– STELLAR-305 is Exelixis’ first pivotal
study in squamous cell carcinoma of the head and neck –
– Trial will evaluate the potential of
inhibition of VEGF, MET and AXL, which are elevated in these tumors
–
Exelixis, Inc. (Nasdaq: EXEL) today announced the initiation of
STELLAR-305, a phase 2/3 pivotal trial evaluating zanzalintinib in
combination with pembrolizumab versus pembrolizumab alone in
patients with previously untreated PD-L1-positive recurrent or
metastatic squamous cell carcinoma of the head and neck
(SCCHN).
“We are excited to progress zanzalintinib, our next-generation
multi-targeted tyrosine kinase inhibitor, into this population of
patients who otherwise are relegated to immunotherapy plus
chemotherapy, but may benefit from a chemo-free option,” said Amy
Peterson, M.D., Executive Vice President, Product Development &
Medical Affairs, and Chief Medical Officer, Exelixis. “This study
is based on encouraging data from a phase 2 investigator-initiated
trial of cabozantinib and pembrolizumab and demonstrates our
agility to move quickly into indications with sound rationale from
our flagship asset.”
STELLAR-305 is a global, multicenter, randomized, double-blind
phase 2/3 study that will enroll patients with PD-L1-positive
recurrent or metastatic SCCHN that is incurable with local
therapies. Patients must not have received prior systemic therapy
for recurrent or metastatic disease. Patients will be randomized
1:1 to receive zanzalintinib in combination with pembrolizumab or
placebo in combination with pembrolizumab. The primary endpoints of
the study are progression-free survival (PFS) per Response
Evaluation Criteria in Solid Tumors (RECIST) 1.1 by Blinded
Independent Radiology Committee (BIRC) and overall survival.
Secondary endpoints include PFS per RECIST 1.1 by investigator and
objective response rate and duration of response per RECIST 1.1 by
BIRC and by investigator.
STELLAR-305 is sponsored by Exelixis. More information about
STELLAR-305 is available at ClinicalTrials.gov.
About Zanzalintinib
Zanzalintinib is a next-generation oral tyrosine kinase
inhibitor 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.
About SCCHN
SCCHN comprises head and neck cancers that begin in the squamous
cells that line the mucosal surfaces of the head and neck.1
Accounting for about 90% of all head and neck cancers, SCCHN is
classified by its location: it can occur in the oral cavity,
oropharynx, nasal cavity and paranasal sinuses, nasopharynx, larynx
or hypopharynx.1,2 Oral cavity and larynx cancers are generally
associated with tobacco consumption, alcohol abuse or both, whereas
pharynx cancers are increasingly attributed to infection with human
papillomavirus (HPV), primarily HPV-16.3 Approximately 50,000 new
cases of SCCHN are diagnosed in the U.S. every year.1 SCCHN is more
common among men and people over the age of 50.4 Depending on the
site of the cancer and level of metastases, the five-year survival
rate for metastatic SCCHN ranges from 4-35%.5
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: the
therapeutic potential of zanzalintinib in combination with
pembrolizumab as a chemo-free option to improve outcomes for
patients with previously untreated PD-L1-positive recurrent or
metastatic SCCHN, including specifically the clinical potential of
zanzalintinib’s inhibition of VEGF, MET and AXL, which are elevated
in these 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: 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 in
combination with pembrolizumab to demonstrate safety and/or
efficacy in STELLAR-305 and in future clinical testing;
uncertainties inherent in the product development process,
including evolving regulatory requirements, slower than anticipated
patient enrollment or inability to identify a sufficient number of
clinical trial sites; 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 Head and neck squamous cell carcinoma.
MedlinePlus website. Available at:
https://medlineplus.gov/genetics/condition/head-and-neck-squamous-cell-carcinoma/.
Accessed December 2023.
2 Squamous cell carcinoma of the head and
neck. Penn Medicine website. Available at:
https://www.pennmedicine.org/cancer/types-of-cancer/squamous-cell-carcinoma/types-of-squamous-cell-carcinoma/squamous-cell-carcinoma-of-the-head-and-neck.
Accessed December 2023.
3 Johnson, DE, Burtness, B, Leemans, CR,
et al. Head and neck squamous cell carcinoma. Nat Rev Dis Primers.
November 2020;6(1):92.
4 Head and neck cancers. NCI website.
Available at:
https://www.cancer.gov/types/head-and-neck/head-neck-fact-sheet#how-common-are-head-and-neck-cancers.
Accessed December 2023.
5 Beckham, TH, Leeman, JE, Xie, P, et al.
Long-term survival in patients with metastatic head and neck
squamous cell carcinoma treated with metastasis-directed therapy.
Br J Cancer. November 2019;121(11):897-903.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20231201184887/en/
Investors Contact: Susan Hubbard EVP, Public Affairs and
Investor Relations Exelixis, Inc. (650) 837-8194
shubbard@exelixis.com
Media Contact: Stekki Millman Senior Director, Public
Affairs Exelixis, Inc. (650) 837-7187 smillman@exelixis.com
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