Breathing New Life Into Lung Cancer Treatment

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 Outline I. Prognosis/background of lung cancer II. Current platinum chemotherapy III. New chemotherapeutic agents a. pemetrexed b. gefitinib c. topotecan Incidence of Cancer in Canada 2003 25000 Patients 20000 15000 Lung Breast Prostate 10000 5000 0 Incidence Deaths Canadian Cancer Society http://www.cancer.ca Accessed Nov 2003 Incidence of Cancer in BC 2003 3000 2500 Patients 2000 Lung Breast Prostate 1500 1000 500 0 Incidence Deaths Canadian Cancer Society http://www.cancer.ca Accessed Nov 2003 Lung Cancer: Summary NSCLC Frequency 80% SCLC 20% Staging Potential for early metastasis Progression Response to chemo Surgery 5 years survival Stage I, II, III, IV Less likely Slower Lower Potential for cure if caught early Stage 1,II: >40% (30-70%) Stage III, IV: <5-30% Distant mets <1% Limited, extensive High Fast High, potentially curable No role due to early mets Limited: 20-40% Extensive <1% 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 Lung Cancer: Staging NSCLC • stage I, II, IIIA – resectable • stage IIIA, IIIB, IV – chemo mainstay SCLC • chemo for all •  survival Lung Cancer Chemotherapy doxorubicin etoposide cisplatin vincristine cyclophos carboplatin vinorelbine topotecan gemcitabine irinotecan docetaxel paclitaxel Lung Cancer Chemotherapy doxorubicin etoposide cisplatin vincristine cyclophos carboplatin vinorelbine topotecan gemcitabine irinotecan docetaxel paclitaxel 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 2002;346:92-98 Contenders for Second Line and Beyond • Non-small cell lung cancer – pemetrexed – gefitinib • Small cell lung cancer – topotecan Pemetrexed 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 Pemetrexed: Mechanism of Action AMP GARFT PRPP + Gln Membrane IMP RNA & DNA Synthesis GMP 10-CHO-FH4 pemetrexed pemetrexed Folate Carriers 5, 10-CH2-FH4 FH4 dUMP Cell TS (5-Fu) dTMP DNA Synthesis DHFR FH2 (MTX) Pemetrexed vs Docetaxel in Recurrent NSCLC Previously treated patients 95% 1 previous chemo Stage III/IV Randomized Pemetrexed 500mg/m2 iv q21 days dex, vitamin B12, folic acid 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% Docetaxel 75mg/m2 q 21 days dex Proc Am Soc Oncol 200322:622, Ab 2503 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 Gefitinib Gefitinib: Pharmacokinetics • bioavailability 50% • t1/2 27-41 hours • hepatically metabolism – cytochrome P450 3A4 • excreted in feces Gefitinib: Drug Interactions • CYP3A4 inducers – rifampin – ↓gefitinib levels • CYP3A4 inhibitors – itraconazole – ↑gefitinib levels • < 500mg dose • does not induce/inhibit CYP450 Gefitinib: Mechanism of Action EGF/TGFα R R Extracellular Membrane Intracellular EGFR-TKI Proliferation Signalling Growth factors Chemotherapy/ radiotherapy sensitivity  DNA  K K EGFR-TKI Cell survival (anti-apoptosis) Angiogenesis Metastasis R, epidermal growth factor receptor IDEAL = IRESSA Dose Evaluation in Advanced Lung Cancer: Phase II Trials IDEAL- 1: 250mg vs 500mg Gefitinib 250mg Response rate: Po daily 18.4% (11.5-27.3) 1-2 previous platinum R, DB 19.0%(12.1-27.9) chemo regimens Locally Progression free survival: advanced 2.7 vs 2.8 months or metastatic Gefitinib 500 mg overall survival: IDEAL-2: (N=216) Po daily 7.6 vs 8 months ----------------------2 previous chemo IDEAL – 2: regimens including 250mg vs 500mg platinum and docetaxel Response rate: 11.8%(6.2-19.7) 8.8% (4.3-15.5) Continue gefitinib until disease progression or intolerable toxicity Overall survival: 6.1 vs 6.0 months IDEAL-1 (N=210) 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 n=1093 Chemo= gem/cis INTACT -2 n=1037 Chemo = carbo/paclitaxel Chemotherapy x 6 cycles + 250 mg gefitinib Chemotherapy x 6 cycles + 500 mg gefitinib Chemotherapy x 6 cycles + Placebo Gefitinib: Toxicity • diarrhea – loperamide – hydration • skin rash – topical steroids – antibiotics – antihistamines • ↑LFTs • interstitial pneumonitis – < 1% incidence Summary: NSCLC Second Line Therapy Best supportive care Median survival (months) Toxicity 4.6 Docetaxel Pemetrexed Gefitinib 7.8 8.9 6-8 Neutropenia 40% Neutropenic fever 13% Thrombocytopenia <1% Neuropathy 8% Diarrhea 3% Rash 48% Neutropenia 5% Neutropenic fever 2% Thrombocytopenia 2% Neuropathy 3% Diarrhea <1% Rash 46% Diarrhea 32% Elevated LFTs 10% Interstitial pneumonitis <1% Premeds Dexamethasone Folic acid, vit B12, dexamethasone Iv none Route Iv po Topotecan Topotecan: Pharmacokinetics • t1/2=2-3 hours • little hepatic metabolism • renal and biliary elimination Topotecan: Mechanism of Action Topotecan binds topoisomerase I, inhibits DNA replication and prevents cell proliferation Topotecan versus Cyclophosphamide, Doxorubicin, Vincristine (CAV) SCLC Randomized previous chemo > 6 months prior n=211 response rate topotecan vs CAV 24.3% (16.2-32.4) 18.3%(10.8-25.7) Topotecan 1.5mg/m2 X 5 days q21 days 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 Cyclophos 1, 000mg/m2 + doxo 45mg/m2 + vincristine 2mg q21 days JCO 1999;17(2):658-667 Topotecan: Toxicity • Neutropenia • Thrombocytopenia – Grade ¾ 30% topotecan vs 5% CAV • • • • • Anemia Infection Nausea Alopecia Diarrhea Summary: SCLC Second Line Therapy Best supportive care Median survival (months) Toxicity 3 CAV 6.2 Neutropenia 70% Thrombocytopenia 5% Anemia 20% Infection 26% Peripheral neuropathy Alopecia 22% Nausea 40% Cardiac toxicity Hemorrhagic cystitis Topotecan 6.3 Neutropenia 70% Thrombocytopenia 30% Anemia 42% Infection 28% Alopecia 35% Nausea 39% Diarrhea 12% Conclusions: Current Chemotherapy • • • • New agents Second/third line Similar efficacy to standard of practice Different toxicity profiles Conclusion: No Substitute for Quitting Smoking • 1 in 5 smokers will develop lung cancer • > 90% of lung cancer cases are related to smoking – prevention is key • it’s 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,S3:S18-9 Conclusion