Exelixis, Inc. (NASDAQ:EXEL) today reported interim data from the cohort of patients with metastatic castration-resistant prostate cancer (CRPC) treated with XL184 in an ongoing phase 2 adaptive randomized discontinuation trial (RDT). David C. Smith, M.D., Professor, Departments of Internal Medicine and Urology at the University of Michigan, will present the data in the Molecular-Targeted Therapies-Clinical Trials poster session (Abstract #406) on Thursday, November 18th, at the 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Berlin, Germany.
“These data suggest that XL184 has a novel and differentiated clinical profile in CRPC, and will provide critical guidance in defining our high priority development activities for XL184 in 2011.”
XL184 Activity Against Bone and Soft Tissue Lesions in CRPC
As of the November 1, 2010 cut-off date, a total of 99 patients were enrolled in the CRPC cohort, with 34 currently evaluable for tumor response per RECIST criteria and 20 with evidence of bone metastasis evaluable for changes in bone scan. The trial includes patients with (57%) and without (43%) prior docetaxel therapy.
Impact on Metastatic Bone Lesions
Nineteen of 20 patients (95%) achieved either complete or partial resolution of lesions on bone scan by independent review, with most resolving at the first post-baseline assessment at 6 weeks. Bone scans use a radiotracer imaging agent that binds to sites of new bone formation, which reflect sites of metastatic disease in bone. Multiple cases of complete or near complete resolution were observed in both docetaxel-pretreated and docetaxel-naïve subgroups. To date, a single docetaxel-pretreated patient achieved stabilization of bone scan as his best evaluation, and no patient exhibited worsening on bone scan as his best time point assessment.
Bone scan resolution was associated with investigator reported improvements in bone pain, with the majority of symptomatic patients experiencing pain relief. In addition, most patients exhibited decreases in the blood-based bone metabolism biomarkers alkaline phosphatase (ALP) and C-terminal telopeptides of type 1 collagen (CTx), which are often increased in patients with metastatic bone lesions who are at risk for skeletal morbidity. Patients with anemia at baseline exhibited maximal increases in hemoglobin levels ranging from 1.2 to 3.4 g/dL from baseline.
Impact on Soft Tissue Lesions
The week-12 disease control rate (DCR) was 71%. Tumor shrinkage was observed in 38 of 55 patients (69%) with measurable soft-tissue metastatic lesions and at least one post-baseline scan. To date, 3 of 34 patients (9%) evaluable by RECIST achieved a confirmed partial response (PR). Of note, response criteria in common use today (including RECIST) do not incorporate bone scan findings. Stable disease (SD) was reported in 25 patients (74%) including 2 unconfirmed PRs. Changes in PSA are reasonably well correlated with response to hormonally acting agents and cytotoxic chemotherapy. In contrast, XL184 treated patients experiencing tumor regression and improvement in bone pain demonstrated variable impact on PSA levels. Thus, the commonly used PSA marker does not appear to be a reliable indicator for the activity of XL184 in this disease.
Safety and Tolerability
Safety data are available for 49 patients who had at least 6 weeks of follow-up. The most common Grade ≥ 3 AEs, regardless of causality were fatigue (14%), hypertension, PPE syndrome (each 6%), hemorrhage, nausea (each 4%), diarrhea, cough, and rash (each 2%).
"CRPC is a leading cause of cancer-related death in men in the United States and Europe," said Dr. Smith. "Recent advances in systemic therapy have had at best a modest impact on survival, and virtually all patients will succumb to this disease. Bone metastases result in significant morbidity for patients with CRPC, including fractures and pain, which can substantially reduce quality of life and increase mortality. The results of this study to date suggest that XL184 has activity against both soft tissue and bone metastatic lesions. Based on this activity, further evaluation of XL184 in CRPC is clearly indicated, as the data suggest that the compound may provide clinical benefit to a population of patients with few treatment options that effectively target both components of this disease."
"The initial activity of XL184 against metastatic soft-tissue and bone lesions in CRPC patients is very encouraging," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "These data suggest that XL184 has a novel and differentiated clinical profile in CRPC, and will provide critical guidance in defining our high priority development activities for XL184 in 2011."
To access the clinical data poster mentioned in this press release, please visit www.exelixis.com.
XL184 Targets Key Pathways That Contribute to Prostate Cancer
XL184, an inhibitor of tumor growth, metastasis and angiogenesis, simultaneously targets MET and VEGFR2, key kinases involved in the development and progression of many cancers. Prominent expression of MET has been observed in primary and metastatic prostate carcinomas, with evidence for higher levels of expression in bone metastases. Overexpression of hepatocyte growth factor (HGF), the ligand for MET, has also been observed in prostate carcinoma, and increased plasma levels of HGF are associated with decreased overall survival in CRPC. Data from preclinical studies also suggest that both HGF and MET are regulated by the androgen signaling pathway in prostate cancer, where upregulation of MET signaling is associated with the transition to androgen-independent tumor growth. Additionally, both the MET and VEGF signaling pathways also appear to play important roles in the function of osteoblasts and osteoclasts—cells in the bone microenvironment that are often dysregulated during the establishment and progression of bone metastases.
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.
Broad Clinical Activity of XL184 - Randomized Discontinuation Trial
XL184 has demonstrated anti-tumor activity in 9 of 12 indications studied to date. In ongoing trials, compelling activity has been observed in medullary thyroid cancer, glioblastoma, and clear cell renal cancer. In the RDT, XL184 is being evaluated in nine different tumor types, with clear signals of activity in six: prostate, ovarian, hepatocellular, breast, non-small cell lung cancer, and melanoma. The adaptive RDT design allowed for rapid simultaneous assessment of the activity of XL184 across nine different tumor indications. As of the November 1, 2010 cut-off date, a total of 397 patients have been enrolled into the 9 disease-specific cohorts, with 273 evaluable for response, and 312 evaluable for safety. Of 273 patients evaluable for response per RECIST, 39 achieved a PR (either confirmed or unconfirmed) and 100 had SD at week 12. The week-12 DCR for the overall population was 49%, with the highest rates occurring in hepatocellular cancer (75%), CRPC (71%), ovarian cancer (64%), melanoma (45%), non-small cell lung cancer (42%) and breast cancer (42%). Of note, a breast cancer patient with evidence of bone metastasis on bone scan demonstrated evidence of resolution on bone scan accompanied by 29% reduction in tumor size. XL184 has been generally well tolerated with a consistent adverse event profile across the nine different RDT tumor types.
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