Antineoplastic seminar

Anti-Neoplastic Agents Approved by FDA in Last Five Years

(2008-till now)Dr Nitin Kothari

04/12/23 1

Antineoplastic Agents in Last Five Years

04/12/23 2Total Drugs= 43

Cytotoxic Agents

– Alkylating Agents

– Antimetabolites

– Natural Products

– Hormones & its antagonists

04/12/23 3

Alkylating Agents-Bendamustine

• Approved in year 2008 for – CLL- efficacy to first line drugs?– NHL- progressed during or within 6 months of

t/t with rituximab or rituximab with CHOP

04/12/23 4

• Not a true ‘-mustine’( carmustine)

04/12/23 5

MOA

04/12/23 6

• Unique properties– Cross-link repair slow– Lacks resistance to other alkylators– Significant activity CLL & other lymphoma

• Formulation– Powder 100mg vial , reconstitution, – iv infusion

04/12/23 7

• Dose regimen

04/12/23 8

CLL NHL

100 mg/m2 I.V. over 30 min on day 1, 2 on 28 days cycle upto 6 cycles

120 mg/m2 I.V. over 60 min on day 1, 2 on 21 days cycle upto 8 cycles

• ADR– BM toxicity– Mucosal toxicity-

stomatitis, intestinal denudation

– Reproduction– Alopecia– Nausea, vomiting

04/12/23 9

Anti-metabolites-Pralatrexate

• Approved for– t/t of pt with relapsed or refractory peripheral

T-cell lymphoma

• Congener of Mtx

04/12/23 10

Pralatrexate

04/12/23 11

PRALATREXATEPurine Synthesis

• Formulation & Dose– Sol for iv admin– Dose- 30 mg/m2 iv bolus once weekly for 6

weeks in 7 weeks cycles– Vitamin supplementation

Folic acid 1mg – initiate 10 days prior Vit B12 im- 10 weeks prior & every 10 weeks

04/12/23 12

Pralatrexate

• ADRs– BM - Myelosuppression

Anemia

– Infection– Haemorrhage– Intestine– Nausea, Constipation

04/12/23 13

Natural Products

S.No. Name of Drug Approved for Year

1. VinCRIStine sulphate liposomal injection

Ph- ALL Aug2012

2 Paclitaxel protein-bound particles

Non small cell lung cancer

Oct 2012

3 Cabazitaxel Prostate cancer June2010

4 Eribulin Metastatic breast cancer

Nov 2010

5 L-Asparaginase erwinia chrysanthemi

ALL Nov 2011

6 Ingenol Actinic Keratosis Jan2012

04/12/23 14

VinCRIStine Sulphate liposomal Inj

04/12/23 15

• Approved for – Adults with Ph- ALL in second or greater

relapse or whose disease has progressed following > 2 anti-leukemic drugs

• Why liposomal preparation?– “Liposome makes it adult”

• MOA– Cell cycle specific(v/s alkylating agents)– Polymerization of microtubules

• Formulation & Dose– Solution for iv injection– Initial dose 2.25 mg/m2 iv over one hour

weekly

04/12/23 16

• ADR– GI distress

Bulk forming laxative as prophylaxis Diarrohea

– Peripheral neuropathy– Anemia– Febrile neutropenia– Pyrexia

04/12/23 17

Paclitaxel protein-bound particle

• Approved for– First line t/t of locally advanced or metastatic

non-small cell lung cancer, in combination with carboplatin, in pt who are not candidates for curative surgery or radiation therapy

04/12/23 18

• Why nab- preparation of paclitaxel?– To overcome limitations of conventional prep

Poor acqueous solubility vehicle 50%ethanol + 50% polyethoxylated castor

oil ( cremophor)

• Advantage of nab-paclitaxel– No hypersensitivity– Less time in infusion

04/12/23 19

• MOA– Promotes polymerization of microtubules– Binds to beta tubulin

04/12/23 20

• Formulation & dose– Solution for iv infusion– Dose- 100mg/m2 as iv infusion over 30min on day

1, 8 and 15 of each 21days cycle– With carboplatin

• ADR– Neutropenia– Neuropathy- more– Hypersensitivity- less– Fatigue

04/12/2321

Cabazitaxel

• Approved for– t/t of hormone refractory prostate cancer pt– In combination with prednisone who have

previously treated with docetaxel

• MOA- same as paclitaxel

04/12/23 22

• Formulation & Dose– Sol for iv use– 25 mg/m2 over every 3weeks– Oral prednisolone 10mg– Premedicate –antihistaminics, corticosterids

• ADRs– N/V/D– Hematological Rxn– Hypersensitivity Rxn– Anorexia, Fatigue

• 04/12/23 23

Eribulin

• Approved for– t/t of metastatic breast cancer pt who have

previously received atleast two chemotherapeutic regimens

• Isolated from Helichondria okadai• MOA

– Not well known– Acts on microtubules– Affects growth phase– No affect on shortening phase

04/12/23 24

• Formulation & dose– Solution for iv inj

– 1.4mg/m2 iv over 2-5 min on day 1 & 8 of 21 days cycle

• ADR– N/V/D

– Hematological rxn

– Hypersensitivity rxn

– Anorexia, Fatigue

• 04/12/23 25

Asparaginase Erwinia chrysanthemi

• Approved for– As a component of multi-agent chemotherapy

for t/t of ALL who have developed hypersensitivity to E.coli derived asparaginase

o Why aspaginase Erwinia chrysanthemi?Hypersensitivity Rxn 5-20%Gram negative rod bacteria

04/12/23 26

• MOA– Asparagine imp for protein synthesis– Lyphocytic leukemic cells lack asparagine

synthetase– Degrades into metabolites

04/12/23 27

• Formulation & dose– Solution for im use– 25000 IU three times a week for 8 weeks

• ADRs– Hypersensitivity– Inhibition of protein synthesis

Hyperglycemia Hypertriglyceridemia, Pancreatitis Thrombosis Hypoalbuminemia

28

Ingenol

Approved For

Actinic Keratosis

Source- Euphorbia

Formulation & Dose0.015% or 0.05% gel for topical Face, Scalp- once daily for 3 consecutive days 0.015%Trunk, Extremities- once daily for 2consecutive days 0.05%

MOAInducer of apoptosis & cell death-unknown MOA

ADR-Local skin Rxn-Pain-Pruritis-Infection

04/12/23 29

Hormones & its antagonists

S.No. Name of Drug Approved For

MOA Year

1 Enzalutamide

Metastatic castration resistant prostate cancer

Androgen receptor inhibitor

2012

2 Degarelix GnRH analogue

2008

3 Abiraterone Steroid synthesis inhibitor

2011

04/12/23 30

• Hormone therapy in prostate cancer

• Androgen Deprivation Therapy– Surgical– Medical

GnRH agonist- high dose/ continuous GnRH antagonist Androgen Receptor inhibitor

04/12/23 31

04/12/23 32

DEGARELIX

ABIRATERONE

ENZALUTAMIDE

• Degarelix– Avoids “flare” phenomenon of GnRH agonist– Precursor – Abarelix

• Enzalutamide– Potency & libido maintained– Precursor- Flutamide, Bicalutamide

04/12/23 33

• Abiraterone– Non-gonadal source of androgen

Adrenal gland Prostate cancer cells

– Block CYP-17 ( 17 α hydroxylase)– Congener- Ketoconazole

04/12/23 34

S.No.

Name of Drug

Formulation Available

Dose

1 Degarelix Powder for reconstitution 120mg, sc

Initial- 240mgMaintenance-80 mg /month

2 Abiraterone Tablet 1000mg

3 Enzalutamide Oral Capsule 40 mg 4 capsules once

04/12/23 35

• ADRs of ADTs( Degarelix & Abiraterone)– Hot flushes– Loss of libido– Impotence– Gynecomastia– Anemia– Weight gain– ↓ insulin sensitivity– Altered lipid profile– Osteoporosis, fracture, loss of muscle mass

04/12/23 36

- Hypertension- UTI- Diarrohea( Abiraterone)

• ADRs of Enzalutamide– Asthenia(>5%)– Fatigue– Arthralgia– Musculosketal pain– Headache– Dizziness– LRTI– Spinal cord compression

04/12/23 37

Targeted Therapeutic Agents

• TK inhibitors

• mTOR inhibitors

• Inhibitors of angiogenesis

• Immunomodulators

• Monoclonal antibodies

• Others

04/12/23 38

Tyrosine Kinase Inhibitor

S.No. Name of Drug Approved for Year

1 Bosutinb Ph+ CML 2012

2 Crizotinb ALK + Non small cell lung cancer

2011

3 Vandetanib Metastatic MCT 2011

4 Cabontanib Metastatic MCT 2012

04/12/23 39

Bosutinib

• Congener of Imatinib

• Approved for– Ph+ CML with resistance to prior therapies

04/12/23 40

04/12/23 41

• Formulation & Dose– Tablet for oral admn– Dose 500 mg once daily

04/12/23 42

• Drug interaction

• Protease inhibitors

• Azoles antifunguals

• Antiepileptics

• PPI

• Antacid

04/12/23 43

Common to D, I, N

Common to Dasatinib

• ADRs ( common with congeners)– GI distress– Myelosuppression– Liver problems– Fluid retention– Others

Rash Pyrexia Fatigue

04/12/23 44

No QT prolongation( Nilotinib)

Crizotinib

• MOA– Dual inhibitor

C-Met-GF ALK-TK

• Formulation & Dose– Tablet for oral admn– 250 mg twice daily

• ADRs– GI Distress-N/V/D/C– Vision disorders

04/12/23 45

Vandetanib• MOA

– TK R inhibitors VEGF EGF

• Formulation & Dose– Tablet for oral admn

300 mg once daily

• ADRs– GI distress– Headache, fatigue– Rash, acne

04/12/23 46

Cabozantinib

• MOA– Pan-tyrosine kinase inhibitor

RET,MET,KIT VEGFR-1,2,3 TRKB, FLT-3,AXL, TIE-2

04/12/23 47

04/12/23 48

Formulation & DoseCap 80mg, 20 mgDose 140 mg, without food

ADRsGI distressHair color changesHypertension

Inhibitors of AngiogenesisS. No.

Name of Drug

Approved for Year

1 Sunitinib Pancreatic NET 2011

2 Axitinib Advanced RCC 2012

3 Pazopanib Advanced RCC 2009

Advanced Soft tissue sarcoma

2012

4 Bevacizumab

Metastatic RCC in combination with iFN-alpha

2009

5 Ziv-afilabercept

Metastatic CRC with FOLFIRI

201251

MOA

• Role of angiogenic factors– VEGF, PDGF, TGF-b, FGF

• VEGF-most studied

• Angiogenesis inhibitors– Binding of angiogenesis facors to its receptor

activate the intracellular TK activity -- mitogenic and antiapoptotic pathway within endothelial cells-- cell proliferation

04/12/23 52

• Sunitinb- VEGF-R, PDGF-R

• Axitinib- VEGF-R 1, 2 ,3

• Pazopanib- VEGF-R 1, 2 ,3

• Ziv-afilabercept- VEGF, Placental GF

• Bevacizumab- Antibody against VEGF

04/12/23 53

ADRs common to angiogenesis Inhibitors

• Potential for vessel injury & bleeding– Pulmonary haemorrhage<2%– C/I

Bleeding diathesis Hemoptysis Brain metastasis

– Operation should be avoided

04/12/23 54

• Hypertension– Reason- decreased eNO– Antihypertensive drugs– Complications

Reversible posterior leucoencepalopathy CCF

04/12/23 55

• Sunitinib ( pan TK-I)– Fatigue- 50-70%– Hypothyroid- 40%– Severe neutropenia- 10%

• Recommendations– Regular blood examination– Thyroid test– ECG

04/12/23 56

• Axitinib– GI distress– Palmer planter keratosis

• Pazopanib– Dysguesia, Dyspnoea– Skin hypopigmentation, hair color change

• Ziv-aflibercept– Liver– Kidney

04/12/23 57

Everolimus

• Approved by FDA for– Advanced RCC after failure of

Suniti-/Sorafenib- 2009– Progressive Pancratic NET with unresectable

or metastatic disease- 2011– Renal Angiomyolipoma associated with

tuberous sclerosis- 2012– Hormone receptor +, her2 - Ca Breast after

failure of t/t with letrozole ,anastrozole- 2012

04/12/23 58

Everolimus: MOA

04/12/23 59

Raf

• Formulation & Dose– 5mg, 10 mg tablet– Dose-

10 mg once daily Can be increased by 5 mg( max dose 20 mg)

04/12/23 60

• ADR– Common ( 30-50%)

Maculopapuar rash Mucositis Anemia Fatigue

– Less common Leucopenia,Thrombocytopenia Hyper-glycemia, -triglyceridemia Pulmonary infilterates

04/12/23 61

ImmunomodulatorsS.No.

Name of Drug Year

1 Peg-interferon alpha-2b

2011

2 Plerixafor 2008

3 Pomalidomide Feb 08,2013

4 Sipuleuceucel-T( Provenge)

2010

5 Recombinant HPV Type 16, 18 Vaccine(Cervarix)

2009

62

Peginterferon alpha 2b

• Approved for– Adjuvant t/t of melanoma with nodal

involvemont within 84 days of definitive surgical resection( + lymphadenectomy)

• Why PEGylation?

04/12/23 63

• MOA– Pleiotropic cytokine

• Formulation– Powder for reconstitution, sc

• Dose– Initial-6mcg/kg/week eight doses– Then 3mcg/kg/week upto 5 years– Premedicate with PCM

04/12/23 64

• ADRs– Flu like symptoms

Fever, chills, headache Fatigue, myalgia

– Liver

04/12/23 65

Plerixafor

• Approved for– In combination with G-CSF to mobilize

hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in pt with NHL & MM

04/12/23 66

• Transplantation of hematopoitic stem cells• Indication• Source

– BM– Peripheral blood

• Role of interaction of CXCR4 & SDF-1• MOA of Plerixafor

– Hematopoietic stem cells are mobilized in peripheral blood

04/12/23 67

• Formulation– Solution for sc

• Dose– Given sc after 4 days of G-CSF t/t– Dose 0.24mg/kg

• ADRs– Injection site reactions– GI distress– Fatigue, headache, dizziness

04/12/23 68

Pomalidomide

• Approved for– Pt with MM who have received atleast 2 prior

therapies including lenalidomide & bortezomib and have demonstrated disease progression within 60 days of last therapy

04/12/23 69

Pomalidomide

04/12/23 70

• Formulation– Capsule for oral administration

• Dose– 4 mg once daily without food on day 1-21 of

repeated 28 days cycles untill disease progression

04/12/23 71

• ADRs– No sedation– Less constipation– No sensory neuropathy– Myelosuppression

Anemia Neutropenia

– Fatigue, asthenia

04/12/23 72

Sipuleucel- T

• Autologus immunotherapy– Against PAP

• Approved for– Asymptomatic or minimally symptomatic

metastatic hormone refractory prostate cancer

04/12/23 73

Sipuleucel-T(Provenge)

04/12/23 74

• Formulation & Dose– IV infusion 50 million autologous CD54+ cells

activated with PAP, GM-CSF designed– 3 completed doses at 2 weeks interval

• ADRs– Flu like

Chills, headache, fever

04/12/23 75

Recombinant Bivalent HPV Vaccine

• Recombinant vaccine that contains L1 protein, major antigenic protein of HPV type 16 & type18

• Approved for– Prevention of the CIN & cervical cancer

• Formulation & Dose– Suspension for im inj– 3 doses, 0.5 ml, at 0,1 , 6 months

04/12/23 76

• ADRs– Local reactions

Pain, redness, swelling

– Fatigue, headache, myalgia

04/12/23 77

• Formulation & Dose– Tablet for oral admn- 240 mg

• Dose-– 4 tablets twice daily atleast gap of 12 hours

• ADRs– Skin menifestation

rash, skin papilloma, pruritis, photosensitivity

04/12/23 78

Monoclonal AntibodiesS.No. Name of Drug Approved for Year

1. Trastuzumab Gastric cancer Oct 2010

2. Ado- trastuzumab Metastatic breast cancer

Feb 22, 2013

3. Ofatumumab CLL Oct 2009

4. Pertuzumab Her+ metastatic breast cancer

June 2012

5. Denosumab Prevention of metastatic skeletal related events

Nov 2010

6. Ipilimumab Metastaic melanoma March 2011

7. Brentuximab HL, anaplastic large cell lymphoma

August 2011 04/12/23 79

Trastuzumab

• Approved for– t/t of her+ overexpressing metastatic gastric

or gastroesophageal adenocarcinoma in combination with cisplatin & capecitabine or 5-FU who have not received prior t/t for it

04/12/23 80

MOA

04/12/23 81

• Formulation & Dose– Sol for iv dose– 8mg/kg 90 min iv infusion– Followed by 6 mg/kg over 30-90 min in every

3 weeks untill disease progression

04/12/23 82

• ADRs– Immunogenic

Fever, chills, rashes Premedication

– Cardiac Toxicity Most serious, Fatal, 1% Baseline ECG, Cardiac ejection fraction careful follow-up- signs of CCF

• 04/12/23 83

Ado- trastuzumab

• Approved for her2+ metastatic breast cancer

• MOA– DM1 interferes cell growth

• ADRs– Nausea,constipation,– Headache, myalgia, fatigue– Raised liver enzymes

04/12/23 84

Liver Toxicity, Heart ToxicityBirth defects

Ofatumumab

• Approved for– t/t of pt with CLL refractory to fludarabine and

alemtuzumab

04/12/23 85

• Formulation- 20mg/ml• Regimen- 12 dose

– Ist dose-300mg 1st week– Dose 2-8-2gm/week– Dose 9-12-2gm/4 weeks

• Infusion rate– Dose 1-3.6mg/hr– Dose 2-24mg/hr– Dose3-12-50mg/hr

04/12/23 86

• ADRs– Immunosuppresion

Reactivation of viral infections Not with hepatitis B infection URTI, pneumonia

– Myelosuppresion

– Hypersensitivity

04/12/23 87

Pertuzumab

• Approved for– t/t of her+ metastatic breast cancer (+

trastuzumab and docetaxel)

• MOA– Similar to trastuzumab

04/12/23 88

• Formulation & Dose– 420 mg/ 14 ml vial iv infusion– Initial Dose-840 mg administered as 60 min iv

infusion

• Maintenance dose- 420 mg administered in 30-60min

• ADRs– GI Distress– Neutropenia– Neuropathy– Rashes

04/12/23 89

Denosumab

• Approved for – prevention of skeletal related events in pt with

bone metastasis

• Tumor with common bone metastasis– In adults– In children

• MOA– Binds to RANKL– RANK present on osteoclast

04/12/23 90

• Formulation & Dose– sc preparation– 120 mg every 4 weeks

• ADRs– Fatigue– Hypophoshatemia– Nausea

04/12/23 91

Ipillitumumab

• Approved for– t/t of metastatic melanoma

• MOA– Blockade of CTLA-4– CTLA-4 suppresses immune response

04/12/23 92

• Formulation & Dose– Sol for iv– 3mg/ kg iv over 90 mins every 3 weeks total 4

doses

• ADRs– Fatigue– Diarrhea– Rash, Pruritus– Colitis

04/12/23 93

Brentuximab

• Approved for– HL

After failure of autologous stem cell transplant, or, After failure of atleast 2 prior multiagent

chemotherapy regimen

– Systemic anaplastic large cell lymphoma After failure of one prior multiagent chemotherapy

regimen

04/12/23 94

• MOA– Antibody-drug conjugate

04/12/23 95

• Formulation & Dose– Sol for iv infusion– Dose 1.8 mg/kg over 30 min

• ADRs– GI Distress– Myelosupression– Neuropathy

04/12/23 96

Others

S.No. Name of Drug Approved For Year

1 Carfilzomib MM 2012

2 Romidepsin Cutaneous T-cell lymphoma

2009

3 Vismodegib BCC 2012

4 Omacetaxine CML 2012

5 Vemurafenib Melanoma 2011

04/12/23 97

Carfilzomib

• Approved for– t/t of MM in pt who have received atleast 2

prior therapies (+ bortezomib & immunomodulators) & have demonstrated disease progression within 60 days of completion of last therapy

04/12/23 98

MOA• NF-KB – cell survival & proliferation

• IkB is degraded by proteasome- NF-KB promotes cell proliferation

04/12/23 99

β 5

CARFILZOMIB

• Formulation & Dose– 28 days t/t cycle– For 3 weeks, given on 2 consecutive days in

each week followed by rest– Cycle 1- dose 20mg/m2---- 27mg/m2

04/12/23 100

• ADRs– Fatigue– Thrombocytopenia– Anemia– Diarrhoea– Pyrexia– No peripheral neuropathy– No Hypotension

04/12/23 101

Romidepsin

• Approved for– Cutaneous T-cell lymphoma who have

received atleast one prior systemic therapy

04/12/23 102

04/12/23 103

Acetylation---- transcription increasesDeacetylation---- transcription decreases

Romidepsin Increases Transcription

• Formulation & Dose– Sol for iv– 14 mg/m2 over 4 hour period on day 1, 8and

15 of a 28 day cycles– Cycle repeated till relief or toxicity

04/12/23 104

• ADRs– GIT distress

N/V/ D

– Anorexia– Fatigue– Pyrexia

04/12/23 105

Vismodegib

• Approved for– t/t of adults with metastatic or locally

advanced BCC that has recurred following surgery or who are not candidates for surgery or radiation

04/12/23 106

Vismodegib

• MOA– Inhibitor of Hedgehog signaling pathway

04/12/23 107

• Formulation & Dose– Tablets for oral admin– 150 mg once daily untill disease progression

of toxicity

• ADRs– GI distress- N/V/ D/ C, appetite, wt loss– Dysguesia, Aguesia– Muscle spasm, Arthralgia, Fatigue

04/12/23 108

Omacetaxine

• Approved for– t/t of adults with CML with resistance to

atleast 2 TKI

• MOA– Protein synthesis inhibitor– Binds to A-site of peptidyl transferase

04/12/23 109

• Formulation & Dose– Solution for sc

04/12/23 110

Induction Scedule Maintenance dose

1.25 mg/m2 s.c. Twice daily14 consecutive daysIn 28 days cycle

1.25 mg/m2 s.c. Twice daily07 consecutive daysIn 28 days cycle

• ADRs– Myelosuppression

Anemia Neutropenia Thrombocytopenia

– Fatigue– Asthenia– Pyrexia

04/12/23 111

Vemurafenib

• Approved for– Unresectable or metastatic metastatic

melanoma with BRAF V600E mutation

04/12/23 112

04/12/23 113

Raf

Vemurafenib

Drugs Approved for MM

Peg-interferon

04/12/23 114

THANK YOU

04/12/23 115