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This seminar presentation on recent antineoplastic agents.
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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