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– Combination of cabozantinib and atezolizumab is well tolerated and shows promising anti-tumor activity –
– Safety and efficacy data support 18 expansion cohorts evaluating the combination in 12 different tumor types –
Twelve patients with previously untreated advanced RCC including ten patients with clear cell RCC and two patients with non-clear cell RCC were treated in the dose-escalation stage, with six patients at each cabozantinib dose level — 40 mg or 60 mg daily — in combination with the standard dosing regimen of atezolizumab (1,200 mg infusion once every three weeks).
As of the
No dose-limiting toxicities or serious adverse events were noted at either cabozantinib dose. Dose reductions and higher grade AEs were less frequent with the 40 mg cabozantinib dosing cohort. Grade 3 adverse events (83 percent of patients) in the 40 mg cabozantinib dose cohort included hypertension (50 percent), hypophosphatemia (17 percent), hyperglycemia (17 percent), gamma glutamyltransferase increased (17 percent) and muscular weakness (17 percent). Grade 3 adverse events (100 percent of patients) in the 60 mg cabozantinib dose cohort included diarrhea (33 percent), hypertension (33 percent), aspartate aminotransferase increased (17 percent), alanine aminotransferase increased (17 percent), lymphopenia (17 percent), hypophosphatemia (17 percent) and lipase increased (17 percent). No Grade 4 or 5 adverse events were observed.
“These early stage results demonstrate that the combination of
cabozantinib and atezolizumab was well tolerated and showed promising
anti-tumor activity in advanced kidney cancer,” said
“As we explore cabozantinib in combination with a variety of immune
checkpoint inhibitors in a broad spectrum of tumor types, we are pleased
with the initial results in the dose-escalation phase of COSMIC-021,”
As previously announced, the cabozantinib starting dose for the expansion phase is 40 mg. The expansion phase includes multiple solid tumor types, including RCC. More information about this trial is available at ClinicalTrials.gov.
About the COSMIC-021 Study
COSMIC-021 is a multicenter, phase 1b, open-label study that is divided into two parts: a dose-escalation phase and an expansion cohort phase. The dose-escalation phase was designed to enroll patients either with advanced RCC with or without prior systemic therapy or with inoperable, locally advanced, metastatic or recurrent UC (including renal, pelvis, ureter, urinary bladder and urethra) after prior platinum-based therapy. Ultimately, all patients enrolled in this stage of the trial were patients with advanced RCC. The dose-escalation phase of the study determined the optimal dose of cabozantinib to be 40 mg daily when given in combination with atezolizumab (1200 mg infusion once every 3 weeks).
In the expansion phase, the trial is enrolling 18 expansion cohorts in 12 tumor types: RCC, urothelial carcinoma (UC), non-small cell lung cancer (NSCLC), castration-resistant prostate cancer, triple-negative breast cancer, epithelial ovarian cancer, endometrial cancer, hepatocellular carcinoma (HCC), gastric or gastroesophageal junction adenocarcinoma, colorectal adenocarcinoma, head and neck cancer, and differentiated thyroid cancer. Up to a total of 1,000 patients may enroll in this phase of the trial: each expansion cohort will initially enroll approximately 30 patients; up to 80 patients may enroll in up to eight of those cohorts, including the cohorts with UC or NSCLC patients who have been previously treated with an immune checkpoint inhibitor; and in two exploratory cohorts, approximately 30 patients in each cohort will be treated with cabozantinib as a single-agent.
About Advanced Renal Cell Carcinoma
The American Cancer Society’s 2018 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 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.1 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. 3
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.4,5 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.6,7,8,9 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.5,6
About CABOMETYX® (cabozantinib)
CABOMETYX tablets are approved in
The combination of cabozantinib and atezolizumab is not indicated for previously untreated advanced RCC.
U.S. Important Safety Information
- Hemorrhage: Severe and fatal hemorrhages have occurred with CABOMETYX. In two RCC studies, the incidence of Grade ≥ 3 hemorrhagic events was 3% in CABOMETYX-treated patients. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.
- Gastrointestinal (GI) Perforations and Fistulas: In RCC studies, fistulas were reported in 1% of CABOMETYX-treated patients. Fatal perforations occurred in patients treated with CABOMETYX. In RCC studies, gastrointestinal (GI) perforations were reported in 1% of CABOMETYX-treated patients. Monitor patients for symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula which cannot be appropriately managed or a GI perforation.
- Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. In RCC studies, venous thromboembolism occurred in 9% (including 5% pulmonary embolism) and arterial thromboembolism occurred in 1% of CABOMETYX-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, including hypertensive crisis. In RCC studies, hypertension was reported in 44% (18% Grade ≥ 3) of CABOMETYX-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: In RCC studies, diarrhea occurred in 74% of patients treated with CABOMETYX. Grade 3 diarrhea occurred in 11% of patients treated with CABOMETYX. 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.
- Palmar-Plantar Erythrodysesthesia (PPE): In RCC studies, palmar-plantar erythrodysesthesia (PPE) occurred in 42% of patients treated with CABOMETYX. Grade 3 PPE occurred in 8% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade 3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced dose.
- Reversible Posterior Leukoencephalopathy Syndrome (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 may be associated with CABOMETYX. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during CABOMETYX treatment and for 4 months after the last dose.
- Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, hypertension, PPE, weight decreased, vomiting, dysgeusia, and stomatitis.
- Strong CYP3A4 Inhibitors: If concomitant use with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage.
- Strong CYP3A4 Inducers: If concomitant use with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.
- Lactation: Advise women not to breastfeed while taking CABOMETYX and for 4 months after the final dose.
- Hepatic Impairment: In patients with mild to moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment.
Founded in 1994,
Forward-Looking Statement Disclaimer
This press release contains forward-looking statements, including,
without limitation, statements related to: the further evaluation of the
combination of cabozantinib with the standard dose of atezolizumab as
part of the expansion phase of COSMIC-021; the potential of the
combination of cabozantinib and atezolizumab to benefit patients with
multiple tumor types; 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: risks and uncertainties related to
regulatory review and approval processes and Exelixis’ compliance with
applicable legal and regulatory requirements; the potential failure of
the combination of cabozantinib and atezolizumab to demonstrate safety
and/or efficacy in COSMIC-021; uncertainties inherent in the product
development process; the costs of conducting clinical trials, including
the ability or willingness of Exelixis’ collaboration partners to invest
in the resources necessary to complete the trials, as well as Exelixis’
dependence on third-party vendors for the development, manufacture and
supply of cabozantinib; Exelixis’ ability to protect its intellectual
property rights; market competition; changes in economic and business
conditions; and other factors affecting Exelixis and its development
programs discussed under the caption “Risk Factors” in Exelixis’
Quarterly Report on Form 10-Q filed with the Securities and Exchange
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2 Jonasch, E., Gao, J., Rathmell, W. Renal cell carcinoma. BMJ. 2014; 349:g4797.
3 Decision Resources Report: Renal Cell Carcinoma.
4 Harshman, L., and Choueiri, T. Targeting the hepatocyte growth factor/c-Met signaling pathway in renal cell carcinoma. Cancer J. 2013; 19:316-323.
5 Rankin, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET.
6 Zhou, L., Liu, X-D., Sun, M., et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016; 35:2687-2697.
7 Koochekpour, et al. The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol. 1999; 19:5902–5912.
8 Takahashi, A., Sasaki, H., Kim, S., et al. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 1994; 54:4233-4237.
9 Nakagawa, M., Emoto, A., Hanada, T., Nasu, N., Nomura, Y. Tubulogenesis by microvascular endothelial cells is mediated by vascular endothelial growth factor (VEGF) in renal cell carcinoma. Br J Urol. 1997; 79:681-687.
EVP, Public Affairs and Investor Relations
Senior Director, Public Affairs and Advocacy Relations