1. Antineoplastic Prescribing II
Brian Boulmay, MD

2. From poisons to targeted agents

4. Hitting the Wall 70’s-80’s-90’s- More = better :
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

5. Targeting strategies Shift in management from transplantdaily pill.
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.

6. Targeting Pathways Multiple receptor (VEGF-R, EGF-R) VEGF PI3K Ras
EML4-Alk Protein
AKT
Raf
mTOR
MEK

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

8. Antineoplastic Prescribing- II
Small Molecules
Imatinib, nilotinib, erlotinib…..
Hormones
Tamoxifen, leuprolide, flutamide…..
mTor inhibitors

9. 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
I131-tositumumab
temsirolimus
pembrolizumab
nivolumab

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

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

12. Aldesleukin- IL2 Dosing range Indications Common Toxicities IV
Renal Cell Carcinoma
Hypotension
Capillary leak
Fever

13. “–mAbs”: Monoclonal antibodies

14. “-ibs and –mAbs”: Nomenclature
Beva- ci- zu- mab
Monoclonal antibodies, or –mAbs:
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

15. “-ibs and –mAbs”: Nomenclature
Beva- ci- zu- mab
Monoclonal antibodies, or –mAbs:
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

16. “-ibs and –mAbs”: Nomenclature
Beva- ci- zu- mab
Monoclonal antibodies, or –mAbs:
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

17. “-ibs and –mAbs”: Nomenclature
Beva- ci- zu- mab
Monoclonal antibodies, or –mAbs:
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

18. Den-os-u-mab Beva- ci- zu- mab Ri- tu- xi- mab Ce- tu- xi- mab
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

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

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

21. -mAbs Cetuximab Mechanism of Action:
IgG1 binds EGFR with higher affinity than other EGF.
Blocks ligand induced phosphorylation of EGFR
Decreased MAP-K
Decreased Akt Pathway activity
Dosing range
Indications
Common Toxicities IV
Kras wild-type colon cancer
Infusion reaction
400mg/m2 loading dose
Acne
250mg/m2 weekly
Interstitial lung disease
Cetuximab

22. -mAbs Cetuximab Mechanism of Action:
IgG1 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
Dosing range
Indications
Common Toxicities IV
Kras wild-type colon cancer
Infusion reaction
400mg/m2 loading dose
Acne
250mg/m2 weekly
Interstitial lung disease
Cetuximab

23. -mAbs Cetuximab Irinotecan Sensitivity:
Cetuximab can restore irinotecan sensitivity in irinotecan-insensitive cells.
May do the same in oxaliplatin resistant patients
Combined with XRT in H+N cancer.
Dosing range
Indications
Common Toxicities IV
Kras wild-type colon cancer
Infusion reaction
400mg/m2 loading dose
Acne
250mg/m2 weekly
Interstitial lung disease
Cetuximab
Cunningham NEJM 2004, Souglakos Annals Onc 2007

24. -mAbs
KRAS:
Intracellular proto-oncogenic mediator of downstream signaling
Activating mutations render Kras independent of EGFR signaling.
Kras mutant tumors do not respond to cetuximab in colon cancer.
Does not matter in lung cancer.
Dosing range
Indications
Common Toxicities IV
Kras wild-type colon cancer
Infusion reaction
400mg/m2 loading dose
Acne
250mg/m2 weekly
Interstitial lung disease
Cetuximab
Krapetis NEJM 2008

25. Cetuximab Rash

26. -mAbs Bevacizumab Mechanism of action: Inhibition of angiogenesis
Dosing range
Indications
Common Toxicities IV
Kras wild-type colon cancer
Infusion reaction
400mg/m2 loading dose
Acne
250mg/m2 weekly
Interstitial lung disease
Mechanism of action:
Inhibition of angiogenesis
Pruning of existing vessels.
Bevacizumab

27. -mAbs Bevacizumab Mechanism of action: Inhibition of angiogenesis
Dosing range
Indications
Common Toxicities IV
Kras wild-type colon cancer
Infusion reaction
400mg/m2 loading dose
Acne
250mg/m2 weekly
Interstitial lung disease
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
Bevacizumab

28. -mAbs Bevacizumab Mechanism of action: Inhibition of angiogenesis
Dosing range
Indications
Common Toxicities IV
Kras wild-type colon cancer
Infusion reaction
400mg/m2 loading dose
Acne
250mg/m2 weekly
Interstitial lung disease
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.
Bevacizumab

29. -mAbs- Bevacizumab Clinical Uses: Metastatic colorectal cancer
Metastatic lung cancer
Renal cell carcinoma
Ovarian cancer
Cervical cancer (GOG240)
NSABP C-08:
No role in colorectal cancer adjuvant setting
Tewari JCO 2013, Allegra JCO 2010

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

31. -mAbs- Rituximab Rituximab Rituximab: CD20 positive
Dosing range
Indications
Common Toxicities IV
NHL (CD20+)
Infusion reaction
375mg/m2
TLS
Rituximab:
CD20 positive
Diffuse large B-cell lymphomas
Low grade lymphomas
Rheumatologic disorders
TTP/ ITP
? Hodgkin Lymphoma
Lymphocyte predominant
Anecdotal reports in relapse
Rituximab

32. -mAbs- Rituximab Mechanism of Action: CD20 positive:
Regulates cell cycle initiation
May function as calcium channel
Activate complement mediated cytotoxicity
Antibody mediated cytotoxicity

33. -mAbs- Trastuzumab Trastuzumab Indications:
Her2/neu positive breast cancer.
Adjuvant and metastatic
Her2/neu positive gastric cancer.
Metastatic only
No known human ligand for Her2.
Dosing range
Indications
Common Toxicities IV
Breast
Infusion reaction
4mg/kg loading dose
Stomach
CHF
2 mg/m weekly
Myalgias
Trastuzumab

34. -mAbs- trastuzumab Mechanism of Action: Toxicity:
Prevention of Her2 receptor dimerization
Immune activation
Endocytic destruction of the receptor
Toxicity:
Cardiac
Not to be used concurrently with doxorubicin/epirubicin

35. The –ibs: Small molecule antineoplastic agents

36. 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

37. Targeting Pathways Multiple receptor (VEGF-R, EGF-R, BCR/abl) VEGF
PI3K
Ras
EML4-Alk Protein
AKT
Raf
mTOR
MEK

38. ibs- Small molecules Name Target afatinib EGFR/Erb2 Imatinib Bcr-Abl
Gefitinib
EGFR
Sorafenib
multiple targets
Dasatinib
Sunitinib
Erlotinib
Erb1
Nilotinib
Lapatinib
Erb1/Erb2
Vandetanib
RET/VEGFR/EGFR
Pazopanib
VEGFR2/PDGFR/c-kit

39. Imatinib A tyrosine kinase inhibitor Inhibits ABL
Used in CML
Inhibits c-Kit (CD117)
Used in GIST
Toxicity
Cytopenias
Periorbital edema
Rash

40. Dasatinib Inhibits ABL, c-kit, SRC kinases; but not EGFR, erb2
Used in GIST and CML
Toxicities:
Neutropenia
Pleural effusion
Peripheral edema

41. Nilotinib Inhibits ABL Used in CML
Like imatinib and dasatinib, T315i mutation confers resistance to nilotinib

42. Sunitinib Targets multiple receptor kinases
Targets PDGFR, VEGFR, KIT (CD117)
Used in renal cell carcinoma and imatinib resistant GIST
Toxicity:
Hand-foot syndrome, diarrhea, stomatitis

43. 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

44. Vemurafenib Braf V600E mutated melanoma Reactions: QTc prolongation
Rash:
Keratosis pilaris
Different from cetuximab and erlotinib

45. Hormone Therapy

46. 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

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

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

49. 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.)

50. 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.

52. 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

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

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

55. Hormonal Agents Abiraterone:
Inhibits 17α-hydroxylase/C17,20 lyase (aka CYP17A1)
 CYP17 catalyzes two reactions in adrenals, testes, and prostate cancer:
the conversion of pregnenolone and progesterone to 17-α- hydroxy derivatives by its 17 α-hydroxylase activity
subsequent formation of dehydroepiandrosterone and androstenedione

56. Hormonal Agents
Abiraterone:
Consequence of CYP17A inhibition?

57. Hormonal Agents Abiraterone: Consequence of CYP17A inhibition?
Inhibition of cortisol production?

58. Hormonal Agents Abiraterone: Consequence of CYP17A inhibition?
Inhibition of cortisol production increased ACTH production?

59. Hormonal Agents Abiraterone: Consequence of CYP17A inhibition?
Inhibition of cortisol production increased ACTH production hypokalemia, hypertension, fluid retention
Side effects prevented with prednisone 5mg po BID.

60. mTOR Intracellular Pathway
PI3K
AKT
mTOR
Nucleus

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