On June 6, 2016 Exelixis, Inc. (NASDAQ:EXEL) and Ipsen (Euronext: IPN; ADR: IPSEY) reported the presentation of positive data from subgroup analyses of the pivotal METEOR trial comparing CABOMETYX (cabozantinib) tablets with everolimus in 658 patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy (Press release, Exelixis, JUN 6, 2016, View Source [SID:1234513040]). Schedule your 30 min Free 1stOncology Demo! The data will be presented in two posters today at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which is being held June 3-7 in Chicago, by Bernard Escudier, M.D., chair, Genitourinary Oncology Committee, Institut Gustave Roussy and Thomas Powles, M.D., clinical professor of genitourinary oncology, Barts Cancer Institute. The findings demonstrate that benefits of CABOMETYX in progression-free survival (PFS) and overall survival (OS) were independent of the presence of bone metastases, prior anti-PD-1/PD-L1 therapy, and the type of prior vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) therapy.
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"These additional analyses demonstrate the value of CABOMETYX for advanced kidney cancer, showing consistent improvement in PFS and OS across multiple subgroups of patients in the METEOR trial," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "We are dedicated to exploring the full potential of CABOMETYX to help as many patients as possible."
In the first of the two presentations, treatment with CABOMETYX was associated with improved PFS and OS in patients who had bone metastases at baseline (n=142). Median PFS was 7.4 months with CABOMETYX versus 2.7 months with everolimus (HR=0.33, 95% CI 0.21-0.51), and median OS was 20.1 months versus 12.1 months, respectively (HR=0.54, 95% CI 0.34-0.84).
For patients who had both bone and visceral metastases (n=112), median PFS was 5.6 months with CABOMETYX and 1.9 months with everolimus (HR=0.26, 95% CI 0.16-0.43). Median OS was 20.1 months versus 10.7 months, respectively (HR=0.45, 95% CI 0.28-0.72). The safety profile of CABOMETYX for the subgroup with bone metastases was consistent with that of the overall METEOR trial.
"Patients whose kidney cancer has spread to their bones traditionally have a poorer prognosis and worse treatment outcomes compared with those who do not have bone involvement," said Dr. Escudier. "CABOMETYX demonstrated a clinically meaningful benefit for those with bone metastases, which is encouraging for physicians and patients who are seeking additional therapeutic options."
In the second presentation, outcomes were evaluated based on the prior therapy patients had received before entering the METEOR trial. OS and PFS benefits were consistent across all subgroups evaluated (see table below), including number of prior VEGFR TKIs (one or more than one), specific prior VEGFR TKI (sunitinib or pazopanib) in patients who had only one prior VEGFR TKI therapy, and prior treatment with anti-PD-1/PD-L1 therapies. Adverse events in the treatment subgroups were similar to those in the overall study population and were managed with dose reductions.
Table. OS and PFS in METEOR by Subgroup
Subgroup n Median OS (months)
OS
Hazard
Ratio
(95% CI)
Median PFS (months)
PFS
Hazard
Ratio
(95% CI)
CABOMETYX Everolimus CABOMETYX Everolimus
Number of prior VEGFR TKIs
1 464 21.4 16.5 0.65 (0.50-0.85) 7.4 3.8 0.52 (0.41-0.66)
≥2 194 20.8 17.2 0.73 (0.48-1.10) 7.4 4.0 0.51 (0.35-0.74)
Only prior VEGFR TKI
Sunitinib 267 21.4 16.5 0.66 (0.47-0.93) 9.1 3.7 0.43 (0.32-0.59)
Pazopanib 171 22.0 17.5 0.66 (0.42-1.04) 7.4 5.1 0.67 (0.45-0.99)
Prior anti-PD-1/PD-L1 therapy
No 626 21.4 16.5 0.68 (0.54-0.85) 7.4 3.9 0.54 (0.44-0.66)
Yes 32 Not estimable 16.3 0.56 (0.21-1.52) Not estimable 4.1 0.22 (0.07-0.65)
"These findings demonstrate that the benefit of CABOMETYX for patients was robust and consistent regardless of prior treatment, location and extent of tumor metastases," said Marc de Garidel, Chairman and CEO, Ipsen.
On April 25, 2016 CABOMETYX was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy. CABOMETYX, which was granted Fast Track and Breakthrough Therapy designations by the FDA, is the first approved single agent therapy to demonstrate, in a phase 3 trial for patients with advanced RCC, robust and clinically meaningful improvements in all three key efficacy parameters — OS, PFS and objective response rate.
Please see Important Safety Information below and full U.S. prescribing information for CABOMETYX (cabozantinib) tablets at View Source
About the METEOR Phase 3 Pivotal Trial
METEOR was an open-label, event-driven trial of 658 patients with advanced renal cell carcinoma who had failed at least one prior VEGFR TKI therapy. The primary endpoint was PFS in the first 375 patients treated. Secondary endpoints included OS and objective response rate in all enrolled patients. The trial was conducted at approximately 200 sites in 26 countries, and enrollment was weighted toward Western Europe, North America, and Australia. Patients were randomized 1:1 to receive 60 mg of CABOMETYX daily or 10 mg of everolimus daily and were stratified based on the number of prior VEGFR TKI therapies received and on MSKCC risk criteria. No cross-over was allowed between the study arms.
METEOR met its primary endpoint of significantly improving PFS. Compared with everolimus, CABOMETYX was associated with a 42 percent reduction in the rate of disease progression or death. Median PFS for CABOMETYX was 7.4 months versus 3.8 months for everolimus (HR=0.58, 95% CI 0.45-0.74, P<0.0001). CABOMETYX also significantly improved the objective response rate compared with everolimus (P<0.0001). These data were presented at the European Cancer Congress in September 2015 and published in The New England Journal of Medicine.1
CABOMETYX also demonstrated a statistically significant and clinically meaningful increase in OS in the METEOR trial. Compared with everolimus, CABOMETYX was associated with a 34 percent reduction in the rate of death. Median OS was 21.4 months for patients receiving CABOMETYX versus 16.5 months for those receiving everolimus (HR=0.66, 95% CI 0.53-0.83, P=0.0003).
Cabozantinib benefit in OS was robust and consistent across all pre-specified subgroups. In particular, benefit was observed regardless of risk category, location and extent of tumor metastases, and tumor MET expression level. These results were presented on June 5, 2016 at the ASCO (Free ASCO Whitepaper) Annual Meeting and concurrently published in The Lancet Oncology.2
At the time of the analysis, the median duration of treatment in the trial was 8.3 months with CABOMETYX versus 4.4 months with everolimus. Dose reductions occurred for 62 percent and 25 percent of patients, respectively. Discontinuation rate due to an adverse event not related to disease progression was 12 percent with CABOMETYX and 11 percent with everolimus.
About Advanced Renal Cell Carcinoma
The American Cancer Society’s 2016 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.3 Clear cell RCC is the most common type of kidney cancer in adults.4 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, with no identified cure for the disease.3 Approximately 17,000 patients in the U.S. and 37,000 globally require second-line or later treatment.5
The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.6,7 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.8-11 MET and AXL may provide escape pathways that drive resistance to VEGFR inhibitors.7,8
About CABOMETYX
CABOMETYX targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.
CABOMETYX, the tablet formulation of cabozantinib, is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.
On April 25, 2016, the FDA approved CABOMETYX tablets for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy.
On January 28, 2016, the European Medicines Agency (EMA) validated Exelixis’ Marketing Authorization Application (MAA) for cabozantinib as a treatment for patients with advanced renal cell carcinoma who have received one prior therapy. The MAA has been granted accelerated assessment, making it eligible for a 150-day review, versus the standard 210 days. On February 29, 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan.
Important Safety Information
Hemorrhage: Severe hemorrhage occurred with CABOMETYX. The incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred in the cabozantinib clinical program. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.
Gastrointestinal (GI) Perforations and Fistulas: Fistulas were reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated patients and 0% of everolimus-treated patients. GI perforations were reported in 0.9% of CABOMETYX-treated patients and 0.6% of everolimus-treated patients. Fatal perforations occurred in the cabozantinib clinical program. Monitor patients for symptoms of fistulas and perforations. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. Venous thromboembolism was reported in 7.3% of CABOMETYX-treated patients and 2.5% of everolimus-treated patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Events of arterial thromboembolism were reported in 0.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.
Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension. Hypertension was reported in 37% (15% Grade ≥3) of CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of everolimus-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.
Diarrhea: Diarrhea occurred in 74% of patients treated with CABOMETYX and in 28% of patients treated with everolimus. Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and in 2% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to diarrhea occurred in 26% of patients.
Palmar-Plantar Erythrodysesthesia Syndrome (PPES): Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 42% of patients treated with CABOMETYX and in 6% of patients treated with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated patients and in <1% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to PPES occurred in 16% of patients.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient 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 when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, and constipation.
Drug Interactions: Strong CYP3A4 inhibitors and inducers: Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided.
Lactation: Advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose.
Reproductive Potential: Contraception―Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose. Infertility ―CABOMETYX may impair fertility in females and males of reproductive potential.
Hepatic Impairment: Reduce the CABOMETYX dose in patients with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment.
Please see full Prescribing Information at View Source.