Press Release
| Cabozantinib Meets Primary Endpoint of Progression Free Survival in Phase 3 Pivotal Trial in Medullary Thyroid Cancer |
-- Nearly three-fold increase in median progression-free survival --
Dr. “As the first phase 3 trial to enroll patients with independently confirmed radiographic progressing medullary thyroid cancer, EXAM represents an important milestone for this orphan disease in which there have been very few rigorous prospective clinical trials,” said Dr. Schöffski. “The data presented today are highly compelling and demonstrate that cabozantinib can provide a significant benefit to patients with advanced MTC. Taken as a whole, the results clearly show that cabozantinib is an important advance in the treatment of MTC and has the potential to improve the care and outcomes for MTC patients.” Efficacy Results
All 330 patients were included in the efficacy analysis. Cabozantinib
met the primary endpoint of the trial, with a median PFS of 11.2 months
vs. 4.0 months for placebo [HR 0.28, p<0.0001] based on the independent
radiology committee (IRC) evaluation. The Kaplan Meier estimate for the
proportion of patients alive and progression-free at 1 year was 47.3% in
the cabozantinib arm and 7.2% in the placebo arm. Other sensitivity
analyses (investigator assessment, uniform date, and per protocol
assessment) were consistent with the primary analysis. Cabozantinib’s
benefit on PFS was seen across a number of pre-specified subgroups
including RET mutational status or prior tyrosine kinase inhibitor (TKI)
therapy. With respect to secondary endpoints, the ORR, per RECIST
evaluated by the IRC, was 28% in the cabozantinib arm and 0% in the
placebo group. Median duration of response was 14.6 months. At
the time of the
“As seen in the initial topline results, and again today at the Patient Demographics The trial enrolled 330 patients with locally advanced or metastatic MTC that had progressed per RECIST within 14 months of screening. Patients were randomized 2:1 to cabozantinib (N=219) or placebo (N=111). Median age in both arms was 54 years, and almost all patients had ECOG performance status of 0-1 (95% and 90% in the cabozantinib and placebo arms, respectively). Prior TKI exposure (20%, 22%), measurable disease (95%, 94%), and bone metastases at baseline (each 51%) were also balanced between the cabozantinib and placebo arms, respectively. RET mutations were seen at a similar rate between arms (46%, 52%).
As of the Safety Results The safety analysis included the 323 patients in both arms of the trial who had received at least one dose of study treatment (214 in the cabozantinib arm and 109 in the placebo arm). Consistent with the much longer PFS, the median duration of exposure was twice as long in the cabozantinib arm (6.7 months) versus the placebo arm (3.4 months). Overall AE results for the trial are consistent with a long duration of exposure to an active agent in a patient population with advanced disease. The most frequent adverse events (AEs) of grade ≥ 3 with greater than 2% incidence in the cabozantinib arm were: diarrhea (16%), palmar-plantar erythrodysesthesia (13%), fatigue (9%), hypertension (8%), decreased weight (5%), decreased appetite (5%), and stomatitis (2%). The most frequent adverse events (AEs) of grade ≥ 3 with greater than 2% incidence in the placebo arm were: diarrhea (2%) and fatigue (2%). Diarrhea and decreased weight are commonly associated with advanced and progressive MTC. Cabozantinib is a potent inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2), and investigators reported infrequent adverse events that have previously been associated with VEGF-pathway inhibition. Grade ≥ 3 adverse events in the cabozantinib arm that are generally associated with VEGF-pathway inhibition were: hypertension (8%), venous thrombosis (4%), hemorrhage (3%), GI perforation (3%), and non-GI fistula (2%). In some cases, these events may also be the result of an anti-tumor effect. For example, two patients who experienced non-GI fistulas had involvement of the lungs or bronchus and had partial responses. Deaths were generally balanced between treatment arms, and most were due to progressive disease. Deaths for reasons other than progressive disease and within 30 days of treatment cessation occurred in 5.6% of patients on the cabozantinib arm and in 2.8% of patients on the placebo arm. The difference is largely accounted for by 1.9% of the total number of deaths in the cabozantinib arm that were due to events commonly associated with VEGF-pathway inhibition. Biochemical Response Results Biochemical responses assessed as additional secondary endpoints were consistent with the observed anti-tumor activity of cabozantinib. Calcitonin levels dropped by 45% in the cabozantinib arm, but rose by 57% in the placebo arm during the first three months on study. Similar effects were seen with CEA. EXAM Trial Design
EXAM is an international, randomized, placebo-controlled, double-blinded
study of cabozantinib in patients with progressive, unresectable,
locally advanced, or metastatic MTC. The study enrolled 330 patients who
were randomized in a 2:1 ratio to receive cabozantinib (N=219) or
placebo (N=111) administered at a daily dose of 140 mg (free base
equivalent). The study did not allow for crossover from the placebo arm
to cabozantinib. The first patient was randomized in About Cabozantinib Cabozantinib is a potent targeted therapy that inhibits MET, VEGFR2, and RET, all of which play an important role in the biology of medullary thyroid cancer. 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:
About
Forward-Looking Statements
This press release contains forward-looking statements, including,
without limitation, statements related to: the continued development and
clinical, therapeutic and commercial potential of, and opportunities
for, cabozantinib; the belief that EXAM represents an important
milestone and advance for the treatment of MTC; the belief that the
referenced data are highly compelling and demonstrate that cabozantinib
can provide a significant clinical benefit to patients with advanced
MTC; the belief that MTC has the potential to improve the care and
outcomes for MTC patients; potential approval by the
Source:
Exelixis, Inc. |