new and emerging chemotherapies pharmacists ......3/2/2016 1 new and emerging chemotherapies luis...
TRANSCRIPT
3/2/2016
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New and Emerging Chemotherapies
Luis Hernandez
PGY-1 Pharmacy Resident
University of Miami Hospital
www.fshp.org
Disclosure
• Author has nothing to disclose
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Goals & Objectives
• Distinguish key differences between new oral and parenteral
chemotherapies
– Pharmacists: Discuss relevant side effects of new oral and parenteral
chemotherapies
– Technicians: Discuss proper handling and storage of new oral and
parenteral chemotherapies
• Learn about immunotherapies in Hematology/Oncology
– Pharmacists: Review recent FDA approvals of immunotherapies
– Technicians: Review preparation of recently approved immunotherapies
• Recognize and analyze the drugs and trends in the
Hematology/Oncology pipeline
– Pharmacists, Technicians: Examine the most promising pipeline drugs
3
Abbreviations
• AE: Adverse event
• APC: Antigen presenting cell
• CA: Cancer
• CINV: Chemotherapy Induced
Nausea & Vomiting
• CTLA-4: Cytotoxic T-
lymphocyte-associated
protein 4
• GI: Gastrointestinal
• GM-CSF: Granulocyte
macrophage colony
stimulating factor
• PD-1: Programmed death
receptor 1
• PD-L1: Programmed death
ligand 1
• HR: Hormone receptor
• HSV: Herpes Simplex Virus
• IL: Interleukin
• NSCLC: Non small cell lung
cancer
• PFUs: Plaque forming units
• TNF: Tumor necrosis factor
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New Chemotherapies
Oral vs. Parenteral
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2015 FDA Approvals
Drug Indication Drug Indication
Odomzo (sonidegib) Basal cell CA Alecensa (alectinib) NSCLC
Ibrance (palbociclib) Breast CA Tagrisso (osimertinib) NSCLC
Lonsurf
(tipiracil/trifluridine)
Colorectal CA Portrazza
(necitumumab)
NSCLC
Yondelis (trabectedin) Liposarcoma or
leiomyosarcoma
Unituxin (dinutuximab) Neuroblastoma
Imlygic (talimogene
laherparepvec)
Melanoma Lenvima (lenvatinib) Thyroid CA
Cotellic (cobimetinib) Melanoma Varubi (rolapitant) CINV
Farydak
(panobinostat)
Multiple Myeloma Empliciti (elotuzumab) Multiple
Myeloma
Ninlaro (ixazomib) Multiple Myeloma Darzalex
(daratumumab)
Multiple
Myeloma
6FDA. 2016. Novel Drug Approvals for 2015. [ONLINE] Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm430302.htm. [Accessed 2/4/16].
Immunotherapy AWP per vial Price of treatment for 1 year (70 kg pt)
Darzalex (daratumumab) 100 mg/5 ml= $540400 mg/20 ml= $2,160
$149,000
Empliciti (elotuzumab) 300 mg=$2,131400 mg= $2,842
$149,000
Imlygic (talimogene laherparepvec)
1,000,000 units/ml= $52.80100,000,000 units/ml= $5,280
2 ml per visit for 6 months: ~$253,000
Unituxin (dinutuximab) 17.5 mg/5 ml= $9,000 **Peds pt w/ BSA= 1: $180,000
Oral chemos AWP for 30 day supply Price of treatment for 1 year
Odomzo (sonidegib) $12,072 $144,864
Cotellic (cobimetinib) $7,274 $87,288
Ibrance (palbociclib) $12,411 $148,932
Tagrisso (osimertinib) $15,300 $183,600
Alecensa (alectinib) $14,793 $177,516
Lenvima (lenvatinib) $5,776 $69,312
Farydak (panobinostat) $8,800 (21 day cycle) $140,800 (16 cycles)
Ninlaro (ixazomib) $10,404 $124,848 7
Ibrance (palbociclib)
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• Advanced breast cancer (HR+, HER-2 negative)
o First-line in combination with Femara (letrozole)
o Second-line with Faslodex (fulvestrant)
• 125 mg PO daily for 21 days, then 7 off (with food)
• Bone marrow suppression, GI toxicity, infections and
thromboembolic events
• Major CYP3A4 substrate
Ibrance (palbociclib) [prescribing information]. New York, NY: Pfizer Labs; February 2015.
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Ibrance (palbociclib)
9
https://ikrispharmanetwork.com/buy-ibrance-palbociclib-breast-cancer-pfizer.html. Accessed 2/12/16
https://www.pfizerpro.com/product/ibrance/hcp/moa. Accessed 2/12/16
Farydak (panobinostat)
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• Multiple Myeloma (with bortezomib, dexamethasone)
• 20 mg PO every other day for 3 doses/week (D1, 3, 5,
8, 10, 12) of weeks 1, 2 of each 21-day cycle x 8 cycles
• Boxed Warnings: Diarrhea & cardiovascular events
• Moderate emetogenic potential
• CYP3A4 substrate; moderate CYP2D6 inhibitor
Farydak (panobinostat) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; February 2015.
Farydak (panobinostat)
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http://www.managingmyeloma.com/index.php?option=com_continued&view=material&Itemid=210&course=181&nocredit=1&token=33d2a02765b2ed16e7848cbdcf98ea0a. Accessed 2/12/16
http://www.neurologyadvisor.com/farydak/drug/34436/. Accessed 2/12/16
Ninlaro (ixazomib)
• Multiple Myeloma (with lenalidomide, dexamethasone)
• 4 mg PO weekly on Days 1, 8, 15 of each 28-day cycle
• Take 1 hour prior or 2 hours after eating
• CrCl < 30 ml/min or dialysis- decrease dose to 3 mg
• Hematologic, dermatologic, GI toxicities, neuropathies
12Ninlaro (ixazomib) [prescribing information]. Cambridge, MA: Takeda Pharmaceutical Company Limited; November 2015.
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Ninlaro (ixazomib)
13
http://www.drugdevelopment-technology.com/projects/ninlaro-ixazomib-treatment-multiple-myeloma/. Accessed 2/12/16
http://www.discoverymedicine.com/Taskeen-Mujtaba/2011/12/14/advances-in-the-understanding-of-mechanisms-and-therapeutic-use-of-bortezomib/. Accessed 2/12/16
Empliciti (elotuzumab)
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• Multiple myeloma (relapsed/refractory) with
lenalidomide and dexamethasone
• Interferes with serological testing
• Higher incidence of second primary malignancies
Cycle 28-Day Cycles 1 & 2 28-Day Cycles 3+
Day of Cycle 1 8 15 22 1 8 15 22
Empliciti (mg/kg) IV 10 10 10 10 10 10
Lenalidomide (25 mg) PO Days 1-21 Days 1-21
Dexamethasone (mg) PO 28 28 28 28 28 40 28 40
Dexamethasone (mg) IV 8 8 8 8 8 8
Empliciti (elotuzumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; November 2015.
Empliciti (elotuzumab)
15
https://pharmacologyupdate.wordpress.com/category/multiple-myeloma/. Accessed 2/12/16
http://www.techtimes.com/articles/112247/20151201/fda-gives-approval-to-blood-cancer-drug-empliciti.htm. Accessed 2/12/16
Darzalex (daratumumab)
• Multiple Myeloma (relapsed/refractory): Single agent
• 16 mg/kg IV weekly (1-8), q2 weeks (9-24), q4 weeks
• Delayed infusion reactions
• Prophylaxis for Herpes Zoster Virus is recommended:
1 week prior and for 3 months after treatment
• Refrigerate for up to 24 hours and protect from light
• Interferes with serological testing16
Darzalex (daratumumab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc.; November 2015.
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Darzalex (daratumumab)
17http://clincancerres.aacrjournals.org/content/21/12/2660/F1.expansion.html. Accessed 2/12/16
http://www.healthaim.com/darzalex-first-biological-drug-treat-blood-cancer/32636. Accessed 2/12/16
Imlygic (talimogene laherparepvec)
• Genetically modified, live attenuated, herpes simplex
virus 1 oncolytic virus
• Indication: Unresectable melanoma
• Dosing:
o Initial visit: Inject up to 4 ml of 106 PFUs/ml intralesionally
o Second visit: Inject up to 4 ml of 108 PFUs/ml intralesionally
(3 weeks after initial)
o Future visits: Inject up to 4 ml of 108 PFUs/ml intralesionally
every 2 weeks for at least 6 months
18Imlygic (talimogene laherparepvec) [prescribing information]. Thousand Oaks, CA: BioVex, Inc; October 2015.
Imlygic (talimogene laherparepvec)
• Do not administer to immunocompromised, pregnant
• Store and transport at -90°C to -70°C
• Protect from light
• Common adverse events: fatigue, chills, pyrexia, nausea
• Limitation: Has not been shown to improve overall
survival or have an effect on visceral metastases
19Imlygic (talimogene laherparepvec) [prescribing information]. Thousand Oaks, CA: BioVex, Inc; October 2015.
Imlygic (talimogene laherparepvec)
20https://en.wikipedia.org/wiki/Talimogene_laherparepvec#/media/File:Talimogene_laherparepvec_MOA.jpg
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The Future of Cancer Treatment:
Immunotherapies
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Cancer Pathogenesis
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Sustaining proliferative
signaling
Deregulatingcellular
energetics
Avoidingimmune
destruction
Enabling replicative immortality
Inducingangiogenesis
Resisting cell death
Evading growth
suppressors Activating invasion and metastasis
Hanahan D, Weinberg RA. Cell. 2011;144(5):646-674.
Hallmarks
of Cancer
Pathogenesis
(2011)
Initiation of Immune Response
23Abbas AK, Lichtman AH. Basic Immunology. 3rd ed. 2011.
Lymphoid Organs
Antigen
recognition
Activated
APC
T-cell
interaction
T-cell
activation
Replication of antigen-
specific
T-cells
Naive T-cell
Antigen receptors
Antigen
presenting
cell (APC)
Antigen
Antigen
fragments
Activated
T-cell
Activation
Peripheral Tissues
T-cells become
specialized
Effector cells:
1. Activate other
immune cells
2. Kill “target cells”
Memory cells:
1. Circulate for months � years
2. Ready to rapidly respond to same
antigen again
Immune Cells in Tumors
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• T-cell infiltration within tumors is associated with
overall survival (OS) in patients with different cancers
Zhang L, Coukos G, et al. N Engl J Med. 2003;348(3):203-213.
Intratumoral T cells (n=102)Median OS = 50.3 months
No intratumoral T cells (n=72)Median OS = 18 months
P<0.001
0 1321201089684726048362412
Month
OS
(%
)
0
25
50
75
100
Kaplan-Meier Curve for OS in
Advanced Ovarian Cancer1
n=102
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What is Immunotherapy?
• Treatment to boost or restore the ability of the immune
system to fight cancer, infections, and other diseases
• Examples in cancer:
1) Checkpoint inhibitors
2) Monoclonal antibodies
3) Therapeutic cancer vaccines
4) Cytokines
25National Cancer Institute. Cancer terms. http://www.cancer.gov/dictionary/?print=1&cdrid=45729. Accessed 1/15/2016
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Cancer Type Checkpoint
Inhibitors
Monoclonal
Antibodies
Cancer
Vaccines
Oncolytic
Virus
Bladder 3 2 2 1
Brain 3 2 20 5
Breast 6 2 6 0
Cervical 15 1 6 0
Colorectal 26 9 9 1
Esophageal 12 7 7 0
Head and Neck 4 2 4 0
Kidney 18 4 3 0
Leukemia 5 10 0 0
Liver 10 7 5 1
Lung 12 7 4 0
Lymphoma 27 5 5 0
Melanoma 8 2 7 ***
Multiple Myeloma 6 3 4 0
Ovarian 15 4 9 2
Pancreatic 11 10 10 0
Prostate 7 0 6 1
Sarcoma 1 0 3 0Adapted from http://www.cancerresearch.org/cancer-immunotherapy/impacting-all-cancers
Immunotherapy: Treatment Considerations
• Relative efficacy may be greater with lower tumor
burden
• Patient given immunotherapy earlier in disease may
have better outcomes
27Gulley JL, Drake CG. Clin Cancer Res. 2011;17(12):3884-3891.
Tumor Growth Rate
B
Tu
mo
r B
urd
en
A
† † † Expected clinical outcome if no treatment is provided
Death †
Patient given a vaccine earlier
Patient given a vaccine later
A
B
Time
Checkpoint Inhibition
28http://www.opdivohcp.bmscustomerconnect.com/metastatic-nsclc/opdivo-mechanism-of-action. Accessed 2/2/16.
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OPDIVO (nivolumab)
• “Takes the foot off the brakes”
29http://www.opdivohcp.bmscustomerconnect.com/metastatic-nsclc/opdivo-mechanism-of-action. Accessed 2/2/16.
KEYTRUDA (pembrolizumab)
30https://www.genomeweb.com/molecular-diagnostics/aacr-study-shows-pd-l1-expression-can-id-best-responders-mercks-anti-pd-1. Accessed 2/12/16
YERVOY (ipilimumab)
31http://www.hcp.yervoy.com/mm/mechanism-of-action
Immune-Mediated Adverse Effects
• Rare immune-mediated side effects:
o Pneumonitis
o Colitis
o Hepatitis
o Nephritis and Renal Dysfunction
o Hypothyroidism and Hyperthyroidism
• Treatment:
o Hold or permanently discontinue depending on severity
o Steroids (prednisone 1-2 mg/kg daily or equivalent)
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Monitoring Parameters
1) Hepatic and renal function tests (baseline, periodic)
2) Thyroid function tests (baseline and every 6 weeks)
3) Blood glucose (hyperglycemia)
4) Rash, diarrhea, adrenal insufficiency
5) CBC, platelets ≥ 100,000, ANC ≥ 1.5 (baseline, weekly)
6) Infusion reactions
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Pembrolizumab Infusion
• Vials must be refrigerated and protected from light
• Prepared in NS or D5W; 100 mg/4ml vial→ 1-10 mg/ml
• 2 mg/kg IV q3weeks; no premedications required
• Storage after preparation:
– Room temperature- no more than 6 hours
– Refrigeration- no more than 24 hours
• IV line must have a sterile, non-pyrogenic, low protein
binding 0.2-5 micron in-line filter; infuse over 30 mins
34Opdivo (nivolumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; January 2016.
Nivolumab Infusion
• Vials must be refrigerated and protected from light
• Prepared in NS or D5W; 10 mg/ml vial→ 1-10 mg/ml
• 3 mg/kg IV q2weeks; 1 mg/kg IV q3weeks x 4 with
ipilimumab; no premedications required
• Storage after preparation:
– Room temperature- no more than 4 hours
– Refrigeration- no more than 24 hours
• IV line must have a sterile, non-pyrogenic, low protein
binding 0.2-5 micron in-line filter; infuse over 60 mins
35Opdivo (nivolumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; January 2016.
Ipilimumab Infusion
• Vials must be refrigerated and protected from light
• Prepared in NS or D5W; 5 mg/ml vial→ 1-2 mg/ml
• 3 mg/kg IV q3weeks x 4 doses MAX
• Storage after preparation: no more than 24 hours
• IV line must have a sterile, non-pyrogenic, low protein
binding 0.2-5 micron in-line filter; infuse over 90 mins
36Yervoy (ipilimumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; October 2015.
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Patient Case
• 55 year old woman with metastatic melanoma
• Started Opdivo (Nivolumab) 3 mg/kg IV q2weeks
• She comes to clinic 4 weeks later complaining of
diarrhea, which was occasionally bloody
• She took some Imodium (loperamide) for several days
with no results
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Patient Case
• How do you proceed?
a) Refer her to the emergency department for IV hydration
and steroids; dicontinue nivolumab
b) Counsel patient that this is normal and may be related to
her diet; continue nivolumab
c) Obtain a full history of the diarrhea and recommend a strict
diet, oral hydration; continue nivolumab
d) Recommend oral steroids x 5 days, followed by a month
long taper; continue nivolumab
e) Discontinue nivolumab and the diarrhea will stop
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Management of Diarrhea
39O’Day, et al. Cancer 2007;110:2614-2627
Managing Adverse Events
40
Any Grade 1 AE or isolated
hypothyroidism
Symptom management or
replacement therapy for
hypothyroidism
Continue PD-1 treatment
and monitor
• Grade 2 colitis, nephritis,
hepatitis or pneumonitis
• Symptomatic hypophysitis
• Any Grade 3 AE
• Hold PD-1 treatment and
administer steroids
• Improve to Grade ≤ 1: Taper
steroids for 1+ month
Resume if:
Grade 0/1 AE
after steroid taper
Permanently discontinue if:
• No improvement within
12 weeks
•Cannot taper steroids
within 12 weeks
Nivolumab immune mediated adverse reactions management guide. https://bmsdm.secure.force.com/opdivohcp/servlet/servlet.FileDownload?file=00Pi000000GL6RoEAL. Accessed February 2016.A Guide to Monitoring Patients During Treatment with Pembrolizumab: A Resource for Adverse Reaction Management. Available at: https://www.keytruda.com/static/pdf/adverse-reaction-management-tool.pdf.; Accessed February 2016
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Managing Adverse Events
41
Hepatitis with:
� AST/ALT > 5x ULN
� AST/ALT ≥ 50% ↑ from baseline
� Total bilirubin > 3x ULN
�Grade 3 or 4 pneumonitis or nephritis
�Grade 3 or 4 infusion reaction
�Any life-threatening or Grade 4 adverse event
�Any severe or recurrent Grade 3 adverse event
Initiate steroids and permanently
discontinue checkpoint inhibitor
Nivolumab immune mediated adverse reactions management guide. https://bmsdm.secure.force.com/opdivohcp/servlet/servlet.FileDownload?file=00Pi000000GL6RoEAL. Accessed February 2016.A Guide to Monitoring Patients During Treatment with Pembrolizumab: A Resource for Adverse Reaction Management. Available at: https://www.keytruda.com/static/pdf/adverse-reaction-management-tool.pdf.; Accessed February 2016
Key Role for Pharmacists
• Discuss “Med Rec” findings with physician (monitor
autoimmune disease and/or immunosuppression)
• Monitor toxicities, especially dermatologic and GI
• Anticipate drug-drug interactions
• Evaluate costs/acquisition
• Immunotherapy takes time to work
42
What does the future hold?
43
Selinexor
• SINE (selective inhibitor of nuclear export)
• Oral agent active in highly aggressive lymphomas
• Inhibits I-ĸB export
• Other applications:
o HIV, influenza
o Autoimmune diseases
o Surgical wound healing
44Image: http://karyopharm.com/sinetm-technology/overview/
Multiple Myeloma Research Foundation. 2015. What is Selinexor (KPT-330)?. [ONLINE] Available at: http://www.themmrf.org/multiple-myeloma-knowledge-center/experimental-treatments/selinexor/. [Accessed 2/10/16]
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Acalabrutinib
• 2nd-generation inhibitor of Bruton’s tyrosine kinase
(BTK) for relapsed CLL
• 95% overall response rate; 100% in 17p deletion
• More selective, irreversible inhibition of BTK
• Improved safety profile compared to ibrutinib:
o No major hemorrhage, AFib, tumor lysis, pneumonitis
o Headache, diarrhea and weight gain were most common
45
Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32
Multikine
(Leukocyte Interleukin, Injection)
• Combination of cytokines (IL-1, IL-2, IL-6, TNF-α, etc.)
• Combination immunotherapy: Has both active and
passive immunity with no outside antigens required
• Currently in global Phase III trial for head & neck cancer
o First-line treatment for 3 weeks immediately after diagnosis
o Before any standard of care therapies
o Phase 2 results: reduced or eliminated all signs of tumor
before surgery, radiation and/or chemotherapy
46CEL-SCI. 2015. What is the investigational therapy Multikine® (Leukocyte Interleukin, Injection)?. [ONLINE] Available at: http://www.cel-sci.com/multikine_phase_3_clinical_trial_design.html. [Accessed 2/12/16]
Take Home Points
• There were 16 Hematology/Oncology drugs approved
by the FDA in 2015
• Although only 20% of patients respond to
immunotherapy, responses are long lasting
• Immune mediated reactions from PD-1 and CTLA-4
inhibitors can be managed with steroids
• Starting immunotherapy earlier in the disease course
leads to better outcomes
47
True/False Questions
1) The trend toward immunotherapies in Hematology/Oncology
describes medications that boost the immune system to fight
against malignancy
2) Orally administered chemotherapies are safer than those
administered intravenously
3) Imlygic (talimogene laherparepvec) is a first in class oncolytic
virus that uses HSV-1 along with GM-CSF and is injected
directly into melanoma lesions
4) Imlygic (talimogene laherparepvec) should be stored in a
refrigerator (2°C - 8°C)
48