– Cabozantinib in combination with
atezolizumab reduced the risk of disease progression or death by
35% in patients with metastatic castration-resistant prostate
cancer –
– Findings to be presented during an oral
presentation at ASCO GU 2024 –
Exelixis, Inc. (Nasdaq: EXEL) today announced detailed results
from CONTACT-02, a phase 3 pivotal study evaluating cabozantinib
(CABOMETYX®) in combination with atezolizumab compared with a
second novel hormonal therapy (NHT) in patients with metastatic
castration-resistant prostate cancer (mCRPC) and measurable
extra-pelvic soft tissue disease who have progressed on one prior
NHT. The detailed findings are being presented during Oral Abstract
Session A: Prostate Cancer at 7:55 a.m. PST on January 25 at the
American Society of Clinical Oncology 2024 Genitourinary Cancers
Symposium (ASCO GU).
“Patients with metastatic castration-resistant prostate cancer
with prior progression on a novel hormone therapy and who have
measurable soft tissue metastasis experience the worst outcomes
among advanced prostate cancer patients and have limited treatment
options,” said Neeraj Agarwal, M.D., FASCO, Senior Director for
Clinical Research at Huntsman Cancer Institute at the University of
Utah and the global lead investigator of the trial. “CONTACT-02 is
the only phase 3 study evaluating a tyrosine kinase inhibitor and
an immune checkpoint inhibitor to show a statistically significant
improvement in progression-free survival and a trend for overall
survival in these patients. I am encouraged by these results and
the potential for cabozantinib plus atezolizumab to be a widely
available treatment option for our patients.”
As announced in August 2023, CONTACT-02 met one of its primary
endpoints, demonstrating a statistically significant improvement in
progression-free survival (PFS) as assessed by a blinded
independent radiology committee (BIRC) and per RECIST 1.1. The PFS
analysis was conducted in the first 400 randomized patients in the
intent-to-treat (PFS ITT) population and per protocol. Similar
results were observed for all patients.
Detailed results presented at ASCO GU show that at a median
follow-up of 14.3 months for the PFS ITT population, the hazard
ratio (HR) was 0.65 (95% confidence interval [CI]: 0.50-0.84;
p=0.0007); the median PFS (mPFS) was 6.3 months for cabozantinib in
combination with atezolizumab compared with 4.2 months for second
NHT. This was nearly identical to the PFS for the ITT population
(n=507): HR was 0.64 (95% CI: 0.50-0.81, p=0.0002); mPFS was 6.3
months for cabozantinib in combination with atezolizumab and was
4.2 months for second NHT. At a median follow-up of 12.0 months for
the ITT population, the median overall survival (OS) was 16.7
months for cabozantinib in combination with atezolizumab compared
with 14.6 months for second NHT (HR: 0.79; 95% CI: 0.58-1.07;
p=0.13). While a trend toward OS improvement was observed, the data
were immature and did not meet the threshold for statistical
significance. The study will continue to the next analysis of OS,
anticipated in 2024.
The PFS benefit and the trend for an OS benefit were observed
across subgroups of high-risk populations, as presented in Table
1.
TABLE 1
Liver metastasis
Prior docetaxel for
mCSPC
Bone metastasis
Cabozantinib +
atezolizumab
Second NHT
Cabozantinib +
atezolizumab
Second NHT
Cabozantinib +
atezolizumab
Second NHT
Median PFS per BIRC,
months (95% CI)
6.2 (4.0-9.1)
2.1 (2.0-2.3)
8.8 (6.2-9.2)
4.1 (2.3-4.3)
6.3 (6.0-8.8)
4.1 (2.8-5.7)
Patients, n
51
48
45
44
162
155
PFS HR (95% CI)
0.43 (0.27-0.68)
0.57 (0.34-0.97)
0.67 (0.50-0.88)
Median OS, months (95%
CI)
16.4 (8.3-NE)
9.8 (5.5-11.3)
20.9 (10.1-NE)
11.3 (9.0-NE)
16.4 (11.4-18.8)
11.4 (10.4-14.6)
Patients, n
59
60
57
58
206
196
OS HR (95% CI)
0.60 (0.35-1.02)
0.56 (0.29-1.08)
0.74 (0.54-1.02)
BIRC = blinded independent radiology
committee; CI = confidence interval; HR = hazard ratio; mCSPC =
metastatic castration-sensitive prostate cancer; NE = not
evaluable; NHT = novel hormone therapy; OS = overall survival; PFS
= progression-free survival
Treatment-emergent adverse events (AEs) occurred in 97% of
patients treated with cabozantinib in combination with atezolizumab
(n=248) compared with 87% of patients treated with a second NHT
(n=253), 48% and 23% of which were grade 3/4, respectively. Grade 5
treatment-emergent AEs occurred in 8% of patients treated with the
combination regimen compared with 12% of patients treated with a
second NHT; no grade 5 treatment-related AEs occurred in either
arm. Treatment-related AEs led to the discontinuation of any
treatment component in 13% of patients treated with the combination
regimen and 2% of patients treated with a second NHT. For all
treatment components, the treatment-related AEs leading to
discontinuation were 5% vs. 2%, respectively.
“Given there are limited options after progression on novel
hormonal therapy, we recognize the need for a regimen that can
delay disease progression, that has an acceptable tolerability
profile and that is widely available to patients who may not have
the means or desire to travel to specialized centers for other
therapies,” said Amy Peterson, M.D., Executive Vice President,
Product Development & Medical Affairs, and Chief Medical
Officer, Exelixis. “Our decision to conduct CONTACT-02, based upon
a signal we observed in COMET-01, underscores our commitment to
patients with advanced prostate cancer and to improving their
standard of care. We look forward to discussing these important
results with the U.S. Food and Drug Administration, and to learning
more in the next analysis of overall survival, anticipated this
year.”
About CONTACT-02
CONTACT-02 is a global, multicenter, randomized, phase 3,
open-label study that randomized 507 patients 1:1 to the
experimental arm of cabozantinib in combination with atezolizumab
and the control arm of a second NHT (either abiraterone and
prednisone or enzalutamide). The two primary endpoints of the trial
are PFS and OS. The study included patients with mCRPC who have
measurable extra-pelvic soft tissue metastasis and who have
progressed on one prior NHT. The secondary endpoint is objective
response rate per BIRC. The trial is sponsored by Exelixis and
co-funded by Ipsen, Roche and Takeda Pharmaceutical Company Limited
(Takeda). Takeda is conducting the trial in Japan. More information
about CONTACT-02 is available at ClinicalTrials.gov.
About CRPC
According to the American Cancer Society, approximately 299,000
new cases of prostate cancer will be diagnosed in the U.S., and
over 35,000 people will die from the disease in 2024.1 Prostate
cancer that has spread beyond the prostate and does not respond to
androgen-suppression therapies – a common treatment for prostate
cancer – is known as mCRPC.2 Men diagnosed with mCRPC often have a
poor prognosis, with an estimated survival of 1-2 years.3,4
About CABOMETYX® (cabozantinib)
In the U.S., CABOMETYX tablets are approved for the treatment of
patients with advanced renal cell carcinoma (RCC); for the
treatment of patients with hepatocellular carcinoma (HCC) who have
been previously treated with sorafenib; for patients with advanced
RCC as a first-line treatment in combination with nivolumab; and
for adult and pediatric patients 12 years of age and older with
locally advanced or metastatic differentiated thyroid cancer (DTC)
that has progressed following prior VEGFR-targeted therapy and who
are radioactive iodine-refractory or ineligible. CABOMETYX tablets
have also received regulatory approvals in the European Union and
additional countries and regions worldwide. In 2016, Exelixis
granted Ipsen Pharma SAS exclusive rights for the commercialization
and further clinical development of cabozantinib outside of the
U.S. and Japan. In 2017, Exelixis granted exclusive rights to
Takeda for the commercialization and further clinical development
of cabozantinib for all future indications in Japan. Exelixis holds
the exclusive rights to develop and commercialize cabozantinib in
the U.S.
CABOMETYX in combination with atezolizumab is not indicated as a
treatment for mCRPC.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage: Severe and fatal hemorrhages occurred with
CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5%
in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue
CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as
recommended. Do not administer CABOMETYX to patients who have a
recent history of hemorrhage, including hemoptysis, hematemesis, or
melena.
Perforations and Fistulas: Fistulas, including fatal
cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI)
perforations, including fatal cases, occurred in 1% of CABOMETYX
patients. Monitor patients for signs and symptoms of fistulas and
perforations, including abscess and sepsis. Discontinue CABOMETYX
in patients who experience a Grade 4 fistula or a GI
perforation.
Thrombotic Events: CABOMETYX increased the risk of
thrombotic events. Venous thromboembolism occurred in 7% (including
4% pulmonary embolism) and arterial thromboembolism in 2% of
CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX
patients. Discontinue CABOMETYX in patients who develop an acute
myocardial infarction or serious arterial or venous thromboembolic
events that require medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause
hypertension, including hypertensive crisis. Hypertension was
reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX
patients. Do not initiate CABOMETYX in patients with uncontrolled
hypertension. Monitor blood pressure regularly during CABOMETYX
treatment. Withhold CABOMETYX for hypertension that is not
adequately controlled with medical management; when controlled,
resume at a reduced dose. Permanently discontinue CABOMETYX for
severe hypertension that cannot be controlled with
anti-hypertensive therapy or for hypertensive crisis.
Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients.
Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and
manage patients using antidiarrheals as indicated. Withhold
CABOMETYX until improvement to ≤ Grade 1, resume at a reduced
dose.
Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in
45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX
patients. Withhold CABOMETYX until improvement to Grade 1 and
resume at a reduced dose for intolerable Grade 2 PPE or Grade 3
PPE.
Hepatotoxicity: CABOMETYX in combination with nivolumab
can cause hepatic toxicity with higher frequencies of Grades 3 and
4 ALT and AST elevations compared to CABOMETYX alone.
Monitor liver enzymes before initiation of and periodically
throughout treatment. Consider more frequent monitoring of liver
enzymes than when the drugs are administered as single agents. For
elevated liver enzymes, interrupt CABOMETYX and nivolumab and
consider administering corticosteroids.
With the combination of CABOMETYX and nivolumab, Grades 3 and 4
increased ALT or AST were seen in 11% of patients. ALT or AST >3
times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%)
received systemic corticosteroids; ALT or AST resolved to Grades
0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT
or AST who were rechallenged with either CABOMETYX (n=9) or
nivolumab (n=11) as a single agent or with both (n=24), recurrence
of Grade ≥2 increased ALT or AST was observed in 2 patients
receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients
receiving both CABOMETYX and nivolumab. Withhold and resume at a
reduced dose based on severity.
Adrenal Insufficiency: CABOMETYX in combination with
nivolumab can cause primary or secondary adrenal insufficiency. For
Grade 2 or higher adrenal insufficiency, initiate symptomatic
treatment, including hormone replacement as clinically indicated.
Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a
reduced dose depending on severity.
Adrenal insufficiency occurred in 4.7% (15/320) of patients with
RCC who received CABOMETYX with nivolumab, including Grade 3
(2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency
led to permanent discontinuation of CABOMETYX and nivolumab in 0.9%
and withholding of CABOMETYX and nivolumab in 2.8% of patients with
RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency
received hormone replacement therapy, including systemic
corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the
15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was
withheld for adrenal insufficiency, 6 reinstated treatment after
symptom improvement; of these, all (n=6) received hormone
replacement therapy and 2 had recurrence of adrenal
insufficiency.
Proteinuria: Proteinuria was observed in 8% of CABOMETYX
patients. Monitor urine protein regularly during CABOMETYX
treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until
improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced
dose. Discontinue CABOMETYX in patients who develop nephrotic
syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of
CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis,
osteitis, bone erosion, tooth or periodontal infection, toothache,
gingival ulceration or erosion, persistent jaw pain, or slow
healing of the mouth or jaw after dental surgery. Perform an oral
examination prior to CABOMETYX initiation and periodically during
treatment. Advise patients regarding good oral hygiene practices.
Withhold CABOMETYX for at least 3 weeks prior to scheduled dental
surgery or invasive dental procedures, if possible. Withhold
CABOMETYX for development of ONJ until complete resolution, resume
at a reduced dose.
Impaired Wound Healing: Wound complications occurred with
CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to
elective surgery. Do not administer CABOMETYX for at least 2 weeks
after major surgery and until adequate wound healing. The safety of
resumption of CABOMETYX after resolution of wound healing
complications has not been established.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS):
RPLS, a syndrome of subcortical vasogenic edema diagnosed by
characteristic findings on MRI, can occur with CABOMETYX. Evaluate
for RPLS in patients presenting with seizures, headache, visual
disturbances, confusion, or altered mental function. Discontinue
CABOMETYX in patients who develop RPLS.
Thyroid Dysfunction: Thyroid dysfunction, primarily
hypothyroidism, has been observed with CABOMETYX. Based on the
safety population, thyroid dysfunction occurred in 19% of patients
treated with CABOMETYX, including Grade 3 in 0.4% of patients.
Patients should be assessed for signs of thyroid dysfunction
prior to the initiation of CABOMETYX and monitored for signs and
symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid
function testing and management of dysfunction should be performed
as clinically indicated.
Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on
the safety population, hypocalcemia occurred in 13% of patients
treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1%
of patients. Laboratory abnormality data were not collected in
CABOSUN.
In COSMIC-311, hypocalcemia occurred in 36% of patients treated
with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of
patients.
Monitor blood calcium levels and replace calcium as necessary
during treatment. Withhold and resume at reduced dose upon recovery
or permanently discontinue CABOMETYX depending on severity.
Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm.
Advise pregnant women and females of reproductive potential of the
potential risk to a fetus. Verify the pregnancy status of females
of reproductive potential prior to initiating CABOMETYX and advise
them to use effective contraception during treatment and for 4
months after the last dose.
ADVERSE REACTIONS
The most common (≥20%) adverse reactions are:
CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased
appetite, hypertension, nausea, vomiting, weight decreased, and
constipation.
CABOMETYX in combination with nivolumab: diarrhea, fatigue,
hepatotoxicity, PPE, stomatitis, rash, hypertension,
hypothyroidism, musculoskeletal pain, decreased appetite, nausea,
dysgeusia, abdominal pain, cough, and upper respiratory tract
infection.
DRUG INTERACTIONS
Strong CYP3A4 Inhibitors: If coadministration with strong
CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage.
Avoid grapefruit or grapefruit juice.
Strong CYP3A4 Inducers: If coadministration with strong
CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.
Avoid St. John’s wort.
USE IN SPECIFIC POPULATIONS
Lactation: Advise women not to breastfeed during
CABOMETYX treatment and for 4 months after the final dose.
Hepatic Impairment: In patients with moderate hepatic
impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in
patients with severe hepatic impairment.
Please see accompanying full Prescribing Information
https://www.cabometyx.com/downloads/CABOMETYXUSPI.pdf.
You are encouraged to report negative side effects of
prescription drugs to the FDA.
Visit www.FDA.gov/medwatch or call
1-800-FDA-1088.
About Exelixis
Exelixis is a globally ambitious oncology company innovating
next-generation medicines and regimens at the forefront of cancer
care. Powered by drug discovery and development excellence, we are
rapidly evolving our product portfolio to target an expanding range
of tumor types and indications with our clinically differentiated
pipeline of small molecules, antibody-drug conjugates and other
biotherapeutics. This comprehensive approach harnesses decades of
robust investment in our science and partnerships to advance our
investigational programs and extend the impact of our flagship
commercial product, CABOMETYX® (cabozantinib). Exelixis is driven
by a bold scientific pursuit to create transformational treatments
that give more patients hope for the future. For information about
the company and its mission to help cancer patients recover
stronger and live longer, visit www.exelixis.com, follow
@ExelixisInc on X (Twitter), like Exelixis, Inc. on Facebook and
follow Exelixis on LinkedIn.
Forward-Looking Statements
This press release contains forward-looking statements,
including, without limitation, statements related to: the
presentation of detailed results from the CONTACT-02 trial at ASCO
GU 2024; the therapeutic potential of cabozantinib in combination
with atezolizumab as an additional and readily available treatment
option for patients with mCRPC and measurable extra-pelvic soft
tissue disease who have progressed on one prior NHT; Exelixis’
commitment to patients with advanced prostate cancer and to
improving their standard of care; Exelixis’ plans to discuss the
CONTACT-02 results with the U.S. Food and Drug Administration, and
Exelixis’ anticipation that the next analysis of overall survival
will be available in 2024; and Exelixis’ scientific pursuit to
create transformational treatments that give more patients hope for
the future. 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: the availability of data at the referenced
times; complexities and the unpredictability of the regulatory
review and approval processes in the U.S. and elsewhere; Exelixis’
continuing compliance with applicable legal and regulatory
requirements; the potential failure of cabozantinib in combination
with atezolizumab to demonstrate safety and/or efficacy in future
clinical testing; unexpected concerns that may arise as a result of
the occurrence of adverse safety events or additional data analyses
of clinical trials evaluating cabozantinib; the costs of conducting
clinical trials; Exelixis’ dependence on third-party vendors for
the development, manufacture and supply of cabozantinib; Exelixis’
ability to protect its intellectual property rights; market
competition, including the potential for competitors to obtain
approval for generic versions of CABOMETYX; changes in economic and
business conditions; and other factors affecting Exelixis and its
development programs detailed from time to time under the caption
“Risk Factors” in Exelixis’ most recent Annual Report on Form 10-K
and subsequent Quarterly Reports on Form 10-Q, and in Exelixis’
future filings with the Securities and Exchange Commission. All
forward-looking statements in this press release are based on
information available to Exelixis as of the date of this press
release, and Exelixis undertakes no obligation to update or revise
any forward-looking statements contained herein, except as required
by law.
Exelixis, the Exelixis logo and CABOMETYX are
registered U.S. trademarks of Exelixis.
1 Cancer Facts & Figures 2024. ACS website. Available at:
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2024/2024-cancer-facts-and-figures-acs.pdf.
Accessed January 2024. 2 Prostate Cancer: Types of Treatment.
Cancer.Net. Available at:
https://www.cancer.net/cancer-types/prostate-cancer/types-treatment.
Accessed January 2024. 3 Moreira, D. M., et al. Predicting Time
From Metastasis to Overall Survival in Castration-Resistant
Prostate Cancer: Results From SEARCH. Clin Genitourin Cancer. 2017;
15: 60–66.e2. 4 Freedland, S. J., et al. Real-world treatment
patterns and overall survival among men with Metastatic
Castration-Resistant Prostate Cancer (mCRPC) in the US Medicare
population. Prostate Cancer Prostatic Dis. 2023.
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Investors Contact: Susan Hubbard EVP, Public Affairs and
Investor Relations (650) 837-8194 shubbard@exelixis.com Media
Contact: Claire McConnaughey Senior Director, Public Affairs
(650) 837-7052 cmcconn@exelixis.com
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