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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.

July 3, 2019, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212306s000lbl.pdf

On July 3, 2019 the U.S. Food and Drug Administration granted accelerated approval to Selinexor (Xpovio tablets) in combination with the corticosteroid dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

“While there is no cure for multiple myeloma, there are FDA-approved treatments to target the cancer and slow down the spread of the disease. Sadly, often over time, patients can exhaust all available treatments and still see their disease progress,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today we approved a treatment under our accelerated approval program that provides a treatment option for patients with multiple myeloma with no available therapy.”

Multiple myeloma is cancer that begins in plasma cells (white blood cells that produce antibodies) and may also be referred to as plasma cell myeloma. Abnormal plasma cells build up in the bone marrow, forming tumors in many bones of the body. As more antibodies are made, it can cause blood to thicken and keep the bone marrow from making enough healthy blood cells. The exact causes of multiple myeloma are unknown, but it is more common in older people and African Americans.

Efficacy was evaluated in 83 patients with RRMM who were treated with Xpovio in combination with dexamethasone. At the end of the study, the overall response rate was measured at 25.3%. The median time to first response was four weeks, with a range of one to ten weeks. The median duration of response was 3.8 months. The efficacy evaluation was supported by additional information from an ongoing, randomized trial in patients with multiple myeloma.

Common side effects of patients taking Xpovio in combination with dexamethasone include a low white blood cell count (leukopenia), a low count of neutrophils, a type of white blood cell (neutropenia), low count of platelets (thrombocytopenia) and low amount of red blood cells (anemia). Patients also reported vomiting, nausea, fatigue, diarrhea, fever, decreased appetite and weight, constipation, upper respiratory tract infections and low blood sodium levels (hyponatremia).

View full prescribing information for XPOVIO.

Health care professionals are advised to monitor patients for low blood counts, platelets and sodium levels. Patients should avoid taking Xpovio with other medications that may cause dizziness or confusion and avoid situations where dizziness may be a problem. Health care professionals are advised to optimize the patient’s hydration status, blood counts and other medications to avoid dizziness or confusion. The FDA advises health care professionals to tell females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment with Xpovio. Women who are pregnant or breastfeeding should not take Xpovio because it may cause harm to a developing fetus or newborn baby. Xpovio must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

Xpovio in combination with dexamethasone was granted accelerated approval, which enables the FDA to approve drugs for serious conditions to fill an unmet medical need based on an endpoint that is reasonably likely to predict a clinical benefit to patients. Further clinical trials are required to verify and describe Xpovio’s clinical benefit.

The FDA granted this application Fast Track designation. Xpovio also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The FDA granted the approval of Xpovio to Karyopharm Therapeutics.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Selinexor for the Treatment of Adult Patients with Relapsed or Refractory Multiple Myeloma Who Have Received at Least Four Prior Therapies and Whose Disease Is Refractory to at Least Two Proteasome Inhibitors, at Least Two Immunomodulatory Agents, and an anti-CD38 Monoclonal Antibody

Author: Kirollos S. Hanna, PharmD BCOP BCPS
Assistant Professor of Pharmacy, Mayo Clinic College of Medicine
Hematology/Oncology Clinical Pharmacist, University of Minnesota Medical Center
Minneapolis, MN

What is the potential role for selinexor in the treatment of multiple myeloma?

  • Selinexor is the first exportin 1 (XPO1) inhibitor approved in combination with dexamethasone for adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors (PIs), at least two immunomodulatory agents (IMiDs), and an anti-CD38 monoclonal antibody.1
  • The selection of treatment for patients with multiple myeloma (MM) is often dictated by their transplant eligibility, disease risk factors, and overall health. Frontline therapy for both transplant-eligible and transplant-ineligible patients is often composed of triplet therapy with a PI, an IMiD, and a steroid.2 The National Comprehensive Cancer Network Multiple Myeloma Panel prefers triplet therapy over doublet therapy as the standard of care for all patients because of improved response rates, depth of response, and rates of progression free-survival (PFS) and overall survival (OS).
    • Recent data have demonstrated the efficacy of incorporating anti-CD38 monoclonal antibodies in the frontline setting with select myeloma regimens regardless of the patient’s transplant eligibility.3,4
    • Despite effective therapies throughout various stages of the disease, MM remains incurable, and the 5-year survival rate is 52.2% (2009–2015 data).5 Throughout the disease course, patients (especially those with high-risk disease) may undergo treatment with numerous lines of therapy and various combinations.
  • Novel drug mechanisms and therapeutic combinations continue to be evaluated, with the aim of optimizing treatment outcomes and safety for patients throughout all stages of disease.6-8
    • An example is XPO1 inhibition with selinexor, leading to an accumulation of tumor suppressor proteins (in the nucleus), oncoprotein reduction, cell cycle arrest, and cancer cell apoptosis.1
  • The combination of selinexor and dexamethasone was evaluated in the multicenter, single-arm, open-label STORM Trial.9
    • Eligible patients had measurable MM according to International Myeloma Working Group (IMWG) criteria; had previously received treatment with bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, glucocorticoids, and an alkylating agent; and had disease refractory to at least one IMiD, one PI, daratumumab, glucocorticoids, and their most recent regimen. An Eastern Cooperative Oncology Group performance-status score of 0 to 2 and adequate hepatic function, renal function, and hematopoietic function were also required for enrollment.
    • Patients received oral selinexor 80 mg in combination with dexamethasone 20 mg weekly on days 1 and 3 in 4-week cycles until disease progression, death, or discontinuation of the drug.
      • All patients were required to receive 8 mg of ondansetron (or equivalent) before the first dose of the study drug and 2 or 3 times daily as needed.
    • The primary endpoint was overall response (OR), defined as a confirmed partial response (PR) or better. Secondary endpoints included response duration; clinical benefit, defined as a confirmed minimal response or better; PFS; and OS.
    • Results
      • Intent-to-treat population: n = 122; PR or better = 26% (95% confidence interval [CI], 19–35); 2 stringent complete responses (in 2% of the patients), 6 very good partial responses (in 5%), and 24 partial responses (in 20%).
      • Minimal response according to IMWG criteria was observed in 16 patients (13%), and 48 patients (39%) had stable disease, whereas 26 (21%) had progressive disease or disease that could not be evaluated for response. A minimal response or better was observed in 39% of patients (95% CI, 31–49).
      • Median time to a PR or better = 4.1 weeks (range, 1–14).
      • Median duration of response = 4.4 months (95% CI, 3.7–10.8).
      • Median PFS = 3.7 months (95% CI, 3.0–5.3).
      • Median OS = 8.6 months (95% CI, 6.2–11.3).
      • In patients who had a PR or better or a minimal response or better, the median OS was 15.6 months.
      • Of note, the lower boundary of the confidence interval was more than 10% in this trial, which led to its meeting the primary endpoint.
    • Adverse effects (over 20%; any grade)
      • Thrombocytopenia (74%; grades 3 or greater: 61%), fatigue (73%), nausea (72%), anemia (59%; grades 3 or greater: 40%), decreased appetite (53%), infection (52%), weight loss (47%), diarrhea (44%), vomiting (41%), hyponatremia (39%), neutropenia (34%; grades 3 or greater: 21%), neurological signs and symptoms (30% or less), leukopenia (28%; grades 3 or greater: 11%), constipation (25%), dyspnea (24%), upper respiratory tract infection (21%)

What role can the pharmacist play in the management of patients on selinexor?

  • Selinexor is administered as 80 mg (four 20-mg tablets) on days 1 and 3 of each week in combination with 20 mg of dexamethasone. It is available in blister packs of 32 tablets and should be dispensed in a 28-day cycle (additional package sizes are available).1
  • In the event of a missed dosed or if vomiting occurs following administration, patients should take the next dose at the regularly scheduled time.
  • Antiemetic prophylaxis should be dispensed with selinexor therapy. It is recommended that patients take a 5-HT3 antagonist 30–60 minutes before each selinexor dose. Taking dexamethasone with a meal prior to taking selinexor may provide additional antiemetic coverage. Selinexor can be taken with or without food.
  • Patients should be advised to maintain adequate hydration and caloric intake while on the therapy and should be assessed for excessive weight loss and dehydration with each cycle.
  • Selinexor dose modifications are unique because any reduction changes the dosing schedule to once-weekly administration. Guidelines are available in the package labeling on dose reductions for thrombocytopenia, neutropenia, anemia, hyponatremia, fatigue, nausea and vomiting, diarrhea, weight loss, and any grade 3/4 toxicities.
    • First reduction: 100 mg once weekly
    • Second reduction: 80 mg once weekly
    • Third reduction: 60 mg once weekly
    • Discontinue beyond the third reduction
  • Monitoring of complete blood counts, complete metabolic panel, and body weight should be conducted at baseline and with each cycle. More frequent monitoring should be conducted during cycles 1 and 2 (every 2 weeks or as clinically appropriate).
    • It is important to note that patients on selinexor have received several prior lines of therapy and may have had a transplant. Hematologic toxicities may be associated with the overall disease course and prior therapies. As a result, it is important to keep baseline values in consideration when recommending dose modifications.
  • Selinexor is metabolized via cytochrome P450 3A4 (CYP3A4), but no recommendations are provided for concomitant administration with moderate or strong inhibitors or inducers. More frequent monitoring may be warranted in patients receiving moderate or strong inhibitors because of the potential of increased toxicity.
  • A patient education sheet on selinexor produced by the Association of Community Cancer Centers, HOPA, the National Community Oncology Dispensing Association, and the Oncology Nursing Society can be found at http://oralchemoedsheets.com/sheets/Selinexor_Patient_Education.pdf.

Clinical Pearls

  • Additional package sizes of selinexor according to dosing schedule are available:1
    • 100 mg once weekly: 4 blister packs (20 tablets total)
    • 80 mg once weekly: 4 blister packs (16 tablets total)
    • 60 mg once weekly: 4 blister packs (12 tablets total)
  • Selinexor should be handled as a hazardous medication.
  • In the STORM trial, the median number of prior regimens was 8 (range 4–18); U.S. Food and Drug Administration approval requires four prior therapies, as previously mentioned.1,9 Patients with myeloma receive numerous combination regimens, and there is no widely accepted standard of practice for treating RRMM. It is important to consider efficacy, safety, clinical and financial toxicity, convenience, and prior lines of therapy with treatment selection.
    • Some patients may not be appropriate candidates for selinexor therapy, for example, those who have experienced significant weight loss or anorexia during their disease course or those with a history of uncontrolled nausea and vomiting.
  • Numerous clinical trials are using selinexor in various combinations to treat MM and are listed at https://clinicaltrials.gov/.
  • Copay assistance for selinexor is available through the KARYFORWARD program.10

References

  1. Xpovio (selinexor) [prescribing information]. Newton, MA: Karyopharm Therapeutics, Inc.; July 2019.
  2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 2.2020 (October 9, 2019). Available at https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
  3. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38.
  4. Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115.
  5. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34.
  6. Topp MS, Duell J, Zugmaier G, et al. Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: updated results of a first-in-human (FIH) phase I dose escalation study. J Clin Oncol. 2019;37(Suppl 15):8007.
  7. Trudel S, Lendvai N, Popat R, et al. Antibody-drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and efficacy from dose expansion phase I study. Blood Cancer J. 2019;9(4):37.
  8. Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18):1726-1737.
  9. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor–dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727-738.
  10. KARYFORWARD Assistance Program. Available at https://www.karyforward.com/. Accessed December 21, 2019.
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