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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)

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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)

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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)

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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

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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

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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

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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