On September 9, 2017 Exelixis, Inc. (NASDAQ:EXEL) and Ipsen (Euronext:IPN; ADR:IPSEY) reported updated results from the CABOSUN randomized phase 2 trial of cabozantinib in patients with previously untreated advanced renal cell carcinoma (RCC) with intermediate- or poor-risk disease per the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) (Press release, Exelixis, SEP 9, 2017, View Source [SID1234520441]). Principal investigator Toni K. Choueiri, M.D., will present detailed data from late-breaking CABOSUN abstract [#LBA38_PD] today in the Genitourinary Tumors, Non-Prostate poster discussion session, starting at 2:45 p.m. CEST (local Madrid time) / 8:45 a.m. EDT / 5:45 a.m. PDT at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress, which is being held September 8-12, 2017 in Madrid, Spain.
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CABOSUN is being conducted by The Alliance for Clinical Trials in Oncology as part of Exelixis’ collaboration with the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI-CTEP). The data presented at ESMO (Free ESMO Whitepaper) 2017 included the analysis from a blinded independent radiology review committee (IRC), which confirmed the primary efficacy endpoint results of investigator-assessed progression-free survival (PFS), as well as an updated investigator-assessed analysis. Per the IRC analysis, cabozantinib demonstrated a clinically meaningful and statistically significant 52 percent reduction in the rate of disease progression or death (HR 0.48, 95% CI 0.31-0.74, two-sided P=0.0008). The median PFS for cabozantinib was 8.6 months versus 5.3 months for sunitinib, corresponding to a 3.3 month (62 percent) improvement favoring cabozantinib over sunitinib.
"These updated analyses from CABOSUN consistently show that cabozantinib provided a statistically significant decrease in the rate of disease progression or death compared to sunitinib, a current standard of care – potentially offering a new treatment option for physicians to treat patients in the first-line advanced renal cell carcinoma setting," said Toni K. Choueiri, M.D., Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute. "The CABOSUN trial included patients with intermediate or poor prognostic factors per the IMDC criteria; in addition, patients had a notable number of other independent adverse prognostic risk factors. These included a high rate of bone metastases, two or more sites of metastatic disease, ECOG 2 performance status, and lack of prior nephrectomy. This patient population fares poorly and is in need of new therapies to better control their disease."
The following chart outlines data from the CABOSUN trial presented today at ESMO (Free ESMO Whitepaper) 2017, as compared to the data previously published in the Journal of Clinical Oncology (JCO) in October 2016:
JCO
Investigator-assessed
(April 11, 2016 Cut-off)
ESMO 2017
Investigator-assessed
(Sept 15, 2016 Cut-off)
ESMO 2017
IRC Review
(Sept 15, 2016 Cut-off)
Cabozantinib
N = 79 Sunitinib
N = 78 Cabozantinib
N = 79 Sunitinib
N = 78 Cabozantinib
N = 79 Sunitinib
N = 78
Progression-free survival
Median PFS, months 8.2 5.6 8.3 5.4 8.6 5.3
Stratified HR
(95% CI) 0.66 (0.46-0.95) 0.56 (0.37-0.83) 0.48 (0.31-0.74)
P value 0.012 (1-sided) 0.0042 (2-sided) 0.0008 (2-sided)
Tumor Response
Objective response rate (95% CI),a % 46 (34-57) 18 (10-28) 33 (23-44) 12 (5-21) 20 (12-31) 9 (4-18)
Disease control rate,b % 78 54 76 49 75 47
Progressive disease,c % 18 26 18 24 18 29
Not evaluable or missing, % 4 21 6 27 8 23
Any reduction in target lesions, % 87 44 85 38 80 50
a One complete response was observed with cabozantinib for both investigator assessments, and one complete response was observed with sunitinib for the original investigator assessment, all other responses were partial responses; b Complete response + partial response + stable disease; c Progressive disease as best overall response.
The updated 2017 data sets and methods differ from the initial investigator analyses presented in 2016. The comprehensive image collection for IRC review used a later cut-off point (5 months) than the initial investigator analysis and followed a rigorous IRC review process. The analysis of IRC data applied U.S. Food and Drug Administration (FDA) guidance for PFS analyses in oncology studies, including recommended censoring rules (i.e., censoring at the last adequate tumor assessment prior to initiation of subsequent anti-cancer therapy, and censoring for events that occur after two or more missing adequate tumor assessments).1 Both the updated investigator assessment and IRC analysis demonstrated consistent and statistically significant improvement of PFS with cabozantinib as compared to sunitinib.
The updated overall survival (OS) analysis had a data cut-off of July 1, 2017, and showed a favorable trend for patients randomized to cabozantinib compared to sunitinib that was not statistically significant. Median overall survival was 26.6 months for patients receiving cabozantinib versus 21.2 months for those receiving sunitinib (HR= 0.80, 95% CI 0.53-1.21, two-sided P=0.29).
"We are very encouraged by the clinically meaningful and statistically significant efficacy results on the primary endpoint of progression-free survival, which formed the basis of the recent supplemental New Drug Application submitted to the U.S. Food and Drug Administration for cabozantinib in first-line advanced renal cell carcinoma," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. "The latest CABOSUN data continue to underscore the value that cabozantinib may offer patients with previously untreated renal cell carcinoma, and we are working tirelessly in our efforts to bring this option to patients and their physicians as quickly as possible."
David Meek, Chief Executive Officer of Ipsen stated, "Following the recent European approval of cabozantinib for second-line treatment of patients with advanced renal cell carcinoma following prior VEGF-targeted therapy, the latest data from the CABOSUN study being presented this year at ESMO (Free ESMO Whitepaper) extends the clinical benefit of cabozantinib in first-line therapy setting for patients with advanced RCC. With our partner Exelixis, we are committed to strengthening the medical value of cabozantinib and to continuing to bring innovative therapeutic solutions for the treatment of patients with RCC."
The most common all-causality grade 3 or 4 adverse events in more than 5 percent of patients for cabozantinib (N=78) and sunitinib (N=72), respectively, were diarrhea (10 vs. 11 percent), hypertension (28 vs. 21 percent), fatigue (6 vs. 17 percent), increased alanine aminotransferase (ALT; 5 vs. 0 percent), decreased appetite (5 vs. 1 percent), palmar-plantar erythrodysesthesia syndrome (PPES; 8 vs. 4 percent), decreased platelet count (1 vs. 11 percent) and stomatitis (5 vs. 6 percent). Twenty-one percent of patients in the cabozantinib arm and 22 percent of patients in the sunitinib arm discontinued treatment due to adverse events.
Exelixis filed a supplemental New Drug Application based on the CABOSUN data with the FDA for cabozantinib as a treatment for previously untreated advanced RCC on August 16, 2017. Ipsen also submitted to EMA the regulatory dossier for cabozantinib as a treatment for first-line advanced RCC in the European Union on August 28, 2017; on September 8, 2017, Ipsen announced that the EMA validated the application.
About the CABOSUN Study
On May 23, 2016, Exelixis announced that CABOSUN met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in PFS compared with sunitinib in patients with advanced intermediate- or poor-risk RCC as determined by investigator assessment. The CABOSUN trial is being conducted by The Alliance for Clinical Trials in Oncology as part of Exelixis’ collaboration with the NCI-CTEP. These results were first presented in a plenary session by Dr. Toni Choueiri at the ESMO (Free ESMO Whitepaper) 2016 Congress, and published in the JCO.2 In June 2017, a blinded IRC confirmed that cabozantinib provided a clinically meaningful and statistically significant improvement in the primary efficacy endpoint of investigator-assessed PFS.
CABOSUN is a randomized, open-label, active-controlled phase 2 trial that enrolled 157 patients with advanced RCC determined to be intermediate- or poor-risk by the IMDC criteria. Patients were randomized 1:1 to receive cabozantinib (60 mg once daily) or sunitinib (50 mg once daily, 4 weeks on followed by 2 weeks off). The primary endpoint was PFS. Secondary endpoints included OS and objective response rate.
Eligible patients were required to have locally advanced or metastatic clear-cell RCC, ECOG performance status 0-2 and had to be intermediate or poor risk per the IMDC criteria (Heng, JCO, 2009).3 Prior systemic treatment for RCC was not permitted. Baseline characteristics included:
Characteristic Cabozantinib
(N=79) Sunitinib
(N=78)
ECOG performance status, %
0 46 46
1 42 41
2 13 13
IMDC risk group, %
Intermediate 81 81
Poor 19 19
Bone metastasis per IxRS,a %
Yes 37 36
No 63 64
Prior nephrectomy, %
Yes 72 77
No 28 23
Number of metastatic sites per investigator, %
1 22 33
2 47 26
≥3 32 41
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Please see Important Safety Information below and full U.S. prescribing information at View Source
About Advanced Renal Cell Carcinoma
The American Cancer Society’s 2017 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.4 Clear cell RCC is the most common type of kidney cancer in adults.5 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.6 Approximately 30,000 patients in the U.S. and 68,000 globally require treatment, and an estimated 14,000 patients in the U.S. each year are in need of a first-line treatment for advanced kidney cancer.7
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.8,9 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.10-13 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.8,9
About CABOMETYX (cabozantinib)
CABOMETYX is the tablet formulation of cabozantinib. Its 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 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 RCC who have received prior anti-angiogenic therapy. In February of 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. This agreement was amended in December of 2016 to include commercialization rights for Ipsen in Canada. On September 9, 2016, the European Commission approved CABOMETYX tablets for the treatment of advanced RCC in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland.
On January 30, 2017, Exelixis and Takeda Pharmaceutical Company Limited announced an exclusive licensing agreement for the commercialization and further clinical development of cabozantinib for all future indications in Japan, including RCC.
CABOMETYX is not indicated for the treatment of previously untreated advanced RCC.
U.S. 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