Exelixis, Inc. (NASDAQ:EXEL) today reported positive updated interim
data from an ongoing phase 2 trial of cabozantinib in men with
metastatic castration-resistant prostate cancer (CRPC) and bone
metastases. These data confirm cabozantinib's effects on metastatic bone
lesions and soft tissue disease, and demonstrate a positive impact on
bone related pain and narcotic use, as well as biomarkers of bone
formation and resorption. Matthew R. Smith, M.D., Ph.D., Director of the
Genitourinary Malignancies Program at the Massachusetts General Hospital
Cancer Center and an investigator on the trial, presented the data today
in an oral session at the American Society of Clinical Oncology 2012
Annual Meeting (Abstract #4513), which is taking place in Chicago,
Illinois. In addition, preliminary results from an ongoing phase 1
investigator-sponsored trial (IST) designed to determine the lowest
effective dose of cabozantinib for the treatment of men with CRPC and
bone metastases were also presented at the conference. Richard J. Lee,
M.D., Ph.D., Assistant Physician in the Department of Medicine at
Massachusetts General Hospital Cancer Center, and an investigator on the
study, presented the data yesterday in a poster discussion session
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>
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
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
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 Michael M. Morrissey, Ph.D., president and chief executive officer
of Exelixis. "The durable improvements in bone scans and bone pain, the
high rate of tumor regression, and other indicators of clinical activity
observed in these trials support using overall survival and bone pain
response as the endpoints for our two recently initiated prostate cancer
phase 3 pivotal trials, COMET-1 and COMET-2, respectively. We believe
these two pivotal trials provide us the best opportunity to maximize the
clinical and commercial potential of cabozantinib in CRPC."