– Results for Exelixis’ next-generation
tyrosine kinase inhibitor demonstrated an objective response rate
of 38% and a disease control rate of 88% –
– Anti-tumor activity was observed in
patients who had progressed on prior VEGFR-tyrosine kinase
inhibitors, including cabozantinib –
Exelixis, Inc. (Nasdaq: EXEL) today announced initial results
from an expansion cohort of STELLAR-001 evaluating single-agent
zanzalintinib in patients with previously treated clear cell renal
cell carcinoma (ccRCC). STELLAR-001 is a phase 1b trial evaluating
zanzalintinib alone and in combination with atezolizumab in
patients with locally advanced or metastatic solid tumors. The
findings are being presented today at 2:35 p.m. CST during the Oral
Abstracts session at the 2023 International Kidney Cancer Symposium
(IKCS): North America.
“Following promising activity in the dose-escalation stage, I am
further encouraged by the anti-tumor activity observed in the
monotherapy expansion cohort suggesting that zanzalintinib may be
an effective therapy following disease progression after prior
treatments,” said Sumanta Pal, M.D., Clinical Professor, City of
Hope Comprehensive Cancer Center, who is presenting the findings.
“Many of these patients with advanced kidney cancer have exhausted
their treatment options, having progressed on both immune
checkpoint inhibitors and tyrosine kinase inhibitors including
cabozantinib, so these results showing strong response rates and
durable responses are encouraging for this group of patients.”
In this ccRCC cohort, 97% of patients had received prior
immunotherapy and 81% had received prior VEGFR-tyrosine kinase
inhibitor (TKI), including 53% who had received cabozantinib.
Eighty-one percent of patients were intermediate risk by
International Metastatic RCC Database Consortium.
At a median follow-up of 8.3 months, 12 of the 32 patients
enrolled in the expansion cohort had a confirmed partial response
for an objective response rate of 38%; the disease control rate was
88%. Additional efficacy outcomes by prior therapy subgroups are
shown in Table 1.
All patients
Patients who received a prior
VEGFR-TKI
TABLE 1
Overall (n=32)
Cabozantinib-exposed
(n=17)
Cabozantinib-naïve
(n=14)
Any VEGFR-TKI, including
cabozantinib (n=26)
Non-cabozantinib VEGFR-TKI
(n=8)
Objective response rate,
%
38
24
57
35
63
Disease control rate,
%
88
94
86
92
100
Subgroups are not mutually exclusive.
Prior cabozantinib exposure was unknown for one patient. VEGFR-TKI:
vascular endothelial growth factor receptor-tyrosine kinase
inhibitor.
At data cutoff, 50% of patients were continuing treatment. The
median duration of response was 7.4 months for the
cabozantinib-naïve group and not estimable for the
cabozantinib-exposed group.
“These findings underscore the potential zanzalintinib may hold
for patients with refractory kidney cancer, including those who
have previously progressed on cabozantinib,” said Amy Peterson,
M.D., Executive Vice President, Product Development & Medical
Affairs, and Chief Medical Officer, Exelixis. “As STELLAR-001 and
our phase 3 STELLAR trials progress, we look forward to elucidating
the potential of zanzalintinib in kidney cancer as well as in other
advanced solid tumors.”
The safety population (n=81) included 32 patients from the ccRCC
expansion cohort treated at 100 mg plus 49 patients across
different solid tumors from the dose-escalation stage who received
single-agent zanzalintinib at doses ranging from 10-140 mg. The
safety profile was similar between the ccRCC cohort and the safety
population. Discontinuations due to treatment-related adverse
events (AEs) occurred in 9% of patients in the ccRCC cohort and 12%
of patients in the safety population. There were three grade 5
treatment-emergent AEs in the ccRCC cohort and two more in the
safety population; none were treatment-related, nor was the single
grade 4 event. Of note, the rate of palmar plantar
erythrodysesthesia was low with zanzalintinib (9% in the ccRCC
cohort and 12% in the safety population, all grade 1-2).
About STELLAR-001
STELLAR-001 (NCT03845166) is a global, open-label phase 1b/2
study of zanzalintinib as a single agent or in combination with
atezolizumab in patients with inoperable locally advanced or
metastatic solid tumors. The trial is divided into two parts: a
dose-escalation stage and an expansion cohort stage. The expansion
cohorts evaluating zanzalintinib as a single agent or in
combination with atezolizumab include patients with: ccRCC,
non-clear cell RCC, breast cancer that is hormone receptor-positive
and HER-2 negative, castration-resistant prostate cancer and
colorectal cancer. More information about the trial is available at
ClinicalTrials.gov.
About Zanzalintinib
Zanzalintinib is a next-generation oral TKI that inhibits the
activity of receptor tyrosine kinases implicated in cancer growth
and spread, including VEGF receptors, MET, AXL and MER. These
receptor tyrosine kinases are involved in both normal cellular
function and in pathologic processes such as oncogenesis,
metastasis, tumor angiogenesis and resistance to multiple
therapies, including immune checkpoint inhibitors. With
zanzalintinib, Exelixis sought to build upon its extensive
experience with the target profile of cabozantinib, the company’s
flagship medicine, while improving key characteristics, including
pharmacokinetic half-life. Zanzalintinib is currently being
developed for the treatment of advanced solid tumors, including
genitourinary, colorectal and head and neck cancers.
Zanzalintinib is not approved for ccRCC.
About RCC
Kidney cancer is among the top 10 most commonly diagnosed forms
of cancer among both men and women in the U.S.1 An estimated 81,800
Americans will be diagnosed with kidney cancer in 2023.1 The most
common type of kidney cancer in adults is ccRCC.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 15%.3 In 2022, approximately 32,200
patients with advanced kidney cancer required systemic therapy in
the U.S., with over 20,000 patients receiving first-line
treatment.4
About CABOMETYX® (cabozantinib)
In the U.S., CABOMETYX tablets are approved for the treatment of
patients with advanced 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 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 bi-coastal centers of 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: Exelixis’
presentation of data from STELLAR-001 during the Oral Abstracts
session at the 2023 IKCS: North America; the therapeutic potential
of zanzalintinib to treat patients with refractory ccRCC, including
those who have previously progressed on cabozantinib; Exelixis’
plans to continue studying the therapeutic potential of
zanzalintinib in kidney cancer as well as in other advanced solid
tumors; 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 zanzalintinib, both alone
and in combination with other therapies, to demonstrate safety
and/or efficacy in future clinical testing; uncertainties inherent
in the product development process; the costs of conducting
clinical trials; Exelixis’ dependence on third-party vendors for
the development, manufacture and supply of zanzalintinib; 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 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 Key Statistics About Kidney
Cancer. American Cancer Society website. Available at:
https://www.cancer.org/cancer/kidney-cancer/about/key-statistics.html.
Accessed November 2023. 2 What Is Kidney Cancer? American Cancer
Society website. Available at
https://www.cancer.org/cancer/kidney-cancer/about/what-is-kidney-cancer.html.
Accessed November 2023. 3 Survival Rates for Kidney Cancer.
American Cancer Society website. Available at
https://www.cancer.org/cancer/kidney-cancer/detection-diagnosis-staging/survival-rates.html.
Accessed November 2023. 4 Citeline’s Datamonitor Healthcare: Renal
Cell Carcinoma. March 2023 (internal data on file).
View source
version on businesswire.com: https://www.businesswire.com/news/home/20231106261142/en/
Investors: Susan Hubbard EVP, Public Affairs and Investor
Relations Exelixis, Inc. (650) 837-8194 shubbard@exelixis.com
Media: Stekki Millman Senior Director, Public Affairs
Exelixis, Inc. (650) 837-7187 smillman@exelixis.com
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