Antineoplastic Prescribing II Brian Boulmay MD From poisons

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Antineoplastic Prescribing II Brian Boulmay, MD

Antineoplastic Prescribing II Brian Boulmay, MD

From poisons to targeted agents

From poisons to targeted agents

Hitting the Wall • 70’s-80’s-90’s- ▫ Application of more and more intensive chemotherapy for

Hitting the Wall • 70’s-80’s-90’s- ▫ Application of more and more intensive chemotherapy for solid tumors • More = better : ▫ High-dose chemotherapy: no benefit in advanced breast cancer. ▫ Outcomes in liquid tumors now less from chemo than from better supportive care

Targeting strategies ▫ ▫ Imatinib (Gleevec) IRIS Trial: 98% progression free survival (PFS) Long

Targeting strategies ▫ ▫ Imatinib (Gleevec) IRIS Trial: 98% progression free survival (PFS) Long term disease control t(9; 22) often disappears. �Will return if imatinib stopped. • Shift in management from transplant daily pill.

Targeting Pathways Multiple receptor (VEGF-R, EGF-R) VEGF Ras EML 4 -Alk Protein Raf PI

Targeting Pathways Multiple receptor (VEGF-R, EGF-R) VEGF Ras EML 4 -Alk Protein Raf PI 3 K AKT m. TOR MEK

Antineoplastic Prescribing- II • Immunomodulators ▫ Interferon, Interleukin • Monoclonal Antibodies ▫ ▫ Rituximab

Antineoplastic Prescribing- II • Immunomodulators ▫ Interferon, Interleukin • Monoclonal Antibodies ▫ ▫ Rituximab Trastuzumab, TDM-1 Bevacizumab Cetuximab

Antineoplastic Prescribing- II • Small Molecules ▫ Imatinib, nilotinib, erlotinib…. . • Hormones ▫

Antineoplastic Prescribing- II • Small Molecules ▫ Imatinib, nilotinib, erlotinib…. . • Hormones ▫ Tamoxifen, leuprolide, flutamide…. . • m. Tor inhibitors

A sampling of the last 10 years • • • • brentuximab vedotin abiraterone

A sampling of the last 10 years • • • • brentuximab vedotin abiraterone apatinib obatoclax blinatumomab inotuzumab ozogamycin gemtuzumab ozogamycin vandetanib critozinib bexarotene romidepsin vorinostat ziv-aflibercept denileuken diftitox alemtuzumab • • • • • ipilimumab ofatumumab lapatinib bevacizumab cetuximab panitumumab sunitinib sorafenib nilotinib dasatinib erlotinib pazopanib ibritumomab tiuxetan I 131 -tositumumab temsirolimus pembrolizumab nivolumab

Immunomodulators • Mechanism: Enhance immune function • Cell Cycle Non-Specific • Major Toxicity: ▫

Immunomodulators • Mechanism: Enhance immune function • Cell Cycle Non-Specific • Major Toxicity: ▫ Myalgia ▫ Hypotension • Examples ▫ Interferon ▫ Aldesleukin (IL-2)

Interferon-alpha 2 b Dosing range Indications Common Toxicities SQ or IV Melanoma Depression CML

Interferon-alpha 2 b Dosing range Indications Common Toxicities SQ or IV Melanoma Depression CML Hepatic toxicity Fever

Aldesleukin- IL 2 Dosing range Indications Common Toxicities IV Renal Cell Carcinoma Hypotension Capillary

Aldesleukin- IL 2 Dosing range Indications Common Toxicities IV Renal Cell Carcinoma Hypotension Capillary leak Fever

“–m. Abs”: Monoclonal antibodies

“–m. Abs”: Monoclonal antibodies

“-ibs and –m. Abs”: Nomenclature Beva- ci- zu- mab • Monoclonal antibodies, or –m.

“-ibs and –m. Abs”: Nomenclature Beva- ci- zu- mab • Monoclonal antibodies, or –m. Abs: ▫ The first part of the name: unique and does not mean anything in particular. ▫ The second part of the name: the target of the antibody. ▫ The third part of the name: the source of the antibody. � When the third part of the name starts with a vowel then the second part has three letters. ▫ The fourth part is always -mab World Health Organization

“-ibs and –m. Abs”: Nomenclature Beva- ci- zu- mab • Monoclonal antibodies, or –m.

“-ibs and –m. Abs”: Nomenclature Beva- ci- zu- mab • Monoclonal antibodies, or –m. Abs: ▫ The first part of the name: unique and does not mean anything in particular. ▫ The second part of the name: the target of the antibody. ▫ The third part of the name: the source of the antibody. � When the third part of the name starts with a vowel then the second part has three letters. ▫ The fourth part is always -mab World Health Organization

“-ibs and –m. Abs”: Nomenclature Beva- ci- zu- mab • Monoclonal antibodies, or –m.

“-ibs and –m. Abs”: Nomenclature Beva- ci- zu- mab • Monoclonal antibodies, or –m. Abs: ▫ The first part of the name: unique and does not mean anything in particular. ▫ The second part of the name: the target of the antibody. ▫ The third part of the name: the source of the antibody. � When the third part of the name starts with a vowel then the second part has three letters. ▫ The fourth part is always -mab World Health Organization

“-ibs and –m. Abs”: Nomenclature Beva- ci- zu- mab • Monoclonal antibodies, or –m.

“-ibs and –m. Abs”: Nomenclature Beva- ci- zu- mab • Monoclonal antibodies, or –m. Abs: ▫ The first part of the name: unique and does not mean anything in particular. ▫ The second part of the name: the target of the antibody. ▫ The third part of the name: the source of the antibody. � When the third part of the name starts with a vowel then the second part has three letters. ▫ The fourth part is always -mab World Health Organization

Target of Antibody • • Source of Antibody o(s) bone u human li(m) immune

Target of Antibody • • Source of Antibody o(s) bone u human li(m) immune xi chimeric ci(r) cardiovascular zu humanized tu(m) misc tumor Den-os-u-mab Beva- ci- zu- mab Ce- tu- xi- mab Pani- tum-u- mab • • Ri- tu- xi- mab Alem- tu- zu- mab Inf- li- xi- mab Ab- ci- xi- mab

-m. Abs: Allergy • Non- monoclonals ▫ Rabbit or horse derived ATG • Monoclonal

-m. Abs: Allergy • Non- monoclonals ▫ Rabbit or horse derived ATG • Monoclonal chimerics: �Rituximab �Cetuximab �Pine tree pollen? • Monoclonal humanized: �Pantitumumab �Bevacizumab �Trastuzumab Potential for Allergy + Need for Premeds

-m. ABs • Mechanism: “Destroy specific cells with antigenic markers” • Cell Cycle Non-Specific

-m. ABs • Mechanism: “Destroy specific cells with antigenic markers” • Cell Cycle Non-Specific • Major Toxicities: ▫ Infusion-related ▫ Rash ▫ Long-term effects?

-m. Abs Dosing range Indications Common Toxicities IV Kras wildtype colon cancer Infusion reaction

-m. Abs Dosing range Indications Common Toxicities IV Kras wildtype colon cancer Infusion reaction 400 mg/m 2 loading dose Acne 250 mg/m 2 weekly Interstitial lung disease Cetuximab • Mechanism of Action: ▫ Ig. G 1 binds EGFR with higher affinity than other EGF. ▫ Blocks ligand induced phosphorylation of EGFR �Decreased MAP-K �Decreased Akt Pathway activity

-m. Abs Dosing range Indications Common Toxicities IV Kras wildtype colon cancer Infusion reaction

-m. Abs Dosing range Indications Common Toxicities IV Kras wildtype colon cancer Infusion reaction 400 mg/m 2 loading dose Acne 250 mg/m 2 weekly Interstitial lung disease Cetuximab • Mechanism of Action: ▫ Ig. G 1 binds EGFR with higher affinity than other EGF. ▫ Blocks ligand induced phosphorylation of EGFR �Decreased MAP-K �Decreased Akt Pathway activity �Leads to long-term down regulation �Recruit host immune function �Inhibits EGFR Mediated Repair of DNA Strand breaks

-m. Abs ▫ Irinotecan Sensitivity: Dosing range Indications Common Toxicities IV Kras wildtype colon

-m. Abs ▫ Irinotecan Sensitivity: Dosing range Indications Common Toxicities IV Kras wildtype colon cancer Infusion reaction 400 mg/m 2 loading dose Acne 250 mg/m 2 weekly Interstitial lung disease �Cetuximab can restore irinotecan sensitivity in irinotecan-insensitive cells. �May do the same in oxaliplatin resistant patients ▫ Combined with XRT in H+N cancer. Cetuximab Cunningham NEJM 2004, Souglakos Annals Onc 2007

-m. Abs ▫ KRAS: �Intracellular proto-oncogenic mediator of downstream signaling Dosing range Indications Common

-m. Abs ▫ KRAS: �Intracellular proto-oncogenic mediator of downstream signaling Dosing range Indications Common Toxicities IV Kras wildtype colon cancer Infusion reaction �Activating mutations render Kras independent of EGFR signaling. 400 mg/m 2 loading dose Acne 250 mg/m 2 weekly Interstitial lung disease �Kras mutant tumors do not respond to cetuximab in colon cancer. �Does not matter in lung cancer. Cetuximab Krapetis NEJM 2008

Cetuximab Rash

Cetuximab Rash

-m. Abs Dosing range Indications Common Toxicities IV Kras wildtype colon cancer Infusion reaction

-m. Abs Dosing range Indications Common Toxicities IV Kras wildtype colon cancer Infusion reaction 400 mg/m 2 loading dose Acne 250 mg/m 2 weekly Interstitial lung disease Bevacizumab • Mechanism of action: ▫ Inhibition of angiogenesis ▫ Pruning of existing vessels.

-m. Abs Dosing range Indications Common Toxicities IV Kras wildtype colon cancer Infusion reaction

-m. Abs Dosing range Indications Common Toxicities IV Kras wildtype colon cancer Infusion reaction 400 mg/m 2 loading dose Acne 250 mg/m 2 weekly Interstitial lung disease Bevacizumab • Mechanism of action: ▫ Inhibition of angiogenesis ▫ Pruning of existing vessels. ▫ Normalization of structurally and functionally aberrant vessels �improves drug delivery ▫ Sensitization of tumor endothelium to cytotoxic damage

-m. Abs Dosing range Indications Common Toxicities IV Kras wildtype colon cancer Infusion reaction

-m. Abs Dosing range Indications Common Toxicities IV Kras wildtype colon cancer Infusion reaction 400 mg/m 2 loading dose Acne 250 mg/m 2 weekly Interstitial lung disease Bevacizumab • Mechanism of action: ▫ Inhibition of angiogenesis ▫ Pruning of existing vessels. ▫ Normalization of structurally and functionally aberrant vessels �improves drug delivery ▫ Sensitization of tumor endothelium to cytotoxic damage ▫ Direct cytostatic effects on tumor cells.

-m. Abs- Bevacizumab • Clinical Uses: ▫ Metastatic colorectal cancer ▫ Metastatic lung cancer

-m. Abs- Bevacizumab • Clinical Uses: ▫ Metastatic colorectal cancer ▫ Metastatic lung cancer ▫ Renal cell carcinoma ▫ Ovarian cancer ▫ Cervical cancer (GOG 240) ▫ NSABP C-08: �No role in colorectal cancer adjuvant setting Tewari JCO 2013, Allegra JCO 2010

-m. Abs- Bevacizumab • Toxicities: ▫ Hypertension ▫ Proteinuria �What to do if it

-m. Abs- Bevacizumab • Toxicities: ▫ Hypertension ▫ Proteinuria �What to do if it occurs? ▫ GI perforation � 1% incidence overall ▫ Hemorrhage �All grade rate: 30% Hapani Oncology 2010

-m. Abs- Rituximab Dosing range Indications Common Toxicities IV NHL (CD 20+) Infusion reaction

-m. Abs- Rituximab Dosing range Indications Common Toxicities IV NHL (CD 20+) Infusion reaction 375 mg/m 2 TLS • Rituximab: ▫ CD 20 positive ▫ Diffuse large B-cell lymphomas ▫ Low grade lymphomas ▫ Rheumatologic disorders ▫ TTP/ ITP Rituximab ▫ ? Hodgkin Lymphoma �Lymphocyte predominant �Anecdotal reports in relapse

-m. Abs- Rituximab • Mechanism of Action: ▫ CD 20 positive: �Regulates cell cycle

-m. Abs- Rituximab • Mechanism of Action: ▫ CD 20 positive: �Regulates cell cycle initiation �May function as calcium channel ▫ Activate complement mediated cytotoxicity ▫ Antibody mediated cytotoxicity

-m. Abs- Trastuzumab Dosing range Indications Common Toxicities IV Breast Infusion reaction 4 mg/kg

-m. Abs- Trastuzumab Dosing range Indications Common Toxicities IV Breast Infusion reaction 4 mg/kg loading dose Stomach CHF 2 mg/m weekly Myalgias Trastuzumab • Indications: ▫ Her 2/neu positive breast cancer. �Adjuvant and metastatic ▫ Her 2/neu positive gastric cancer. �Metastatic only ▫ No known human ligand for Her 2.

-m. Abs- trastuzumab • Mechanism of Action: ▫ Prevention of Her 2 receptor dimerization

-m. Abs- trastuzumab • Mechanism of Action: ▫ Prevention of Her 2 receptor dimerization ▫ Immune activation ▫ Endocytic destruction of the receptor • Toxicity: ▫ Cardiac �Not to be used concurrently with doxorubicin/epirubicin

The –ibs: Small molecule antineoplastic agents

The –ibs: Small molecule antineoplastic agents

Small molecule inhibitors • A small molecule inhibitor: ▫ Enzyme inhibitor that blocks the

Small molecule inhibitors • A small molecule inhibitor: ▫ Enzyme inhibitor that blocks the action of one or many protein kinases either on the cell membrane or intracellularly. • Which amino acids’ phosphorylation is inhibited: ▫ Tyrosine kinases: TKIs ▫ Serine/threonine kinases ▫ Dual specificity act on all three �sorafanib

Targeting Pathways Multiple receptor (VEGF-R, BCR/abl) VEGF Ras EML 4 -Alk Protein Raf PI

Targeting Pathways Multiple receptor (VEGF-R, BCR/abl) VEGF Ras EML 4 -Alk Protein Raf PI 3 K AKT m. TOR MEK

ibs- Small molecules Name Target afatinib Imatinib Gefitinib Sorafenib Dasatinib Sunitinib Erlotinib Nilotinib Lapatinib

ibs- Small molecules Name Target afatinib Imatinib Gefitinib Sorafenib Dasatinib Sunitinib Erlotinib Nilotinib Lapatinib Vandetanib EGFR/Erb 2 Bcr-Abl EGFR multiple targets Erb 1 Bcr-Abl Erb 1/Erb 2 RET/VEGFR/EGFR Pazopanib VEGFR 2/PDGFR/c-kit

Imatinib • A tyrosine kinase inhibitor • Inhibits ABL ▫ Used in CML •

Imatinib • A tyrosine kinase inhibitor • Inhibits ABL ▫ Used in CML • Inhibits c-Kit (CD 117) ▫ Used in GIST • Toxicity ▫ Cytopenias ▫ Periorbital edema ▫ Rash

Dasatinib • Inhibits ABL, c-kit, SRC kinases; but not EGFR, erb 2 • Used

Dasatinib • Inhibits ABL, c-kit, SRC kinases; but not EGFR, erb 2 • Used in GIST and CML • Toxicities: ▫ Neutropenia ▫ Pleural effusion ▫ Peripheral edema

Nilotinib • Inhibits ABL • Used in CML • Like imatinib and dasatinib, T

Nilotinib • Inhibits ABL • Used in CML • Like imatinib and dasatinib, T 315 i mutation confers resistance to nilotinib

Sunitinib • Targets multiple receptor kinases • Targets PDGFR, VEGFR, KIT (CD 117) •

Sunitinib • Targets multiple receptor kinases • Targets PDGFR, VEGFR, KIT (CD 117) • Used in renal cell carcinoma and imatinib resistant GIST • Toxicity: ▫ Hand-foot syndrome, diarrhea, stomatitis

Sorafanib • Targets the TKs VEGFR and PDGFR • Targets the serine/threonine kinase raf:

Sorafanib • Targets the TKs VEGFR and PDGFR • Targets the serine/threonine kinase raf: ▫ By extension targets the raf/Map/erk (MAP Kinase) pathway • Used in renal cell carcinoma. • Phase III data shows survival benefit in HCCa

Vemurafenib • Braf V 600 E mutated melanoma • Reactions: ▫ QTc prolongation ▫

Vemurafenib • Braf V 600 E mutated melanoma • Reactions: ▫ QTc prolongation ▫ Rash: �Keratosis pilaris �Different from cetuximab and erlotinib

Hormone Therapy

Hormone Therapy

Hormonal Agents • Anti-hormonal agents block or prevent hormonal signalling as a driven for

Hormonal Agents • Anti-hormonal agents block or prevent hormonal signalling as a driven for malignancy proliferation • Cell cycle non-specific • Examples: ▫ ▫ Tamoxifen Leuprolide Bicalutamide Anastrazole

Hormonal Agents • Tamoxifen: ▫ Indication: �Breast cancer ▫ Toxicities: �Hot flashes �Endometrial cancer

Hormonal Agents • Tamoxifen: ▫ Indication: �Breast cancer ▫ Toxicities: �Hot flashes �Endometrial cancer �Thrombosis ▫ Can be used in premenopausal and post menopausal women

Hormonal Agents • Anastrazole: ▫ Indication: �Breast cancer ▫ Toxicities: �Hot flashes �Endometrial cancer

Hormonal Agents • Anastrazole: ▫ Indication: �Breast cancer ▫ Toxicities: �Hot flashes �Endometrial cancer �Thrombosis �Bone pain �Osteoporosis ▫ Used in post menopausal women only

Hormonal Agents • Anastrozole: 'aromatase inhibitor’ • Aromatase is found in ovarian and adipose

Hormonal Agents • Anastrozole: 'aromatase inhibitor’ • Aromatase is found in ovarian and adipose tissue and accounts for the extraglandular (peripheral) formation of estrogen • Androstenedione is aromatised to estradione which subsequently is converted into estradiol in extra-glandular (peripheral) sites. • Anastrazole preferentially acts on aromatase in the peripheral tissues and not in the ovary: ▫ Thus, ineffective in women whose promary source of estriadiol is the ovary (ie premenopasual women. )

Hormonal Agents • Leuprolide and goserelin: ▫ Sex hormone synthesis from ovaries and testes

Hormonal Agents • Leuprolide and goserelin: ▫ Sex hormone synthesis from ovaries and testes is regulated by the pituitary by realease of LH. ▫ The hypothalamus secretes LHRH in a pulsatile manner, which stimulates LH release and sex hormone production.

Hormonal Agents • Leuprolide and goserelin: ▫ Similar to LHRH, but provides continuous stimulation

Hormonal Agents • Leuprolide and goserelin: ▫ Similar to LHRH, but provides continuous stimulation of the pituitary. ▫ Downregulation of the LHRH receptor in the pituitary and decreased LH production: �Decreased sex hormone production. ▫ Uses: �Prostate cancer �Breast cancer

Hormonal Agents • Bicalutamide: ▫ Binds to the receptor for dihydrotestosterone. ▫ Often used

Hormonal Agents • Bicalutamide: ▫ Binds to the receptor for dihydrotestosterone. ▫ Often used in combination with leuprolide for complete androgen blockade.

Hormonal Agents • Enzalutamide: ▫ Has a 5 -five folding binding affinity for the

Hormonal Agents • Enzalutamide: ▫ Has a 5 -five folding binding affinity for the androgen receptor. ▫ Prevents the AR from binding to DNA.

Hormonal Agents • Abiraterone: ▫ Inhibits 17α-hydroxylase/C 17, 20 lyase (aka CYP 17 A

Hormonal Agents • Abiraterone: ▫ Inhibits 17α-hydroxylase/C 17, 20 lyase (aka CYP 17 A 1) ▫ CYP 17 catalyzes two reactions in adrenals, testes, and prostate cancer: �the conversion of pregnenolone and progesterone to 17 -αhydroxy derivatives by its 17 α-hydroxylase activity �subsequent formation of dehydroepiandrosterone androstenedione

Hormonal Agents • Abiraterone: ▫ Consequence of CYP 17 A inhibition?

Hormonal Agents • Abiraterone: ▫ Consequence of CYP 17 A inhibition?

Hormonal Agents • Abiraterone: ▫ Consequence of CYP 17 A inhibition? �Inhibition of cortisol

Hormonal Agents • Abiraterone: ▫ Consequence of CYP 17 A inhibition? �Inhibition of cortisol production ?

Hormonal Agents • Abiraterone: ▫ Consequence of CYP 17 A inhibition? �Inhibition of cortisol

Hormonal Agents • Abiraterone: ▫ Consequence of CYP 17 A inhibition? �Inhibition of cortisol production increased ACTH production ?

Hormonal Agents • Abiraterone: ▫ Consequence of CYP 17 A inhibition? �Inhibition of cortisol

Hormonal Agents • Abiraterone: ▫ Consequence of CYP 17 A inhibition? �Inhibition of cortisol production increased ACTH production hypokalemia, hypertension, fluid retention �Side effects prevented with prednisone 5 mg po BID.

m. TOR Intracellular Pathway PI 3 K AKT m. TOR Nucleus

m. TOR Intracellular Pathway PI 3 K AKT m. TOR Nucleus

m. TOR Inhibition • Temsirolimus ▫ IV agent ▫ Used in renal cell carcinoma

m. TOR Inhibition • Temsirolimus ▫ IV agent ▫ Used in renal cell carcinoma ▫ Side effects: stomatitis • Everolimus ▫ Oral agent ▫ Used in kidney cancer, breast cancer, neuroendocrine tumors ▫ Side effects: stomatitis • Mechanism of resistance: AKT?