2017 –2018 drug updates in hematology/oncology spring slides/130pm drug...protein •vast majority...

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2017 – 2018 Drug Updates in Hematology/Oncology

L a u r a J . H a c k e t t , P h a r m D , B C O PC l i n i c a l P h a r m a c i s t – H e m a t o l o g y / O n c o l o g y

D a r t m o u t h - H i t c h c o c k M e d i c a l C e n t e r

L a u r a . J . H a c k e t t @ H i t c h c o c k . o r g

Disclosures•No conflicts to disclose

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Objectives•Describe the generic drug naming formulas for monoclonal antibodies and small molecule inhibitors

•Differentiate a biosimilar from a generic drug

•Define gene therapy

•Identify new hematology/oncology agents that were granted FDA‐approval in 2017‐2018

New Drug Approvals by Class

N=1

N=5

N=9

N=2

N=219 New Drugs

oSmall Molecule Inhibitors (n=9)

oMonoclonal Antibodies (n=5)

oBiosimilars (n=2)

oCAR* T‐Cells (n=2)

oTraditional Chemotherapy (n=1)

Food and Drug Administration. Hematology/oncology (cancer) approvals & safety notifications. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm. Accessed February 16, 2018.

*Chimeric Antigen Receptor

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New Drug Approvals by Disease State

N=7

N=4N=4

N=2

N=2

N=1

N=1N=1

19 New drugs / 22 Indications

o Leukemia (n=7)

o Lymphoma (n=4)

o Breast Cancer (n=4)

o Genitourinary Cancer (n=2)

o Lung Cancer (n=2)

o Merkel Cell Carcinoma (n=1)

o Gynecological Cancer (n=1)

o Gastrointestinal Cancer (n=1)


Overview of Targeted Drug Classes

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Monoclonal Antibodies

My Cancer Genome. Overview of targeted therapies for cancer.https://www.mycancergenome.org/content/molecular‐medicine/overview‐of‐targeted‐therapies‐for‐cancer/. Accessed February 19, 2018.

Lymphoma Association. Antibody therapy. https://www.lymphomas.org.uk/about‐lymphoma/treatment/antibody‐therapy‐including‐rituximab. Accessed February 19, 2018.

Monoclonal Antibodies: Naming

Name = prefix + substem(s) + stem

Variable

Target:‐ci(r) circulatory system‐li(m) immune system‐t(u) tumor

Source:‐ximab chimeric human‐mouse‐zumab humanized mouse‐mumab fully human

‐mab monoclonal antibody

Examples:• Beva‐ci‐zumab = target = circulatory; humanized monoclonal antibody • Nivo‐l‐umab = target = immune system; fully human monoclonal antibody• Tras‐tu‐zumab = target = tumor; humanized monoclonal antibody

Adapted from: My Cancer Genome. Overview of targeted therapies for cancer. https://www.mycancergenome.org/content/molecular‐medicine/overview‐of‐targeted‐therapies‐for‐cancer/. Accessed February 19, 2018.

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Monoclonal Antibodies: Immunogenicity

Foltz IN, Karow M, Wasserman SM. Evolution of emergence of therapeutic monoclonal antibodies. Circulation. 2013;127:2222‐2230.

Small Molecule Inhibitors•Small molecular weight allows for this type of targeted therapy to penetrate cell membrane and interact with targets inside the cancer cell

•These drugs typically interfere with the enzymatic activity of the target protein

•Vast majority of these agents are oral, some are given intravenously or subcutaneously

My Cancer Genome. Overview of targeted therapies for cancer. https://www.mycancergenome.org/content/molecular‐medicine/overview‐of‐targeted‐therapies‐for‐cancer/. Accessed February 19, 2018. National Cancer Institute. Targeted cancer therapies. https://www.cancer.gov/about‐cancer/treatment/types/targeted‐therapies/targeted‐therapies‐fact‐sheet. Accessed February 19, 2018.

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Small Molecule Inhibitors: Naming

Name = prefix + substem(s) + stem

Variable

Target:‐tinib tyrosine kinase inhibitor ‐zomib proteasome inhibitor‐ciclib cyclin‐dependent kinase inhibitor‐parib poly ADP‐ribose polymerase inhibitor

‐ib small molecule with inhibitory properties

Examples:• Ima‐tinib = small molecule tyrosine kinase inhibitor• Borte‐zomib = small molecule proteasome inhibitor

Adapted from: My Cancer Genome. Overview of targeted therapies for cancer. https://www.mycancergenome.org/content/molecular‐medicine/overview‐of‐targeted‐therapies‐for‐cancer/. Accessed February 19, 2018.

Gene Therapy• Chimeric Antigen Receptor (CAR) T‐cells

o Immunotherapy that utilizes the patient’s own T cells to fight cancer

•Development of patient‐specific CAR T‐cells typically takes a few weeks

•Cost of therapy is expensive: ~$475,000

•Currently there are ~ 420 ongoing clinical trials with CAR T‐cell therapy for both hematology and oncology indications

American Cancer Society. CAR T‐cell therapies. https://www.cancer.org/treatment/treatments‐and‐side‐effects/treatment‐types/immunotherapy/car‐t‐cell1.html. Accessed February 19. 2018.Goodman A. Future directions for CAR T‐cell therapy. The ASCO Post. December 10, 2017. http://www.ascopost.com/issues/december‐10‐2017/future‐directions‐for‐car‐t‐cell‐therapy/.

Accessed February 19, 2018.

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Overview of CAR T‐Cell Process

Leukemia & Lymphoma Society. Chimeric antigen receptor (CAR) T‐cell therapy.http://www.lls.org/treatment/types‐of‐treatment/immunotherapy/chimeric‐antigen‐receptor‐car‐t‐cell‐therapy. Accessed February 19, 2018.

Biosimilars

Lyman GH, Balaban E, Diaz M, et al. American Society of Clinical Oncology statement: biosimilars in oncology. J Clin Oncol. 2018; 36: DOI: 10.1200/JCO.2017.77.4893.Dranitsaris G, Amir E, Dorward K. Drugs. 2011;71(12):1527‐36.

Guidance for Industry. Scientific considerations in demonstrating biosimilarity to a reference product. 2012.

Biologic • Large, structurally complex protein • Derived from living organisms via recombinant DNA biotechnology• May be referred to as the “reference product”

Biosimilar • Biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components

• No clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency of the product

Generic • Exact copy of the reference product (aka Brand name drug)• Must have the same chemical structure, dosage, strength, route of

administration, quality, safety, performance and intended use as the Brand name product

Biosimilar Naming:• Assigned a nonproprietary name that includes the core name of the product + a

distinguishing FDA‐designated suffix that is devoid of meaning and composed of four lowercase letters

• Example Trastuzumab‐dkst

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New Drug Approvals: Traditional Chemotherapy in a New Formulation

Liposome‐encapsulated combination of daunorubicin + cytarabine (Vyxeos™)Indication(s) Adults with newly‐diagnosed therapy‐related AML (t‐AML) or

AML with myelodysplasia‐related changes (AML‐MRC)

Pharmacological Class liposomal combination of daunorubicin (anthracycline topoisomerase inhibitor) + cytarabine (nucleoside metabolic inhibitor)• 1:5 molar ratio of daunorubicin and cytarabine

Pre‐Medications Classified as moderately emetogenic

Dosing/Schedule • Induction: (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) liposome via intravenous infusion over 90 minutes on days 1, 3, and 5 and on days 1 and 3 for subsequent cycles of induction

• Consolidation: (daunorubicin 29 mg/m2 and cytarabine 65 mg/m2) liposome via intravenous infusion over 90 minutes on days 1 and 3

Daunorubicin and cytarabine liposome [package insert]. Jazz Pharmaceuticals Inc, Palto Alto, CA; 2017.

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Liposome‐encapsulated combination of daunorubicin + cytarabine (Vyxeos™)

Daunorubicin and cytarabine liposome [package insert]. Jazz Pharmaceuticals Inc, Palto Alto, CA; 2017.

Adverse Drug Reactions(ADRs)

Most common ADRs (≥25%) • Hemorrhagic events• Febrile neutropenia• Rash• Edema• Nausea• Mucositis• Diarrhea• Constipation• Musculoskeletal pain• Fatigue

continued: • Abdominal pain• Dyspnea• Headache• Cough• Decreased appetite• Arrhythmia• Pneumonia• Bacteremia• Chills• Sleep disorders • Vomiting

Monitoring CBC with differential, ECG, echocardiogram, liver function tests (LFTs), creatinine/BUN, cumulative anthracycline exposure

Drug‐Drug Interactions Monitor cardiac and hepatic function more frequently when coadministered with cardiotoxic and hepatotoxic agents respectively

New Drug Approvals:Monoclonal Antibodies & Antibody Drug Conjugates

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Avelumab (Bavencio®)

Avelumab [package insert]. EMD Serono, Inc, Rockland, MA; 2017.

Indication(s) 1. Patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum‐containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum‐containing chemotherapy2. Patients 12 years and older with metastatic Merkel cell carcinoma (MCC)

Pharmacological Class Anti‐PD‐L1 Monoclonal Antibody

Pre‐Medications All patients should receive pre‐medication with an antihistamine (e.g., diphenhydramine) and acetaminophen 30 to 60 minutes prior to the first 4 avelumab infusions; premedication may be administered prior to subsequent doses as necessary

Dosing/Schedule 10 mg/kg IV over 60 minutes every 2 weeks until disease progression or unacceptable toxicity

Avelumab (Bavencio®)

Avelumab [package insert]. EMD Serono, Inc, Rockland, MA; 2017.

Adverse Drug Reactions Most common ADRs (≥20%) in patients with metastatic Merkel cell carcinoma:• Fatigue• Musculoskeletal pain• Diarrhea• Nausea• Infusion‐related reaction• Rash• Decreased appetite• Peripheral edema

Most common ADRs (≥20%) in patients with locally advanced or metastatic urothelial carcinoma:• Fatigue• Infusion‐related reaction• Musculoskeletal pain• Nausea• Decreased appetite• Urinary tract infection

Monitoring • Blood glucose• LFTs• Serum creatinine• Thyroid function tests (TFTs)

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Durvalumab (Imfinzi™)

Durvalumab [package insert]. AstraZeneca Pharmaceuticals LP, Wilmington, DE; 2017.

Indication(s) 1. Patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum‐containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum‐containing chemotherapy2. Patients with unresectable stage III non‐small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum‐based chemotherapy and radiation therapy

Pharmacological Class Anti‐PD‐L1 Monoclonal Antibody

Pre‐Medications None

Dosing/Schedule 10 mg/kg once every 2 weeks until disease progression or unacceptable toxicity

Durvalumab (Imfinzi™)

Durvalumab [package insert]. AstraZeneca Pharmaceuticals LP, Wilmington, DE; 2017.

Adverse Drug Reactions Most common ADRs (≥15%) of patients:• Fatigue• Musculoskeletal pain• Constipation• Decreased appetite• Nausea• Peripheral Edema• Urinary tract infection• Infection• Immune‐related adverse events

Monitoring • Blood glucose• LFTs• Serum creatinine/BUN• TFTs

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Rituximab + hyaluronidase (Hycela™)

Rituximab and hyaluronidase human [package insert]. Genentech, Inc, South San Francisco, CA; 2017.

Indication(s) Adult patients with follicular lymphoma, diffuse large B‐cell lymphoma,and chronic lymphocytic leukemia

Pharmacological Class Anti‐CD20 Monoclonal Antibody

Pre‐Medications Acetaminophen + an antihistamine prior to each dose

Dosing/Schedule IV rituximab should be administered in cycle 1Chronic lymphocytic leukemia (CLL)• Rituximab 1,600 mg/hyaluronidase 26,800 units (fixed dose) SC on day 1

of a 28‐day cycle in cycles 2 through 6 in combination with fludarabine and cyclophosphamide

Diffuse large B‐cell lymphoma (DLBCL):• Rituximab 1,400 mg/hyaluronidase 23,400 units (fixed dose) SC on day 1

of cycles 2 through 8 in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)

Follicular lymphoma (FL):• Rituximab 1,400 mg/hyaluronidase 23,400 units (fixed dose) SC on day 1

of a 21‐day cycle in cycles 2 through 8 in combination with chemotherapy (also given as monotherapy in maintenance phase)

Rituximab + hyaluronidase (Hycela™)

Rituximab and hyaluronidase human [package insert]. Genentech, Inc, South San Francisco, CA; 2017.

Adverse Drug Reactions

With the exception of Local Cutaneous Reactions, the incidence and profile of adverse reactions reported for Rituxan HYCELA were comparable with those for rituximab

Most common ADRs (≥20%): FL:• Infections• Neutropenia• Nausea• Constipation• Cough• Fatigue

DLBCL:• Infections• Neutropenia• Alopecia• Nausea• Anemia

CLL: • Infections• Neutropenia• Nausea• Thrombocytopenia• Pyrexia• Vomiting• Injection site erythema

Monitoring CBC with differential, hepatitis B serology, serum creatinine/BUN, serum electrolytes, serum uric acid

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Gemtuzumab ozogamicin (Mylotarg™)

Gemtuzumab ozogamicin [package insert]. Wyeth Pharmaceuticals, Inc, Philadelphia, PA; 2000.

Indication(s) Treatment of newly‐diagnosed CD33‐positive acute myeloid leukemia (AML) in adults and for treatment of relapsed or refractory CD33‐positive AML in adults and in pediatric patients 2 years and older.

Pharmacological Class CD33‐directed antibody‐drug conjugate

Pre‐Medications Acetaminophen 650 mg PO + diphenhydramine 50 mg PO/IV 1 hour prior + methylprednisolone 1 mg/kg 30 minutes prior

Dosing/Schedule Newly‐diagnosed, de novo AML (combination with daunorubicin + cytarabine):• Induction: 3 mg/m2 (up to one 4.5 mg vial) on Days 1, 4, and 7• Consolidation: 3 mg/m2 on Day 1 (up to one 4.5 mg vial) Newly‐diagnosed AML (single‐agent regimen):• Induction: 6 mg/m2 on Day 1 and 3 mg/m2 on Day 8 • Continuation: For patients without evidence of disease progression

following induction, up to 8 continuation courses of 2 mg/m2 on Day 1 every 4 weeks

Relapsed or refractory AML (single‐agent regimen): • 3 mg/m2 on Days 1, 4, and 7 (2.2)

Gemtuzumab ozogamicin (Mylotarg™)

Gemtuzumab ozogamicin [package insert]. Wyeth Pharmaceuticals, Inc, Philadelphia, PA; 2000.

Adverse Drug Reactions Most common ADRs (>15%)• Hemorrhage• Infection• Fever• Nausea• Vomiting• Constipation• Headache• Increased AST and ALT• Rash• Mucositis

Monitoring • CBC with differential• LFTs • Creatinine/BUN • Serum electrolytes • Serum uric acid

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Inotuzumab ozogamicin (Besponsa™)

Inotuzumab ozogamicin [package insert]. Wyeth Pharmaceuticals, Inc, Philadelphia, PA; 2017.

Indication(s) Adults with relapsed or refractory B‐cell precursor acute lymphoblastic leukemia (ALL)

Pharmacological Class CD22‐directed antibody‐drug conjugate

Pre‐Medications Corticosteroid + acetaminophen + antihistamine

Dosing/Schedule

CR = complete remission; CRi = complete remission with incomplete hematologic recovery

Inotuzumab ozogamicin (Besponsa™)

Inotuzumab ozogamicin [package insert]. Wyeth Pharmaceuticals, Inc, Philadelphia, PA; 2017.

Adverse Drug Reactions Most common ADRs (≥20%):• Thrombocytopenia• Neutropenia / febrile neutropenia• Infection• Anemia• Leukopenia• Fatigue• Hemorrhage• Pyrexia• Nausea• Headache• Elevated transaminases and hyperbilirubinemia• Abdominal pain

Monitoring CBC with differential, ECG, LFTs, bilirubin, serum electrolytes

Drug‐Drug Interactions Drugs known to prolong the QT interval or induce Torsades de Pointes may increase the risk of a clinically significant QTc interval prolongation

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New Drug Approvals:Small Molecule Inhibitors

Abemaciclib (Verzenio™)

Abemaciclib [package insert]. Lilly USA, LLC, Indianapolis, IN; 2017.

Indication(s) For use in combination with fulvestrant for women with HR‐positive, HER2‐negative advanced or metastatic breast cancer with disease progression following endocrine therapy

Pharmacological Class Cyclin‐Dependent Kinase Inhibitor


Dosing/Schedule Starting dose in combination with fulvestrant:• 150 mg PO twice daily with or without foodStarting dose as monotherapy: • 200 mg PO twice daily with or without food

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Abemaciclib (Verzenio™)

Abemaciclib [package insert]. Lilly USA, LLC, Indianapolis, IN; 2017.

Adverse Drug Reactions Most common ADRs (≥20%):• Diarrhea• Neutropenia• Nausea• Abdominal pain• Infections• Fatigue• Anemia• Leukopenia• Decreased appetite• Vomiting• Headache• Thrombocytopenia

Monitoring CBC with differential, LFTs

Drug‐Drug Interactions • Reduce the abemaciclib dose with concomitant use of strong CYP3A inhibitors (100 mg twice daily)

• Avoid concomitant use of strong CYP3A inducers

Ribociclib (Kisqali®)

Ribociclib [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, NJ; 2017.

Indication(s) For use in combination with an aromatase inhibitor as initial endocrine‐based therapy for the treatment of postmenopausal women with hormone receptor (HR)‐positive, human epidermal growth factor receptor 2 (HER2)‐negative advanced or metastatic breast cancer

Pharmacological Class Cyclin‐Dependent Kinase Inhibitor


Dosing/Schedule Recommended starting dose: • 600 mg PO (three 200 mg tablets) once daily with

or without food for 21 consecutive days followed by 7 days off treatment

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Ribociclib (Kisqali®)

Ribociclib [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, NJ; 2017.

Adverse Drug Reactions Most common ADRs (≥20%):• Neutropenia• Nausea• Fatigue• Diarrhea• Leukopenia

Continued:• Alopecia• Vomiting• Constipation• Headache• Back pain

Monitoring CBC with differential, ECG, LFTs, serum electrolytes

Drug‐Drug Interactions • Avoid concomitant use with strong CYP3A inhibitors. If strong inhibitors cannot be avoided, reduce ribociclib dose to 400 mg once daily

• Avoid concomitant use with strong CYP3A inducers• The dose of sensitive CYP3A substrates with narrow

therapeutic indices may need to be reduced when given concurrently with ribociclib

• Avoid concomitant use of drugs known to prolong QT interval

Neratinib (Nerlynx®)

Neratinib [package insert]. Puma Biotechnology, Inc, Los Angeles, CA; 2017.

Indication(s) Extended adjuvant treatment of adult patients with early stage HER2‐overexpressed/amplified breast cancer, to follow adjuvant trastuzumab‐based therapy

Pharmacological Class Tyrosine Kinase Inhibitor ‐ Anti‐HER2; Epidermal Growth Factor Receptor (EGFR) Inhibitor

Pre‐Medications Antidiarrheal prophylaxis: • Initiate loperamide with the first dose of neratinib and

continue during first 2 cycles (56 days) of treatment:• Days 1 to 14: Loperamide 4 mg orally 3 times daily• Days 15 to 56: Loperamide 4 mg orally twice daily• Days 57 to 365: Loperamide 4 mg as needed

(maximum: 16 mg/day)• Instruct patients to maintain 1‐2 bowel movements per

day

Dosing/Schedule 240 mg (6 tablets) PO once daily with food, continuously for one year

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Neratinib (Nerlynx®)

Neratinib [package insert]. Puma Biotechnology, Inc, Los Angeles, CA; 2017.

Adverse Drug Reactions

Most common ADRs (>5%):• Diarrhea• Nausea• Abdominal pain• Fatigue• Vomiting• Rash• Stomatitis• Decreased appetite

Continued:• Muscle spasms• Dyspepsia• AST or ALT increase• Nail disorder• Dry skin• Abdominal distention• Weight decreased• Urinary tract infection

Monitoring LFTs

Drug‐Drug Interactions • Avoid concomitant use with proton pump inhibitors (PPI) and H2‐receptor antagonists. Separate neratinib by 3 hours after antacid dosing

• Avoid concomitant use with strong or moderate CYP3A4 inhibitors and inducers

• Monitor for adverse reactions of narrow therapeutic agents that are P‐glycoprotein substrates when used concomitantly with neratinib

Niraparib (Zejula®)

Niraparib [package insert]. Tesaro, Inc, Waltham, MA; 2017.

Indication(s) Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum‐based chemotherapy

Pharmacological Class Poly(ADP‐ribose) polymerase (PARP) inhibitor


Dosing/Schedule 300 mg PO once daily with or withoutfood ‐ continued until disease progression or unacceptable toxicity

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Niraparib (Zejula®)

Niraparib [package insert]. Tesaro, Inc, Waltham, MA; 2017.

Adverse Drug Reactions Most common ADRs (≥10%):• Thrombocytopenia• Anemia• Neutropenia• Leukopenia• Palpitations• Nausea• Constipation• Vomiting• Abdominal pain/distention• Mucositis/stomatitis• Diarrhea• Dyspepsia• Dry mouth• Fatigue/asthenia• Decreased appetite

Continued:• Urinary tract infection• AST/ALT elevation• Myalgia• Back pain• Arthralgia• Headache• Dizziness• Dysgeusia• Insomnia• Anxiety• Nasopharyngitis• Dyspnea• Cough• Rash• Hypertension

Monitoring CBC with differential

Brigatinib (Alunbrig®)

Brigatinib [package insert]. Ariad Pharmaceuticals, Inc, Cambridge, MA; 2017.

Indication(s) Patients with metastatic anaplastic lymphoma kinase (ALK)‐positive non‐small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib

Pharmacological Class Tyrosine Kinase Inhibitor ‐ Anaplastic Lymphoma Kinase (ALK) Inhibitor


Dosing/Schedule • 90 mg PO once daily for the first 7 days; if tolerated, increase to 180 mg PO once daily

• May be taken with or without food• If concurrent therapy with strong CYP3A inhibitor cannot

be avoided:• Reduce the brigatinib dose by approximately 50%

(eg, from 180 mg once daily to 90 mg once daily, or from 90 mg once daily to 60 mg once daily)

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Brigatinib (Alunbrig®)

Brigatinib [package insert]. Ariad Pharmaceuticals, Inc, Cambridge, MA; 2017.

Adverse Drug Reactions Most common ADRs (≥25%):• Nausea• Diarrhea• Fatigue• Cough• Headache

Monitoring Blood glucose, creatine phosphokinase (CPK), serum amylase, serum lipase, blood pressure, heart rate

Drug‐Drug Interactions • Avoid concomitant use with strong CYP3A inhibitors and inducers

Acalabrutinib (Calquence®)

Acalabrutinib [package insert]. AstraZeneca Pharmaceuticals LP, Wilmington, DE; 2017.

Indication(s) Adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy

Pharmacological Class Tyrosine Kinase Inhibitor ‐ Bruton Tyrosine Kinase (BTK) Inhibitor


Dosing/Schedule 100 mg PO twice daily; swallow whole with water and with or without food• Strong CYP3A inhibitors: if strong CYP3A inhibitors will be

used short‐term (eg, anti‐infectives for ≤7 days), interrupt acalabrutinib treatment

• Moderate CYP3A inhibitors: Reduce acalabrutinib dose to 100 mg once daily

• Strong CYP3A inducers: if strong CYP3A inducers cannot be avoided, increase acalabrutinib dose to 200 mg twice daily

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Acalabrutinib (Calquence®)

Acalabrutinib [package insert]. AstraZeneca Pharmaceuticals LP, Wilmington, DE; 2017.

Adverse Drug Reactions Most common ADRs (≥20%): • Anemia• Thrombocytopenia• Headache• Neutropenia• Diarrhea• Fatigue• Myalgia• Bruising

Monitoring CBC with differential, ECG

Drug‐Drug Interactions • Avoid co‐administration with strong CYP3A Inhibitors and inducers

• Avoid co‐administration with proton pump inhibitors (PPIs); stagger dosing with H2‐receptor antagonists and antacids by at least 2 hours

Copanlisib (Aliqopa™)

Copanlisib [package insert]. Bayer HealthCare Pharmaceuticals, Inc, Whippany, NJ; 2017.

Indication(s) Adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies

Pharmacological Class Phosphatidylinositol 3‐Kinase (PI3K) Inhibitor


Dosing/Schedule 60 mg administered as a 1‐hour intravenousinfusion on Days 1, 8, and 15 of a 28‐day treatment cycle on an intermittent schedule

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Copanlisib (Aliqopa™)

Copanlisib [package insert]. Bayer HealthCare Pharmaceuticals, Inc, Whippany, NJ; 2017.

Adverse Drug Reactions Most common ADRs (≥20%):• Hyperglycemia• Diarrhea• Decreased general strength and energy• Hypertension• Leukopenia• Neutropenia• Nausea• Lower respiratory tract infections• Thrombocytopenia

Monitoring Blood glucose, CBC with differential, blood pressure

Drug‐Drug Interactions • Avoid concomitant use with strong CYP3A inducers• Reduce dose to 45 mg when concomitantly

administered with strong CYP3A inhibitors

Enasidenib (Idhifa®)

Enasidenib [package insert]. Agios Pharmaceuticals, Cambridge, MA; 2017.

Indication(s) Adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase‐2 (IDH2) mutation

Pharmacological Class Isocitrate dehydrogenase‐2 (IDH2) inhibitor


Dosing/Schedule 100 mg PO once daily with or without fooduntil disease progression or unacceptable toxicity

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Enasidenib (Idhifa®)

Enasidenib [package insert]. Agios Pharmaceuticals, Cambridge, MA; 2017.

Adverse Drug Reactions Most common ADRs (≥20%):• Nausea• Vomiting• Diarrhea• Elevated bilirubin• Decreased appetite

Monitoring CBC with differential, LFTs, serum bilirubin, serum creatinine/BUN, serum electrolytes, serum uric acid

Midostaurin (Rydapt®)

Midostaurin [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, NJ; 2017.

Indication(s) Adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation‐positive (FLT3+), in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation

Pharmacological Class Tyrosine Kinase Inhibitor ‐ FLT3 Inhibitor

Pre‐Medications Administer prophylactic antiemetics prior to midostaurin therapy (e.g. ondansetron)

Dosing/Schedule 50 mg PO twice daily with food on days 8 to 21 of each induction cycle (in combination with daunorubicin and cytarabine) and on days 8 to 21 of each consolidation cycle (in combination with high‐dose cytarabine)

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Midostaurin (Rydapt®)

Midostaurin [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, NJ; 2017.

Adverse Drug Reactions Most common ADRs (≥20%):• Febrile neutropenia• Nausea• Mucositis• Vomiting• Headache• Petechiae

Continued:• Musculoskeletal pain• Epistaxis• Device‐related

infection• Hyperglycemia• Upper respiratory tract

infection

Monitoring CBC with differential

Drug‐Drug Interactions • Strong CYP3A4 inhibitors may increase exposure to midostaurin and its active metabolites. Consider alternative therapies that do not strongly inhibit CYP3A4 or monitor for increased risk of adverse reactions

• Avoid concomitant use as strong CYP3A4 inducers decrease exposure to midostaurin and its active metabolites

New Drug Approvals:Gene Therapy (CAR T‐Cells)

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Tisagenlecleucel (Kymriah™)

Tisagenlecleucel [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, NJ; 2017.

Indication(s) Patients up to age 25 years with B‐cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse

Pharmacological Class CAR T Immunotherapy ‐ Anti‐CD19

Pre‐Medications • Acetaminophen + diphenhydramine (or another H1‐antihistamine) ~ 30 to 60 minutes prior to tisagenlecleucel infusion

• Do not use corticosteroids • Confirm availability of tocilizumab prior to infusion

Dosing/Schedule Tisagenlecleucel 2 to 14 days following completion of the fludarabine/cyclophosphamide regimen (dosing based on the number of (CAR) positive viable T cells

Tisagenlecleucel (Kymriah™)

Tisagenlecleucel [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, NJ; 2017.

Adverse Drug Reactions Most common ADRs (>20%): • Cytokine release syndrome• Hypogammaglobulinemia• Infections‐pathogen

unspecified• Pyrexia• Decreased appetite• Headache• Encephalopathy• Hypotension• Bleeding episodes

Continued: • Tachycardia• Nausea• Diarrhea• Vomiting• Viral infectious

disorders• Hypoxia• Fatigue• Acute kidney injury• Delirium

Monitoring CBC with differential, hepatitis B serology, neurologic function, viral studies, serum creatinine/BUN, serum electrolytes, serum IgG concentrations, serum uric acid

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Axicabtagene ciloleucel (Yescarta™)

Axicabtagene ciloleucel [package insert]. Kite Pharma, Inc, Santa Monica, CA; 2017.

Indication(s) Adult patients with relapsed or refractory large B‐cell lymphoma after two or more lines of systemic therapy, including diffuse large B‐cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B‐cell lymphoma, high‐grade B‐cell lymphoma, and DLBCL arising from follicular lymphoma

Pharmacological Class CAR T Immunotherapy ‐ Anti‐CD19

Pre‐Medications • Acetaminophen 650 mg PO + diphenhydramine 12.5 mg IV/PO ~60 minutes prior to axicabtagene ciloleucel infusion

• Do not use corticosteroids• Confirm availability of tocilizumab prior to infusion

Dosing/Schedule Lymphodepleting chemotherapy with fludarabine and cyclophosphamide on the 5th, 4th, and 3rd day prior to axicabtagene ciloleucel infusion

Axicabtagene ciloleucel (Yescarta™)

Axicabtagene ciloleucel [package insert]. Kite Pharma, Inc, Santa Monica, CA; 2017.

Adverse Drug Reactions Most common ADRs (≥20%):• Cytokine release syndrome• Fever• Hypotension• Encephalopathy• Tachycardia• Fatigue• Headache• Decreased appetite• Chills• Diarrhea

Continued:• Febrile neutropenia• Infections‐pathogen

unspecified• Nausea• Hypoxia• Tremor• Cough• Vomiting• Dizziness• Constipation• Cardiac arrhythmias

Monitoring CBC with differential, hepatitis B serology, neurologic function, viral studies, serum IgG concentrations

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New Drug Approvals:Biosimilars

Trastuzumab‐dkst (Ogivri™)Biosimilar to trastuzumab HERCEPTIN®

Pharmacological Class HER2/neu receptor antagonist

Indications • Treatment of HER2‐overexpressing breast cancer• Treatment of HER2‐overexpressing metastatic

gastric or gastroesophageal junction adenocarcinoma

Trastuzumab‐dkst [package insert]. Mylan GmbH, Zurich Switzerland; 2017.

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Bevacizumab‐awwb (Mvasi®)

Bevacizumab‐awwb [package insert]. Amgen, Inc, Thousand Oaks, CA; 2017.

Biosimilar to bevacizumab AVASTIN®

Pharmacological Class Vascular endothelial growth factor‐specific angiogenesis inhibitor

Indications • Metastatic colorectal cancer, with intravenous 5‐fluorouracil–based chemotherapy for first‐ or second‐line treatment

• Metastatic colorectal cancer, with fluoropyrimidine‐irinotecan‐or fluoropyrimidine‐oxaliplatin‐based chemotherapy for second‐line treatment in patients who have progressed on a first‐line bevacizumab product‐containing regimen

• Non‐squamous non‐small cell lung cancer, with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease

• Glioblastoma, as a single agent for adult patients with progressive disease following prior therapy.

• Metastatic renal cell carcinoma with interferon alfa • Cervical cancer, in combination with paclitaxel and cisplatin or

paclitaxel and topotecan

New Indications

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New Indications by Class

N=13

N=6

N=2

N=1 22 Drugs with New Indications

oSmall Molecule Inhibitors (n=13)

oMonoclonal Antibodies (n=6)

oTraditional Chemotherapy (n=2)

oHormone Therapy (n=1)


New Indications by Disease State

N=6

N=6

N=3N=3

N=3

N=3

N=2

N=1N=1

N=1

22 Drugs / 29 Indications

o Lung Cancer (n=6)

o Genitourinary Cancer (n=6)

o Gastrointestinal Cancer (n=3)

o Leukemia (n=3)

o Lymphoma (n=3)

o Breast Cancer (n=3)

o Hepatocellular Carcinoma (n=2)

o Gynecological Cancer (n=1)

o Skin Cancer (n=1)

o Multiple Myeloma (n=1)


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Monoclonal Antibodies•Blinatumomab BLINCYTO®: Relapsed or refractory B‐cell precursor acute lymphoblastic leukemia (ALL) in adults and children

•Brentuximab vedotin ADCETRIS®: Adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30‐expressing mycosis fungoides (MF) who have received prior systemic therapy

•Obinutuzumab GAZYVA®: Adult patients with previously untreated stage II bulky, III, or IV follicular lymphoma (FL) ‐ in combination with chemotherapy, followed by obinutuzumab monotherapy in patients achieving at least a partial remission

•Pertuzumab PERJETA®: In combination with trastuzumab HERCEPTIN® and chemotherapy as adjuvant treatment of patients with HER2‐positive early breast cancer at high risk of recurrence


Monoclonal Antibodies•Nivolumab OPDIVO™: • Adjuvant treatment of patients with melanoma with involvement of lymph nodes or in patients with metastatic disease who have undergone complete resection

• Treatment of hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib

• Patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum‐containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum‐containing chemotherapy

• Patients 12 years and older with mismatch repair deficient (dMMR) and microsatellite instability high (MSI‐H) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan


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Monoclonal Antibodies•Pembrolizumab KEYTRUDA®: • In combination with pemetrexed and carboplatin for the treatment of patients with previously untreated metastatic non‐squamous non‐small cell lung cancer (NSCLC)

• Adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or those who have relapsed after three or more prior lines of therapy

• Patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum‐containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum‐containing chemotherapy

• Patients with recurrent locally advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma whose tumors express PD‐L1

• Adult and pediatric patients with unresectable or metastatic, MSI‐H or dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options or with MSI‐H or dMMR colorectal cancer that have progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan


Small Molecule Inhibitors•Afatinib GILOTRIF®: Broadened indication in first‐line treatment of patients with metastatic non‐small cell lung cancer (NSCLC) whose tumors have non‐resistant epidermal growth factor receptor (EGFR) mutations

•Alectinib ALECENSA®: Patients with anaplastic lymphoma kinase (ALK)‐positive metastatic non‐small cell lung cancer (NSCLC)

•Bosutinib BOSULIF®: Patients with newly‐diagnosed chronic phase (CP) Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML)

•Cabozantinib CABOMETYX™: Patients with advanced renal cell carcinoma (RCC)

•Ceritinib ZYKADIA®: Patients with metastatic anaplastic lymphoma kinase (ALK)‐positive metastatic non‐small cell lung cancer (NSCLC)


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Small Molecule Inhibitors•Dabrafenib TAFINLAR® and Trametinib MEKINIST®: Patients with metastatic non‐small cell lung cancer (NSCLC) with BRAF V600E mutation

•Dasatinib SPRYCEL®: Pediatric patients with Philadelphia chromosome‐positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase

•Palbociclib IBRANCE®: Hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women

•Olaparib LYNPARZA®: • Patients with deleterious or suspected deleterious germline BRCA‐mutated (gBRCAm), HER2‐negative metastatic breast cancer who have been treated with chemotherapy either in the neoadjuvant, adjuvant, or metastatic setting

• Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum‐based chemotherapy


Small Molecule Inhibitors•Osimertinib TAGRISSO®: Patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation‐positive non‐small cell lung cancer (NSCLC), whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy

•Regorafenib STIVARGA®: Patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

•Sunitinib malate SUTENT®: Adult patients at high risk of recurrent renal cell carcinoma (RCC) following nephrectomy


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Miscellaneous •Abiraterone acetate ZYTIGA®: In combination with prednisone for metastatic high‐risk castration‐sensitive prostate cancer (CSPC)

•Low‐dose (20 mg/m2 every 3 weeks) Cabazitaxel JEVTANA®: In combination with prednisone for the treatment of patients with metastatic castration‐resistant prostate cancer previously treated with a docetaxel‐containing treatment regimen

•Lenalidomide REVLIMID®: Maintenance therapy for patients with multiple myeloma following autologous stem cell transplant


2017 – 2018 Drug Updates in Hematology/Oncology

L a u r a J . H a c k e t t , P h a r m D , B C O PC l i n i c a l P h a r m a c i s t – H e m a t o l o g y / O n c o l o g y

D a r t m o u t h - H i t c h c o c k M e d i c a l C e n t e r

L a u r a . J . H a c k e t t @ H i t c h c o c k . o r g

2017 –2018 drug updates in hematology/oncology spring slides/130pm drug...protein •vast majority...

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