On November 6, 2023 Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, reported 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 (Press release, Karyopharm, NOV 6, 2023, View Source [SID1234637033]).
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
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 FoundationOneCDx, 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: [email protected]
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.