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– New findings demonstrate the significant progression-free survival benefit seen in the intent-to-treat population was also consistent across subgroups –
– Results from COSMIC-311 served as basis for Exelixis’ recent supplemental New Drug Application to
– Data are in press to be published in The Lancet Oncology –
“Following disease progression on anti-VEGFR therapy, patients with radioactive iodine-refractory differentiated thyroid cancer currently have no standard of care available to them, making the positive results of the COSMIC-311 trial an important clinical advance for this community in need of additional treatment options,” said
Results from COSMIC-311 served as the basis for the supplemental New Drug Application that
As previously announced, at a planned interim analysis, cabozantinib demonstrated a significant reduction in the risk of disease progression or death of 78% versus placebo (hazard ratio [HR]: 0.22; 96% confidence interval [CI]: 0.13-0.36; P<0.0001) in the intent-to-treat (ITT) population. At a median follow-up of 6.2 months, median PFS was not reached (96% CI: 5.7 months – not estimable) in patients treated with cabozantinib and was 1.9 months (96% CI: 1.8-3.6 months) for placebo. The data presented at the 2021 ASCO Annual Meeting demonstrate that HRs for PFS consistently favored cabozantinib over placebo for prespecified subgroups, including age ≤65 vs. >65; prior treatment with lenvatinib (yes vs. no), and number of prior vascular endothelial growth factor receptor (VEGFR)-targeting therapies (1 vs. 2).
The results for the co-primary endpoint of objective response rate in the first 100 randomized patients after six months favored cabozantinib at 15% versus 0% for placebo, although this difference was not statistically significant (P=0.028). In the ITT population, a reduction in target lesion size was found in 76% of patients receiving cabozantinib versus 29% of patients receiving placebo; median overall survival was not reached in either treatment arm but favored cabozantinib (HR: 0.54; 95% CI: 0.27-1.11).
The safety profile was consistent with that previously observed for cabozantinib and adverse events (AEs) were managed with dose modifications. The discontinuation rate due to treatment-emergent AEs was 5% for cabozantinib versus 0% for placebo. The most common (≥5%) all-causality grade 3 or 4 AEs with cabozantinib were palmar-plantar erythrodysesthesia (10%), hypertension (9%), fatigue (8%), diarrhea (7%) and hypocalcemia (7%). There were no treatment-related deaths per investigator.
“We’re excited to offer a more detailed picture of results from the COSMIC-311 trial following the previous announcements that the trial met its co-primary endpoint of PFS, and that we received Breakthrough Therapy Designation for cabozantinib earlier this year,” said
“The results from the COSMIC-311 phase 3 trial have been highly anticipated, with the current survival time for people living with this uncommon form of differentiated thyroid cancer at just three to five years from the time metastatic lesions are detected,” said
COSMIC-311 is a global, multicenter, randomized, double-blind, placebo-controlled phase 3 pivotal trial that aimed to enroll approximately 300 patients at 150 sites globally. Patients were randomized in a 2:1 ratio to receive either cabozantinib 60 mg or placebo once daily. The co-primary endpoints are PFS and ORR, both assessed by BIRC. Patients randomized to placebo were eligible to cross over to open label cabozantinib upon BIRC-confirmed disease progression.
About Differentiated Thyroid Cancer
Approximately 44,000 new cases of thyroid cancer will be diagnosed in the
About CABOMETYX® (cabozantinib)
CABOMETYX is not indicated for the treatment of differentiated thyroid cancer.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC and HCC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.
Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.
Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.
Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.
Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.
With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab.
Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab depending on severity.
Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.
Proteinuria: Proteinuria was observed in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution.
Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing is observed. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.
The most common (≥20%) adverse reactions are:
CABOMETYX as a single agent: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, vomiting, weight decreased, constipation, and dysphonia.
CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.
Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.
Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.
USE IN SPECIFIC POPULATIONS
Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.
Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.
Please see accompanying full Prescribing Information https://www.cabometyx.com/downloads/CABOMETYXUSPI.pdf.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.
For detailed recommendations on the use of CABOMETYX in the
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Exelixis Forward-Looking Statements
This press release contains forward-looking statements, including, without limitation, statements related to: the presentation of data from the COSMIC-311 pivotal trial at ASCO 2021 and forthcoming publication of such data in The Lancet Oncology; the therapeutic potential of CABOMETYX for patients with radioactive iodine-refractory DTC; Exelixis’ and Ipsen’s commitment to exploring the potential of cabozantinib across a range of hard-to-treat cancers; and Exelixis’ plans to reinvest in its business to maximize the potential of the company’s pipeline, including through targeted business development activities and internal drug discovery. Any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements and are based upon Exelixis’ current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: the availability of data at the referenced times; complexities and the unpredictability of the regulatory review and approval processes in the
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2 Cooper DS, et al. 2009.
3 Worden F. 2014. Treatment strategies for radioactive iodine-refractory differentiated thyroid cancer. Ther Adv Med Oncol. 6:267–279.
4 Fugazzola L, et al. 2019. 2019 European Thyroid Association Guidelines for the Treatment and Follow-Up of Advanced Radioiodine-Refractory Thyroid Cancer. Eur Thyroid J. 8:227–245.
5 Pacini F, et al. 2012. Radioactive iodine-refractory differentiated thyroid cancer: unmet needs and future directions. Expert Rev Endocrinol Metab. 7:541–554.
6 Durante C, et al. 2006. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab. 91:2892–2899.
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