update on oral oncolytics: a focus on hematology drugs
TRANSCRIPT
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1-11-2020
Update on Oral Oncolytics: A Focus on Hematology Drugs Update on Oral Oncolytics: A Focus on Hematology Drugs
Monica Tadros Miami Cancer Institute, [email protected]
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Citation Citation Tadros, Monica, "Update on Oral Oncolytics: A Focus on Hematology Drugs" (2020). All Publications. 3382. https://scholarlycommons.baptisthealth.net/se-all-publications/3382
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Update on Oral Oncolytics: A Focus on Hematology Drugs
Presenter: Monica Tadros, Pharm.D., BCPS
Miami Cancer Institute, Baptist Health South Florida
Objectives
Review the history of oral oncolytics for hematologic malignancies
Explore the different challenges associated with oral oncolytics
Discuss recently approved oral oncolytics for hematologic malignancies
Explain the role of the pharmacist in mitigating the challenges associated with oral oncolytics
Abbreviations/Acronyms CML: Chronic myeloid leukemia
BTK: Bruton’s tyrosine kinase
IDH: Isocitrate dehydrogenase
PI3K: Phosphoinositide 3-kinase
FLT3: FMS-like receptor tyrosine kinase-3
HDAC: Histone deacetylase
JAK: Janus Kinase
BCL-2: B-cell lymphoma 2
AML: Acute myeloid leukemia
MOA: Mechanism of action
FDA: Food and Drug Administration
LFT: Liver function tests
CR: Complete response / remission
CRh: Complete response with partial hematologic recovery
CRi: Complete remission with incomplete count recovery
LDAC: Low dose cytarabine
CLL: Chronic lymphocytic leukemia
SLL: Small lymphocytic lymphoma
FL: Follicular lymphoma
URI: Upper respiratory infection
PCP: Pneumocystis pneumonia; Primary care physician
ORR: Overall response rate
CI: Confidence interval
ECOG: Eastern Cooperative Oncology Group
MCL: Mantle cell lymphoma
AE: Adverse effects
GI: Gastrointestinal
PFS: Progression free survival
GVHD: Graft-versus-host disease
HSCT: Hematopoietic stem cell transplant
HR: Hazard ratio
OS: Overall survival
R/R: Relapsed refractory
SC: Subcutaneous
Definitions
What is an oral oncolytic?
Oral cytotoxic agent or small molecule inhibitor that targets surface proteins, tumor pathways, or receptors
Macker E, et al. J Clin Oncol. 2018; 15(4):e346-355.
History Traditional oral chemotherapy agents available since 1950’s
Examples: Chlorambucil, cyclophosphamide, MTX
In subsequent 50 years, 27 oral agents approved (~1 every 2 years)
Shifting mechanisms of action
Alkylating agents & antimetabolites targeted therapies
First FDA-approved small molecular inhibitor for the
treatment of CML
American Association for Cancer Research. Landmarks in Cancer Research. Retrieved from: https://www.aacr.org/Documents/Landmarks.pdf
Current Landscape Prescription of oral oncolytics is becoming more common
Substantial increase in oral oncolytic approvals in the past several years
Make up ~25% of the oncology market
Up to 35% of drugs in clinical trials are oral oncolytics
Dillmon MS, et al. J Clin Oncol. 2019; 37:1-12
Mosely WG, Nystrom JS. Community Oncology. 2009; 6:358-61
Advantages of Oral Chemotherapy
Patient convenience Fewer clinic visits (less travel time, time away from work, associated costs)
Flexibility for timing and location of administration
No need for intravenous access (less infections, pain)
Limited use of healthcare resources (inpatient/ambulatory services) Less use of supplies, ancillary equipment and personnel (nurses)
Better quality of life More time home with family
Less interruptions of daily activities closer to normality
Halfdanarson TR, Jatoi A. Curr Oncol Rep 2010;12:247-52.
Aisner J. Am J Health-Syst Pharm 2007;64(Suppl 5):S4-S7
Pros and Cons
Pros Cons
Convenient
Hospitalization not required
Patient autonomy and more in control of care
Less missed work days due to infusion
Patients responsible for adherence
Financial toxicity treatment start delays
Specific administration &storage requirements
Less contact with treating providers
Dillmon MS, et al. J Clin Oncol. 2019; 37:1-12.
Challenges of Oral Oncolytics Adherence (average rate 40-50%)
Complex dosing schedules weeks on/off, certain days of week
Pill burden
Inadequate follow up
Cognitive impairment
Storage and handling
Cost
ASCO Best Practices. J Oncol Pract. 2008; 4(4): 175-77
Mancini R, et al. Practice & Policy, Oncology Journal. 2013; 27 (8).
Challenges of Oral Oncolytics
Work flow
Patients moved out of infusion center
Decreased income for institution if prescriptions sent to other pharmacies
Accessibility/Dispensing
Prior authorizations
Specialty licenses required
Not always stocked
Insurance dictating which pharmacy patient must go to
ASCO Best Practices. J Oncol Pract. 2008; 4(4): 175-77
Mancini R, et al. Practice & Policy, Oncology Journal. 2013; 27 (8).
Challenges of Oral Oncolytics
Interactions/Adjustments
Drug-drug interactions
Absorption interactions
Dose adjustment needs
Side Effects
Can be severe
Patients have less follow up to address toxicities
Financial
High costs
Variable insurance coverage
ASCO Best Practices. J Oncol Pract. 2008; 4(4): 175-77
Mancini R, et al. Practice & Policy, Oncology Journal. 2013; 27 (8).
Financial Toxicity
Patients required to pay upfront vs. going through insurance claims
High out of pocket costs for patients (~25-50% of the total cost!) In 2009, oral oncology medication monthly out-of-
pocket costs averaged $2,942, up 17% from 2008
~10% of patients choose not to fill their initial prescriptions for oral oncolytic due to cost (Avalere Health study)
Mancini R, et al. Practice & Policy, Oncology Journal. 2013; 27 (8).
Mosely WG, Nystrom JS. Community Oncology. 2009; 6:358-61
Orals for Hematologic Malignancies
BTK inhibitors Acalabrutinib Ibrutinib Zanubrutinib
Tyrosine kinase inhibitors Bosutinib Dasatinib Nilotinib Ponatinib Imatinib
Immunomodulators Lenalidomide Thalidomide
Proteasome inhibitor Ixazomib
IDH inhibitors Enasidenib Ivosidenib
PI3K inhibitors Idelalisib
Duvelisib
Copanlisib
FLT3 inhibitors Midostaurin
Gilteritinib
Sorafenib
HDAC inhibitors Panobinostat
Vorinostat
JAK inhibitor Ruxolitinib
Fedratinib
BCL2-inhibitor Venetoclax
https://www.fda.gov
What’s new on the market?
New drugs
2018
• Gilteritinib (Xospata)
• Glasdegib (Daurismo)
• Duvelisib (Copiktra)
• Ivosidenib (Tibsovo)
2019
• Zanubrutinib (Brukinsa)
• Fedratinib (Inrebic)
• Selinexor (Xpovio)
New indications
Acalabrutinib (Calquence)
Ruxolitinib (Jakafi)
Venetoclax (Venclexta)
https://www.fda.gov
Newly Approved Agents
FMS-like receptor tyrosine kinase-3(FLT3) inhibitor
Gilteritinib (Xospata) Date approved: November 28, 2018 [orphan product designation]
Indication: Relapsed, refractory AML with FLT3 mutation as detected by an FDA-approved test
Dose: 120 mg once daily for a minimum of 6 months taken w/ or w/o food
AE: Serious: QTc prolongation, pancreatitis, differentiation syndrome [US
boxed warning]
Common: Elevated LFTs, myalgia, nausea, headache
Drug interactions: Avoid with strong CYP3A4 inhibitors
Clinical Pearls: MOA also has AXL inhibition (may play role in therapeutic resistance)
Differs from midostaurin (Rydapt) monotherapy and refractory setting
Xospata (gilteritinib) [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; May 2019.Serious = Grade 3 & 4 toxicity
Common = ≥ 20% incidence
• N=138 adult patients with R/R AML w/ a FLT3 ITD, D835, or I836 mutation
ADMIRAL trial
• Gilteritinib 120 mg daily until unacceptable toxicity or lack of clinical benefit vs. salvage chemotherapy
Intervention• Median follow-up:
4.6 months
• 29 patients achieved CR or CRh (21%, 95% CI: 14.5, 28.8)
Outcomes
Gilteritinib (Xospata)
Perl AE, et al: 2019 AACR Annual Meeting. Abstract CT184. Presented April 2, 2019.
Hedgehog pathway inhibitor
Glasdegib (Daurismo) Date approved: November 21, 2018 [orphan product designation]
Indications: Newly diagnosed AML in patients ≥75 years old or have comorbidities that preclude use of intensive induction chemo
Dose: 100 mg once daily taken w/ or w/o food
AE: Serious: QTc prolongation
Common: Anemia, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash
Drug Interactions Strong CYP3A4 inhibitors and QTc prolonging drugs
Clinical Pearls: Approved in combination with low-dose cytarabine
Patients may not donate blood for at least 30 days after last dose
Daurismo (glasdegib) [prescribing information]. New York, NY: Pfizer Labs; November 2018.
Serious = Grade 3 & 4 toxicity
Common = ≥ 20% incidence
• N=115 patients with newly-diagnosed AML
BRIGHT AML 1003
Study
• Glasdegib 100 mg daily + LDAC 20 mg SC twice daily vs. LDAC alone
Intervention• Median follow-up:
20 months
• Median survival: 8.3 months (95% CI: 4.4, 12.2) vs. 4.3 months (95% CI: 1.9, 5.7) and HR of 0.46 (95% CI: 0.30, 0.71; p=0.0002).
Outcomes
Glasdegib (Daurismo)
Cortes JE, et al. Am J Hematol. 2018;93(11):1301-1310.
Phosphoinositide 3-Kinase (PI3K) inhibitor
Duvelisib (Copiktra) Date approved: September 24, 2018
Indications: CLL/SLL after at least 2 prior therapies
Relapsed/refractory FL after 2 prior systemic therapies
Dose: 25 mg twice daily taken w/ or w/o food
AE: [US Boxed warnings]: Fatal infections (31%), diarrhea (18%), cutaneous reactions
(5%), pneumonitis (5%)
Serious: Hepatotoxicity, neutropenia, embryo-fetal toxicity
Common: Transient lymphocytosis, diarrhea, neutropenia, rash, fatigue, cough, nausea, URI/pneumonia, anemia
Drug Interactions: Avoid CYP3A4 inducers, dose reduce with inhibitors
Acts as CYP3A4 inhibitor monitor for toxicities of drugs that are substrates
Clinical Pearls: Differs from idelalisib (Zydelig) blocks both delta and gamma isoforms of PI3K
PCP pneumonia prophylaxis recommended during treatment, until CD4 count > 200 cells/microliter
Copiktra (duvelisib) [prescribing information]. Needham,
MA: Verastem, Inc; July 2019.
Serious = Grade 3 & 4 toxicity
Common = ≥ 20% incidence
PI3K inhibitorsDuvelisib (Copiktra) - FL and CLL Idelalisib (Zydelig) - FL and CLLCopanlisib (Aliqopa) - FL
CLL/SLL - NCT02004522 FL - NCT02204982
Patients N=196 patients N=83 patients
Interventions Duvelisib 25 mg twice daily vs. ofatumumab
Duvelisib 25 mg twice daily + rituximab vs. placebo + rituximab
Outcomes • Estimated median PFS: 16.4 months vs. 9.1 months (hazard ratio of 0.40; standard error 0.2)
• ORR: 78% vs. 39% (39% difference, standard error 6.5%)
• ORR: 42% (95% CI: 31, 54), with 41% of patients experiencing partial responses and one patient having a complete response
• 15 (43%) maintained responses for at least 6 months and 6 (17%) maintained responses for at least 12 months
Duvelisib (Copiktra)
Flinn IW, Hillmen P, Montillo M, et al. Blood. 2018 Dec 6;132(23):2446-2455.
https://clinicaltrials.gov/ct2/show/results/NCT02204982
Isocitrate-dehydrogenase type 1 (IDH1) inhibitor
Ivosidenib (Tibsovo) Date approved: July 20, 2018 [orphan product designation] Indications: AML with susceptible IDH1 mutation as detected by FDA
approved test Relapsed/refractory AML As of 2019: Newly-diagnosed AML who are ≥ 75 years old or have
comorbidities that preclude use of intensive induction chemotherapy
Dose: 500 mg once daily taken w/ or w/o food (do NOT administer with a high fat meal)
AE: Serious: QTc prolongation, differentiation syndrome [US Boxed Warning] Common: Fatigue, arthralgia, leukocytosis, electrolytes abnormalities
Drug Interactions: Avoid with CYP3A4 inducers/substrates & QTc prolonging drugs Dose reduce with CYP3A4 inhibitors
Clinical Pearls: Differs from enasidenib (IDH2 inhibitor) Treatment recommended for minimum 6 months to allow for clinical response
Tibsovo (ivosidenib) [prescribing information]. Cambridge, MA: Agios Pharmaceuticals; May 2019.Serious = Grade 3 & 4 toxicity
Common = ≥ 20% incidence
Differentiation Syndrome
Tibsovo (ivosidenib) [prescribing information]. Cambridge, MA: Agios Pharmaceuticals; May 2019.
Xospata (gilteritinib) [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; May 2019.
Causative agents
• IDH inhibitors (19%), gilteritinib (3%), arsenic trioxide, all-trans retinoic acid
Symptoms
• Fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, hypotension, renal dysfunction
Treatment
• Corticosteroids Dexamethasone 10 mg (or equivalent) IV every 12 hours for a minimum of 3 days
• Interrupt treatment w/ offending agent if symptoms for > 48 hrs after starting steroid
Monitoring &Follow up
• Hemodynamic monitoring
• Resume agent when signs/symptoms improve to ≤ grade 2 (mild to moderate)
Ivosidenib (Tibsovo)
• N=28 patients at least 75 years old with one of the following:
• Baseline ECOG status of ≥ 2
• Severe cardiac or pulmonary disease
• Hepatic impairment with bilirubin > 1.5 times the upper limit of normal
• CrCL < 45 mL/min
Study AG120-C-001
• Ivosidenib 500 mg daily
Intervention • Twelve (42.9%) of the 28 achieved CR+CRh (95% CI: 24.5, 62.8)
• 7 (41.2%) of the 17 transfusion-dependent patients achieved transfusion independence lasting at least 8 weeks
Outcomes
https://clinicaltrials.gov/ct2/show/NCT02074839
Bruton’s tyrosine kinase (BTK) inhibitor
Zanubrutinib (Brukinsa) Date approved: November 14, 2019 [orphan product and
breakthrough therapy designation] Indications: MCL after at least one prior therapy Dose: 160 mg twice daily or 320 mg once daily taken w/ or w/o food AE:
Serious: Hemorrhage, infections, cytopenias, secondary primary malignancies, cardiac arrhythmias
Common: Hypertension, decreased neutrophils/platelets/WBC, URI, rash, bruising, diarrhea, cough
Drug Interactions: Modify dose with moderate and strong CYP3A4 inhibitors Avoid CYP3A4 inducers
Clinical Pearls: Selectivity: Acalabrutinib (Calquence) > Zanubrutinib (Brukinsa) >
Ibrutinib (Imbruvica) Less bleeding, atrial fibrillation, and hypertension compared to ibrutinib
Brukinsa (zanubrutinib) [prescribing information]. San Mateo, CA: BeiGene USA Inc; November 2019.Serious = Grade 3 & 4 toxicity
Common = ≥ 20% incidence
Zanubrutinib (Brukinsa)Phase 2 open-label clinical trial (BGB-3111-206)
Phase 1/2 open label clinical trial (BGB-3111-AU-003)
Patients N=86 patients N=32 patients
Interventions 160 mg twice daily until disease progression or unacceptable toxicity
160 mg twice daily and 320 mg once daily
Outcomes ORR was 84% (95% CI: 74, 91), with a CR rate of 59%(95% CI 48, 70) and a median response duration of 19.5 months (95% CI: 16.6, not estimable)
ORR was 84% (95% CI: 67, 95), with a CR rate of 22% (95% CI: 9, 40) and a median response duration of 18.5 months (95% CI: 12.6, not estimable)
Song Y, et al. Blood. 2018;132(suppl 1):S132.
Tam CS, et al. Blood. 2019;134(11):851-859.
Janus Kinase 2 (JAK-2) inhibitor
Fedratinib (Inrebic) Date approved: August 16, 2019 [orphan drug designation] Indications: Adults with intermediate-2 or high-risk primary or secondary
(post-polycythemia vera or post-essential thrombocythemia) myelofibrosis Dose: 400 mg once daily taken w/ or w/o food (high fat meal reduces
nausea/vomiting) AE:
Serious: anemia, thrombocytopenia, GI toxicity, hepatotoxicity, amylase/lipase elevation, fatal encephalopathy [US Boxed Warning]
Common: diarrhea, nausea, vomiting
Drug Interactions: Avoid w/ strong & moderate CYP3A4 inducers Reduce dose w/ strong CYP3A4 inhibitors Avoid w/ dual CYP3A4 + 2C19 inhibitor
Clinical Pearls: Assess thiamine levels in patients prior to starting and periodically during
treatment Baseline platelet level of 50,000/mm3 required to start treatment Differs from ruxolitinib (Jakafi) JAK-2 only inhibition, more toxicities
Inrebic (fedratinib) [prescribing information]. Summit, NJ; Celgene Corporation; August 2019.Serious = Grade 3 & 4 toxicity
Common = ≥ 20% incidence
Fedratinib (Inrebic)
• N=289 patients
JAKARTA trial
• Fedratinib 500 mg (N=97) or 400 mg (N=96) once daily for 6 cycles
Intervention
• In 400 mg group (recommended dose):
• 35 (37%) achieved a ≥ 35% reduction in spleen volume
• Median duration of spleen response: 18.2 months
• 40% of patients experienced a ≥ 50% reduction in myelofibrosis-related symptoms
Outcomes
Pardanani A, et al. JAMA Oncol. 2015;1(5):643-651
Nuclear export (XPO1) inhibitor
Selinexor (Xpovio) Date approved: July 3, 2019
Indications: Relapsed/refractory multiple myeloma in combination with dexamethasone
Dose: 80 mg/dose twice weekly on days 1 and 3 each week (in combination with dexamethasone) taken without regard to food
AE: Serious: Hematologic toxicities (thrombocytopenia, neutropenia) GI
toxicity, hyponatremia, infectious, neurological toxicity
Common: Fatigue, nausea (72%), anemia, diarrhea, vomiting, dyspnea, URI
Clinical Pearls: Patients must have received at least 4 prior therapies and disease is
refractory to at least 2 proteasome inhibitors, at least 2 immunomodulators, and an anti-CD38 monoclonal antibody
Antiemetics are recommended prior to and during treatment
Xpovio (selinexor) [prescribing information]. Newton, MA: Karyopharm Therapeutics Inc; July 2019.Serious = Grade 3 & 4 toxicity
Common = ≥ 20% incidence
Selinexor (Xpovio)
• N=122 patients
STORM trial
• 80 mg in combination with dexamethasone 20 mg on days 1 and 3 of every week
Intervention
• ORR: 25.3% (95% CI: 16.4, 36)• 1 stringent CR
• No CR
• 4 very good partial responses
• 16 partial responses
• Median time to first response: 4 weeks (range: 1 to 10 weeks)
• Median response duration: 3.8 months (95% CI: 2.3, not estimable)
Outcomes
Chari A, et al. N Engl J Med. 2019;381(8):727-738.
New Indications
Drug Previous Indications New Indications
Acalabrutinib(Calquence)
Patients with MCL who have received at
least one prior therapy
• CLL and SLL
Ruxolitinib(Jakafi)
Intermediate or high-risk myelofibrosis
• Steroid-refractory acute graft-versus-host disease in adults and pediatrics 12 years and older
Venetoclax(Venclexta)
Patients with CLL and SLL with 17p
deletion who have received at least one
prior therapy
• Newly-diagnosed AML in adults 75 years or older, or have comorbidities that preclude use of intensive induction chemotherapy (in combination with azacitidineor decitabine or low-dose cytarabine)
• Previously untreated CLL and SLL
https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications
Acalabrutinib (Calquence) MOA: BTK inhibitor
Dose: 100 mg every 12 hours
Labeling Updates for CLL/SLL based on two randomized controlled clinical trials
ELEVATE-TN ASCEND
N= 535 patients N=310 patients
3 arms: acalabrutinib monotherapy, acalabrutinib plus obinutuzumab, or obinutuzumab plus chlorambucil
Treatment arms: acalabrutinib or investigator’s choice (idelalisib plus a rituximab product, or bendamustineplus a rituximab product)
Outcomes:• Median follow up: 28.3 months• PFS was significantly improved in acalabrutinib arms• Compared to the obinutuzumab plus chlorambucil
arm, the hazard ratio (HR) for PFS was 0.10 (95% CI: 0.06, 0.17; p < 0.0001) with acalabrutinib plus obinutuzumab and 0.20 (95% CI: 0.13, 0.30; p < 0.0001) with single agent acalabrutinib.
Outcomes:• Median follow-up: 16.1 months• PFS was significantly longer in the
acalabrutinib arm compared to the investigator’s choice arm (HR 0.31; 95% CI, 0.20, 0.49; p < 0.0001)
Sharman JP, et al. Blood. 2019;134(Supplement_1):31.
Ghia P, et al. Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, Netherlands. Abstract LB2606
Ruxolitinib (Jakafi) MOA: JAK1/2 selective inhibitor Dose: 5 mg twice daily may increase to 10 mg twice daily after 3 days Labeling updates for GVHD based on Study INCB 18424-271
https://clinicaltrials.gov/ct2/show/NCT02970318
Study INCB 18424-271 (NCT02953678)
Patients N=49 patients with steroid-refractory acute GVHD Grades 2 to 4 occurring after allogeneic HSCT
Intervention 5 mg twice daily (could be increased to 10 mg twice daily after 3 days in the absence of toxicity) + steroids
Outcomes • Day-28 ORR was 100% for Grade 2 GVHD, 40.7% for Grade 3 GVHD, and 44.4% for Grade 4 GVHD
• Median response duration: 16 days (95% CI: 9, 83)
• Median time from day-28 response to either death or need for new therapy for acute GVHD: 173 days (95% CI 66, not estimable)
Venetoclax (Venclexta)
MOA: BCL-2 inhibitor
Dose: Varies based on indication Usually includes ramp-up schedule to avoid tumor lysis syndrome
Venetoclax (Venclexta)
CLL14 trial
• N=432 patients with previously untreated CLL and SLL
Interventions
• Venetoclax in combination with obinutuzumab(VEN+G) vs. obinutuzumab in combination with chlorambucil (GClb)
Outcomes
• Median follow up: 28 months
• Improvement in PFS for patients who received VEN+G (HR 0.33; 95% CI: 0.22, 0.51; p<0.0001)
• Median PFS was not reached in either arm
• ORR: 85% in VEN+G arm compared to 71% in GClb arm, p=0.0007
Fischer K, et al. N Engl J Med 2019; 380:2225-2236
Labeling update for previously untreated CLL and SLL based on the CLL14 trial
Venetoclax (Venclexta) Labeling update for newly-diagnosed AML in combination with
azacitidine, decitabine or low- dose cytarabine in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemo based on phase Ib clinical trial
Phase Ib clinical trial
• N=145 patients
Interventions
• Venetoclax 400, 800, or 1200 mg daily in combination with either decitabine or azacitidine
Outcomes
• Complete remission (CR) + CR within incomplete count recovery (CRi): 67%
• Median duration of response: 11.3 months
• Overall survival: 17.5 months (ongoing)
DiNardo C, et al. Blood. 2019 Jan 3;133(1):7-17.
Role of the Pharmacist
Keys to a Successful Oral Oncolytic Program
1. Multidisciplinary approach
2. Assign responsibilities
3. Collaborate with specialty pharmacy
4. Provide financial advocacy services
5. Develop a robust patient education program
6. Put in place effective processes for monitoring adherence and toxicity
7. Maximize the use of technology
Association of Community Cancer Centers. Steps to Success: Implementing Oral Oncolytics. Retrieved
from: https://www.accc-cancer.org/docs/projects/resources/pdf/implementing-oral-oncolytics-final
Pharmacist’s Role
Uniquely positioned to enhance care for cancer patients who receive oral oncolytic therapy through:
Medication management
Patient education
Self-care management
Quality and safety management
Dispensing assistance
Macker E, et al. J Clin Oncol. 2018; 15(4):e346-355.
Role of the Pharmacist
Prescribing
Education
Dispensing & Distribution
Monitoring & Follow Up
Macker E, et al. J Clin Oncol. 2018; 15(4):e346-355.
Prescribing Patient consent should be obtained
Provide comprehensive review of new oral oncolytics and determine place in therapy via interprofessional formulary committee
Creation of oral oncolytic templates for electronic prescribing that include required components, standard supportive care, & monitoring
Perform comprehensive medication review at the time of prescription
Oncology team should communicate the intent of oral oncolytic therapy, pertinent drug–drug interactions, and potential implications for the patient’s comorbidities and management strategies to the patient’s PCP
Macker E, et al. J Clin Oncol. 2018; 15(4):e346-355.
Education Involvement in the development/endorsement of
standardized education materials
A separate education visit—in person or over the phone—should occur after the oncologist’s initial prescribing visit and before the start of oral oncolytic therapy to supplement and reiterate the information provided during the oncologist visit
Education should be comprehensive and focus on patient self-care management of adverse effects and the importance of adherence
An assessment of patient knowledge, confidence to manage adverse effects, and need for follow-up should occur during the education session
Macker E, et al. J Clin Oncol. 2018; 15(4):e346-355.
Dispensing/Distribution Dedicated medication assistance team prospectively screen
& provide financial support
The dispensing pharmacy should have access to necessary information for safe filling (laboratory values and progress notes)
Dedicated liaison available for the clinic to provide information on financial toxicities, refills, medication adherence, and any identified medication adverse effects
Specialty pharmacists and oncology pharmacy organizations should partner to promote the education of oncology pharmacists and optimize oncology patient care
Macker E, et al. J Clin Oncol. 2018; 15(4):e346-355.
Name of Organization/Study Tool for Oral Oncolytic Dispensing
National Community Oncology Dispensing Association (ncoda.org)
Oral chemotherapy education: • Cost avoidance and waste tracker• Patient satisfaction survey• Positive quality interventions
Chemocare.com Web resource for drug and side-effect information, wellness information, and other
Hematology Oncology Pharmacy Association Oral Chemotherapy resources (hoparx.org)
Tools and resources for:• Best practices, therapy initiation, financial resources,
education, monitoring, symptoms, and adherence
Cancer Care Ontario Drug and safety administration:• Recommended criteria of a preprinted order: oral
chemotherapy take-home prescriptions • Clinical verification of cancer drug prescriptions checklist:
cancer centers and specialty pharmacies
Michigan Oncology Quality Consortium
Oral oncolytics resource guide:• Therapy initiation resources, oral oncolytic checklist,
medication reconciliation process summary, oral oncolytic initiation template, initial dose mailer, calendar, education and monitoring
Oncology Nursing Society Checklist for a new start oral chemotherapy Dillmon MS, et al. J Clin Oncol. 2019; 37:1-12.
Monitoring/Follow Up Involvement in creation of monitoring and follow-up materials
Initial monitoring of symptoms & adherence should occur 7 -14 days after start
Ongoing monitoring of symptoms & adherence should occur at each clinical encounter, at least before each refill
Medication reconciliation should occur at each assessment point
Adherence assessment should be user friendly, reliable, cost effective, and practical
Collaborative practice agreement for laboratory and symptom monitoring, should exist where pharmacists are part of the interdisciplinary oncology care team
Ongoing communication
Macker E, et al. J Clin Oncol. 2018; 15(4):e346-355.
Practice Management
Pharmacist involvement in an oral oncolytic program
Perform baseline gap assessment to assess areas for improvement and baseline performance on oral oncolytic quality measures
Assess the following for continuous quality improvement: Pre- and post-financial, clinical quality measures, including interprofessional and patient experience
Macker E, et al. J Clin Oncol. 2018; 15(4):e346-355.
Example Workflow
Macker E, et al. J Clin Oncol. 2018; 15(4):e346-355.
Inpatient Setting Drug selection
Inter-professional interactions in formulary committees Evaluate clinical data, national guidelines, comparison of same-
class agents/biosimilars, financial toxicity, clinical cancer pathways
Standardize the ordering process Safety checks Symptom management protocols Proper dosing, dosage forms, lab testing
Identification of oral chemotherapy toxicities Is the oral oncolytic causing the toxicities that led to admission? Prescriber education
Macker E, et al. J Clin Oncol. 2018; 15(4):e346-355.
Outpatient Setting
Comprehensive medication reviews Drug-drug interactions Drug-food interactions Assess comorbidities Dosage adjustments Dosing schedules Counseling
Financial assistance Collaborating with insurance companies Enrolling patients in patient assistance programs
Macker E, et al. J Clin Oncol. 2018; 15(4):e346-355.
Conclusions
Oral oncolytic therapy development and prescribing is continuing to rise
Oral oncolytic therapy is associated with challenges in adherence, safety, and costs
Pharmacists in all settings are uniquely positioned to mitigate the risks associated with oral oncolytic therapy
Test Your Knowledge
T/F? Oral oncolytics comprise ~5% of the oncology pipeline
T/F? Venetoclax (Venclexta) was recently FDA approved for chronic lymphocytic leukemia
T/F? Selinexor (Xpovio) is an oral nuclear export inhibitor indicated for the treatment of refractory multiple myeloma in combination with dexamethasone
False
True
True
References Macker E, Segal EM, Muluneh B, et al. 2018 Hematology/Oncology Pharmacist Association Best Practices for the
Management of Oral Oncolytic Therapy: Pharmacy Practice Standard. J Clin Oncol. 2018; 15(4):e346-355. Dillmon MS, Kennedy EB, Anderson MK, et al. Patient-centered standards for medically integrated
dispensing:ASCO/NCODA standards. J Clin Oncol. 2019; 37:1-12. American Association for Cancer Research. Landmarks in Cancer Research. Retrieved from:
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https://www.communityoncology.org/pdfs/fact-sheet-oral-oncolytics.pdf https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-
notifications Mancini R, McBride A, Kruczynski A. Oral Oncolytics: Part 1—Financial, Adherence, and Management Challenges.
Practice & Policy, Oncology Journal. 2013; 27 (8). ASCO Best Practices. J Oncol Pract. 2008; 4(4): 175-77 Association of Community Cancer Centers. Steps to Success: Implementing Oral Oncolytics. Retrieved from:
https://www.accc-cancer.org/docs/projects/resources/pdf/implementing-oral-oncolytics-final Xospata (gilteritinib) [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; May 2019. Daurismo (glasdegib) [prescribing information]. New York, NY: Pfizer Labs; November 2018. Copiktra (duvelisib) [prescribing information]. Needham, MA: Verastem, Inc; July 2019. Tibsovo (ivosidenib) [prescribing information]. Cambridge, MA: Agios Pharmaceuticals; May 2019. Brukinsa (zanubrutinib) [prescribing information]. San Mateo, CA: BeiGene USA Inc; November 2019. Inrebic (fedratinib) [prescribing information]. Summit, NJ; Celgene Corporation; August 2019. Xpovio (selinexor) [prescribing information]. Newton, MA: Karyopharm Therapeutics Inc; July 2019. DiNardo C, et al. Blood. 2019 Jan 3;133(1):7-17.
References Perl AE, Martinelli G, Cortes JE, et al: Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated
relapsed/refractory acute myeloid leukemia: Results from the phase III ADMIRAL trial. 2019 AACR Annual Meeting. Abstract CT184. Presented April 2, 2019.
Cortes JE, Douglas Smith B, Wang ES, et al. Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results. Am J Hematol. 2018;93(11):1301-1310.
https://clinicaltrials.gov/ct2/show/NCT02074839
Song Y, Zhou K, Zou D, et al. Safety and activity of the investigational Bruton tyrosine kinase inhibitor zanubrutinib(BGB-3111) in patients with mantle cell lymphoma from a phase 2 trial. Blood. 2018;132(suppl 1):S132. [Abstract 132 from ASH 20187 Annual meeting].
Tam CS, Trotman J, Opat S, et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019;134(11):851-859.
Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643-651. doi: 10.1001/jamaoncol.2015.1590.
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. doi: 10.1056/NEJMoa1903455.
Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: Phase 3 study of acalabrutinib combined with obinutuzumab(O) or alone vs O plus chlorambucil (Clb) in patients (Pts) with treatment-naive chronic lymphocytic leukemia (CLL). Blood. 2019;134(Supplement_1):31. doi: 10.1182/blood-2019-128404.
Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelasib (IDR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, Netherlands. Abstract LB2606
https://clinicaltrials.gov/ct2/show/NCT02970318
Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 2019; 380:2225-2236
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15(4):e346-355.
Update on Oral Oncolytics: A Focus on Hematology Drugs
Presenter: Monica Tadros, Pharm.D., BCPS
Miami Cancer Institute, Baptist Health South Florida