“Efficacy data from our ongoing STOMP study investigating selinexor in combination with standard of care anti-myeloma agents continue to demonstrate a strong rationale for selinexor’s potential expanded role in the future multiple myeloma treatment paradigm,” said
Updated Data from Phase 1b/2 STOMP Study Evaluating Selinexor in Combination with Kyprolis and Low-dose Dexamethasone (SKd) in Patient with Relapsed or Refractory Multiple Myeloma
In this arm of the Phase 1b/2 STOMP study, oral selinexor (dosed once-weekly) is being evaluated in combination with Kyprolis (56mg/m2 or 70mg/m2 once weekly) and low dose dexamethasone (orally, 40mg once weekly or 20mg twice weekly) in patients with relapsed refractory multiple myeloma who have received at least two prior therapies, which can include previous treatment with a proteasome inhibitor, one or more immunomodulatory drugs (e.g., Revlimid or Pomalyst) or Darzalex. The median number of prior treatments was four (range: 2-8). The following table is a summary of the efficacy results:
| Best Responses1 in Evaluable SKd Patients as of 1-Oct-20192 | |||||
| Category | N | ORR | CR | VGPR | PR |
| All (Kyprolis-naïve) | 14 | 10 (71%) | 3 (21%) | 7 (50%) | - |
Key: ORR=Overall Response Rate (CR+VGPR+PR); CR=Complete Response; VGPR=Very Good Partial Response; PR=Partial Response
1 Responses were adjudicated according to the
2 Based on interim unaudited data
All patients had reductions in M-protein from baseline, with 71% of patients experiencing a reduction of ≥90%. Median progression-free survival (PFS) has not yet been reached.
Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related adverse events (AEs) were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were nausea (71%), fatigue (43%), anorexia (36%), vomiting (36%) and weight loss (36%), and were mostly Grade 1 and 2 events. As expected, the most common treatment-related Grade ≥3 AEs were hematologic AEs and included thrombocytopenia (64%), anemia (14%) and leukopenia (14%). The recommended Phase 2 dose (RP2D) was identified as selinexor 80mg and Kyprolis 56mg/m2 and enrollment continues using this regimen.
New Data from Phase 1b/2 STOMP Study Evaluating the All Oral Combination of Selinexor with Revlimid and Low-dose Dexamethasone (SRd) in Patients with Newly Diagnosed Multiple Myeloma
In this all oral arm of the Phase 1b/2 STOMP study in patients with newly diagnosed multiple myeloma, selinexor (60mg once-weekly) is being combined with Revlimid (25mg orally, once daily) and low dose dexamethasone (orally, 40mg once weekly or 20mg twice weekly). The following table is a summary of the efficacy results:
| Best Responses1 in Evaluable SRd Patients as of 1-Oct-20192 | |||||
| Category | N3 | ORR | CR | VGPR4 | PR |
| All | 7 | 6 (86%) | 1 (14%) | 4 (57%) | 1 (14%) |
Key: ORR=Overall Response Rate (CR+VGPR+PR)
1 Responses were adjudicated according to the
2 Based on interim unaudited data
3 One patient was not evaluable for response due to withdrawn consent prior to disease follow-up
4 One VGPR was confirmed on
The data are early and the median PFS was not reached. Among the patients evaluable for safety, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were diarrhea (63%), weight loss (63%), nausea (50%), constipation (38%), fatigue (38%), hypokalemia (38%) and insomnia (38%) and were mostly Grade 1/2. The most common Grade ≥3 AEs were neutropenia (75%), anemia (50%) and thrombocytopenia (25%). Amongst the five patients evaluable for dose limiting toxicities (DLTs), there were no DLTs observed.
Comparison of Overall Survival Rates Between the Phase 2b STORM Study and the MAMMOTH Study
Another key presentation at ASH 2019 highlights encore data comparing the overall survival (OS) rate from the retrospective MAMMOTH study (Leukemia, 2019). The MAMMOTH study evaluated outcomes of patients with relapsed or refractory multiple myeloma (RRMM) treated at major academic medical centers. This ASH presentation highlighted results from a comparison of outcomes from patients with RRMM after their disease became refractory to CD38 monoclonal antibodies with a matched cohort of patients from Karyopharm’s Phase 2b STORM study, which served as the basis for the XPOVIO accelerated approval. Thus, patients in STORM who received selinexor and dexamethasone as first line of therapy after their disease became triple class refractory (n=64) were compared with matched patients receiving currently available therapies from the MAMMOTH cohort (n=128), showed an unadjusted hazard ratio (HR) for death of 0.64 (p=0.043), while an adjusted analysis, which takes into consideration differences in baseline characteristics between the two groups, showed a HR of 0.55 (p=0.009). The median OS of patients in STORM was 10.4 months and in MAMMOTH was 6.9 months. These results are consistent with previous presented results of STORM patients versus those from the Flatiron Health Analytics Database (FHAD) from patients with RRMM treated primarily in the community setting (Richardson, et al.
Updated Phase 1/2 Clinical Data for Oral Eltanexor in Elderly Patients with Higher-Risk MDS
This Phase 1/2 study is evaluating the safety, tolerability and anti-tumor activity of single-agent oral eltanexor (10mg or 20mg once-daily for 5 days per week) in elderly patients with higher-risk MDS. All patients were refractory to hypomethylating agents. The following table is a summary of the efficacy results:
| Best Responses1 in Eltanexor Patients2 | ||||
| Category | N | ORR | mCR | SD |
| All patients | 20 | 7 (35%) | 7 (35%) | 5 (25%) |
Key: ORR=Overall Response Rate (mCR+HI [not observed]); mCR=Complete Response without marrow recovery; HI=Hematologic Improvement; SD=Stable Disease
1 Responses assessments were made by the treating physician according to the 2006
2 Based on interim unaudited data
Median overall survival was 10.6 months. The most common treatment-related AEs were hematologic, gastrointestinal and constitutional. The most common non-hematologic treatment-related AEs were nausea (45%), decreased appetite (40%), fatigue (35%), diarrhea (35%) and dysgeusia (25%); the vast majority were Grade 1 or 2. The most common Grade ≥3 AEs were anemia (30%), neutropenia (25%), thrombocytopenia (20%) and leukopenia (15%). AEs were dose-dependent and managed with supportive care and dose modification. This Phase 1/2 study remains ongoing.
Other Key Selinexor Presentations
An additional investigator-sponsored study, which will be presented on
Details for these ASH 2019 presentations are as follows:
Poster Presentations – Company-Sponsored Studies
Title: Safety and Efficacy of the Combination of Selinexor, Lenalidomide and Dexamethasone (SRd) in Patients with Newly Diagnosed Multiple Myeloma
Presenter:
Abstract #: 3165
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
Date and Time:
Location:
Title: A Phase 1b/2 Study of Selinexor, Carfilzomib, and Dexamethasone (SKd) in Relapsed/ Refractory Multiple Myeloma (RRMM)
Presenter:
Abstract #: 3157
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
Date and Time:
Location:
Title: Overall Survival of Triple Class Refractory, Penta-Exposed Multiple Myeloma (MM) Patients Treated with Selinexor Plus Dexamethasone or Conventional Care: A Combined Analysis of the STORM and Mammoth Studies
Presenter:
Abstract #: 3125
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
Date and Time: Date:
Location:
Title: Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Higher-Risk Myelodysplastic Syndrome
Presenter:
Abstract #: 2997
Session: 637. Myelodysplastic Syndromes—Clinical Studies: Poster II
Date and Time:
Location:
Poster Presentations – Investigator-Sponsored Studies
Title: Selinexor Combined with Ibrutinib Demonstrates Tolerability and Efficacy in Advanced B-Cell Malignancies: A Phase I Study
Presenter:
Abstract #: 4310
Session: 642. CLL: Therapy, excluding Transplantation: Poster III
Date and Time:
Location:
PDF copies of these presentations will be available here following conclusion of the presentations at the meeting.
About XPOVIO® (selinexor)
XPOVIO is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). XPOVIO blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. In addition to receiving accelerated
IMPORTANT SAFETY INFORMATION
Thrombocytopenia
XPOVIO can cause thrombocytopenia, leading to potentially fatal hemorrhage. Thrombocytopenia was reported as an adverse reaction in 74% of patients, and severe (Grade 3-4) thrombocytopenia occurred in 61% of patients treated with XPOVIO. The median time to onset of the first event was 22 days. Bleeding occurred in 23% of patients with thrombocytopenia, clinically significant bleeding occurred in 5% of patients with thrombocytopenia and fatal hemorrhage occurred in <1% of patients.
Monitor platelet counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Institute platelet transfusion and/or other treatments as clinically indicated. Monitor patients for signs and symptoms of bleeding and evaluate promptly. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.
Neutropenia
XPOVIO can cause neutropenia, potentially increasing the risk of infection. Neutropenia was reported as an adverse reaction in 34% of patients, and severe (Grade 3-4) neutropenia occurred in 21% of patients treated with XPOVIO. The median time to onset of the first event was 25 days. Febrile neutropenia was reported in 3% of patients.
Obtain neutrophil counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF). Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.
Gastrointestinal Toxicity
Gastrointestinal toxicities occurred in patients treated with XPOVIO.
Nausea/Vomiting
Nausea was reported as an adverse reaction in 72% of patients, and Grade 3 nausea occurred in 9% of patients treated with XPOVIO. The median time to onset of the first nausea event was 3 days.
Vomiting was reported in 41% of patients, and Grade 3 vomiting occurred in 4% of patients treated with XPOVIO. The median time to onset of the first vomiting event was 5 days.
Provide prophylactic 5-HT3 antagonists and/or other anti-nausea agents, prior to and during treatment with XPOVIO. Manage nausea/vomiting by dose interruption, reduction, and/or discontinuation. Administer intravenous fluids and replace electrolytes to prevent dehydration in patients at risk. Use additional anti-nausea medications as clinically indicated.
Diarrhea
Diarrhea was reported as an adverse reaction in 44% of patients, and Grade 3 diarrhea occurred in 6% of patients treated with XPOVIO. The median time to onset of diarrhea was 15 days.
Manage diarrhea by dose modifications and/or standard anti-diarrheal agents; administer intravenous fluids to prevent dehydration in patients at risk.
Anorexia/Weight Loss
Anorexia was reported as an adverse reaction in 53% of patients, and Grade 3 anorexia occurred in 5% of patients treated with XPOVIO. The median time to onset of anorexia was 8 days.
Weight loss was reported as an adverse reaction in 47% of patients, and Grade 3 weight loss occurred in 1% of patients treated with XPOVIO. The median time to onset of weight loss was 15 days.
Monitor patient weight at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Manage anorexia and weight loss with dose modifications, appetite stimulants, and nutritional support.
Hyponatremia
XPOVIO can cause hyponatremia; 39% of patients treated with XPOVIO experienced hyponatremia, 22% of patients experienced Grade 3 or 4 hyponatremia. The median time to onset of the first event was 8 days.
Monitor sodium level at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Correct sodium levels for concurrent hyperglycemia (serum glucose >150 mg/dL) and high serum paraprotein levels. Treat hyponatremia per clinical guidelines (intravenous saline and/or salt tablets), including dietary review. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.
Infections
In patients receiving XPOVIO, 52% of patients experienced any grade of infection. Upper respiratory tract infection of any grade occurred in 21%, pneumonia in 13%, and sepsis in 6% of patients. Grade ≥3 infections were reported in 25% of patients, and deaths resulting from an infection occurred in 4% of patients. The most commonly reported Grade ≥3 infections were pneumonia in 9% of patients, followed by sepsis in 6%. The median time to onset was 54 days for pneumonia and 42 days for sepsis. Most infections were not associated with neutropenia and were caused by non-opportunistic organisms.
Neurological Toxicity
Neurological toxicities occurred in patients treated with XPOVIO.
Neurological adverse reactions including dizziness, syncope, depressed level of consciousness, and mental status changes (including delirium and confusional state) occurred in 30% of patients, and severe events (Grade 3-4) occurred in 9% of patients treated with XPOVIO. Median time to the first event was 15 days.
Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes.
Embryo-Fetal Toxicity
Based on data from animal studies and its mechanism of action, XPOVIO can cause fetal harm when administered to a pregnant woman. Selinexor administration to pregnant animals during organogenesis resulted in structural abnormalities and alterations to growth at exposures below those occurring clinically at the recommended dose.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose.
ADVERSE REACTIONS
The most common adverse reactions (incidence ≥20%) are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection.
The treatment discontinuation rate due to adverse reactions was 27%; 53% of patients had a reduction in the XPOVIO dose, and 65.3% had the dose of XPOVIO interrupted. The most frequent adverse reactions requiring permanent discontinuation in 4% or greater of patients who received XPOVIO included fatigue, nausea, and thrombocytopenia. The rate of fatal adverse reactions was 8.9%.
Please see XPOVIO Full Prescribing Information available at www.XPOVIO.com.
About Eltanexor (KPT-8602)
Eltanexor (KPT-8602) is a second generation oral SINE compound, which is currently being investigated in clinical trials. Eltanexor functions by binding to and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. Eltanexor has demonstrated minimal brain penetration in animals, which has been associated with reduced toxicities in preclinical studies while maintaining potent anti-tumor effects.
About
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 Karyopharm’s expectations relating to XPOVIO for the treatment of patients with heavily pretreated multiple myeloma, commercialization of XPOVIO or any of its drug candidates, submissions to, and the review and potential approval of selinexor by, regulatory authorities, including the anticipated availability of data to support such submissions, timing of such submissions and actions by regulatory authorities and the potential availability of accelerated approval pathways, and the therapeutic potential of and potential clinical development plans for Karyopharm's drug candidates, especially 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; that regulators will agree that selinexor qualifies for conditional approval in the E.U. as a result of data from the STORM study or confirmatory approval in the U.S. or EU based on the
Velcade® is a registered trademark of
Revlimid® and Pomalyst® are registered trademarks of
Kyprolis® is a registered trademark of
Contacts:
Investors:
857-297-2241 | ikarp@karyopharm.com
Media:
Simona Kormanikova or Robert Stanislaro
212-850-5600 | Simona.Kormanikova@fticonsulting.com or robert.stanislaro@fticonsulting.com
Source: Karyopharm Therapeutics Inc.