Exelixis, Inc. (Nasdaq: EXEL) today announced detailed final
overall survival (OS) results from CONTACT-02, a phase 3 pivotal
study evaluating cabozantinib (CABOMETYX®) in combination with
atezolizumab (Tecentriq®) 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. These data are being
presented today at the 2024 European Society for Medical Oncology
Congress (ESMO 2024) during the Proffered Paper Session: GU
Tumours, Prostate at 2:45 p.m. CEST.
“Despite recent advancements, outcomes remain poor for patients
with metastatic castration-resistant prostate cancer whose disease
progresses after novel hormonal therapy – particularly those with
liver metastases,” 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.
“I believe there is a critical need for novel agents with a new
mechanism of action that are broadly accessible to patients and can
delay disease progression. The positive results from CONTACT-02,
especially in the subset of patients with liver metastasis,
reinforce the therapeutic potential of cabozantinib in combination
with atezolizumab for these patients.”
The two primary endpoints for CONTACT-02 were progression-free
survival (PFS) and OS. At a median follow-up of 24.0 months, the
final analysis of OS showed a numerical but not statistically
significant improvement favoring cabozantinib in combination with
atezolizumab (hazard ratio: 0.89; 95% confidence interval:
0.72-1.10; P=0.296). An improvement in OS was observed in multiple
clinical subgroups, notably in patients with bone or liver
metastases, with the latter category representing a population
whose disease may be evolving away from androgen receptor
signaling. Additional OS efficacy findings are included in Table 1
below.
TABLE 1
ITT population
Bone metastases
Liver metastases
Patients, n
575
446
132
HR (95% CI)
P-value
0.89
(0.72, 1.10)
P=0.30
0.79
(0.63, 1.00)
P=0.046
0.68
(0.47, 1.00)
P=0.051
Median OS (C+A);
months
14.8
(13.4, 16.7)
13.8
(11.9, 16.3)
12.2
(8.8, 13.8)
Median OS (NHT);
months
15.0
(13.0, 18.5)
11.6
(10.5, 14.1)
7.1
(5.3, 10.4)
C+A: cabozantinib + atezolizumab; CI:
confidence interval; HR: hazard ratio; ITT: intent-to-treat; NHT:
novel hormonal therapy; OS: overall survival
“Within the current treatment landscape, there is a growing
population of patients with metastatic castration-resistant
prostate cancer with extra-pelvic soft tissue metastases whose
disease has progressed after novel hormonal therapy, leaving a high
unmet need for effective, widely available treatments for these
patients,” said Amy Peterson, M.D., Executive Vice President,
Product Development & Medical Affairs, and Chief Medical
Officer, Exelixis. “Collectively, the results from the CONTACT-02
trial suggest that there are patients who could benefit from
cabozantinib in combination with atezolizumab and that this regimen
could be a valuable addition to the treatment landscape for
patients with advanced prostate cancer.”
Treatment-related grade 3-4 adverse events (AEs) occurred in 40%
of patients receiving cabozantinib in combination with atezolizumab
and 8% of those receiving NHT. Treatment-related AEs leading to
discontinuation of all treatment components were similar (5% for
cabozantinib in combination with atezolizumab and 2% of those
receiving NHT). The time to clinically meaningful deterioration in
quality of life was similar between arms, and the combination of
cabozantinib and atezolizumab did not impair quality of life
relative to generally well-tolerated NHT.
As previously announced, CONTACT-02 met one of its two primary
endpoints, demonstrating a statistically significant benefit in PFS
in the predefined PFS ITT population (i.e., the first 400
randomized patients). Detailed results were presented at the
American Society of Clinical Oncology 2024 Genitourinary Cancers
Symposium in January 2024. Exelixis intends to submit a
supplemental New Drug Application with the U.S. Food and Drug
Administration for cabozantinib in combination with atezolizumab
for mCRPC later this year.
About CONTACT-02 CONTACT-02 is a global, multicenter,
randomized, phase 3, open-label study that randomized 575 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 blinded independent radiology
committee. 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 as monotherapy for the treatment of
patients with advanced renal cell carcinoma (RCC) and in
combination with nivolumab as a first-line treatment for patients
with advanced RCC; for the treatment of patients with
hepatocellular carcinoma (HCC) who have been previously treated
with sorafenib; 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 over 65 countries outside the U.S. and Japan,
including the European Union. 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 Pharmaceutical
Company Limited 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 is not indicated as a treatment for CRPC.
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 final OS
results from the CONTACT-02 trial at ESMO 2024; the therapeutic
potential of cabozantinib in combination with atezolizumab to
benefit patients with mCRPC and measurable extra-pelvic soft tissue
disease who have progressed on one prior NHT, especially in the
subset of patients with liver metastasis, and Exelixis’ belief that
this combination regimen could be a valuable addition to the
treatment landscape for patients with advanced prostate cancer;
Exelixis’ plans to submit a supplemental New Drug Application with
the U.S. Food and Drug Administration for cabozantinib in
combination with atezolizumab for mCRPC later this year; 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; unexpected concerns
that may arise as a result of the occurrence of adverse safety
events or additional data analyses of clinical trials evaluating
cabozantinib; Exelixis’ dependence on its relationships with its
cabozantinib commercial collaboration partners, including the level
of their investment in the resources necessary to pursue regulatory
approvals and successfully commercialize cabozantinib in the
territories where approved; 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.
TECENTRIQ is registered U.S. trademark of
Genentech, a member of the Roche Group.
1 Cancer Facts & Figures 2024. ACS. 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 September 2024.
2 Patient education: Treatment for advanced prostate cancer
(Beyond the Basics). UpToDate website. Available at:
https://www.uptodate.com/contents/treatment-for-advanced-prostate-cancer-beyond-the-basics.
Accessed September 2024.
3 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.
4 Moreira, D. M., Howard, L. E., Sourbeer, K. N., 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
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Investors: Susan Hubbard EVP, Public Affairs and Investor
Relations Exelixis, Inc. (650) 837-8194 shubbard@exelixis.com
Media: Claire McConnaughey Senior Director, Public Affairs
Exelixis, Inc. (650) 837-7052 cmcconn@exelixis.com
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