Exelixis’ Cabozantinib Phase 2 Data Demonstrate Reduction in Bone Pain and Narcotic Analgesic Use in Patients with Previously Treated mCRPC
48% of Patients with Moderate to Severe Pain at Baseline Achieve Durable Pain Response
SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Exelixis, Inc. (NASDAQ:EXEL - News) today reported interim data on pain relief and related reduction in narcotic analgesic use with cabozantinib in castration-resistant prostate cancer (CRPC) patients with bone metastases. Howard Scher, M.D., chief of the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center, will present the data on November 14, 2011 in a poster session at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in San Francisco (Abstract B57). The poster will be available at www.exelixis.com/resources/presentations.
Study Results
Effects on pain intensity were measured prospectively in CRPC patients enrolled in the ongoing non-randomized expansion (NRE) cohort of the company’s phase 2 randomized discontinuation trial. Sixty-seven patients were enrolled in the NRE cohort at least 6 weeks prior to data cutoff. All patients had bone metastases and 29 (43%) had measurable soft tissue disease. All patients had received prior docetaxel, 16 (24%) had received prior cabazitaxel, 15 (22%) had prior abiraterone or MDV3100, 4 (6%) had prior radionuclides, and 53 (79%) had previously been treated with bisphosphonates and/or denosumab. The median of the average worst pain at baseline determined by the Brief Pain Inventory (BPI) was 3.3 (range 0-7.9). Twenty-nine patients (43%) had moderate to severe pain as evidenced by average worst pain =4 at baseline, of which 27 (40%) were taking narcotics for pain. This latter population is the focus of the poster presentation.
Patient compliance with scheduled pain assessment was high; 67 patients completed a total of 268 of 295 (91%) pain assessment intervals. Twenty-nine patients with average worst pain =4 at baseline completed 115 of 126 (91%) pain assessment intervals.
Average worst pain improved in 28 of the 29 patients with average worst pain =4 at baseline, including 17 patients previously treated with docetaxel alone and 11 previously treated with docetaxel plus abiraterone and/or cabazitaxel. Three of these patients also previously received a systemic radionuclide therapy. Median best pain reduction from baseline was 46%, and 17 (59%) patients had at least a 30% decrease in average worst pain, including patients with 1-3 prior therapies. Of 25 patients with average worst pain =4 at baseline and a minimum of 12 weeks of follow-up, 12 (48%) had a durable =30% decrease in average worst pain relative to baseline at 2 completed time points which were at least 6 weeks apart. Onset of pain improvement was documented at the first pain assessment at 3 weeks in the majority of patients.
Of the 27 patients with average worst pain =4 and taking narcotics at baseline, 15 (56%) decreased their dose by at least 30%, including 7 (26%) who discontinued narcotic drugs completely, 4 (15%) had a stable dose (no change or change =30%), and 8 (30%) increased narcotic drug usage.
Pain relief (=30% pain alleviation relative to baseline) was also accompanied by improved sleep and reduced interference with activities of daily living. Twelve patients with a = 30% pain alleviation at week 12 had a 32% median improvement in sleep and 17% median improvement in interference with activities of daily living. Six patients not experiencing pain relief (<30% improvement in pain relative to baseline) had worsening median interference with sleep (16%) and activities of daily living (20%).
“The improvements in pain observed in this study are significant and suggest that cabozantinib could have an important role in the control of pain related to bone metastases in men with progressive CRPC,” said Howard Scher, M.D., an investigator on the trial and chief of the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center. “Cancer-related pain is one of the most feared complications of prostate cancer and a predictor for increased mortality from the disease. New treatment options to relieve and control these debilitating symptoms are urgently needed.”
“These prospectively collected data indicate that cabozantinib has a meaningful impact on pain and narcotic use in CRPC patients with bone metastases,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “These results importantly corroborate our initial investigator-reported data presented at this year’s ASCO meeting, and suggest that cabozantinib can provide meaningful clinical benefit to patients suffering from pain and who have limited treatment options.”
Patients in this single-arm study received a starting dose of 100 mg of cabozantinib daily. All patients in the NRE cohort had bone metastases, had received prior docetaxel chemotherapy, and could have received additional systemic therapy including cabazitaxel. Upon study entry, patients were required to have demonstrated objective evidence of disease progression during or within 6 months of docetaxel or cabazitaxel therapy.
Pain and Analgesic Medication Assessment
Pain was assessed using an Interactive Voice Response System comprising a 4-item questionnaire. The questionnaire assessed pain at its worst, disturbed sleep at its worst, and interference with activities of daily living, all within the previous 24 hours. These three items were measured using an 11-point rating scale (0-10), in which 0 indicates absence of the symptom. The worst pain intensity rating is derived from the BPI, which is widely used and accepted in contemporary pain studies (Atkinson et al., 2010). Changes in a patient’s pain were assessed relative to their baseline pain score. Narcotic analgesic medication use was assessed by Patient Diary. All pain and analgesic medication use assessments were reported as the average daily score over a 7-day interval. The baseline assessment was taken within 14 days prior to the first dose of cabozantinib, while the post-baseline assessments were taken at Week 3, Week 6, and every 6 weeks thereafter. For the assessment interval to be considered valid, the patient had to complete a minimum of 4 of the 7 questionnaires administered during the 7-day assessment interval.
Changes in pain assessment were evaluated in patients with moderate-to-severe baseline pain, defined as an average daily worst pain score =4. Patients were evaluated for achieving a =30% decrease in average daily worst pain relative to baseline. Patients were also evaluated for changes in narcotic analgesic use relative to baseline.
Safety and anti-tumor activity in the NRE cohort of CRPC patients will be summarized in a future presentation.
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 ALP 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, dual inhibitor of 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: • Extensive apoptosis of malignant cells • Decreased tumor invasiveness and metastasis • Decreased tumor and endothelial cell proliferation • Blockade of metastatic bone lesion progression • Disruption of tumor vasculature
About Exelixis
Exelixis, Inc. is a biotechnology company committed to developing small molecule therapeutics for the treatment of cancer. Exelixis is focusing its proprietary resources and development efforts exclusively on cabozantinib, its most advanced solely-owned product candidate, in order to maximize the therapeutic and commercial potential of this compound. Exelixis believes cabozantinib has the potential to be a high-quality, differentiated pharmaceutical product that can make a meaningful difference in the lives of patients. Exelixis has also established a portfolio of other novel compounds that it believes have the potential to address serious unmet medical needs. For more information, please visit the company's web site at www.exelixis.com.
Preliminary Data Demonstrate that 40 mg Daily Dose of Cabozantinib Yields a High Rate of Bone Scan Response in mCRPC
- Encouraging signs of activity also observed in NSCLC at 40 mg daily dose -
SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Exelixis, Inc. (NASDAQ:EXEL - News) reported data from two ongoing clinical trials exploring lower starting doses of cabozantinib in cancer patients, including a phase 1 investigator-sponsored trial (IST) designed to assess the lowest effective dose of cabozantinib for treatment of metastatic bone lesions in patients with metastatic castration-resistant prostate cancer (CRPC) as assessed by post-treatment changes in bone scans. Preliminary data from the ongoing IST demonstrate that a daily starting dose of 40 mg resulted in high rates of bone scan response assessed by computer-aided detection (CAD) by an independent radiology facility (IRF) in men with CRPC and bone metastases. The 40 mg dose was also associated with improved tolerability compared with the 100 mg daily dose used in the ongoing phase 2 randomized discontinuation trial of cabozantinib. Richard J. Lee, M.D., Instructor in Medicine at the Massachusetts General Hospital Cancer Center, will present the data from the IST tomorrow in a poster session at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in San Francisco (Abstract A90). The poster will be available at www.exelixis.com/resources/presentations.
Bone Scan Results
The study enrolled 23 patients as of the 1 October 2011 cut-off. Bone scan response at week 6 is the primary endpoint of this study and is defined as a =30% reduction in the bone scan lesion area on the week 6 bone scan relative to baseline as assessed by a CAD system at an IRF.
Twelve patients were enrolled in the 40 mg cohort. One of the these patients discontinued the study at Week 2 due to worsening of pre-existing anorexia and fatigue, and another patient discontinued at Week 6 after experiencing a pathologic hip fracture. Eleven patients were evaluable at Week 6, of which 10 had bone scan responses. The median decrease in bone scan lesion area was 61.5%. Eight of the 10 responding patients had a confirmation of the bone scan response at week 12 and continue on treatment with a median duration of treatment of 19 weeks.
Based on the bone scan findings of the 40 mg cohort, a second cohort of 11 patients was enrolled and is receiving cabozantinib at a dose of 20 mg daily. Nine of these patients were evaluable at 6 weeks, of which two had a bone scan response. Six other patients had stable disease (SD) by bone scan (<30% decrease to <30% increase in bone scan lesion area), and one patient had progressive disease by bone scan (=30% increase in bone scan lesion area). Based on the results to date in the 20 mg and 40 mg cohorts, an expanded cohort of 13 patients at the 40 mg daily dose is expected to open shortly. Additional imaging, circulating tumor cell, and bone biomarker data are planned to be collected in the expanded cohort.
Safety and Tolerability Results
Daily cabozantinib at 40 mg or below was well tolerated. There were no dose reductions or interruptions during the first 12 weeks for the 40 mg cohort and during the first 6 weeks in the 20 mg cohort. A single patient in the 40 mg cohort experienced =Grade 3 (G3) drug-related adverse events of worsening of pre-existing anorexia (G3) and fatigue (G3) and discontinued study treatment at week 2.
“The 100 mg starting dose of cabozantinib has shown important signs of clinical benefit in men with CRPC, including tumor shrinkage, extension of progression-free survival and resolution of metastatic bone lesions by bone scans,” said Matthew Smith M.D., Ph.D., Professor of Medicine and Director of the Genitourinary Malignancies Program at the Massachusetts General Hospital Cancer Center. “The preliminary results from the ongoing dose ranging study clearly demonstrate that a 40 mg dose yields high rates of bone scan response with improved tolerability. I believe these data support continued evaluation of lower doses as both treatment and potential prevention of bone metastases in men with CRPC.”
Trial Design
The phase 1 IST uses an adaptive design to determine the lowest effective dose of cabozantinib that yields a high rate of bone scan response in men with CRPC and bone metastases. Bone scan response at week 6 is the primary endpoint of this study and is defined as a =30% reduction in the bone scan lesion area on the week 6 bone scan relative to baseline as assessed by a CAD system at an IRF. Cohorts of 11 patients are enrolled, starting with 40 mg daily cabozantinib as the first cohort. In the second cohort, daily dosing is decreased to 20 mg if at least 8 patients in the first cohort have bone scan responses, and increased to 60 mg if fewer than 8 patients have a bone scan response. Based on the observed bone scan response rate in the second cohort of 11 patients, a dose level is selected for expansion to treat an additional 13 patients.
Low-Dose Data from Phase 1 Study in Japanese Patients
Preliminary data from a phase 1 clinical trial of cabozantinib in Japanese patients with advanced solid tumors, which will be the subject of a poster presentation at the conference on November 15 (Abstract C26), also support the potential utility of a 40 mg daily dose of cabozantinib in treating soft tissue and visceral tumors. In the phase 1 trial (N=6), two patients with non-small cell lung cancer (NSCLC) in the 40 mg arm had confirmed partial responses with target lesion shrinkage of 38% and 41%; three patients had stable disease, and one patient had disease progression. No dose-limiting toxicities, serious adverse events, or Grade 4 or 5 adverse events have been reported to date in this trial. The only Grade 3 adverse events reported were neutropenia in one patient and increased lipase in one patient, both at the 40 mg dose level. Additional safety and efficacy data from this trial will be presented on November 15. The poster will be available at www.exelixis.com/resources/presentations.
“The high rates of bone scan response at the 40 mg starting dose level suggest that this lower starting dose could be effective in CRPC with improved tolerability, as demonstrated by the reported absence of dose interruptions and reductions,“ said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “Additionally, data from a phase 1 trial of cabozantinib in Japanese patients, which will be presented later this week, show that two patients with NSCLC achieved partial responses with the 40 mg daily dose of cabozantinib, suggesting that this lower dose may also provide clinical benefit in the treatment of malignancies primarily metastasizing to or residing in soft tissue. These data support the emerging clinical differentiation for cabozantinib from the perspective of both broad clinical activity and improved tolerability in patients with cancer.”
Additional cabozantinib data will also be presented at the conference, including results of a pain study in CRPC patients with bone metastases (Abstract B57) and results of a CAD imaging study in CRPC patients with bone metastases (Abstract B114), each of which will be the subject of poster presentations on November 14.
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 ALP 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, dual inhibitor of 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: • Extensive apoptosis of malignant cells • Decreased tumor invasiveness and metastasis • Decreased tumor and endothelial cell proliferation • Blockade of metastatic bone lesion progression • Disruption of tumor vasculature
About Exelixis
Exelixis, Inc. is a biotechnology company committed to developing small molecule therapeutics for the treatment of cancer. Exelixis is focusing its proprietary resources and development efforts exclusively on cabozantinib, its most advanced solely-owned product candidate, in order to maximize the therapeutic and commercial potential of this compound. Exelixis believes cabozantinib has the potential to be a high-quality, differentiated pharmaceutical product that can make a meaningful difference in the lives of patients. Exelixis has also established a portfolio of other novel compounds that it believes have the potential to address serious unmet medical needs. For more information, please visit the company's web site at www.exelixis.com.
Market Data 
Markets 
AI
