Signal of PFS Improvement in SIENDO for
Selinexor-Treated Patients was Observed Only in Subgroup Who are
TP53 Wild-Type with a Median Progression-Free Survival of 27.4
Months
Median PFS Not Reached for Selinexor-Treated
Patients Who are TP53 Wild-Type MSS (pMMR)
Updated Analysis Provides Further Rationale
for XPORT-EC-042, the Ongoing Pivotal Phase 3 Study (NCT05611931)
Evaluating Selinexor as Maintenance Therapy in TP53 Wild-Type
Endometrial Cancer
NEWTON,
Mass., July 25, 2023 /PRNewswire/ -- Karyopharm
Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical
company pioneering novel cancer therapies, today announced the
presentation of updated exploratory subgroup analyses from the
SIENDO study (NCT03555422) in patients with advanced or recurrent
TP53 wild-type endometrial cancer at the virtual American
Society of Clinical Oncology (ASCO) Plenary Series.
![(PRNewsfoto/Karyopharm Therapeutics Inc.) (PRNewsfoto/Karyopharm Therapeutics Inc.)](https://mma.prnewswire.com/media/1890042/Karyopharm_Therapeutics_Logo.jpg)
Currently, there are no specific targeted therapies available
for patients with TP53 wild-type endometrial cancer.
Advanced and recurrent endometrial cancer is associated with a poor
prognosis, including limited disease control for patients who
relapse after first-line systemic treatment.1
TP53 wild-type is found in approximately 50% of
advanced/recurrent tumors in patients with endometrial
cancer.2,3 TP53 wild-type is observed
in both MSS (pMMR) and MSI-H (dMMR) populations. Recently there has
been progress in potential treatment options in the MSI-H (dMMR)
subgroup with new targeted treatments. However, a large unmet need
continues to exist for MSS (pMMR), which comprises approximately
70% of all endometrial cancer patients and of that population,
approximately 70% are TP53 wild-type.
The primary analysis of the Phase 3 SIENDO study of selinexor
maintenance therapy in advanced or recurrent endometrial cancer
showed improvements in median progression-free survival (PFS) for
the intent-to-treat (ITT) population but were not clinically
meaningful. However, an exploratory analysis of a pre-specified
subgroup of patients with TP53 wild-type endometrial cancer
showed a promising efficacy signal. In the SIENDO study, 263
patients were randomly assigned, with 174 patients allocated to the
selinexor arm and 89 patients to the placebo arm. One hundred and
thirteen patients with TP53 wild-type endometrial cancer
were randomized to receive selinexor (n=77) vs placebo (n=36) as
maintenance therapy. As of the March 30,
2023 data cut-off date, and a median duration of follow-up
of 25.3 months, selinexor-treated patients with TP53
wild-type endometrial cancer had a median PFS of 27.4 months
compared to 5.2 months for patients with TP53 wild-type
endometrial cancer receiving placebo. Additionally, median PFS was
not reached for selinexor-treated TP53 wild-type MSS (pMMR)
endometrial cancer patients compared to 4.9 months for TP53
wild-type MSS (pMMR) endometrial cancer patients treated with
placebo.
No new safety signals were identified as of the last data
cut-off date on March 30, 2023. The
most common adverse events (AEs) in TP53 wild-type patients
were nausea (91%), vomiting (61%) and diarrhea (40%), the majority
of which were grades 1-2. The most common reported grade 3-4
treatment-emergent AEs (TEAEs) included neutropenia (18%), nausea
(12%), and thrombocytopenia (9%). TEAEs leading to discontinuations
were reported in 16% of patients.
The SIENDO exploratory subgroup data provides further rationale
for the ongoing pivotal Phase 3 study (XPORT-EC-042; NCT05611931)
of selinexor as a maintenance therapy following systemic therapy in
patients with TP53 wild-type advanced or recurrent
endometrial cancer with the strongest signal in TP53
wild-type, MSS (pMMR). Karyopharm is currently enrolling patients
in the pivotal Phase 3 study of selinexor as a maintenance therapy
following systemic therapy in patients with TP53 wild-type
advanced or recurrent endometrial cancer (XPORT-EC-042;
NCT05611931) to better understand the exploratory subgroup
analysis. This trial includes a companion diagnostic tool under
development by Foundation Medicine, Inc. Karyopharm entered into a
global collaboration with Foundation Medicine, Inc. to develop
FoundationOne®CDx, a tissue-based comprehensive genomic
profiling test to identify and enroll patients whose tumors are
TP53 wild-type.
"The updated results from SIENDO suggest that selinexor may have
the potential to prolong systemic therapy response in patients
whose disease is TP53 wild-type. Particularly encouraging
are the data observed in the subgroup of patients whose disease are
both TP53 wild-type and MSS," said Reshma Rangwala, MD, PhD, Chief Medical Officer
of Karyopharm. "We are encouraged by the updated results from this
study as it further strengthens the rationale for our ongoing
EC-042 Phase 3 study."
"Treatment options for women with advanced or recurrent
endometrial cancer are rapidly evolving with the identification of
molecular subgroups. Limited options, however, still persist among
certain subgroups, including patients with mismatch
repair-proficient disease (pMMR), who comprise about 70% of
endometrial cancers," said Dr. Ignace
Vergote, principal investigator and gynecologist oncologist,
ENGOT and the Belgium and
Luxembourg Gynaecological Oncology Group (BGOG), University of
Leuven, Leuven Cancer Institute, Leuven, Belgium. "TP53 is a well-recognized
molecular marker in endometrial cancer. About 50% of patients with
advanced, recurrent endometrial cancer have disease identified as
TP53 wild-type and about 70% of those further classified as
a pMMR. The EC-042 study is designed to show that inhibition of
XPO1 with selinexor may provide a potential new therapeutic option
for these patients."
"The long-term follow-up in the TP53 wild-type subgroup
from the SIENDO trial is extremely encouraging and suggests that
TP53 status could be an important biomarker that can
identify patients who benefit from XPO1 inhibition with selinexor,"
said Dr. Brian Slomovitz, Director
of Gynecologic Oncology and Co-Chair of the Cancer Research
Committee at Mount Sinai Medical Center, and Uterine Cancer Trial
Advisor for GOG Partners, Inc. "Given the unmet need that remains
for patients whose disease is pMMR as well as the encouraging
exploratory data in the subgroup of patients who are classified as
TP53 wild-type and pMMR, a potential new paradigm for both
the diagnosis and treatment of women with endometrial cancer may be
identified. I look forward to the ongoing progress of EC-042 to
further explore this hypothesis."
ASCO Plenary Series
Program
Title: Long-term follow up
of selinexor maintenance in patients with TP53wt advanced or
recurrent endometrial cancer: A pre-specified subgroup analysis
from the phase 3 ENGOT-EN5/GOG-3055/SIENDO study.
Presenter: Brian Slomovitz, MD, Mount Sinai
Medical Center
Session Date and Time: Tuesday July 25, 2023, 3:00pm - 4:00pm (ET)
This livestream event presented by ASCO is free to register at:
https://old-prod.asco.org/meetings-education/monthly-plenary-series/program
About the EC-042 Study
EC-042 (XPORT-EC-042;
NCT05611931) is a global, Phase 3, randomized, double-blind study
evaluating selinexor as a maintenance therapy following systemic
therapy in patients with TP53 wild-type advanced or
recurrent endometrial cancer. The EC-042 study was initiated in
November 2022 and is expected to
enroll up to 220 patients who will be randomized 1:1 to receive
either a 60 mg, once-weekly, administration of oral selinexor or
placebo until disease progression. The primary endpoint of the
study is progression free survival (PFS), as assessed by an
investigator, with overall survival as a key secondary endpoint.
Further, in connection with the EC-042 Study, Karyopharm entered
into a global collaboration with Foundation Medicine, Inc. to
develop FoundationOne®CDx, a tissue-based comprehensive
genomic profiling test to identify and enroll patients whose tumors
are TP53 wild-type.
About the SIENDO Study
Karyopharm's evaluation of
selinexor to treat patients with TP53 wild-type advanced or
recurrent endometrial cancer is supported by data from an
exploratory subgroup analysis from its ongoing SIENDO Study, a
European Network of Gynaecological Oncological Trial Groups
(ENGOT)-led trial in collaboration with the Gynecologic Oncology
Group (GOG) Foundation, Inc. The SIENDO Study is a multicenter,
randomized, double-blinded Phase 3 study evaluating the efficacy
and safety of oral selinexor versus placebo as a front-line
maintenance therapy in patients with advanced or recurrent
endometrial cancer following at least one prior platinum-based
combination chemotherapy treatment (NCT03555422). Participants in
this study with advanced or recurrent disease who had a partial
response or a complete response after at least 12 weeks of
taxane-platinum combination chemotherapy were randomized in a 2:1
manner to receive either maintenance therapy of 80 mg of selinexor
or placebo taken once per week, until disease progression. The
primary endpoint in the study was PFS from time of randomization
until death or disease progression as assessed by an investigator,
with the goal of the study demonstrating a HR of 0.6. In the
first quarter of 2022, Karyopharm presented top-line data from the
SIENDO study, including preliminary exploratory subgroup analyses.
Selinexor-treated patients had a median PFS of 5.7 months compared
to 3.8 months for patients on placebo in the full trial population,
which was not clinically meaningful. Patients in the
exploratory subgroup of TP53 wild-type advanced or recurrent
endometrial cancer treated with selinexor had a median PFS of 13.7
months compared to 3.7 months for the exploratory subgroup patients
on placebo. There were no new safety signals identified, and a
discontinuation rate of 10.5% due to adverse events (AEs). The most
common treatment-emergent AEs in the SIENDO study of any grade
were: nausea (84%), vomiting (52%), constipation (37%) and
thrombocytopenia (37%). The most common grade 3 treatment-emergent
AEs were nausea (10%), neutropenia (9%), thrombocytopenia (7%) and
asthenia (6%).
About Endometrial Cancer
Endometrial cancer is the
most common cancer of the female reproductive organs in the U.S.,
with approximately 66,000 new cases expected in 2023 leading to
nearly 13,000 deaths.4 In 2020, there were
approximately 130,000 new cases and 29,000 deaths
in Europe from endometrial cancer, while on a global
scale there were 417,000 new cases and approximately 97,000
deaths.5 Since 2002, the incidence of new cases and
deaths from endometrial cancer have risen.6 Risk factors
include obesity, Type 2 diabetes, high-fat diets, use of tamoxifen
and oral estrogens, and delayed menopause.7 There
are no approved therapies in the maintenance setting for patients
with advanced or recurrent endometrial cancer.8
About XPOVIO® (selinexor)
XPOVIO is a
first-in-class, oral exportin 1 (XPO1) inhibitor and the first of
Karyopharm's Selective Inhibitor of Nuclear Export (SINE) compounds
to be approved for the treatment of cancer. XPOVIO functions by
selectively binding to and inhibiting the nuclear export protein
XPO1. XPOVIO is approved in the U.S. and marketed by Karyopharm in
multiple oncology indications, including: (i) in combination with
Velcade® (bortezomib) and dexamethasone (XVd) in
patients with multiple myeloma after at least one prior therapy;
(ii) in combination with dexamethasone in patients with heavily
pre-treated multiple myeloma; and (iii) in patients with diffuse
large B-cell lymphoma (DLBCL), including DLBCL arising from
follicular lymphoma, after at least two lines of systemic therapy.
XPOVIO (also known as NEXPOVIO® in certain countries)
has received regulatory approvals in various indications in a
growing number of ex-U.S. territories and countries, including but
not limited to the European Union, the United Kingdom, China, South
Korea, Canada, Israel and Taiwan. XPOVIO and NEXPOVIO is marketed by
Karyopharm's partners, Antengene, Menarini, Neopharm and FORUS, in
China, South Korea, Singapore, Australia, Hong
Kong, Germany, Austria, Israel and Canada.
Please refer to the local Prescribing Information for full
details.
Selinexor is also being investigated in several other mid- and
late-stage clinical trials across multiple high unmet need cancer
indications, including in endometrial cancer and myelofibrosis.
For more information about Karyopharm's products or clinical
trials, please contact the Medical Information department at:
Tel: +1 (888) 209-9326
Email: medicalinformation@karyopharm.com
SELECT IMPORTANT SAFETY INFORMATION
Warnings and
Precautions
- Thrombocytopenia: Monitor platelet counts throughout treatment.
Manage with dose interruption and/or reduction and supportive
care.
- Neutropenia: Monitor neutrophil counts throughout treatment.
Manage with dose interruption and/or reduction and granulocyte
colony–stimulating factors.
- Gastrointestinal Toxicity: Nausea, vomiting, diarrhea,
anorexia, and weight loss may occur. Provide antiemetic
prophylaxis. Manage with dose interruption and/or reduction,
antiemetics, and supportive care.
- Hyponatremia: Monitor serum sodium levels throughout treatment.
Correct for concurrent hyperglycemia and high serum paraprotein
levels. Manage with dose interruption, reduction, or
discontinuation, and supportive care.
- Serious Infection: Monitor for infection and treat
promptly.
- Neurological Toxicity: Advise patients to refrain from driving
and engaging in hazardous occupations or activities until
neurological toxicity resolves. Optimize hydration status and
concomitant medications to avoid dizziness or mental status
changes.
- Embryo–Fetal Toxicity: Can cause fetal harm. Advise females of
reproductive potential and males with a female partner of
reproductive potential, of the potential risk to a fetus and use of
effective contraception.
- Cataract: Cataracts may develop or progress. Treatment of
cataracts usually requires surgical removal of the cataract.
Adverse Reactions
- The most common adverse reactions (≥20%) in patients with
multiple myeloma who receive XVd are fatigue, nausea, decreased
appetite, diarrhea, peripheral neuropathy, upper respiratory tract
infection, decreased weight, cataract and vomiting. Grade 3–4
laboratory abnormalities (≥10%) are thrombocytopenia, lymphopenia,
hypophosphatemia, anemia, hyponatremia and neutropenia. In the
BOSTON trial, fatal adverse
reactions occurred in 6% of patients within 30 days of last
treatment. Serious adverse reactions occurred in 52% of patients.
Treatment discontinuation rate due to adverse reactions was
19%.
- The most common adverse reactions (≥20%) in patients with
multiple myeloma who receive Xd are thrombocytopenia, fatigue,
nausea, anemia, decreased appetite, decreased weight, diarrhea,
vomiting, hyponatremia, neutropenia, leukopenia, constipation,
dyspnea and upper respiratory tract infection. In the STORM trial,
fatal adverse reactions occurred in 9% of patients. Serious adverse
reactions occurred in 58% of patients. Treatment discontinuation
rate due to adverse reactions was 27%.
- The most common adverse reactions (incidence ≥20%) in patients
with DLBCL, excluding laboratory abnormalities, are fatigue,
nausea, diarrhea, appetite decrease, weight decrease, constipation,
vomiting, and pyrexia. Grade 3–4 laboratory abnormalities (≥15%)
are thrombocytopenia, lymphopenia, neutropenia, anemia, and
hyponatremia. In the SADAL trial, fatal adverse reactions occurred
in 3.7% of patients within 30 days, and 5% of patients within 60
days of last treatment; the most frequent fatal adverse reactions
was infection (4.5% of patients). Serious adverse reactions
occurred in 46% of patients; the most frequent serious adverse
reaction was infection (21% of patients). Discontinuation due to
adverse reactions occurred in 17% of patients.
Use In Specific Populations
Lactation: Advise not to
breastfeed.
For additional product information, including full prescribing
information,
please visit www.XPOVIO.com.
To report SUSPECTED ADVERSE REACTIONS, contact Karyopharm
Therapeutics Inc. at 1–888–209–9326 or FDA at 1–800–FDA–1088 or
www.fda.gov/medwatch.
About Karyopharm Therapeutics
Karyopharm Therapeutics
Inc. (Nasdaq: KPTI) is a commercial-stage pharmaceutical company
pioneering novel cancer therapies. Since its founding, Karyopharm
has been an industry leader in oral Selective Inhibitor of Nuclear
Export (SINE) compound technology, which was developed to address a
fundamental mechanism of oncogenesis: nuclear export dysregulation.
Karyopharm's lead SINE compound and first-in-class, oral exportin 1
(XPO1) inhibitor, XPOVIO® (selinexor), is approved in
the U.S. and marketed by the Company in three oncology indications
and has received regulatory approvals in various indications in a
growing number of ex-U.S. territories and countries, including
Europe and the United Kingdom (as NEXPOVIO®) and
China. Karyopharm has a focused
pipeline targeting multiple high unmet need cancer indications,
including in multiple myeloma, endometrial cancer, myelodysplastic
neoplasms and myelofibrosis. For more information about our people,
science and pipeline, please visit www.karyopharm.com, and follow
us on Twitter at @Karyopharm and LinkedIn.
Forward-Looking Statements
This press release contains forward-looking statements within
the meaning of The Private Securities Litigation Reform Act of
1995. Such forward-looking statements include those regarding the
ability of selinexor to treat patients with endometrial cancer; and
expectations related to the clinical development of selinexor and
potential regulatory submissions of selinexor. Such statements are
subject to numerous important factors, risks and uncertainties,
many of which are beyond Karyopharm's control, that may cause
actual events or results to differ materially from Karyopharm's
current expectations. For example, there can be no guarantee that
Karyopharm will successfully commercialize XPOVIO or that any of
Karyopharm's drug candidates, including selinexor and eltanexor,
will successfully complete necessary clinical development phases or
that development of any of Karyopharm's drug candidates will
continue. Further, there can be no guarantee that any positive
developments in the development or commercialization of
Karyopharm's drug candidate portfolio will result in stock price
appreciation. Management's expectations and, therefore, any
forward-looking statements in this press release could also be
affected by risks and uncertainties relating to a number of other
factors, including the following: the adoption of XPOVIO in the
commercial marketplace, the timing and costs involved in
commercializing XPOVIO or any of Karyopharm's drug candidates that
receive regulatory approval; the ability to obtain and retain
regulatory approval of XPOVIO or any of Karyopharm's drug
candidates that receive regulatory approval; Karyopharm's results
of clinical trials and preclinical studies, including subsequent
analysis of existing data and new data received from ongoing and
future studies; the content and timing of decisions made by the
U.S. Food and Drug Administration and other regulatory authorities,
investigational review boards at clinical trial sites and
publication review bodies, including with respect to the need for
additional clinical studies; the ability of Karyopharm or its third
party collaborators or successors in interest to fully perform
their respective obligations under the applicable agreement and the
potential future financial implications of such agreement;
Karyopharm's ability to enroll patients in its clinical trials;
unplanned cash requirements and expenditures; development or
regulatory approval of drug candidates by Karyopharm's competitors
for products or product candidates in which Karyopharm is currently
commercializing or developing; the direct or indirect impact of the
COVID-19 pandemic or any future pandemic on Karyopharm's business,
results of operations and financial condition; and Karyopharm's
ability to obtain, maintain and enforce patent and other
intellectual property protection for any of its products or product
candidates. These and other risks are described under the caption
"Risk Factors" in Karyopharm's Quarterly Report on Form 10-Q for
the quarter ended March 31, 2023,
which was filed with the Securities and Exchange Commission (SEC)
on May 4, 2023, and in other filings
that Karyopharm may make with the SEC in the future. Any
forward-looking statements contained in this press release speak
only as of the date hereof, and, except as required by law,
Karyopharm expressly disclaims any obligation to update any
forward-looking statements, whether as a result of new information,
future events or otherwise.
XPOVIO® and NEXPOVIO® are registered
trademarks of Karyopharm Therapeutics Inc. Any other trademarks
referred to in this release are the property of their respective
owners.
References
1 Cosgrove C, Backes, F,
O'Malley D. The Oncol. 2021;26:10441051.
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3 Nakamura M, Obata T, Diakoku T, et al. Int J Mol
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(accessed July 14, 2023)
5 International Agency for Research on Cancer,
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2020: https://gco.iarc.fr/today/data/factsheets/cancers/24-Corpus-uteri-fact-sheet.pdf
(accessed July 14, 2023)
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https://seer.cancer.gov/statistics/preliminary-estimates/ (accessed
July 17, 2023)
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(accessed July 14, 2023)
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