXEL) today announced the initiation of an investigator-sponsored trial (IST) of cabozantinib in women with hormone receptor-positive breast cancer with bone metastases. This study is currently being conducted at the Massachusetts General Hospital Cancer Center under the direction of Michaela J. Higgins, M.D., MRCPI, (Principal Investigator) and José Baselga, M.D., Ph.D. (Chief of Hematology/Oncology and Associate Director of the Massachusetts General Hospital Cancer Center). This multi-center trial will also be conducted at the Memorial Sloan-Kettering Cancer Center under the direction of Monica Fornier, M.D. (Assistant Professor), and at Dana-Farber/Brigham and Women's Cancer Center and at Beth Israel Deaconess Medical Center under the direction of Sara M. Tolaney, M.D., M.P.H., and Steven Come M.D., respectively.
“The results from this IST will play a critical role in evaluating the clinical and commercial potential of cabozantinib in a large indication with substantial unmet medical need”
"The previously reported positive responses observed with cabozantinib in the breast cancer cohort of the phase 2 randomized discontinuation trial are encouraging and suggest that cabozantinib may have a positive impact on bone and soft tissue lesions in these patients. This new phase 2 trial should provide important insight into the potential role that cabozantinib could play in the treatment of hormone receptor-positive metastatic breast cancer," said Dr. Baselga.
"This phase 2 trial will enroll women with hormone receptor-positive breast cancer that has metastasized to the bone and whose disease has progressed after initial treatment for metastatic disease. Important therapeutic goals for the treatment of these women are to control the disease in the bone and in other tissues, decrease the risk of bone complications and pain, and delay the need for chemotherapy," said Dr. Higgins.
The open label, single arm trial is expected to enroll 50 women. Patients will receive cabozantinib once daily until disease progression or unacceptable toxicity, and will have their disease evaluated every 12 weeks. At baseline and at the 12-week assessment, subjects may undergo an optional bone biopsy to obtain tissue samples for correlative studies.
The primary endpoint of the trial is bone scan response rate determined by local institutions and by an independent radiology facility. Secondary endpoints are objective response rate, overall survival, progression-free survival, effects of cabozantinib on tumor markers and biochemical markers of bone turnover, skeletal-related events, and positron emission tomography (PET) response rate. The identification of surrogate biomarkers associated with the clinical activity of cabozantinib is included as an exploratory endpoint.
"The results from this IST will play a critical role in evaluating the clinical and commercial potential of cabozantinib in a large indication with substantial unmet medical need," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "With its primary endpoint of bone scan response rate, this trial will complement our first pivotal trial of cabozantinib in metastatic castration-resistant prostate cancer, the '306 trial, which will use bone scan response as a secondary endpoint and is expected to start by the end of the year. We believe that these two trials together should provide important further insights into the compound's activity on bone metastases, and build a foundation for further clinical inquiry. The initiation of this IST reflects a high level of enthusiasm for cabozantinib among oncologists, and we are pleased to support the efforts of Dr. Higgins and her colleagues."
Trial Rationale
Despite the availability of multiple treatment options for women with breast cancer, including surgery, radiation, hormonal therapy, and cytotoxic agents, there is still a significant unmet medical need for new treatment options. Hormonal therapy is the main option for patients with hormone receptor-positive breast cancer, although resistance to this treatment is often associated with ligand-independent activation of the estrogen receptor. Several studies have implicated MET, VEGFR2, and RET, targets of cabozantinib, in the onset, progression, metastasis, and recurrence of breast cancer.
The phase 2 randomized discontinuation trial of cabozantinib included 20 women with measurable metastatic breast cancer (ASCO 2011). Despite the typically poor prognosis of these patients, 2 of 20 experienced a partial response and 15 of 20 patients had tumor shrinkage as their best response with cabozantinib treatment. The responders had hormone receptor-positive disease. Three patients had baseline and on-treatment bone scans. Two of these patients had partial resolution of their lesions on bone scan, which was associated with a decrease in pain. The third patient had stable disease on bone scan.
Metastatic bone lesions from cancer as imaged on bone scan, FDG-PET scan or X-ray are not considered 'measurable' by the RECIST criteria. As a result, patients with bone-only or bone-predominant metastatic breast cancer without measurable disease have typically been excluded from clinical trials that include response measurements as a primary endpoint. However, such patients are common in the breast clinic and there is an unmet need to evaluate novel agents that may effectively treat their metastatic disease burden in bone as well as soft tissue sites.
The Significance of Bone Metastases in Metastatic Breast Cancer
Overall, bone is the most common site to which breast cancer metastasizes, and the site of first metastasis in approximately 50% of patients with breast cancer. Up to 75% of patients with metastatic breast cancer will develop bone metastases during the course of their disease and this number is even higher among those with hormone receptor-positive disease. For 20-25% of patients with metastatic breast cancer, especially those with hormone receptor-positive disease, bone will be their only site of metastatic involvement. Bone metastases in women with breast cancer are associated with considerable morbidity including hypercalcemia, increased fracture risk, need for surgery or radiotherapy, and spinal cord compression.
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