xpovio® (selinexor) | rr dlbcl clinician's guide...*includes cr + pr. ci=confidence interval,...

INDICATIONXPOVIO® (selinexor) is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy.

This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

APPROVED FOR RR DLBCL1

THE FIRST AND ONLY FDA-APPROVED ORAL XPO1 INHIBITOR1

Learn more at XPOVIOpro.com

CLINICIAN’S GUIDE

Please see Important Safety Information throughout, and full Prescribing Information.

IMPORTANT SAFETY INFORMATION• Thrombocytopenia: XPOVIO can cause life-threatening thrombocytopenia, potentially leading to hemorrhage. Thrombocytopenia is

the leading cause of dose modifications.

https://www.karyopharm.com/wp-content/uploads/2019/07/NDA-212306-SN-0071-Prescribing-Information-01July2019.pdf

2

IMPORTANT SAFETY INFORMATION (cont’d)• Thrombocytopenia (cont’d): Monitor platelet counts at baseline and throughout treatment. Monitor more frequently during

the first 3 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, reduce dose, or permanently discontinue based on severity of adverse reaction (AR).

• Neutropenia: XPOVIO® (selinexor) can cause life-threatening neutropenia, potentially increasing the risk of infection.

• Obtain white blood cell counts with differential at baseline and throughout treatment. Monitor more frequently during the first 3 months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF). Interrupt, reduce dose, or permanently discontinue based on severity of ARs.



3


Table of contents

Mechanism of action 4

SADAL trial design 6

Efficacy 8

Adverse reactions (ARs) 10

Dosing 12

Dose modifications 13

How supplied 16

KaryForward® support program 17

Summary 20


4

In healthy cells:• XPO1 is a nuclear export protein1-3

• It is responsible for carrying cargos out of the nucleus, including1-3:

– TSPs: p53, p73, FOXO3a, IĸB, pRb, BRCA13,6

– Growth regulators: glucocorticoid receptors7

– Oncoprotein mRNAs: c-Myc, cyclin D, Bcl-2, Bcl-64,6,8,9

• The process is highly regulated to maintain the appropriate balance of cell growth and apoptosis4,10

*The identified cargos do not represent all cargos exported by XPO1.TSP=tumor suppressor protein.

Overexpression of XPO1, a nuclear export protein, is one of the mechanisms of oncogenesis2-5

CargosXPO1 Nucleus Cytoplasm

For illustrative purposes only.

5


XPOVIO® (selinexor) is the first and only FDA-approved oral XPO1 inhibitor that gets to the cell’s core to cause cell cycle arrest and apoptosis1-3,11

For illustrative purposes only.

Rather than targeting cancer cells on their surface, such as at the B-cell receptor, XPOVIO targets the cell at its core to inhibit XPO11,12

IMPORTANT SAFETY INFORMATION (cont’d)• Gastrointestinal Toxicity: XPOVIO can cause severe gastrointestinal toxicities.

• XPOVIO blocks XPO1 so it can’t carry cargos out of the nucleus

• The cargos accumulate in the nucleus

• This accumulation causes cell cycle arrest and apoptosis

• XPO1 is overexpressed2-5

• The nuclear export of cargos into the cytoplasm is increased4,6,8

• With these important cargos mislocalized, the cancer cell is free to grow and survive3,4,10

In this cancer cell not exposed to XPOVIO

In this cancer cell exposed to XPOVIO1-3,11

XPOVIO


6


SADAL: a multicenter, single-arm, open-label study of XPOVIO® (selinexor) monotherapy for adult patients with RR DLBCL1

IMPORTANT SAFETY INFORMATION (cont’d)• Nausea/Vomiting: Provide prophylactic antiemetics. Administer 5-HT3 receptor antagonists and other

anti-nausea agents prior to and during treatment with XPOVIO. Interrupt, reduce dose, or permanently discontinue based on severity of ARs. Administer intravenous fluids to prevent dehydration and replace electrolytes as clinically indicated.

Baseline patient characteristics (N=134)1,13

Median age: 67 years (range: 35-91)

Median time from progression to start of XPOVIO therapy: 7.3 weeks

Median time from last systemic therapy to the start of XPOVIO: 5.4 months (3.6 months in patients with refractory disease)

ECOG performance status score0 or 1: 88%

CLCR (mL/minute)

7


Baseline disease characteristics in the SADAL clinical trial

Baseline disease characteristics (N=134)1,13

De novo DLBCL NOSTransformed DLBCL

75%23%

GCBNon-GCBNot classified

47%49%4%

Double/triple expressor 20%

Median prior systemic therapies • 2 prior systemic therapies• 3 prior systemic therapies• 4 or 5 prior systemic therapies

2 (range: 1-5)63%24%10%

Prior autologous HSCT 30%

Disease refractory to most recent therapy 28%

Disease relapse

8


Overall response rates with XPOVIO® (selinexor)

*Includes CR + PR.CI=confidence interval, CR=complete response, PR=partial response, SD=stable disease.

†The first clinical evaluation was conducted at 8 weeks.

50% of responses to XPOVIO were evident at the time of first disease assessment (median time to first response: 1.9 months)1,13†

XPOVIO (N=134)CR: 13%PR: 16%

10 20 30 40 500

(95% CI: 22-38)ORR*: 29%

• Responses were assessed by an Independent Review Committee (IRC) using Lugano 2014 criteria

IMPORTANT SAFETY INFORMATION (cont’d)• Anorexia/Weight Loss: Monitor weight, nutritional status, and volume status at baseline and throughout

treatment. Monitor more frequently during the first 3 months of treatment. Interrupt, reduce dose, or permanently discontinue based on severity of ARs. Provide nutritional support, fluids, and electrolyte repletion as clinically indicated.

Single-agent, oral XPOVIO demonstrated clinically significant responses1

Response per IRC (%)

An additional 8.2% of patients achieved SD13


9


1 2 3 4 5 6 7 8 9 10 11 121 2

9.3 months*Median duration of response (DOR)

(95% CI: 4.9-not estimable)

1.9 monthsMedian time

to first response

3 6 12

56%of patients

still hada response

38%of patients

still hada response

15%of patients

still hada response

Start ofXPOVIO

Mon

ths

Start ofDOR assessment

Time to first response and duration of response with XPOVIO® (selinexor)

IMPORTANT SAFETY INFORMATION (cont’d)• Hyponatremia: XPOVIO can cause severe or life-threatening hyponatremia.

Percentage of patients (N=39) who still had a response at 3, 6, and 12 months

* The median DOR was determined using a pre-specified secondary Kaplan-Meier (K-M) analysis. Limitations to this analysis include small patient numbers and the effect of outliers with prolonged remission durations. Approximately half of the responders in this analysis had a DOR lasting

10


Adverse Reactions All Grades (%)Grades 3 or 4 (%)

≥3 3 4General Conditions Fatiguea 63 15 15 0Pyrexia 22 4.5 4.5 0Edemab 17 2.2 1.5 0.7GastrointestinalNausea 57 6 6 0Diarrheac 37 3 3 0Constipation 29 0 0 0Vomiting 28 1.5 1.5 0Abdominal paind 10 0 0 0Metabolism and NutritionAppetite decreasee 37 3.7 3.7 0Weight decrease 30 0 0 0RespiratoryCoughf 18 0 0 0Dyspneag 10 1.5 0.75 0.75

Adverse Reactions All Grades (%)Grades 3 or 4 (%)

≥3 3 4Infections Upper respiratory tract infectionh 17 1.5 1.5 0Pneumonia 10 6 6 0Urinary tract infectioni 10 3 3 0Nervous System Dizzinessj 16 0.7 0.7 0Taste disorderk 13 0 0 0Mental status changesl 11 3.7 3 0.7Peripheral neuropathy, sensorym 10 0 0 0Musculoskeletal Musculoskeletal painn 15 2.2 2.2 0VascularHypotension 13 3 3 0Hemorrhageo 10 0.7 0.7 0Eye DisordersVision blurredp 11 0.7 0.7 0

Adverse reactions with oral XPOVIO® (selinexor)1,13 Adverse reactions (ARs) ≥10% in RR DLBCL (N=134)

a Fatigue includes fatigue and asthenia. b Edema includes edema, swelling, swelling face, edema peripheral, peripheral swelling,

acute pulmonary edema. c Diarrhea includes diarrhea, post-procedural diarrhea, gastroenteritis. d Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort,

epigastric discomfort. e Appetite decrease includes decreased appetite and hypophagia. f Cough includes cough and productive cough. g Dyspnea includes dyspnea and dyspnea exertional. h Upper respiratory tract infection includes upper respiratory tract infection, sinusitis,

nasopharyngitis, pharyngitis, rhinitis, viral upper respiratory infection. i Urinary tract infection includes urinary tract infection and specific types of

urinary tract infection. j Dizziness includes dizziness and vertigo.

k Taste disorder includes taste disorder, dysgeusia, ageusia. l Mental status changes include confusional state, amnesia, cognitive disorder,

hallucination, delirium, somnolence, depressed level of consciousness, memory impairment.

m Peripheral neuropathy includes peripheral neuropathy, peripheral sensory neuropathy, sensory disturbance, paresthesia, neuralgia.

n Musculoskeletal pain includes musculoskeletal pain, back pain, musculoskeletal chest pain, neck pain, pain in extremity, bone pain.

o Hemorrhage includes hemorrhage, hematoma, hematuria, epistaxis, rectal hemorrhage, injection site hematoma, subdural hematoma, upper gastrointestinal hemorrhage, corneal bleeding.

p Vision blurred includes vision blurred, visual acuity reduced, visual impairment.


11


Laboratory Abnormality All Grades (%)Grades 3 or 4 (%)

≥3 3 4HematologicPlatelet count decrease 86 49 31 18Hemoglobin decrease 82 25 25 0Lymphocyte count decrease 63 37 32 5Neutrophil count decrease 58 31 21 10 ChemistrySodium decrease 62 16 16 0Glucose increase 57a 5 3 2Creatinine increase 47 3.9 1.6 2.3Phosphate decrease 34 11 10 1Magnesium decrease 30 2.6 0.8 1.8Calcium decrease 30 0.9 0.9 0Potassium increase 26 3.9 3.1 0.8Potassium decrease 23 7 6 1CK increaseb 21 1.9 1.9 0

Laboratory Abnormality All Grades (%)Grades 3 or 4 (%)

≥3 3 4HepaticALT increase 29 0.8 0 0.8Albumin decrease 25 0 0 0AST increase 24 3.1 2.3 0.8Bilirubin increase 16 1.6 1.6 0

Laboratory abnormalities worsening from baseline ≥15% in RR DLBCL (N=134) Select laboratory abnormalities with oral XPOVIO® (selinexor)1,13

The denominator used to calculate the rate varied from 107 to 128, based on the number of patients or at least 1 post-treatment value.aNot fasting.bCK increase was not associated with reports of myopathy or myalgia.ALT=alanine aminotransferase, AST=aspartate aminotransferase, CK=creatine kinase.

Clinically relevant adverse reactions in

12


Getting patients started on single-agent, oral XPOVIO® (selinexor) therapy for RR DLBCL1

The recommended dosage of XPOVIO is 60 mg (three 20-mg tablets) taken orally on Days 1 and 3 of each week until disease progression or unacceptable toxicity

DAY 1 DAY 2 DAY 3 DAY 4 DAY 5 DAY 6 DAY 7

XPOVIO 60 mg

20 mg tablet x 3

K20 K20 K20

XPOVIO 60 mg

20 mg tablet x 3

K20 K20 K20

IMPORTANT SAFETY INFORMATION (cont’d)• Hyponatremia (cont’d): Monitor sodium level at baseline and throughout treatment. Monitor more frequently during the first

2 months of treatment. Correct sodium levels for concurrent hyperglycemia (serum glucose >150 mg/dL) and high serum paraprotein levels. Assess hydration status and manage hyponatremia per clinical guidelines, including intravenous saline and/or salt tablets as appropriate and dietary review. Interrupt, reduce dose, or permanently discontinue based on severity of the ARs.

1. Set expectations• Counsel patients on what to expect with XPOVIO therapy

– Advise patients to maintain adequate fluid and caloric intake throughout treatment2. Prescribe XPOVIO

• XPOVIO is a monotherapy taken orally on Days 1 and 3 of each week• Administer a 5-HT3 receptor antagonist, such as ondansetron, and other

anti-nausea agents,1 such as olanzapine or rolapitant, prior to and during treatment15* – The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommends olanzapine for the prevention of nausea and vomiting15*

3. Monitor your patient• Monitor CBC with differential, standard blood chemistries, body weight, nutritional status, and volume status at baseline and during

treatment, more frequently during the first 3 months of treatment• Consider intravenous hydration for patients at risk of dehydration• Assess the need for dose modifications (see table on page 13)


13


In most cases, ARs with XPOVIO® (selinexor) were preventable, manageable, and reversible with supportive care and/or dosing adjustments1,13

Dose modifications for RR DLBCL1

• Discontinuation due to ARs occurred in 17% of patients who received XPOVIO

• ARs which resulted in discontinuation in ≥2% of patients included infection, fatigue, thrombocytopenia, and nausea

• ARs led to XPOVIO dose interruption in 61% of patients and dose reduction in 49%, with 17% of all patients having ≥2 dose reductions

• Serious ARs occurred in 46% of patients who received XPOVIO

• Fatal ARs occurred in 3.7% of patients within 30 days, and 5% of patients within 60 days of last treatment; the most frequent fatal AR was infection in 4.5% of patients

Recommended dosage

DAY 1 DAY 3 TOTAL WEEKLY DOSE

K20 K20 K20

60 mgK20 K20 K20

60 mg 120 mg

First reductionK20 K20

40 mgK20 K20

40 mg 80 mg

Second reductionK20 K20 K20

60 mg 60 mg

Third reductionK20 K20

40 mg 40 mg

PERMANENTLY DISCONTINUE

DOSE REDUCTION

= 20 mgK20

IMPORTANT SAFETY INFORMATION (cont’d)• Serious Infection: XPOVIO can cause serious and fatal infections. Most of these infections were not

associated with Grade 3 or higher neutropenia. Atypical infections reported after XPOVIO include, but are not limited to, fungal pneumonia and herpesvirus infection.

• Monitor for signs and symptoms of infection and evaluate and treat promptly.


14


Recommended dose modifications for hematologic ARs1

Thrombocytopenia Occurrence Actions

Platelet count 50,000 to

15


Nausea and Vomiting Occurrence Actions

Grade 1 or 2 nausea (oral intake decreased without significant weight loss, dehydration, or malnutrition)OR Grade 1 or 2 vomiting (≤5 episodes per day)

Any• Maintain XPOVIO® (selinexor)

and initiate additional anti-nausea medications

Grade 3 nausea (inadequate oral caloric or fluid intake) OR Grade ≥3 vomiting (≥6 episodes per day)

Any

• Interrupt XPOVIO• Monitor until nausea or vomiting

has resolved to Grade ≤ 2 or baseline

• Initiate additional anti-nausea medications

• Restart XPOVIO at 1 dose level lower

Diarrhea Occurrence Actions

Grade 2 (increase of 4 to 6 stools per day over baseline)

1st • Maintain XPOVIO and institute supportive care

2nd and subsequent

• Reduce XPOVIO by 1 dose level• Institute supportive care

Grade ≥3 (increase of ≥7 stools per day over baseline; hospitalization indicated)

Any

• Interrupt XPOVIO and institute supportive care

• Monitor until diarrhea resolves to Grade 2 or lower


Weight Loss and Anorexia Occurrence Actions

Weight loss of 10% to 130 mmol/L


Fatigue Occurrence Actions

Grade 2 lasting >7 days OR Grade 3 Any

• Interrupt XPOVIO• Monitor until fatigue resolves to

Grade 1 or baseline• Restart XPOVIO at 1 dose level lower

Ocular Toxicity Occurrence Actions

Grade 2, excluding cataract Any

• Perform ophthalmologic evaluation• Interrupt XPOVIO and provide

supportive care• Monitor until ocular symptoms resolve to

Grade 1 or baseline• Restart XPOVIO at 1 dose level lower

Grade ≥3 Any• Permanently discontinue XPOVIO• Perform ophthalmologic evaluation

Cataract (Grade ≥2) Any

• Perform ophthalmologic evaluation• Reduce XPOVIO by 1 dose level• Monitor for progression• Hold XPOVIO dose 24 hours prior to

surgery and for 72 hours after surgery

Other Non-Hematologic ARs Occurrence Actions

Grade 3 or 4 Any• Interrupt XPOVIO• Monitor until resolved to Grade ≤ 2;

restart XPOVIO at 1 dose level lower

Recommended dose modifications for non-hematologic ARs1


16


How XPOVIO® (selinexor) is supplied1

NDC Contents Tablets per blister pack Weekly dose Carton

NDC 72237-101-034 blister packs (24 tablets total per carton)

Six 20-mg tablets 60 mg twice weekly


Four 20-mg tablets 40 mg twice weekly


Three 20-mg tablets 60 mg once weekly


Two 20-mg tablets 40 mg once weekly

IMPORTANT SAFETY INFORMATION (cont’d)• Neurological Toxicity: XPOVIO can cause life-threatening neurological toxicities. Coadministration of

XPOVIO with other products that cause dizziness or mental status changes may increase the risk of neurological toxicity.

• Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until the neurological toxicity fully resolves. Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes. Institute fall precautions as appropriate.


17

KaryForward is a patient support program by Karyopharm Therapeutics dedicated to providing assistance and resources to patients and their caregivers for XPOVIO® (selinexor) treatment

Financial AssistanceGain access to programs that can help your eligible patients with the cost of Karyopharm medications.• Patient Assistance Program: Patients who are uninsured or

underinsured may be eligible to receive XPOVIO at no cost• XPOVIO Copay Program: Patients with commercial insurance may

be eligible to pay as little as $5 for each XPOVIO prescription

Insurance CoverageGet assistance navigating the insurance process, including benefits investigations, claims assistance, prior authorizations, and appeals.• Quick Start Program: Gain rapid access to XPOVIO for patients

who experience a delay in insurance coverage• Bridge Program: Get an emergency supply of free XPOVIO for

patients who experience an unexpected disruption in therapy

Support and ResourcesDedicated Nurse Case Managers can provide additional information about XPOVIO treatment such as:• Prescription instructions• Psychosocial support and additional nonclinical education• Highlight what to expect when taking Karyopharm medications and the

importance of talking to healthcare providers about the treatment journey• Determine if additional third-party support is available, such as

transportation assistance

ENROLL YOUR PATIENTS OR LEARN MORE:CALL1-877-KARY4WD (1-877-527-9493)Monday through Friday, 8 am to 8 pm ET

VISIT KaryForward.com

http://www.KaryForward.com

18

Please see full Prescribing Information.

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.

IMPORTANT SAFETY INFORMATION (cont’d)• Embryo-Fetal Toxicity: XPOVIO® (selinexor) can cause fetal harm when administered to a pregnant woman.

• 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 (ARs), excluding laboratory abnormalities, in ≥20% of patients are fatigue, nausea, diarrhea,

appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Grade 3-4 laboratory abnormalities in ≥15% included thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. Grade 4 laboratory abnormalities in ≥5% were thrombocytopenia, lymphopenia, and neutropenia.

• Fatal ARs occurred in 3.7% of patients within 30 days, and 5% of patients within 60 days of last treatment; the most frequent fatal AR was infection. Serious ARs occurred in 46% of patients who received XPOVIO; the most frequent serious AR was infection.

• Discontinuation due to ARs occurred in 17% of patients who received XPOVIO. ARs resulting in discontinuation in ≥2% of patients included: infection, fatigue, thrombocytopenia, and nausea.

• Adverse reactions led to XPOVIO dose interruption in 61% of patients and dose reduction in 49%, with 17% of all patients having 2 or more dose reductions.

USE IN SPECIFIC POPULATIONS• Clinical studies of XPOVIO in patients with relapsed or refractory DLBCL did not include sufficient numbers of patients aged 65 and

over to determine whether they respond differently from younger patients.

• The effect of end-stage renal disease (CLCR

19

References: 1. XPOVIO (selinexor) [package insert]. Newton, MA: Karyopharm Therapeutics Inc.; June 2020. 2. Yang J, et al. PLoS One. 2014;9(7):e102983. 3. Gupta A, et al. J Thorac Oncol. 2017;12(9):1446-1450. 4. Sun Q, et al. Signal Transduct Target Ther. 2016;1:16010. 5. Mor A, et al. Curr Opin Cell Biol. 2014;28:28-35. 6. Gravina GL, et al. J Hematol Oncol. 2014;7:85. 7. Vandevyver S, Dejager L, Libert C. Traffic. 2012;13(3):364-374. 8. Gandhi UH, et al. Clin Lymphoma Myeloma Leuk. 2018;18(5):335-345. 9. Zinkel S, Gross A, Yang E. Cell Death Differ. 2006;13(8):1351-1359. 10. Tai YT, et al. Leukemia. 2014;28(1):155-165. 11. Ben-Barouch S, et al. Expert Opin Investig Drugs. 2020;29(1):15-21. 12. Chao MP. Cancer Manag Res. 2013;5:251-269. 13. Data on file. Karyopharm Therapeutics Inc. 14. Kalakonda N, et al. Lancet Haematol. 2020;7(7):e511-e522. 15. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Antiemesis, V.2.2020. © 2020 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed September 3, 2020. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Notes

20

XPOVIO® (selinexor) oral monotherapy delivered rapid and clinically significant responses for adult patients with RR DLBCL in the SADAL trial (N=39)1

XPO1 inhibitionXPOVIO blocks XPO1 (a nuclear export protein) to reversibly inhibit nuclear export of TSPs, growth regulators, and mRNAs of oncogenic proteins to cause cell cycle arrest and apoptosis.

ORR in RR DLBCLORR with XPOVIO monotherapy was 29% (95% CI: 22-38). The percentage of patients who still had a response at 3, 6, and 12 months was 56%, 38%, and 15%, respectively.

Safety profileThe most common adverse reactions, excluding laboratory abnormalities, in ≥20% of patients were fatigue, nausea, appetite decrease, diarrhea, weight decrease, constipation, vomiting, and pyrexia. Grade 3-4 laboratory abnormalities in ≥15% included thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. Grade 4 laboratory abnormalities in ≥5% were thrombocytopenia (18%), lymphopenia (5%), and neutropenia (9%).

Oral monotherapy taken twice weeklyThe recommended dosage of XPOVIO is 60 mg (three 20-mg tablets) taken orally on Days 1 and 3 of each week until disease progression or unacceptable toxicity.

Learn more at XPOVIOpro.com

© 2020 Karyopharm Therapeutics Inc. All rights reserved. US-XPOV-03/20-00042 (9/20)


xpovio® (selinexor) | rr dlbcl clinician's guide...*includes cr + pr. ci=confidence interval,...

Documents