Exelixis Announces Phase 1 Trial Results for Cabozantinib in Combination with Nivolumab with or without Ipilimumab in Refractory Metastatic Urothelial Carcinoma and Other Genitourinary Tumors

SOUTH SAN FRANCISCO, Calif.–(BUSINESS WIRE)–Exelixis, Inc. (NASDAQ:EXEL) today announced results from a phase 1
trial of cabozantinib in combination with either nivolumab or nivolumab
plus ipilimumab in patients with refractory genitourinary tumors. The
primary endpoint of the trial is to determine the dose limiting toxicity
(DLT) and recommended phase 2 doses of the doublet and triplet
combinations. The findings were presented during a poster session
(Abstract #293) on February 17 at the 2017 Genitourinary Cancers
Symposium, which is being held in Orlando, Florida, February 16 – 18,
2017.

Between July 22, 2015 and December 31, 2016, 48 patients were accrued
with previously treated metastatic urothelial carcinoma (mUC, n=19),
urachal adenocarcinoma (n=4), squamous cell carcinoma of the bladder or
urethra (n=2), germ cell tumor (n=4), castration-resistant prostate
cancer (n=9), renal cell carcinoma (n=4), trophoblastic tumor (n=1),
sertoli cell tumor (n=1) or penile squamous cell carcinoma (n=4) and
treated in two parts. In Part I, 30 patients were treated with the
doublet combination of cabozantinib and nivolumab at four dose levels.
In Part II, 18 patients were treated with the triplet combination of
cabozantinib, nivolumab and ipilimumab at three dose levels.

Among the 43 patients who were evaluable for response, the objective
response rate (ORR) for all tumor types was 30 percent (38 percent for
the doublet dosing schedule and 18 percent for the triplet dosing
schedule), with a 7 percent complete response (CR) rate and a 23 percent
partial response (PR) rate. Stable disease (SD) was reported in 56
percent of patients. The ORR for patients with mUC was 38 percent, and 2
of 16 patients achieved a CR, while 2 patients with squamous cell
carcinoma of the bladder had objective responses (1 CR and 1 PR). In the
mUC cohort, 15 of 16 patients had a CR, PR or SD as their best response.

Grade 3 adverse events (>5 percent of patients) observed in the doublet
combination included neutropenia (17 percent), hypophosphatemia (13
percent), hypertension (10 percent), lipase increase (7 percent),
fatigue (7 percent), diarrhea (7 percent) and dehydration (7 percent).
Grade 3 adverse events (>5 percent of patients) observed in the triplet
combination included hypertension (17 percent), hypophosphatemia (17
percent), fatigue (13 percent), hyponatremia (13 percent), lipase
increase (13 percent), nausea (13 percent) and rash (6 percent). There
were limited numbers of grade 4 adverse events (10 percent including
thrombocytopenia and lipase increase in the doublet combination, and 6
percent (lipase increase) in the triplet combination), and no grade 5
adverse events observed in either part of the trial.

“There is a significant unmet need for treatment regimens that can slow
tumor progression in advanced, intractable cancers such as metastatic
urothelial carcinoma. The use of combination therapies may be a strategy
that could increase anti-tumor activity in these patients,” said Andrea
Apolo, M.D., Genitourinary Malignancies Branch, Center for Cancer
Research, National Cancer Institute, National Institutes of Health, the
principal investigator of the trial. “Previously reported data from Part
I of the trial showed that cabozantinib in combination with nivolumab
provided an encouraging objective response rate and tolerability profile
across a diverse range of genitourinary tumors. Data from Part II also
demonstrate that using cabozantinib with two immunotherapy agents is
well-tolerated with promising early activity. These results support the
further evaluation of both regimens in these tumor types.”

The recommended doses for the ongoing expansion cohorts were determined
to be cabozantinib 40 mg daily plus nivolumab 3 mg/kg once every 2 weeks
for the doublet and cabozantinib 40 mg daily, nivolumab 3 mg/kg plus
ipilimumab 1 mg/kg every 3 weeks for 4 doses, then nivolumab 3 mg/kg
every 2 weeks for the triplet.

“These early clinical results generated by our collaborators at the
NCI-CTEP suggest that the combination of cabozantinib with either
nivolumab or nivolumab and ipilimumab in patients with genitourinary
malignancies is associated with an encouraging tolerability, safety and
activity profile,” said Michael M. Morrissey, Ph.D., president and Chief
Executive Officer of Exelixis. “With these results in hand, we are
committed to further examining the potential of cabozantinib in
combination with a variety of immunotherapies to treat a broad range of
genitourinary and other cancers.”

About the Trial

The trial is sponsored by the U.S. National Cancer Institute (NCI)
through Cooperative Research and Development Agreements between the
NCI’s Cancer Therapy Evaluation Program (CTEP), Division of Cancer
Treatment and Diagnosis, and both Bristol-Myers Squibb and Exelixis.
Andrea Apolo, M.D., of the NCI’s Genitourinary Malignancies Branch, is
the principal investigator. The trial is being conducted by the NCI and
includes centers from its Experimental Therapeutics Clinical Trials
Network.

The primary endpoint of the phase 1 trial is to determine the dose
limiting toxicity (DLT) and recommended phase 2 doses of the doublet and
triplet combinations. The secondary endpoint is clinical response rate
as assessed by RECIST 1.1. Part I of the study included four dosing
levels: cabozantinib 40 mg daily plus nivolumab 1 mg/kg once every 2
weeks; cabozantinib 40 mg daily plus nivolumab 3 mg/kg once every 2
weeks; cabozantinib 60 mg daily plus nivolumab 1 mg/kg once every 2
weeks; and cabozantinib 60 mg daily plus nivolumab 3 mg/kg once every 2
weeks.

Part II of the study included three dosing levels: cabozantinib 40 mg
daily, nivolumab 1 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4
doses, then nivolumab 1 mg/kg every 2 weeks; cabozantinib 40 mg daily,
nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses,
then nivolumab 3 mg/kg every 2 weeks; and cabozantinib 60 mg daily,
nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses,
then nivolumab 3 mg/kg every 2 weeks.

Data from Part I of the study evaluating the combination of cabozantinib
with nivolumab in patients with previously treated genitourinary tumors
were presented by Dr. Apolo at the European Society for Medical Oncology
2016 Congress. Expansion cohorts assessing cabozantinib and nivolumab
are currently being accrued with bladder, renal and rare genitourinary
cancer patients. Data from these patients will be reported at a later
date.

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 and urothelial carcinoma.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 2016 statistics.2 Clear cell renal cell
carcinoma 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 2,850,000 men were living
with prostate cancer in the U.S. in 2013,7 and 180,000 new
cases are diagnosed each 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 2013, an estimated 587,426
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.

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 September 9, 2016, the European Commission
approved CABOMETYX tablets for the treatment of advanced renal cell
carcinoma in adults who have received prior vascular endothelial growth
factor (VEGF)-targeted therapy in the European Union, Norway and
Iceland. 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. On December 21, 2016, this agreement was amended to
include commercialization rights for Ipsen in Canada. 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.

Cabozantinib is not indicated for the treatment of refractory mUC and
other genitourinary tumors.

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

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 https://cabometyx.com/downloads/cabometyxuspi.pdf.

About Exelixis

Exelixis, Inc. (Nasdaq: EXEL) is a biopharmaceutical company committed
to the discovery, development and promotion of new medicines with the
potential to improve care and outcomes for people with cancer. Since its
founding in 1994, three products discovered at Exelixis have progressed
through clinical development to receive regulatory approval. Currently,
Exelixis is focused on advancing cabozantinib, an inhibitor of multiple
tyrosine kinases including MET, AXL and VEGF receptors, which has shown
clinical anti-tumor activity in more than 20 forms of cancer and is the
subject of a broad clinical development program. Two separate
formulations of cabozantinib have received regulatory approval to treat
certain forms of kidney and thyroid cancer and are marketed for those
purposes as CABOMETYX™ tablets (U.S. and EU) and COMETRIQ®
capsules (U.S. and EU), respectively. Another Exelixis-discovered
compound, COTELLIC® (cobimetinib), a selective inhibitor of
MEK, has been approved in major territories including the United States
and European Union, and is being evaluated for further potential
indications by Roche and Genentech (a member of the Roche Group) under a
collaboration with Exelixis. For more information on Exelixis, please
visit www.exelixis.com
or follow @ExelixisInc on Twitter.

Forward-Looking Statement Disclaimer

This press release contains forward-looking statements, including,
without limitation, statements related to: the further evaluation of
cabozantinib in combination with immunotherapies to treat a variety of
genitourinary tumors; future data results from expansion cohorts
assessing cabozantinib and nivolumab in bladder, renal and rare
genitourinary cancer patients; Exelixis’ commitment to the discovery,
development and commercialization of new medicines with the potential to
improve care and outcomes for people with cancer; Exelixis’ focus on
advancing cabozantinib; and the continued development of cobimetinib.
Words such as “may,” “further,” “committed,” “focused,” or other similar
expressions identify forward-looking statements, but the absence of
these words does not necessarily mean that a statement is not
forward-looking. In addition, any statements that refer to expectations,
projections or other characterizations of future events or circumstances
are forward-looking statements. These forward-looking statements 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: Exelixis’ ability and the ability of its collaborators to
conduct clinical trials of cabozantinib sufficient to achieve a positive
completion; risks related to the potential failure of cabozantinib to
demonstrate safety and efficacy in clinical testing; the availability of
data at the referenced times; risks and uncertainties related to
regulatory review and approval processes and Exelixis’ compliance with
applicable legal and regulatory requirements; the degree of market
acceptance of CABOMETYX and the availability of coverage and
reimbursement for CABOMETYX; the risk that unanticipated developments
could adversely affect the commercialization of CABOMETYX; Exelixis’
dependence on its relationships with Ipsen and Takeda, including, the
level of their investment in the resources necessary to successfully
commercialize cabozantinib in the territories where it is approved;
Exelixis’ dependence on its relationship with Genentech/Roche with
respect to cobimetinib and Exelixis’ ability to maintain its rights
under the collaboration; Exelixis’ dependence on third-party vendors;
Exelixis’ ability to protect the company’s intellectual property rights;
market competition; changes in economic and business conditions, and
other factors discussed under the caption “Risk Factors” in Exelixis’
quarterly report on Form 10-Q filed with the Securities and Exchange
Commission (SEC) on November 3, 2016, and in Exelixis’ future filings
with the SEC. The forward-looking statements made in this press release
speak only as of the date of this press release. Exelixis expressly
disclaims any duty, obligation or undertaking to release publicly any
updates or revisions to any forward-looking statements contained herein
to reflect any change in Exelixis’ expectations with regard thereto or
any change in events, conditions or circumstances on which any such
statements are based.

 

1.

The University of Arizona Cancer Center. What are genitourinary
cancers? http://uacc.arizona.edu/patients/clinic/gucancer/what-are-gu-cancers.
Accessed September 27, 2016.

2.

American Cancer Society. Cancer Facts & Figures 2016. Atlanta:
American Cancer Society; 2016.

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).

5.

American Cancer Society. Key statistics for prostate cancer.
Available at http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics.
Accessed September 28, 2016.

6.

American Cancer Society. Survival rates for prostate cancer.
Available at http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-survival-rates.
Accessed September 28, 2016.

7.

National Cancer Institute. SEER Stat Fact Sheets: Prostate Cancer.
Available at http://seer.cancer.gov/statfacts/html/prost.html.
Accessed September 28, 2016.

8.

Hurwitz, M. et al. Urothelial and Kidney Cancers. Cancer
Management. http://www.cancernetwork.com/cancer-management/urothelial-and-kidney-cancers.
Accessed September 27, 2016.

9.

American Cancer Society. Bladder Cancer Key Statistics. http://www.cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-key-statistics.
Accessed May 23, 2016.

10.

National Cancer Institute. SEER Stat Fact Sheets: Bladder Cancer. http://seer.cancer.gov/statfacts/html/urinb.html.
Accessed May 23, 2016.