Breathing New Life Into Lung Cancer Treatment: Recent Advances

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Breathing New Life Into Lung Cancer Treatment
Recent Advances

• BCCA Annual Cancer Conference
• November 29, 2003
• Saira Mithani, BSc Pharm, Pharm D
• Clinical Pharmacy Specialist, Drug Information
• BC Cancer Agency

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Outline

• I. Prognosis/background of lung cancer
• II. Current platinum chemotherapy
• III. New chemotherapeutic agents
• a. pemetrexed
• b. gefitinib
• c. topotecan

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Incidence of Cancerin Canada 2003
Patients
Canadian Cancer Society http//www.cancer.ca
Accessed Nov 2003
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Incidence of Cancer in BC 2003
Patients
Canadian Cancer Society http//www.cancer.ca
Accessed Nov 2003
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Lung Cancer Summary
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Lung Cancer Staging

• Goal
• identify surgical candidates
• highest potential for cure
• Prognostic factors
• performance status
• tumour stage
• Overall Prognosis of lung cancer
• untreated 3-6 months survival
• treated 9-12 months

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Lung Cancer Staging

• NSCLC
• stage I, II, IIIA
• resectable
• stage IIIA, IIIB, IV
• chemo mainstay
• SCLC
• chemo for all
• ? survival

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Lung Cancer Chemotherapy
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Lung Cancer Chemotherapy
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Chemotherapy Rules of Thumb

• first line
• cisplatin based regimen
• usually two agents
• comparable
• second line
• CAV, cisplatin, etoposide
• SCLC
• Docetaxel
• NSCLC

Shiller et al. N Engl J Med 200234692-98
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Contenders for Second Line and Beyond

• Non-small cell lung cancer
• pemetrexed
• gefitinib
• Small cell lung cancer
• topotecan

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Pemetrexed
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Pemetrexed Pharmacokinetics

• t1/2 2-4 hours
• t1/2 plasma ? long t1/2 in cells
• 80 eliminated unchanged in the urine
• ? renal clearance ?risk of toxicity

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Pemetrexed Mechanism of Action
AMP
RNA DNA Synthesis
PRPP Gln
IMP
GMP
Membrane
10-CHO-FH4
pemetrexed
pemetrexed
5, 10-CH2-FH4
Folate Carriers
FH4
dUMP
Cell
DHFR (MTX)
TS (5-Fu)
FH2
dTMP
DNA Synthesis
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Pemetrexed vs Docetaxel in Recurrent NSCLC
Pemetrexed vs docetaxel response rate 9.1 vs
8.8 HR 0.99 (0.8-1.2) median survival 8.3 vs
7.9 mnths Grade III/IV toxicity 10 vs 24
Previously treated patients 95 1 previous
chemo Stage III/IV Randomized
Pemetrexed 500mg/m2 iv q21 days dex, vitamin
B12, folic acid
Docetaxel 75mg/m2 q 21 days dex
Proc Am Soc Oncol 200322622, Ab 2503
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Pemetrexed Toxicity

• diarrhea (2)
• skin rash
• dexamethasone 4mg/day before, day of, day after
  therapy
• reduce risk of skin rash
• neutropenia (5)
• folic acid 400mcg daily
• begin 1-3 weeks before therapy
• vitamin B12 1000ug im q 9 weeks
• ? frequency of adverse reactions including
• bone marrow suppression, diarrhea
• no effect on cytotoxic activity

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Gefitinib
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Gefitinib Pharmacokinetics

• bioavailability 50
• t1/2 27-41 hours
• hepatically metabolism
• cytochrome P450 3A4
• excreted in feces

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Gefitinib Drug Interactions

• CYP3A4 inducers
• rifampin
• ?gefitinib levels
• CYP3A4 inhibitors
• itraconazole
• ?gefitinib levels
• lt 500mg dose
• does not induce/inhibit CYP450

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Gefitinib Mechanism of Action
EGF/TGFa
R
R
Extracellular
Membrane
Intracellular
K
K
EGFR-TKI
EGFR-TKI
Cell survival (anti-apoptosis)
Proliferation
Signalling
DNA
Growth factors
Angiogenesis
Chemotherapy/ radiotherapy sensitivity
Metastasis
R, epidermal growth factor receptor
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IDEAL IRESSA Dose Evaluation in Advanced Lung
Cancer Phase II Trials

• IDEAL- 1
• 250mg vs 500mg
• Response rate
• 18.4 (11.5-27.3)
• 19.0(12.1-27.9)
• Progression free survival
• 2.7 vs 2.8 months
• overall survival
• 7.6 vs 8 months
• -----------------------
• IDEAL 2
• 250mg vs 500mg
• Response rate
• 11.8(6.2-19.7)
• 8.8 (4.3-15.5)
• Overall survival
• 6.1 vs 6.0 months

IDEAL-1 (N210) 1-2 previous platinumchemo
regimens
Gefitinib 250mg Po daily

• R, DB
• Locally
• advanced
• or metastatic

IDEAL-2 (N216) ³2 previous chemo regimens
including platinum and docetaxel
Gefitinib 500 mg Po daily
Continue gefitinib until diseaseprogression or
intolerable toxicity
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INTACT IRESSA NSCLC Trial Assessing Combination
Therapy Phase III Trials
INTACT 1 Placebo vs 250mg vs 500mg Overall
survival 11.1 months vs 9.9 vs
9.9months ---------------------- INTACT-2 Placebo
vs 250mg vs 500mg Overall survival 9.9 vs 9.8 vs
8.7 months
Stage III/IV Chemo-naïve R,DB, PC INTACT -1
n1093 Chemo gem/cis INTACT -2 n1037 Chemo
carbo/paclitaxel
500 mg gefitinib
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Gefitinib Toxicity

• diarrhea
• loperamide
• hydration
• skin rash
• topical steroids
• antibiotics
• antihistamines
• ?LFTs
• interstitial pneumonitis
• lt 1 incidence

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SummaryNSCLC Second Line Therapy
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Topotecan
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Topotecan Pharmacokinetics

• t1/22-3 hours
• little hepatic metabolism
• renal and biliary elimination

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Topotecan Mechanism of Action
Topotecan binds topoisomerase I, inhibits DNA
replication and prevents cell proliferation
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Topotecan versus Cyclophosphamide, Doxorubicin,
Vincristine (CAV)
response rate topotecan vs CAV 24.3
(16.2-32.4) 18.3(10.8-25.7) median survival
(months) 6.3 vs 6.2 Improved sx () Dyspnea
27.9vs 6.6 Anorexia 32.1v15.8 Hoarse 32.5 v
13.2 Daily living activities 26.9v11.1
SCLC Randomized previous chemo gt 6 months
prior n211
Topotecan 1.5mg/m2 X 5 days q21 days
Cyclophos 1, 000mg/m2 doxo 45mg/m2
vincristine 2mg q21 days
JCO 199917(2)658-667
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Topotecan Toxicity

• Neutropenia
• Thrombocytopenia
• Grade ¾ 30 topotecan vs 5 CAV
• Anemia
• Infection
• Nausea
• Alopecia
• Diarrhea

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SummarySCLC Second Line Therapy
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Conclusions Current Chemotherapy

• New agents
• Second/third line
• Similar efficacy to standard of practice
• Different toxicity profiles

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Conclusion No Substitute for Quitting Smoking

• 1 in 5 smokers will develop lung cancer
• gt 90 of lung cancer cases are related to smoking
• prevention is key
• its never too late to quit
• before middle age, ? risk risk of non-smoker
• by 50 years old, ? risk by 50

Burns, D. Lung Cancer 2003 41,S3S18-9
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Conclusion