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| Cabozantinib Demonstrates Durable Effects in Bone and Soft Tissue in Advanced Prostate Cancer |
-- Improved Bone Scans, Reduced Pain & Narcotic Requirements -- Decreased Circulating Tumor Cells and Bone Biomarkers Also Seen Both presentations are available at http://www.exelixis.com/resources/events/asco-2012. Cabozantinib in Chemotherapy-Pretreated Metastatic CRPC: Interim Results from a Phase 2 Non-Randomized Expansion Cohort The interim results reported today include data from 93 men enrolled in the ongoing non-randomized expansion (NRE) 100 mg cohort of the company’s phase 2 randomized discontinuation trial. All patients had bone metastases on bone scan and 46% had measurable soft tissue disease. All patients had received prior docetaxel, 35% had prior abiraterone or MDV3100, and 24% had received prior cabazitaxel. Bone directed therapies such as zoledronic acid, denosumab and alpharadin were used in 57%, 14% and 1% of patients, respectively. Seventy-three percent of patients had received at least 2 prior lines of therapy for CRPC. Clinically significant pain, defined as baseline pain score by Brief Pain Inventory (BPI) ≥4, was present in 44% of patients, with the majority requiring chronic narcotic administration. Bone Scan Response (BSR). Computer-assisted evaluation of bone scan lesion area (BSLA) was determined by an Independent Radiology Committee (IRC) and showed an overall BSR rate (complete response + partial response) of 67%. Another 16% of patients had stable disease and 8% had a best response of progressive disease. Median best BSLA change was a reduction of 60%, and reductions were observed in patients with prior abiraterone, MDV3100, cabazitaxel, and/or radionuclide therapy. The median duration of bone scan response was 5.4 months (range 5.0 – 6.9 months). Pain Palliation. In 39 patients with clinically significant baseline pain, the median maximal reduction in pain from baseline was 46%. A clinically significant reduction of pain, defined as a ≥30% decrease in pain score, was observed in 25 patients (64%). Fifty-six percent of patients decreased their use of narcotics, including 31% who discontinued narcotics. These improvements were observed in patients with a variety of prior therapies. Circulating Tumor Cells. Robust reductions in circulating tumor cells (CTCs) were observed regardless of prior therapy in 62 patients with baseline CTC counts ≥5/7.5 mL of blood and a week 6 and/or week 12 assessment. Fifty-seven patients (92%) had ≥30% decrease in their CTC count. Thirty-nine percent of evaluable patients converted to <5 CTCs at week 6. Progression-Free Survival (PFS). Analyses of progression free survival based on radiographic progression per IRC in soft tissue and/or bone included either the total population (N=93) or only patients who had received prior docetaxel and abiraterone (n= 29). Median progression-free survival was 4.2 months (95% CI 4.1, 6.6) for the total population, and 4.6 months (95% CI 2.9, 8.3) for patients who had previously received docetaxel and abiraterone. Bone Biomarkers. Substantial decreases were seen in serum levels of cross-linked C-terminal telopeptides of type 1 collagen (CTx) and bone-specific alkaline phosphatase (BSAP), which are biomarkers of bone metabolism. Reductions occurred in patients previously treated with bone directed therapy such as zoledronic acid or denosumab. Safety Results. The most frequently reported adverse events (AEs) of grade 3 or higher, regardless of causality, were: fatigue (28%), diarrhea (11%), nausea (10%), hypertension (9%), back pain (7%), decreased appetite (6%), venous thrombosis (6%), hand-foot syndrome (5%), dyspnea (5%), vomiting (4%), and decreased weight (3%). A single related grade 5 event was observed in a patient with extensive liver metastases and abnormal liver function tests at baseline who went on to experience portal vein thrombosis and subsequent liver failure. “The effects of cabozantinib on bone metastases, soft-tissue metastases, and pain are compelling. In men with bone-predominant disease, the most common phenotype in metastatic CRPC, the impact was particularly profound,” said Dr. Smith. “The scope of activity of cabozantinib as a single agent is unique relative to approved agents or agents in development. The compound’s ability to positively impact PFS, bone scan response, circulating tumor cells, pain, and bone turnover markers demonstrates its potential as an important new agent in CRPC.” Trial Results of Low-Dose Cabozantinib in Treating Bone Metastases in CRPC This dose-ranging study used an adaptive design. Dose levels of 20 and 40 mg daily cabozantinib were explored, with BSR as the primary endpoint. Additionally, CTCs and safety were assessed. In Cohort 1 (40 mg daily cabozantinib), 10 of 11 evaluable patients (91%) had a BSR at week 6, comprising 1 complete response (CR) and 9 partial responses (PRs). A lower BSR rate (10%) was observed in Cohort 2, with 10 evaluable patients receiving 20 mg. Therefore, an expansion cohort of 13 patients was enrolled at 40 mg. The week 6 BSR rate among all 24 patients who received a 40 mg daily dose of cabozantinib was 67%. Patients receiving 40 mg of cabozantinib were included in the CTC assessment. Twelve of 21 evaluable patients had baseline CTCs ≥5/7.5 mL of blood. Eleven of these 12 patients (92%) demonstrated best CTC decrease ≥30%, and 7 patients (58%) converted to <5 CTCs. None of the patients receiving cabozantinib at either 20 or 40 mg daily required dose reductions or interruptions during the first 12 weeks of treatment. A patient in Cohort 1 discontinued treatment at week 2 for worsening of preexisting fatigue, weight loss, and anorexia. In Cohort 2 and the expansion cohort, a total of three patients discontinued treatment due to a venous thromboembolic event.
“These new data reinforce cabozantinib’s differentiated clinical profile
and potential utility for the treatment of men with metastatic CRPC,”
said The Significance of Bone Metastases in CRPC The primary cause of morbidity and mortality in patients with CRPC is metastasis to the bone, which occurs in about 90% of cases. Bone metastases cause local disruption of normal bone remodeling, with lesions generally showing a propensity for an osteoblastic (bone-forming) phenotype on imaging. These lesions often lead to increased skeletal fractures, spinal cord compression, and severe bone pain. Osteoblastic lesions are typically visualized in CRPC patients by bone scan, which detects rapid incorporation of 99mTc-labeled methylene-diphosphonate radiotracer into newly forming bone. In addition, increased blood levels of BSAP and CTx, markers for osteoblast and osteoclast activity, respectively, are often observed in CRPC patients with bone metastases, and are associated with shorter overall survival. About Cabozantinib Cabozantinib is a potent targeted therapy that inhibits MET and VEGFR2. Cabozantinib is an investigational agent that provides coordinated inhibition of metastasis and angiogenesis to kill tumor cells while blocking their escape pathways. The therapeutic role of cabozantinib is currently being investigated across several tumor types. MET is upregulated in many tumor types, thus facilitating tumor cell escape by promoting the formation of more aggressive phenotypes, resulting in metastasis. MET-driven metastasis may be further stimulated by hypoxic conditions in the tumor environment, which are often exacerbated by selective VEGF-pathway inhibitors. In preclinical studies, cabozantinib has shown powerful tumoricidal, antimetastatic and antiangiogenic effects, including:
About
Forward-Looking Statements
This press release contains forward-looking statements, including,
without limitation, statements related to: the continued development and
clinical, therapeutic and commercial potential of, and opportunities
for, cabozantinib; the potential of cabozantinib as an important new
agent in CRPC; the belief that the referenced data support using overall
survival and bone pain response as the endpoints for Exelixis’ two
recently initiated prostate cancer phase 3 pivotal trials, COMET-1 and
COMET-2; and the belief that the COMET-1 and COMET-2 trials provide
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Exelixis, Inc. |
