Exelixis announces interim data from cabozantinib phase 2 trial on metastatic CRPC

Exelixis, Inc. (NASDAQ:EXEL) today announced interim data from 51 patients with metastatic castration-resistant prostate cancer (CRPC) and bone metastases receiving a 40 mg daily dose of cabozantinib in an ongoing non-randomized expansion (NRE) cohort of a phase 2 randomized discontinuation trial. The data suggest that the 40 mg daily dose has similar clinical activity to the 100 mg daily dose previously reported from this trial for key parameters, including reduction of metastatic bone and soft tissue disease, and reduction of bone-related pain and narcotic use, with apparent improvement in adverse event rates and tolerability. Johann de Bono, M.D., Ph.D., leader of the prostate cancer targeted therapy team at The Institute of Cancer Research, London, and honorary consultant at The Royal Marsden NHS Foundation Trust, and an investigator on the trial, presented the data today in an oral presentation session on prostate cancer at the European Society for Medical Oncology (ESMO) 2012 Annual Meeting (Abstract #897O) in Vienna, Austria.    

"The results presented today at ESMO are consistent with interim data previously reported for the 40 mg cohort of an ongoing investigator-sponsored trial evaluating low-dose cabozantinib in men with CRPC and bone metastases," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "The data suggest that the 40 mg daily dose has activity with respect to a number of key metrics, including bone and soft tissue responses, as well as changes in pain scores and narcotic use. Additionally, the 40 mg daily dose appears to be well-tolerated in patients with metastatic CRPC."

The interim results reported today include data from 51 men enrolled in the 40 mg NRE cohort of an ongoing phase 2 randomized discontinuation trial. All patients had bone metastases on bone scan and 41% had measurable soft tissue disease. All patients had received prior docetaxel, 67% had received prior abiraterone or enzalutamide (MDV3100), and 25% had received prior cabazitaxel. Bone-directed therapies such as zoledronic acid, denosumab, and radionuclides were used in 45%, 41% and 6% of patients, respectively. Seventy-one 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 53% of patients, with 45% of these patients receiving chronic narcotic administration.

Bone Scan Response (BSR). Computer-assisted evaluation of bone scan lesion area (BSLA) was performed and response evaluated by an Independent Radiology Committee (IRC). An overall BSR rate (complete response + partial response) of 49% was observed, with another 29% of patients having stable disease, and 14% having a best response of progressive disease.

Initial results from ongoing efforts focused on documenting the direct impact of cabozantinib on tumor lesions in the bone of prostate cancer patients were presented, and suggest that cabozantinib's effects on bone scan may be linked to induction of tumor necrosis in bone metastases. In a patient with complete resolution of pelvic metastatic lesions on bone scan, diffusion-weighted magnetic resonance imaging (MRI) findings were consistent with tumor necrosis occurring within the bone metastases. Additional evidence for the tumor selective effect of cabozantinib on bone scans was also presented, based on an analysis of a patient with concurrent osteoarthritis. In this patient, near complete resolution of bone scan tracer uptake at sites of metastatic tumor lesions was observed, while bone scan tracer uptake was maintained at sites of osteoarthritis. To gain further insights into the effects of cabozantinib on bone lesions, there are other ongoing clinical trials using MRI, other imaging techniques, and bone-metastatic tumor biopsies.

Soft Tissue Response. Twenty-one patients had measurable soft tissue or visceral lesions at baseline and 19 patients had at least one post-baseline assessment. Evidence of tumor regression was seen in 79% of the 19 patients with at least one post-baseline assessment. Overall response by RECIST among 21 patients with at least baseline data was partial response in 10%, stable disease in 71%, and progressive disease in 10%. Soft tissue responses were independent of prior therapy.

Pain Palliation. In 26 patients with clinically significant baseline pain, the median maximal reduction in pain from baseline was 49%. A clinically significant reduction of pain, defined as a ≥30% decrease in BPI pain score, was observed in 18 patients (69%). Fifty-four percent of patients decreased their use of narcotics, including one patient who discontinued narcotics. The majority of patients in whom these improvements were observed had received both prior docetaxel and prior abiraterone or enzalutamide.

Biomarkers. Improvements were also seen in circulating tumor cells (CTCs), and two markers of bone metabolism: cross-linked C-terminal telopeptides of type 1 collagen (CTx) and bone-specific alkaline phosphatase (BSAP). Substantial reductions in CTCs were observed regardless of prior therapy in patients with baseline CTC counts ≥5/7.5 mL of blood and a week 6 and/or week 12 assessment. Twenty-six of 39 patients (67%) had a ≥30% decrease in their CTC count, and 22% converted to <5 CTCs at week 6. Median CTC change was a 70% decrease. Median change in CTx at Week 12 was a 31% reduction, and 50% of evaluable patients had decreased BSAP at Week 12 or later.

Progression-Free Survival (PFS). Analyses of PFS based on radiographic progression per IRC in soft tissue and/or bone included either the total population>

Adverse Events. The most frequently reported adverse events (AEs) of grade 3 or higher, regardless of causality, were: hypertension (14%), venous thrombosis (14%), fatigue (12%), decreased appetite (8%), and back pain (4%). No grade 5 AEs were reported. Only 25% of patients experienced a dose reduction due to an AE.

"The adverse event and clinical activity data observed with the 40 mg daily dose of cabozantinib support the design of the ongoing phase 3 trials," said Dr. de Bono. "Additionally, the MRI data suggest that cabozantinib's effect on bone metastases may involve tumor-specific cell death, which potentially would differentiate cabozantinib from purely bone-targeted agents. Additional studies in CRPC and other malignancies with high rates of bone metastases are warranted."

 Source: Exelixis, Inc.

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