Long-Term Safety and Efficacy Data from SIENDO
Study in the TP53 Wild-Type Exploratory Subgroup Showed Signals of
Improvement in Overall Survival (OS) Regardless of Mismatched
Repair Status (MMR)
Median OS Not Reached for Selinexor-Treated
Patients Who are TP53 Wild-Type pMMR
NEWTON, Mass., Nov. 6, 2023 /PRNewswire/ -- Karyopharm
Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical
company pioneering novel cancer therapies, today announced the
presentation of updated long-term safety and efficacy data from a
pre-specified exploratory subgroup analysis of the SIENDO study
(NCT03555422) in patients with advanced or recurrent TP53
wild-type endometrial cancer at the International Gynecological
Cancer Society (IGCS) Annual Global Meeting in Seoul, South Korea.
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 exploratory subgroup analysis, 113 patients with
wild-type endometrial cancer received selinexor (n=77) or placebo
(n=36) as maintenance therapy. Although the survival data are
immature, as of the September 1,
2023, data cut-off date, the study showed an encouraging OS
signal in the TP53 wild-type population: hazard ratio
0.76 (95% Confidence Interval [CI]: 0.36-1.59), with median
OS not reached in either arm after a median follow up of 28.9
months. Similarly, encouraging preliminary OS was observed in
patients with TP53 wild-type/pMMR endometrial cancer: hazard
ratio 0.57 (95% CI: 0.24-1.35), with median OS not reached in
selinexor arm, and 35 months in placebo arm after median follow-up
of 31.6 months , and a HR of 0.62 (95% CI: 0.06-6.81), with median
OS not reached in either arm after median follow-up of 27.3 months
in patients with TP53 wild-type/dMMR endometrial cancer.
"The preliminary OS data from this exploratory subset analysis
of the SIENDO study corroborate the PFS results observed, which is
compelling in this novel biomarker-driven population with high
unmet need," said Reshma Rangwala,
MD, PhD, Chief Medical Officer of Karyopharm. "These results
showcase selinexor's potential as a foundational treatment for
patients with TP53 wild-type endometrial cancer. We
look forward to additional data in the first half of 2025 from the
company's ongoing pivotal Phase 3 trial that may support U.S. and
global regulatory filings."
No new safety signals were identified as of the last data
cut-off date on September 1,
2023. The most common treatment-emergent adverse events (AEs)
with selinexor treatment were nausea (90%), vomiting (60%),
thrombocytopenia (42%) and diarrhea (42%), the majority of which
were grades 1-2. Of note, the rate of nausea in the placebo
patients was 34%, vomiting 11%, and diarrhea 37%. The most common
reported grade 3-4 treatment-emergent AEs included neutropenia
(18%), nausea (12%), and thrombocytopenia (10%). TEAEs leading to
discontinuations in the selinexor group were reported in 16% of
patients.
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 There are
about 16,000 patients diagnosed with advanced and recurrent
endometrial cancer in the U.S. each year2. More than 50%
of these patients have TP53 wild-type cancer.2,3
TP53 wild-type is observed in both pMMR and dMMR
populations. Recently there has been progress in potential
treatment options in the dMMR subgroup with new targeted
treatments; however, a large unmet need continues to exist for
pMMR and for TP53 wild-type endometrial cancer.
"Given the unmet need that remains for patients whose disease is
pMMR, I'm excited by the results demonstrating an encouraging,
preliminary trend in OS, coupled with signals of improvement in
disease progression," said Dr. Giovanni Scambia, oncology gynecologist at MITO
and Fondazione Policlinico Universitario A. Gemelli IRCCS,
Rome, Italy. "These results
highlight the potential opportunity to further personalize
therapies and provide a strong rationale to further evaluate
selinexor as maintenance therapy in TP53 wild-type
endometrial cancer in the ongoing Phase 3 trial".
IGCS Oral
Presentation
Title: Selinexor
maintenance for patients with TP53wt advanced or recurrent
endometrial cancer: Long-term follow up of efficacy and safety
subgroup analysis of the ENGOT-EN5/GOG-3055/SIENDO study
Presenter: Giovanni Scambia, MD, MITO and
Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Session Title: Plenary 02: Changing the Landscape
of Endometrial Cancer
Date and
Time: Sunday, November 5,
2023, 4:30pm - 5:30pm (GMT+9)/ 3:30am
- 4:30am (ET)
IGCS Poster
Presentation
Title: ENGOT-EN20/GOG-3083/XPORT-EC-042
A phase 3, randomized, placebo-controlled, double-blind,
multicenter trial of selinexor in maintenance therapy for patients
with P53 Wild-type, advanced or recurrent endometrial carcinoma
Presenter: Brian Slomovitz, MD, Mount Sinai
Medical center and Florida International
University
Date and Time: Sunday,
November 5, 2023, through Tuesday,
November 7, 2023
IGCS Industry Sponsored Symposium in Partnership with
Gynecologic Oncology Group
(GOG)
Title: The evolving
landscape in molecular-driven investigational therapies for
advanced endometrial cancer
Presenters: Bradley J. Monk, MD, US Cancer
Associates; Domenica Lorusso, MD,
PhD, Catholic University of
Rome and Fondazione Policlinico
Gemelli IRCCS; Ritu Salani, MD, MS,
UCLA Medical Center
Date and Time: Monday,
November 6, 2023, 7:15am –
8:15am (GMT+9)/ 6:15pm - 7:15pm
(ET)
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 Mainland
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 September 30, 2023,
which was filed with the Securities and Exchange Commission (SEC)
on November 2, 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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4 American Cancer Society, About Endometrial
Cancer: https://www.cancer.org/cancer/endometrial-cancer/about/key-statistics.html
(accessed July 14, 2023)
5 International Agency for Research on Cancer, World
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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
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