Summary Basis of Decision for Xpovio
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Xpovio is located below.
Recent Activity for Xpovio
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
The following table describes post-authorization activity for Xpovio, a product which contains the medicinal ingredient selinexor. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the 
Management of Drug Submissions and Applications Guidance.
Updated: 2023-07-17
Drug Identification Number (DIN):
DIN 02527677 - 20 mg selinexor, tablet, oral administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02527677) market notification | Not applicable | Date of first sale: 2022-07-07 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 253182 | 2021-05-28 | Issued NOC 2022-05-31 | NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Xpovio
Date SBD issued: 2022-10-12
The following information relates to the New Drug Submission for Xpovio.
Selinexor
Drug Identification Number (DIN):
- DIN 02527677 - 20 mg selinexor, tablet, oral administration
FORUS Therapeutics Inc.
New Drug Submission Control Number: 253182
On May 31, 2022, Health Canada issued a Notice of Compliance to FORUS Therapeutics Inc. for the drug product Xpovio. The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit‑harm-uncertainty profile of Xpovio is favourable in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
1 What was approved?
Xpovio, an antineoplastic agent, was authorized in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
Xpovio is not authorized for use in pediatric patients (younger than 18 years of age), as no data are available to Health Canada for this population.
No overall differences in effectiveness were observed between geriatric patients (65 years of age or older) and those younger than 65 years of age. A higher incidence of treatment discontinuation due to an adverse reaction and a higher incidence of serious adverse reactions were observed in geriatric patients in comparison to those younger than 65 years of age.
The use of Xpovio is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Xpovio (20 mg selinexor) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains colloidal silicon dioxide, croscarmellose sodium, FD&C Blue No.2/Indigo Carmine Aluminum Lake, FD&C Blue No.1 Brilliant Blue FCF Aluminum Lake, glycerol monostearate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, polyvinyl alcohol-partially hydrolyzed, polyvinylpyrrolidone, sodium lauryl sulfate, talc, and titanium dioxide.
The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Xpovio Product Monograph is available through the Drug Product Database.
For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
2 Why was Xpovio approved?
Health Canada considers that the benefit-harm-uncertainty profile of Xpovio is favourable in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
Multiple myeloma is a hematologic cancer characterized by proliferation of clonal plasma cells in the bone marrow, resulting in an overabundance of monoclonal paraprotein. This can lead to cytopenias, bone pain and fracture, hypercalcemia, and renal dysfunction. Multiple myeloma accounts for approximately 10% of all hematologic malignancies. It is largely a disease of the elderly, with a median age at diagnosis of 70 years. In 2021, in Canada, it was estimated that there were 3,800 new cases of multiple myeloma and 1,620 deaths from the disease. Approximately 10 people in Canada are diagnosed with multiple myeloma each day.
Despite the approval of a variety of novel agents in recent years, multiple myeloma remains an incurable and fatal disease, as it inevitably relapses following therapy and becomes refractory to treatment. At each relapse, multiple myeloma typically recurs more aggressively and the choice of treatment is determined by patient-specific factors, tumor characteristics, and prior therapy. Given the complex and multifactorial treatment of relapsed and refractory multiple myeloma, a single standard of care is difficult to define. With at least seven different classes of approved agents, which can be combined in doublet, triplet or even quadruplet regimens, many patients will undergo treatment with all the major anti-myeloma drug classes in the first- and second-line settings, leaving no therapies with a novel mechanism of action in the relapsed or refractory setting.
Selinexor, the medicinal ingredient in Xpovio, is a first-in-class selective inhibitor of the nuclear export protein exportin 1 (XPO1). In non-clinical settings, selinexor reversibly inhibits nuclear export of tumor suppressor proteins, growth regulators, and messenger ribonucleic acids (mRNAs) of growth promoting (oncogenic) proteins by specifically blocking XPO1. Inhibition of XPO1 by selinexor leads to marked accumulation of tumor suppressor proteins in the nucleus, cell cycle arrest, reductions in several oncoproteins such as c-Myc and cyclin D1, and apoptosis of cancer cells. The combination of selinexor and dexamethasone has demonstrated activity and synergy both in cell lines and in patients with disease that is refractory/resistant to dexamethasone and proteasome inhibitors, including when proteasome inhibition is present. The combination of selinexor and bortezomib has been evaluated in cells and murine xenograft multiple myeloma models in vivo, including cells and models resistant to proteasome inhibitors.
The efficacy and safety of Xpovio in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma was evaluated in the pivotal Phase III BOSTON study (KCP-330-023). This randomized, active comparator-controlled, open-label study assessed the efficacy of Xpovio (selinexor), bortezomib, and dexamethasone (the SVd treatment arm) versus bortezomib and dexamethasone (the Vd treatment arm) in patients 18 years of age and older who had received one to three prior anti-multiple myeloma regimens. Following confirmation of progressive disease, patients were enrolled and randomized in a 1:1 ratio to one of two treatment arms (SVd or Vd). Upon confirmation of progressive disease on Vd therapy, patients were allowed to cross over to receive SVd treatment or selinexor and dexamethasone for those patients who were intolerant to bortezomib.
The assessment of efficacy was based on the intent-to-treat population of 402 patients. The median age of patients was similar in both treatment arms (SVd arm: 66 years; Vd arm: 67 years).The majority of patients were 65 years of age or older (SVd arm: 55.9%; Vd arm: 63.8%) when enrolled. More males (SVd arm: 59.0%; Vd arm: 55.6%) were enrolled in the study than females and patients were predominantly White (SVd arm: 82.6%; Vd arm: 79.7%). The baseline Eastern Cooperative Oncology Group performance status score was 0 to 1 for 89.7% and 92.3% of patients in the SVd and Vd arms, respectively. Upon confirmation of progressive disease, 74 (36%) patients crossed over from the Vd treatment arm to receive a regimen that included selinexor.
The primary efficacy endpoint of the BOSTON study was progression-free survival (PFS) according to the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma, as assessed by an Independent Review Committee. In the efficacy population (number of patients [n] = 402), the median PFS was 13.93 months (95% confidence interval [CI]: 11.73, non-estimable [NE]) in the SVd arm and 9.46 months (95% CI: 8.11, 10.78) in the Vd arm (p = 0.0075; hazard ratio [HR] = 0.7020). The overall response rate, a key secondary endpoint, was 76.4% (95% CI: 69.8, 82.2) in the SVd arm and 62.3% (95% CI: 55.3, 68.9) in the Vd arm. In addition, the rate of deep responses (≥ very good partial response) in the SVd arm was higher (44.6%) compared to the Vd arm (32.4%). Another key secondary endpoint was the incidence of any Grade 2 or higher peripheral neuropathy events in patients randomized to the SVd arm versus the Vd arm. The overall incidence of Grade 2 or higher peripheral neuropathy events was significantly lower in the SVd arm compared to the Vd arm (21.0% versus 34.3%; p = 0.0013).
The most common (>20%) treatment-emergent adverse events (TEAEs) in the SVd arm, which occurred at a higher frequency compared to the Vd arm, were thrombocytopenia (60.0%), nausea (50.3%), fatigue (42.1%), anemia (36.4%), decreased appetite (35.4%), diarrhea (32.3%), decreased weight (26.2%), asthenia (24.6%), cataract (21.5%), and vomiting (20.5%). Peripheral neuropathy was the most frequently reported TEAE in the Vd arm (47.1%) compared to the SVd arm (32.3%). Serious adverse events (SAEs) were reported in 44.6% of patients (51.8% of patients in the SVd arm and 37.7% of patients in the Vd arm). Pneumonia was the most commonly reported SAE with a similar incidence in both arms (14.4% of patients in the SVd arm versus 12.7% of patients in the Vd arm).
There is a potential for drug-drug interactions between selinexor and cytochrome P450 (CYP) 3A4 inhibitors or inducers. Concomitant use of a strong CYP3A4 inducer may lead to lower exposure of selinexor. Patients should be monitored closely when initiating therapy with concomitant moderate or strong modulators of CYP3A4.
A food-effect and bioequivalence study showed that concomitant administration of a high-fat meal (800 to 1,000 calories with approximately 50% of total caloric content of the meal being from fat) or a low-fat meal (500 to 600 calories with approximately 20% of total caloric content from fat) did not have a clinically significant effect on the pharmacokinetics of selinexor. This study supported the recommendation that selinexor can be taken with or without food.
A Risk Management Plan (RMP) for Xpovio was submitted by FORUS Therapeutics Inc. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable.
The submitted inner and outer labels, package insert, and Patient Medication Information section of the Xpovio Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements. The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Xpovio was accepted.
Overall, based on the submitted non-clinical and clinical information, Xpovio has been shown to have a favourable benefit-harm-uncertainty profile in adult patients with relapsed and refractory multiple myeloma who have received at least one prior therapy. The identified safety issues can be managed through labelling, adequate monitoring, and dose modifications. Appropriate warnings and precautions are in place in the Xpovio Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Xpovio?
The review of the New Drug Submission (NDS) for Xpovio was based on a critical assessment of the data package submitted to Health Canada and of the foreign reviews completed by the United States Food and Drug Administration, the European Medicines Agency, and Australia's Therapeutic Goods Administration as described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. Method 3 was used for the review of quality and clinical efficacy and safety components, and Method 1 for the review of non-clinical components of the submission.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Xpovio
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2021-04-13 |
| New Drug Submission filed | 2021-05-28 |
| Screening | |
| Screening Deficiency Notice issued | 2021-07-16 |
| Response to Screening Deficiency Notice filed | 2021-07-20 |
| Screening Acceptance Letter issued | 2021-08-06 |
| Review | |
| Biostatistics evaluation completed | 2022-01-28 |
| Non-clinical evaluation completed | 2022-05-11 |
| Review of Risk Management Plan completed | 2022-05-20 |
| Quality evaluation completed | 2022-05-26 |
| Labelling review completed | 2022-05-30 |
| Clinical/medical evaluation completed | 2022-05-31 |
| Notice of Compliance issued by Director General, Pharmaceutical Products Directorate | 2022-05-31 |
4 What follow-up measures will the company take?
In addition to requirements outlined in the Food and Drugs Act and Regulations, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. Commitments include (but are not limited to) submitting:
- The final clinical study report for the BOSTON study (KCP-330-023)
- The pharmacokinetic results for selinexor from an ongoing drug-drug interaction study (NCT02343042) in patients receiving a strong CYP3A4 inhibitor (clarithromycin)
- The pharmacokinetic and safety results from a dedicated hepatic impairment study (KCP-330-027) of selinexor in patients with moderate and severe hepatic impairment.
6 What other information is available about drugs?
Up-to-date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
As described above, the clinical review of the New Drug Submission for Xpovio was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Clinical Pharmacology
The clinical pharmacology of selinexor, the medicinal ingredient in Xpovio, has been investigated in eight clinical studies conducted in patients with hematologic malignancies and advanced solid tumors. The pharmacokinetics of selinexor has been characterized through four population pharmacokinetic analyses based on data from 801 patients.
Selinexor has a linear pharmacokinetics that is not affected by cancer type. Selinexor exhibited dose-proportional exposures (as measured by the area under the concentration-time curve [AUC] and the maximum plasma concentration [Cmax]) across a dose range of 3 to 85 mg/m2 (approximately 5 to 150 mg), with moderate interindividual variability of approximately 20%. At the target dose of 100 mg, the mean Cmax was 693 ng/mL and the AUC from the time of dosing extrapolated to infinity (AUC0-∞) was 6,998 ng ng•h/mL; time to peak plasma concentration (Tmax) was 2 hours and the mean terminal half-life (t1/2) was 6 hours. The absolute bioavailability of selinexor has not been studied in humans.
Concomitant administration of a high-fat meal (800 to 1,000 calories with approximately 50% of the total caloric content being from fat) did not have a clinically significant effect on the pharmacokinetics of selinexor. Selinexor is 95% bound to human plasma proteins.
Selinexor is metabolized by cytochrome P450 (CYP) 3A4, multiple uridine 5'-diphospho-glucuronosyltransferases, and glutathione S‑transferases. A major metabolite had a plasma concentration of less than 5% of the parent drug concentration and is not expected to be a significant factor in the pharmacological profile of selinexor, accounting for approximately 10% of the exportin 1 (XPO1) inhibition activity of selinexor. Most of the other metabolites were inactive against XPO1 and occurring at less than 1% of parent drug concentrations.
No dedicated clinical drug interaction studies have been conducted. There is a potential for drug-drug interactions between selinexor and CYP3A4 inhibitors or inducers. Concomitant use of a strong CYP3A4 inducer might lead to lower exposure of selinexor. Patients should be closely monitored for safety and efficacy when initiating therapy with concomitant moderate or strong modulators of CYP3A4.
The impact of body weight (less than a 20% change in the AUC) and sex (less than a 10% change in the AUC) on the pharmacokinetics of selinexor was moderate and modest. Age and race had no clinically significant effect on the pharmacokinetics of selinexor. The population mean estimate of apparent total clearance and apparent central volume of distribution was 18.6 L/h and 113 L, respectively.
The recommended starting dose of Xpovio is 100 mg (five 20 mg tablets) taken orally once weekly on Day 1 of each week along with bortezomib 1.3 mg/m2 administered subcutaneously once weekly on Day 1 of each week for 4 weeks, followed by 1 week off, and dexamethasone 20 mg taken orally twice weekly on days 1 and 2 of each week in a 35‑day cycle.
No dose adjustment for Xpovio is recommended for patients with renal impairment. There are limited data to determine the best dosing options for patients with moderate or severe hepatic impairment; these patients should be closely monitored for safety and efficacy.
Based on exposure-QT analysis, no clinically relevant QT prolongation is expected at the recommended therapeutic dose of 100 mg.
Overall, the clinical pharmacology data support the use of Xpovio in combination with bortezomib and dexamethasone for the specified indication.
For further details, please refer to the Xpovio Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy and safety of Xpovio (selinexor) in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma was evaluated in the pivotal Phase III BOSTON study (KCP-330-023). This randomized, active comparator-controlled, open-label study assessed the efficacy of Xpovio, bortezomib, and dexamethasone (the SVd treatment arm) versus bortezomib and dexamethasone (the Vd treatment arm) in patients 18 years of age and older who had received one to three prior anti-multiple myeloma regimens. Following confirmation of progressive disease, patients were enrolled and randomized in a 1:1 ratio to one of two treatment arms (SVd or Vd). Randomization was stratified based on prior proteasome inhibitor therapies (Yes or No), number of prior anti-multiple myeloma regimens (1 versus >1), and disease stage (Stage III versus I or II; according to the Revised International Staging System by the International Myeloma Working Group [IMWG]). Upon confirmation of progressive disease on Vd therapy, patients were allowed to cross over to receive SVd treatment or selinexor and dexamethasone for those patients who were intolerant to bortezomib.
Patients enrolled in the study had histologically confirmed multiple myeloma with measurable disease by conventional measurements of paraprotein in the serum or urine, or by measurements of free light chain in the serum. Prior treatment with bortezomib or another proteasome inhibitor was allowed. Eligible patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of less than or equal to 2 and adequate hepatic, renal, and hematopoietic functions. Patients were excluded if they had systemic light chain amyloidosis, central nervous system involvement, or neuropathy (Grade >2) or neuropathy (Grade ≥2) with pain at baseline. Treatment continued in both arms until progressive disease or unacceptable toxicity occurred. Data analyses were completed at two points: February 18, 2020 (primary analysis) and February 15, 2021 (updated ad hoc analysis). The results of the primary analysis are presented below.
The assessment of efficacy was based on the intent-to-treat (ITT) population of 402 patients. The median age of patients was similar in both treatment arms (SVd arm: 66 years; Vd arm: 67 years). The majority of patients were 65 years of age or older (SVd arm: 55.9%; Vd arm: 63.8%) when enrolled. More males (SVd arm: 59.0%; Vd arm: 55.6%) were enrolled in the study than females and patients were predominantly White (SVd arm: 82.6%; Vd arm: 79.7%). Baseline ECOG performance status score was 0 to 1 for 89.7% and 92.3% of patients in the SVd and Vd arms, respectively. Upon confirmation of progressive disease, 74 (36%) patients crossed over from the Vd arm to receive a regimen that included selinexor.
The primary efficacy endpoint of the BOSTON study was progression-free survival (PFS) according to the IMWG Uniform Response Criteria for Multiple Myeloma, as assessed by an Independent Review Committee. In the efficacy population (number of patients [n] = 402), the median PFS was 13.93 months (95% CI: 11.73, non-estimable [NE]) in the SVd arm and 9.46 months (95% CI: 8.11, 10.78) in the Vd arm (p = 0.0075; hazard ratio [HR] = 0.7020). Improvement in PFS in the SVd arm was maintained during all sensitivity analyses other than when treatment discontinuation for any reason was counted as a PFS event. Exploratory subgroup analyses for PFS were performed for age, prior proteasome inhibitor treatment, and renal function. The results were supportive of the overall ITT PFS analysis results. However, the study was not statistically powered to make robust statements about subgroups, as some subgroups had very small sample sizes.
The overall response rate, a key secondary endpoint, was 76.4% (95% CI: 69.8, 82.2) in the SVd arm and 62.3% (95% CI: 55.3, 68.9) in the Vd arm. In addition, the rate of deep responses (≥ very good partial response) in the SVd arm was higher (44.6%) compared to the Vd arm (32.4%).
Patients in the SVd arm had a numerically longer, albeit not statistically significant, duration of response (DOR) compared to Vd arm. The median DOR in patients with confirmed partial response (PR) or better was 20.3 months (95% CI: 12.55, NE) in the SVd arm and 12.9 months (95% CI: 9.26, 15.77) in the Vd arm (p = 0.1364, stratified log-rank test).
Another key secondary endpoint was the incidence of any Grade 2 or higher peripheral neuropathy events in patients randomized to the SVd arm versus the Vd arm. The overall incidence of peripheral neuropathy events (Grade ≥2) was significantly lower in the SVd arm compared to the Vd arm (21.0% versus 34.3%; p = 0.0013). The proportion of patients who experienced severe (Grade 3/4) peripheral neuropathy was nearly twice as high in the Vd arm (8.8%) compared to the SVd arm (4.6%). Despite this improvement, peripheral neuropathy remained the most common cause of study treatment discontinuation in both arms, with a higher incidence in the Vd arm (7.4%) compared with the SVd arm (4.6%).
The median overall survival (OS) was not reached for the SVd arm and was 24.97 months (95% CI: 23.49, NE) in the Vd arm (p = 0.1852). Although some subgroups were too small for meaningful analysis, the results of subgroup analyses for OS suggest favourable, though not statistically significant, results for most subgroups studied. Despite the numerically longer OS of patients in the SVd arm, the interpretability of the results are uncertain due to immature data and the fact that patients were allowed to cross over, which contaminates OS data. A sensitivity analysis of OS was conducted to assess the effect of treatment with SVd compared to Vd on OS, if patients treated with Vd had not crossed over to receive SVd treatment or to receive selinexor and dexamethasone. A switch-adjusted HR value of 0.77 (95% CI: 0.52, 1.14) for OS based on the two-stage estimation method was reported.
A key issue with the efficacy assessment was the choice of control group in the BOSTON study. The two-drug regimen of bortezomib and dexamethasone (Vd) is considered an inferior control group as compared to the current standard of care, according to the National Comprehensive Cancer Network (NCCN) Guidelines for Multiple Myeloma, Version: 5.2022. However, the sponsor provided the rationale that the Vd doublet regimen was listed as a preferred therapy in the NCCN 2016 guidelines at the time of the BOSTON study design, and the study protocol was approved by the United States Food and Drug Administration and European Union Committee for Medicinal Products. Furthermore, using Vd as the comparator arm allows for evaluation of the addition of a third drug (selinexor) and is consistent with the pivotal trials supporting the approval of the combination regimen of pomalidomide, bortezomib, and dexamethasone and the combination regimen of daratumumab, bortezomib, and dexamethasone.
Additionally, there are concerns with respect to patient demographics. For enrollment in the BOSTON trial, patients were required to have an ECOG performance status score of 2 or greater and adequate hepatic, renal, and hematopoietic functions. Given the study population, it is uncertain whether the PFS benefits and reported safety profile would extend to patients with poor performance status. Furthermore, of the 402 patients enrolled in the BOSTON trial, only 36 patients were from North America and only 11 were Black/African American. However, the sponsor provided pharmacokinetic analyses which do not reveal any significant differences in the pharmacokinetics of selinexor between Black/African American and White patients.
Overall, Xpovio (selinexor), in combination with bortezomib and dexamethasone, has been found to be favourable for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
Indication
The New Drug Submission for Xpovio was filed by the sponsor with the following indication, which Health Canada subsequently approved:
- Xpovio (selinexor) is indicated in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
For more information, refer to the Xpovio Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The primary safety assessment of Xpovio (selinexor) in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma was based on comparison of the safety data between the SVd and Vd treatment arms (prior to crossover) in the BOSTON study (see Clinical Efficacy). The safety population consisted of 399 patients (195 patients in the SVd arm and 204 patients in the Vd arm) who received at least one dose of their assigned treatment.
Treatment-emergent adverse events (TEAEs) occurred in 98.2% of patients. The proportion of patients experiencing a TEAE was comparable between the SVd arm (99.5%) and the Vd arm (97.1%). The most common (>20%) TEAEs in the SVd arm, which occurred at a higher frequency compared to the Vd arm, were thrombocytopenia (60.0%), nausea (50.3%), fatigue (42.1%), anemia (36.4%), decreased appetite (35.4%), diarrhea (32.3%), decreased weight (26.2%), asthenia (24.6%), cataract (21.5%), and vomiting (20.5%). Peripheral neuropathy was the most frequently reported TEAE in the Vd arm (47.1%) compared to the SVd arm (32.3%).
Serious adverse events (SAEs) were reported in 44.6% of patients (51.8% of patients in the SVd arm and 37.7% of patients in the Vd arm). Pneumonia was the most commonly reported SAE with a similar incidence in both arms (14.4% of patients in the SVd arm versus 12.7% of patients in the Vd arm). As there were no meaningful differences between the treatment arms in the occurrence rates of pneumonia, its severity and duration, the types of causative microorganisms, and because of the lack of association with neutropenia, it appears that Xpovio does not increase the risk of pneumonia in this population.
At the time of the primary analysis, among the 399 patients, 109 (27%) had died: 47 (11.7%) patients from the SVd arm and 62 (15.4%) patients from the Vd arm. The most common cause of death was progressive disease in both the SVd (25 patients out of 47 [53%]) and Vd arm (29 patients out of 62 [47%]). Death due to TEAE occurred in 5.8% of all patients (6.2% of patients in the SVd arm and 5.4% of patients in the Vd arm).
Treatment-emergent adverse events leading to study treatment modification, dose reduction, dose interruption, and permanent study treatment discontinuation occurred in 82.2%, 63.4%, 76.7%, and 18.3% of all patients, respectively. Peripheral neuropathy was the most common cause of discontinuation in both arms (4.6% of patients in the SVd arm and 7.4% of patients in the Vd arm). Other TEAEs leading to discontinuation of study treatment occurring in 4 or more patients were fatigue (3.6% versus 0.5%), nausea (3.1% versus 0%), decreased appetite (2.1% versus 0.5%), thrombocytopenia (2.1% versus 0.5%), vomiting (2.1% versus 0%), and asthenia (1.0% versus 1.0%) in the SVd arm versus the Vd arm, respectively.
Shifts to Grade 3/4 in hematological parameters were generally more frequent in the SVd arm compared to the Vd arm. This difference was substantial for thrombocytopenia and leukopenia; however, the higher incidences of Grade 3/4 thrombocytopenia and leukopenia were not associated with a notable increase in the incidences of clinically significant bleeding events and clinically significant infections. The most common Grade 3/4 laboratory abnormalities in the SVd arm were thrombocytopenia (42.6%), lymphocytopenia (38.3%), anemia (16.9%), neutropenia (11.2%), and leukopenia (10.3%).
Thrombocytopenia was the most frequently reported TEAE in the BOSTON study. In the primary analysis, the incidence of a TEAE of thrombocytopenia as reported by the investigator was 60% in the SVd arm compared to 27% in the Vd arm. However, the frequency of laboratory abnormalities of thrombocytopenia (shift to any grade) irrespective of whether or not a TEAE was reported by the investigator was 92%. The incidence of Grade 3/4 TEAEs of thrombocytopenia was 43% in the SVd arm versus 19% in the Vd arm. The incidence of SAEs of thrombocytopenia was low in both arms (1.5% in the SVd arm and 0.5% in the Vd arm). Among the patients with Grade 3 or higher thrombocytopenia, clinically significant (Grade ≥3) bleeding events were uncommon and reported in 4 (5.2%) patients in the SVd arm and 2 (5.7%) patients in the Vd arm.
The majority of thrombocytopenia TEAEs were managed by dose modifications (39% in the SVd arm and 9.8% in the Vd arm) and very few patients discontinued treatment due to thrombocytopenia (2.1% in the SVd arm versus 0.5% in the Vd arm). Supportive care for thrombocytopenia included treatment with thrombopoietin (TPO) receptor agonists and platelet transfusions. Thrombopoietin receptor agonists were given to 29.3% of patients in the SVd arm and 4.5% of patients in the Vd arm. Platelet transfusions were given mostly to patients with Grade 4 events; in total, 12 patients in the SVd arm and 13 patients in the Vd arm received platelet transfusions. Treatment with TPO receptor agonists was shown to reduce the duration of thrombocytopenia and permit a higher intensity of post-event SVd treatment. However, treatment with TPO receptor agonists may be more difficult to access as they are currently not authorized in Canada for the treatment of chemotherapy-induced thrombocytopenia.
As of the primary analysis, the incidence of nausea in the SVd and Vd treatment arms was 50.3% and 9.8%, respectively. Although frequent, nausea was typically mild and manageable with supportive care and dose reductions and interruptions. Treatment discontinuation was seldom required. In the SVd arm, 88.2% of patients were given serotonin (5‑HT3) antagonists prophylactically, which significantly shortened the median duration of nausea as compared to the patients who did not receive any supportive care (5.0 days versus 21.0 days).
Cataracts were identified as an adverse event of clinical interest. Based on ophthalmologic exams, the occurrence of new cataracts was seen in 24% of patients in the SVd arm and 8.5% of patients in the Vd arm. The majority of patients in both arms with new onset cataracts developed a combination of nuclear, cortical, and subcapsular cataracts that occurred after 7 months of treatment. In the SVd arm, 21.5% of patients had at least one TEAE of cataract reported as compared to 6.4% of patients in the Vd arm. Grade 3/4 and Grade 4 cataracts were reported in 8.7% and 0%, respectively, of patients in the SVd treatment arm and 1.5% and 1.5%, respectively, of patients in the Vd arm. Dose modification due to cataracts was reported for 3.6% of patients in the SVd arm. No patient in either arm discontinued treatment due to cataracts and no patient developed blindness due to cataracts.
No new safety signals were identified in the Integrated Assessment of Safety, where safety results were pooled for all patients who received at least one dose of SVd in either the BOSTON study (including those who were initially randomized to Vd and crossed over to SVd) or a supportive Phase Ib/II STOMP study. In the updated analysis, this pooled group included 301 patients: 195 patients from the SVd arm of the BOSTON study, 64 patients from the BOSTON crossover arm, and 42 patients from the supportive STOMP study.
Overall, based on the information reviewed, the safety profile of SVd therapy appears acceptable for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. The identified safety issues can be managed through labelling, adequate monitoring, and dose modifications.
Appropriate warnings and precautions are in place in the approved Xpovio Product Monograph to address the identified safety concerns
For more information, refer to the Xpovio Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
As described above, the review of the non-clinical component of the New Drug Submission for Xpovio was conducted as per Method 1 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Selinexor, the medicinal ingredient in Xpovio, is a first-in-class, oral, potent, slowly reversible, covalent-binding selective inhibitor of nuclear export that specifically blocks exportin 1 (XPO1). Inhibition of XPO1 by selinexor was demonstrated in vitro using cell-based assays. Selinexor showed potent proapoptotic activity across a panel of tumor-derived cell lines and patient samples in culture, through the induction of XPO1 messenger ribonucleic acid (mRNA) and through its high selectivity for malignant cells. Selinexor inhibited proliferation of several multiple myeloma tumor cell lines, and showed dose-dependent antitumor activity in mouse xenograft models at clinically relevant doses. The combination of selinexor and dexamethasone was found to have a synergistic effect on apoptosis relative to either drug alone. At effective doses, selinexor alone and the combination of selinexor and dexamethasone showed selective cytotoxicity to tumor cells while sparing normal hematopoietic cells in vitro.
Pharmacology studies assessing the safety of selinexor did not identify undesirable cardiovascular, respiratory, or central nervous system effects when administered as a single dose. Cardiovascular endpoints were assessed in 4‑ and 13‑week repeat-dose toxicology studies. In vitro selectivity of selinexor showed no binding and/or functional activity against 112 receptors and enzymatic targets, including those with a cysteine-active site.
In single-dose toxicity studies, the maximum tolerated dose of selinexor was 100 mg/kg across both genders in rats. In repeat-dose toxicity studies in rats, the lowest no-observed-adverse-effect level (NOAEL) was 2 mg/kg, which is approximately 0.2‑fold lower than human exposure based on the area under the concentration-time curve (AUC) at the 100 mg dose. In repeat-dose toxicity studies in monkeys, the lowest NOAEL was 1 mg/kg (comparable to human exposure based on the AUC at the 100 mg dose). Toxicities observed included decreased weight, loss of appetite, hematologic changes, and histopathological changes in testes/epididymides, bone marrow, ovaries, uterus, thymus, and lymphoid organs.
Oral administration of selinexor in pregnant rats induced maternal toxicity and effects on embryonic development. The NOAEL for maternal toxicity and embryo-fetal developmental toxicity was 0.25 mg/kg/day, corresponding to approximately 0.02-fold the human exposure associated with a 100 mg dose. Based on these animal data, selinexor has the potential to cause fetal harm if administered to a pregnant woman.
Selinexor does not have the potential for phototoxicity based on absorption of light within the range of sunlight and results from in vitro assays in mouse fibroblasts. No in vivo studies were conducted.
Selinexor was considered highly permeable based on an in vitro assay. Bioavailability was moderately high at 61% to 68% across non-clinical species. Selinexor was rapidly absorbed in systemic circulation and exhibited high permeability in vitro. In the presence of food, the absorption was slightly higher and prolonged.
Selinexor was rapidly distributed to tissues, with a mean blood-to-plasma ratio range of 0.63 to 0.90 in non-clinical species. The highest concentrations were found in the small intestine, kidney (all sections), stomach, and liver.
Protein binding is moderately high in mice, rats, monkeys, and human plasma (approximately 95%), and relatively low in dogs (approximately 54%). No concentration dependence was observed for plasma protein binding. Based on a blood-to-plasma partition study, selinexor was not sequestered into red blood cells.
Selinexor is extensively metabolized. Phase 1 metabolism is dependent on cytochrome p450 (CYP) 3A. Phase 2 metabolism involves UDP-glucuronosyltransferases and glutathione S-transferases, and results in the formation of glucuronide and glutathione-related conjugates in rats and monkeys. Selinexor is eliminated by the hepatobiliary route in feces with minimal excretion in urine.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Xpovio Product Monograph. In view of the intended use of Xpovio, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.
For more information, refer to the Xpovio Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
As described above, the review of the quality component of the New Drug Submission for Xpovio was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
The chemistry and manufacturing information submitted for Xpovio has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 48 months is acceptable when the drug product is stored at 2 ºC to 30 ºC.
Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies).
All sites involved in production are compliant with good manufacturing practices.
None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.
There are no excipients of human or animal origin in the formulation of Xpovio.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| XPOVIO | 02527677 | FORUS THERAPEUTICS INC. | SELINEXOR 20 MG |