“Patients with locally advanced or metastatic urothelial or renal cell
carcinoma are in need of additional therapies that can slow disease
This multicenter phase 1b, open-label study is divided in two parts: a dose-escalation phase and an expansion cohort phase. The dose-escalation phase will enroll 9 to 36 patients with inoperable, locally advanced, metastatic or recurrent UC (including renal, pelvis, ureter, urinary bladder and urethra) after prior platinum-based therapy or RCC with or without prior systemic therapy. The starting dose of cabozantinib will be 40 mg daily and may be increased to 60 mg daily or decreased to 20 mg daily. All patients will receive the standard atezolizumab dosing regimen (1200 mg infusion once every 3 weeks).
The secondary objectives of the dose-escalation stage are to evaluate the plasma pharmacokinetics of daily oral administration of cabozantinib when given in combination with atezolizumab and to assess safety of the combination therapy through the evaluation of incidence and severity of adverse events, including immune-related adverse events. Exploratory endpoints include the correlation of clinical outcome with immune cell, tumor cell and blood biomarker analyses.
Once the recommended dose and schedule are determined, the trial will enroll four expansion cohorts, each with up to 30 patients, for a total of up to 120 patients with advanced or metastatic UC or RCC. The primary objective in the expansion stage of the trial is to determine the objective response rate in each cohort. The three UC expansion cohorts will enroll: 1) patients who have progressed on or after platinum-containing chemotherapy; 2) patients who are ineligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy for inoperable, locally advanced or metastatic disease; and 3) patients who are eligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy for inoperable, locally advanced or metastatic disease. The RCC expansion cohort will enroll patients with clear cell histology who have not had prior systemic anticancer therapy.
“There is a strong rationale for combining cabozantinib with
immunotherapies, including clinical and preclinical observations
consistent with the ability of cabozantinib to promote an
immuno-permissive environment, which might present an opportunity for
synergistic effects from combination treatment with immune checkpoint
inhibitors and other immuno-oncology agents,” said
More information about this trial is available at ClinicalTrials.gov.
TECENTRIQ® (atezolizumab) is a registered trademark of
Genentech, a member of the
About Exelixis’ Collaboration with
About Exelixis’ Collaboration with Takeda
About Genitourinary Cancers
Genitourinary cancers are those that affect the urinary tract, bladder, kidneys, ureter, prostate, testicles, penis or adrenal glands — parts of the body involved in reproduction and excretion — and include renal cell carcinoma (RCC) and urothelial carcinoma (UC).1
Kidney cancer is among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S., according to the American Cancer Society’s 2017 statistics.2 Clear cell RCC is the most common type of kidney cancer in adults.3 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.2 Approximately 30,000 patients in the U.S. and 68,000 globally require treatment.4
Prostate cancer is the second most common cause of cancer death in men, behind only skin cancer.5 There is a high survival rate for patients when prostate cancer is detected early, but once the disease has spread to other parts of the body the five-year survival rate is just 28 percent.6 Approximately 3,085,000 men were living with prostate cancer in the U.S. in 2014,7 and an estimated 160,000 new cases will be diagnosed this year.5
Urothelial cancers encompass carcinomas of the bladder, ureter and renal pelvis at a ratio of 50:3:1, respectively.8 Urothelial carcinoma occurs mainly in older people, with 90 percent of patients aged 55 or older.9 Bladder cancer is the fourth most common cancer in men and accounts for about five percent of all new cases of cancer in the U.S. each year.9 In 2014, an estimated 696,440 people were living with bladder cancer in the U.S.10
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.
Cabozantinib is not indicated for the treatment of locally advanced or metastatic UC.
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.
Forward-Looking Statement Disclaimer
This press release contains forward-looking statements, including,
without limitation, statements related to: the potential of the
cabozantinib and atezolizumab combination to treat patients with locally
advanced or metastatic UC or RCC; the potential opportunity for
synergistic effects from the combination of cabozantinib with immune
checkpoint inhibitors and other immune-oncology agents; the potential
for Takeda to participate in the funding of the phase 1b trial and the
potential for both
The University of Arizona Cancer Center. What are genitourinary cancers? http://uacc.arizona.edu/patients/clinic/gucancer/what-are-gu-cancers. Accessed June 2017.
|2.||American Cancer Society. Cancer Facts & Figures 2017. Atlanta: American Cancer Society; 2017.|
|3.||Jonasch E., Gao J., Rathmell W.K., Renal cell carcinoma. BMJ. 2014; 349:g4797.|
|4.||Decision Resources Report: Renal Cell Carcinoma. October 2014 (internal data on file).|
American Cancer Society. Key statistics for prostate cancer. Available at http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics. Accessed June 2017.
American Cancer Society. Survival rates for prostate cancer. Available at http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-survival-rates. Accessed June 2017.
National Cancer Institute. SEER Stat Fact Sheets: Prostate Cancer. Available at http://seer.cancer.gov/statfacts/html/prost.html. Accessed June 2017.
Hurwitz, M. et al. Urothelial and Kidney Cancers. Cancer Management. http://www.cancernetwork.com/cancer-management/urothelial-and-kidney-cancers. Accessed June 2017.
American Cancer Society. Bladder Cancer Key Statistics. http://www.cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-key-statistics. Accessed June 2017.
National Cancer Institute. SEER Stat Fact Sheets: Bladder Cancer. http://seer.cancer.gov/statfacts/html/urinb.html. Accessed June 2017.
Susan Hubbard, 650-837-8194
EVP, Public Affairs and Investor Relations
Lindsay Treadway, 650-837-7522
Director, Public Affairs and Advocacy Relations