Download New Oncology Drugs 2004: A Year in Review

New Oncology Drugs 2004:
A Year in Review
Susannah E. Koontz, Pharm.D., BCOP
Clinical Practice Specialist – Pediatrics
M.D. Anderson Cancer Center
• The following material was presented to
members of the Department of
Pediatrics at the Children’s Cancer
Hospital at M. D. Anderson Cancer
Center as part of their Oncology Grand
Rounds Series, November 29, 2004
1
Objectives
1. Identify drugs that earned FDA approval for
oncology indications in 2004.
2. With respect to each drug mentioned, be
able to describe their respective
mechanism(s) of action, approved use(s),
dosing strategies and common side effects.
Drugs
• Alimta® (Pemetrexed)
• ErbituxTM (Cetuximab)
• AvastinTM (Bevacizumab)
• VidazaTM (Azacitadine)
• TarcevaTM (Erlotinib)
2
Alimta® (Pemetrexed)
February 2, 2004
Eli Lily and Company
Alimta® (Pemetrexed)
• 1st drug approved in the United States
for the treatment of malignant pleural
mesothelioma (in combination with
cisplatin) whose disease is not
resectable or when patients are not
candidates for curative surgery
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Alimta® (Pemetrexed)
Alimta® (Pemetrexed)
• Antifolate/Folic acid antagonist
• Somewhat similar to methotrexate
• Disrupts folate-dependent metabolic
processes necessary for cellular replication by
enzyme inhibition:
– Thymidylate synthetase (TS)
– Dihydrofolate reductase (DHFR)
– Glycinamide ribonucleotide formyltransferase
(GARFT)
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Alimta® (Pemetrexed)
Alimta® (Pemetrexed)
• Pivotal trial
– Multicenter, randomized, single-blind Phase
III study
– 448 chemotherapy-naïve patients
– Pemetrexed + cisplatin vs. cisplatin alone
• Pemetrexed 500 mg/m2 IV on Day 1
• Cisplatin 75 mg/m2 IV on Day 1
• Regimen repeated every 21 days
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Alimta® (Pemetrexed)
• Trial modified to include vitamin
supplementation
– Folic acid 350-1000 mcg PO Daily
– Vitamin B12 1000 mcg IM 1-3 weeks before
chemo and then Q 9 weeks during chemo)
– Increased toxicity seen in patients with
reduced stores
Alimta® (Pemetrexed)
Pemetrexed
+ Cisplatin
Pemetrexed +
Cis + Vit
Suppl*
Cisplatin alone
Cisplatin alone
+ Vit Suppl*
Response rate (%) (all PR)
41a
45a
17
20
Median survival time
(months)
(primary study endpoint)
12.1b
13.3c
9.3
10
1-year survival rate (%)
50.3d
56.5e
38
41.9
Median time to progression
(months)
5.7f
6.1g
3.9
3.9
Vit Suppl = Vitamin Supplementation
*Among 331 patients receiving vitamin supplementation (folic acid 350 to 1000 mcg orally daily and vitamin B12 1000 mcg intramuscularly every 9
weeks)
ap<0.001 vs cisplatin alone groups
bHazard ratio 0.77, p=0.020 vs. cisplatin alone
c Hazard ratio 0.75, p=0.51 vs. cisplatin alone + vit suppl
dp=0.012 vs. cisplatin alone
ep=0.011 vs. cisplatin + vit suppl
fHazard ratio 0.68, p=0.001 vs. cisplatin alone
gHazard ratio 0.64, p=0.008
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Alimta® (Pemetrexed)
Alimta® (Pemetrexed)
Myelosuppression
Fever
Stomatitis
Nausea
Vomiting
Increase in liver function
Fatigue
Rash
Pharyngitis
Anorexia
Infection
tests
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Alimta® (Pemetrexed)
•
•
•
•
Not extensively metabolized
Cleared by the kidneys
Interaction with NSAIDs
Teratogencity (Category D)
Alimta® (Pemetrexed)
• Non-Small Cell Lung Cancer (NSCLC)
– As a single-agent for the treatment of
patients with locally advanced or
metastatic NSCLC after prior chemotherapy
– Effectiveness based on the surrogate
endpoints and response rate
– No controlled trials demonstrating a clinical
benefit (e.g., favorable survival effect or
improvement of disease-related symptoms)
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Alimta® (Pemetrexed)
• MPM (in combination with cisplatin)
– 500 mg/m2 IV over 10 minutes on Day 1
given every 21 days
– Vitamin supplementation
• NSCLC (single agent)
– 500 mg/m2 IV over 10 minutes on Day 1
given every 21 days
• 500 mg vials
Alimta® (Pemetrexed)
•
•
•
•
•
•
•
Hanauske A-R, Chen V, Paoletti P, Niyikiza C. Pemetrexed disodium: a novel antifolate
clinically active against multiple solid tumors. The Oncologist. 2001;6:363-373.
Gralla RJ, Hollen PJ, Liepa AM, et al. Improving quality of life in patients with malignant
pleural mesothelioma: results of the randomized pemetrexed + cisplatin vs cisplatin trial
using the LCSS-meso instrument. Proc Am Soc Clin Oncol. 2003;22:621. Abstract 2496.
Khalil MY, Mapa M, Shin HJ, Shin DM. Advances in the management of malignant
mesothelioma. Curr Oncol Rep. 2003;5:334-341.
Manegold C, Symanowski J, Gatzemeier U, et al. Secondary (post-study) chemotherapy
in the phase III study of pemetrexed + cisplatin vs. cisplatin in malignant pleural
mesothelioma is associated with longer survival. Proc Am Soc Clin Oncol. 2003;22:667.
Abstract 2684.
Vogelzang NJ, Rusthoven J, Paoletti P, et al. Phase III single-blinded study of
pemetrexed + cisplatin vs. cisplatin alone in chemonaive patients with malignant pleural
mesothelioma. Proc Am Soc Clin Oncol. 2002;21:6a. Abstract 5.
Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed
versus docetazel in patients with non-small cell lung cancer previously treated with
chemotherapy. J Clin Oncol. 2004;22:1589-1597.
www.alimta.com
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ErbituxTM (Cetuximab)
February 12, 2004
Imclone Systems, Inc.
ErbituxTM (Cetuximab)
• Indicated in use with irinotecan for
metastatic colorectal cancer that
expresses epidermal growth factor
receptor (EGFR) and that is resistant to
irinotecan
• As a single agent in patients with
metastatic colorectal cancer that are
intolerant to irinotecan-based
chemotherapy and who express EGFR
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ErbituxTM (Cetuximab)
• Anti-Epidermal Growth Factor Receptor
(EGFR) Monoclonal Antibody
ErbituxTM (Cetuximab)
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ErbituxTM (Cetuximab)
ErbituxTM (Cetuximab)
12
ErbituxTM (Cetuximab)
• 3 clinical trials
• Biologic License Application
– Randomized, controlled trial with 329
patients
– 2:1 ratio of
• Erbitux + irinotecan (66% male; median 71 yrs)
• Erbitux alone (59% male; median 70 yrs)
– Erbitux 400 mg/m2 IV followed by 250 mg/m2
IV weekly; Irinotecan at same dose
ErbituxTM (Cetuximab)
• Licensure Trial
– Median duration of response in the overall
population was 5.7 months with Erbitux +
irinotecan versus 4.2 months with Erbitux
alone.
– Paitents randomized to Erbitux + irinotecan
demonstrated a significantly longer median
time to disease progression compared with
Erbitux alone.
13
ErbituxTM (Cetuximab)
Infusion related reactions
Skin toxicity (rash, acne, dry skin, etc.)
GI toxicity (diarrhea, nausea, vomiting)
Malaise
Fever
ErbituxTM (Cetuximab)
• No known contraindications
• No known drug interactions
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ErbituxTM (Cetuximab)
• Metastatic colorectal cancer (+/irinotecan)
– Load: 400 mg/m2 IV over 2 hours week 1
– Maint: 250 mg/m2 IV over 1 hour weekly
– Premedication with diphenhydramine
• 100 mg vials
ErbituxTM (Cetuximab)
•
•
•
•
•
Herbst RS, Hong WK. IMC-C225, an anti-epidermal growth factor receptor
monoclonal antibody for treatment of head and neck cancer. Semin Oncol 2002
Oct;29(5 Suppl 14):18-30
Herbst RS, Kim ES, Harari PM. IMC-C225, an anti-epidermal growth factor
receptor monoclonal antibody, for treatment of head and neck cancer. Expert
Opin Biol Ther 2001 Jul;1(4):719-32
Kim ES, Khuri FR, Herbst RS. Epidermal growth factor receptor biology (IMCC225). Curr Opin Oncol 2001 Nov;13(6):506-13
Sclabas GM, Fujioka S, Schmidt C, Fan Z, Evans DB, Chiao PJ. Restoring
Apoptosis in Pancreatic Cancer Cells by Targeting the Nuclear Factor-kappaB
Signaling Pathway With the Anti-Epidermal Growth Factor Antibody IMC-C225.
J Gastrointest Surg 2003 Jan;7(1):37-43
www.erbitux.com
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AvastinTM (Bevacizumab)
February 26, 2004
Genentech, Inc.
AvastinTM (Bevacizumab)
• Approved in combination with IV 5fluorouracil-based chemotherapy for the
treatment of previously untreated metastatic
colorectal cancer
• Angiogenesis inhibitor
– Binds vascular endothelial growth factor (VEGF)
– Inhibits binding of VGEF to its receptors (Flt-1 and
KDR) on the surface of endothelial cells
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AvastinTM (Bevacizumab)
AvastinTM (Bevacizumab)
• Pivotal Trial (Phase III)
– Randomized, controlled, double-blind
– 923 patients with previously untreated
metastatic colorectal cancer
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AvastinTM (Bevacizumab)
AvastinTM (Bevacizumab)
18
AvastinTM (Bevacizumab)
AvastinTM (Bevacizumab)
19
AvastinTM (Bevacizumab)
AvastinTM (Bevacizumab)
• Serious toxicities
– GI perforation
– Wound healing complication
– Hemorrhage
– Hypertensive crisis
– Nephrotic syndrome
– Congestive heart failure
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AvastinTM (Bevacizumab)
• Other side effects
Nausea
Vomiting
Diarrhea
Constipation Pain
Headache
Abdominal Pain
Hypertension
Anorexia
Stomatitis
URI
Epistaxis
Dyspnea
Asthenia
Exfoliative dermatitis
Leukopenia
AvastinTM (Bevacizumab)
• Metastaic Colorectal Cancer
– 5 mg/kg IV every 14 days over 90 minutes
(2nd dose over 60 minutes and subsequent
doses over 30 minutes if well tolerated)
• 100 mg and 400 mg vials
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AvastinTM (Bevacizumab)
• Hurwitz H, Novotny W, Cartwright T et al. Bevacizumab plus
irinotecan, fluorouracil, and leucovorin for metastatic colorectal
cancer. N Engl J Med. 2004;350:2335-2342.
• Folprecht G, Kohne CH.The role of new agents in the
treatment of colorectal cancer. Oncology. 2004;66(1):1-17
• Presta LG, Chen H, O'Connor SJ, et al. Humanization of an
anti-vascular endothelial growth factor monoclonal antibody for
the therapy of solid tumors and other disorders. Cancer Res
1997;57:4593-9
• Salgaller ML Technology evaluation: bevacizumab,
Genentech/Roche. Curr Opin Mol Ther. 2003 Dec;5(6):657-67.
• www.avastin.com
VidazaTM (Azacitadine)
May 19, 2004
Pharmion Corporation
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VidazaTM (Azacitadine)
• 1st drug approved in the US for the
treatment of myelodysplastic syndrome
(MDS)
• Antimetabolite
– Pyrimidine nucleoside analog (Cytosine)
VidazaTM (Azacitadine)
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VidazaTM (Azacitadine)
• Dual mechanism of action
– Hypomethylation of DNA  restores
normal gene function to those genes
responsible for cellular division and
differentiation (DNA methyltransferase can
not work adequately)
– Apoptosis to rapidly dividing cells
VidazaTM (Azacitadine)
• Pivotal trial was CALGB 9221
– Randomized, open-label, controlled
– 191 patients were enrolled; 172 evaluable
patients
– All FAB MDS Subtypes were included
– Vidaza + supportive care (99 patients) vs.
supportive care alone (92 patients)
– 55% crossover
24
VidazaTM (Azacitadine)
• 132 males (69%) and 59 females
• Median age 68 years (Range 31-92)
• 75 mg/m2 SQ daily for 7 days every 4
weeks
– Dosed increased to 100 mg/m2 if no
response seen after 2 cycles
VidazaTM (Azacitadine)
VIDAZA
(N=99)
Observation
(N=92)
Gender (n%)
Male
Female
72 (72.7)
27 (27.3)
60 (65.2)
32 (34.8)
Race (n%)
White
Black
Hispanic
Asian/Oriental
93 (93.9)
1 (1.0)
3 (3.0)
2 (2.0)
85 (92.4)
1 (1.1)
5 (5.4)
1 (1.1)
99
67.3 ± 10.39
31 - 92
91
68.0 ± 10.23
35 - 88
21 (21.2)
6 (6.1)
38 (38.4)
16 (16.2)
8 (8.1)
10 (10.1)
18 (19.6)
5 (5.4)
39 (42.4)
14 (15.2)
7 (7.6)
9 (9.8)
70 (70.7)
66 (66.7)
15 (15.2)
0 (0.0)
1 (1.0)
2 (2.0)
59 (64.1)
55 (59.8)
12 (13.0)
1 (1.1)
0 (0.0)
2 (2.2)
Age (years)
N
Mean ± SD
Range
Adjudicated MDS diagnosis at
study entry (n%)
RA
RARS
RAEB
RAEB-T
CMMoL
AML
Transfusion product used in 3
months before study entry (n%)
Any transfusion product
Blood cells, packed human
Platelets, human blood
Hetastarch
Plasma protein fraction
Other
25
VidazaTM (Azacitadine)
•
RA
RARS
RAEB
RAEB-T
CMMoL
Complete
Response
(CR),
duration ≥ 4
weeks
Marrow
< 5% blasts
Peripheral
Blood
Normal CBC if abnormal at baseline
Absence of blasts in the peripheral circulation
Partial
Response
(PR), duration
≥ 4 weeks
Marrow
No marrow requirements
Peripheral
Blood
≥ 50% restoration in the deficit from normal levels of baseline white
cells, hemoglobin and platelets if abnormal at baseline
≥ 50% decrease in blasts
Improvement of marrow dyspoiesis
No blasts in the peripheral circulation
For CMMoL, if WBC is elevated at baseline, a ≥ 75% reduction in the
excess count over the upper limit of normal
VidazaTM (Azacitadine)
Response
Overall (CR+PR)
Complete (CR)
Partial (PR)
VIDAZA
(N=89)
Observation
Before Crossover
(N=83)
n (%)
14 (15.7)
5 (5.6)
9 (10.1)
n (%)
0 (0.0)
0 (0.0)
0 (0.0)
P value
(<0.0001)
(0.06)
--
26
VidazaTM (Azacitadine)
• Decrease in BM blast percentage
• Increase in platelets, Hgb or WBC
• >90% of responders showed a change
in parameters by the 5th cycle
• Transfusion dependent  transfusion
independent during CR or PR
VidazaTM (Azacitadine)
Thrombocytopenia
Neutropenia
Anemia
Leukopenia
Nausea
Anorexia
Vomiting
Diarrhea
Arthalgia
Fatigue
Fever
Ecchymosis
Injection site reactions (pain, erythema)
27
VidazaTM (Azacitadine)
• Potentially hepatotoxic
• Excreted by the kidneys
• Teratogencity (Category D)
VidazaTM (Azacitadine)
• All forms of MDS
• 75 mg/m2 SQ daily for 7 days every 4
weeks
– Increase dose to 100 mg/m2 if no response
after 2 cycles
• Treatment for minimum of 4 cycles
• 100 mg vials
28
VidazaTM (Azacitadine)
•
•
•
•
Suwanawiboon B, Sumida KN. 5-azacitidine: An alternative treatment of
myelodysplastic syndromes in patient with refractory response to hematopoietic
growth factor, a case report and review of literatures. Hawaii Medical Journal.
2004 Jan;63(1):14-6, 25.
Leone G, Voso MT, Teofili L, Lubbert M. Inhibitors of DNA methylation in the
treatment of hematological malignancies and MDS. Clinical Immunologly. 2003
Oct;109(1):89-102.
Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC,
Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM,
Ellerton J, Larson RA, Schiffer CA, Holland JF. Randomized controlled trial of
azacitidine in patients with the myelodysplastic syndrome: a study of the cancer
and leukemia group B. Journal of Clinical Oncology. 2002 May 15;20(10):242940.
www.vidaza.com
TarcevaTM (Erlotinib)
November 18, 2004
OSI Pharmaceuticals, Inc.
29
TarcevaTM (Erlotinib)
• Approved for treatment of patients with
locally advanced or metastatic NonSmall Cell Lung Cancer (NSCLC) after
having failed at least one chemotherapy
regimen
TarcevaTM (Erlotinib)
30
TarcevaTM (Erlotinib)
• Epidermal growth factor receptor
(EGFR) tyrosine kinase inhibitor (TKI)
which inhibits ligand-induced
phosphorylation
– Inhibition of tumor cell growth
– Induction of apoptosis
– Decreased EGFR production
TarcevaTM (Erlotinib)
31
TarcevaTM (Erlotinib)
• Pivotal trial
– Randomized, Double-Blind, PlaceboControlled
– 731 patients
• 2/3 male
• 50% had only 1 prior course of chemo
– 2:1 ratio:
• Erlotinib 150 mg PO daily
• Placebo
TarcevaTM (Erlotinib)
32
TarcevaTM (Erlotinib)
TarcevaTM (Erlotinib)
• Results from 2 multi-center, placebocontrolled trials in more than 1000
patients conducted in first line therapies
showed no clinical benefit when
erlotinib was combined with a platinumbased regimen (carboplatin and
paclitaxel OR cisplatin and gemcitabine)
33
TarcevaTM (Erlotinib)
• Side effects: rash and diarrhea
• Metabolism is mediated by P450
CYP3A4 and excreted in bile
– Inhibitors: azoles, erythromycins,
verapamil, diltiazem, grapefruit juice
– Inducers: rifampin, phenytaoin,
carbamazepine, phenobarbital
• Pregnancy category D
TarcevaTM (Erlotinib)
• NSCLC
– 150 mg PO Daily 1 hour prior to or 2 hours
following ingestion of food
• 25 mg, 100 mg and 150 mg tablets
34
TarcevaTM (Erlotinib)
•
•
•
•
•
Shepherd FA, Pereira J, Ciuleanu TE, et al. A randomized placebocontrolled trial of erlotinib in patients with advanced non-small cell lung cancer
(NSCLC) following failure of 1st line or 2nd line chemotherapy. A National
Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial [abstract].
Proc Am Soc Clin Oncol. 2004;23:abstract 7022
Herbst RS, Prager D, Hermann R, et al. TRIBUTE – a phase III trial of
erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel (CP)
chemotherapy in advanced non-small cell lung cancer (NSCLC) [abstract]. Proc
Am Soc Clin Oncol. 2004;23:abstract 7011.
Gatzemeier U, Pluzanska A, Szczesna A, et al. Results of a phase III trial
of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC)
chemotherapy in advanced non-small cell lung cancer (NSCLC) [abstract]. Proc
Am Soc Clin Oncol. 2004;23:abstract 7010.
Bonomi P. Erlotinib: a new therapeutic approach for non-small cell lung
cancer. Expert Opin Investig Drugs. 2003;12:1395-1401.
www.tarceva.com
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