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,
"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.