LUNG CANCER TREATMENT: AN OVERVIEW

Transcription

1 LUNG CANCER TREATMENT: AN OVERVIEW KONSTANTINOS N. SYRIGOS, M.D., Ph.D. Αναπλ. Καθηγητής Παθολογίας-Ογκολογίας, Ιατρικής Σχολής Αθηνών. Διευθυντής Ογκολογικής Μονάδας, Νοσ. «Η Σωτηρία». Visiting Professor of Thoracic Oncology, Yale Medical School, USA.

2 PRESENTATION OF NSCLC 30% I-II-mIIIA ciiia dry IIIB 20% wet IIIB IV 50%

3 THERAPEUTIC STRATEGY IN NSCLC I-II-mIIIA Surgery ± Chemotherapy ciiia dry IIIB Radiotherapy ± Chemotherapy ± Surgery wet IIIB IV Chemotherapy + Supportive care

4 SURVIVAL of LIMITED NSCLC 1 yr 2 yrs 5 yrs Stage I-II 90% 80% 70% Stage IIIA (resected) 70% 40% 30% Stage IIIA-IV (non operable) 50% 20% 5%

5 YEARS ALPI : OVERALL SURVIVAL P R O B A B I L I T Y Events/Total CT 278/548 Control 288/540 HR=0.96 ( ) p=0.585

6 IALT OVERALL SURVIVAL 100% 80% HR= 0.86 [ ] p<0.03 Chemotherapy ms 50.8 mo. 60% 40% 20% 0% Control ms 44.4 mo YR 44% 40% Years At risk

7 NEOADJUVANT GEMZAR-CISPLATIN STAGE III NSCLC Author Schedule Stage N Pts ORR% MST mos Crinò ASCO 1999 Van Kooten ASCO 1999 Yang ASCO 1999 v. Zandwijk JCO 2000 Rubio ASCO 2000 Crinò ASCO 2001 Santo Lung Cancer 01 Migliorino Lung Cancer 02 Q 28 IIIA/B NA Q 28 IIIA/B Q 28 IIIA/B NA Q 28 IIIA Q 21 IIIA/B Q 21 IIIA/B NA Q 21 IIIA/B NA Q 21 IIIA/B

8 The treatment algorithm for NSCLC Early (stage I/II/IIIa) Surgery + chemotherapy Radiotherapy (if unfit for surgery) NSCLC Advanced (stage IIIb/IV) Locally advanced Chemotherapy (PT doublet) + concomitant radiotherapy PS = performance status; PT = platinum; BSC = best supportive care

9 Advanced NSCLC: what should our treatment goals be for patients? Longer life increased overall survival (OS) Better life improved response rate (RR) prolonged time to progression (TTP) symptomatic improvement reduced toxicity improved quality of life (QoL)

10 Better life... are we meeting the objective? Benefits Chemotherapy Tumour control Improved survival Disadvantages Significant toxicity myelosuppression neuropathy Limited improvement in QoL i.v. administration Need for premedication

11 Chemotherapy: a case of no pain, no gain? Benefits Tumour control Improved survival

12 First-line chemotherapy for NSCLC Survival distribution function Overall survival (all randomised cases) Cisplatin/paclitaxel Cisplatin/gemcitabine Cisplatin/docetaxel Carboplatin/paclitaxel Months Progression-free survival (eligible cases) Months Median survival with chemotherapy is <1 year No clear differences between various combinations of agents Schiller JH, et al. N Engl J Med 2002;346:92 8

13 Gemcitabine + cisplatin vs paclitaxel + carboplatin vs vinorelbine + cisplatin Proportion surviving PCb VC GC PCb VC Median survival (months) year survival (%) GC = gemcitabine + cisplatin Survival (months) PCb = paclitaxel + carboplatin VC = vinorelbine + cisplatin Scagliotti GV, et al. J Clin Oncol 2002;20: GC

14 SWOG 9509: paclitaxel + carboplatin versus vinorelbine + cisplatin Paclitaxel + carboplatin Vinorelbine + cisplatin p=0.73 Survival (%) Months Kelly K, et al. J Clin Oncol 2001;19:3210 8

15 One and 2-year 2 survival rates according to PS Vinorelbine Vinorelbine/ cisplatin Vindesine/ cisplatin 1-year (%) 2-year (%) 1-year (%) 2-year (%) 1-year (%) 2-year (%) PS PS PS 2 patients obtain no clinical benefits from cisplatin-based chemotherapy no improvement in survival more toxicity Le Chevalier T, et al. J Clin Oncol 1994;12:360 7 Soria JC, et al. Ann Oncol 2001;12:

16 Efficacy of doublet chemotherapy according to PS PS 2 (n=6) 1 (n=64) 0 (n=30) Overall response rate (%) TTP (months) Median survival (months) year survival (%) The high incidence of grade 3 5 toxicities in PS 2 patients led to this category of patients being excluded ECOG = Eastern Cooperative Oncology Group Schiller JH, et al. N Engl J Med 2002;346:92 8 Sweeney CJ, et al. Cancer 2001;92:

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19 Targeted Therapies in NSCLC

20 BEVACIZUMAB 93% human, 7% murine Recognizes all isoforms of VEGF, K d = 8 x M Terminal half life days Bergsland et al. Am J Health Pharm 2004, 61, 12.

21 VEGF Ligands D. C. A. (Endothelial Cell (Lymphangiogenesis) (Lymphangiogenesis) VEGF-D Proliferation/Survival E. VEGFR-1S ) VEGF-C (Angiogensis/Vascular Permeability) B. (Extra-Cellular PIGF: (Endogenious VEGF-E VEGF-A VEGF-A Matrix Degredation) VEGF-A Antagonist) ECM VEGF Receptors R1 VEGF-B R2 PIGF NP-1 Neuropilin-1 R3 K Substrate Substrate P Y P Y Y P Y P P Y Substrate K K K K K K P Y P Y P Y Vascular EC Proliferation Migration Differentiation Survival NO Production Vascular Permeability Tumor Angiogenesis P Y P Y P Y Substrate P Y Lymphatic EC Proliferation Migration Lymphangiogenesis Tumor Angiogenesis

22 VEGF Ligands D. C. A. (Endothelial Cell (Lymphangiogenesis) (Lymphangiogenesis) VEGF-D Proliferation/Survival E. (Angiogensis VEGFR-1S ) VEGF-C /Vascular Permeability) B. (Extra-Cellular PIGF: (Endogenious VEGF-E VEGF-A VEGF-A Matrix Degredation) VEGF-A Antagonist) ECM VEGF Receptors R1 VEGF-B R2 PIGF NP-1 Neuropilin-1 R3 K Substrate Substrate P Y P Y Bevacizumab Y P Y P P Y Substrate K K K K K K P Y P Y P Y Vascular EC Proliferation Migration Differentiation Survival NO Production Vascular Permeability Tumor Angiogenesis P Y P Y P Y Substrate P Y Lymphatic EC Proliferation Migration Lymphangiogenesis Tumor Angiogenesis

23 Phase III trial of Avastin in NSCLC Progression-Free Survival Probability Medians: 4.5 vs 6.4 Avastin + CP CP 6 mo. 12 mo. 55.0% 14.6% 32.6% 6.4% HR: 0.62 (0.53, 0.72) P< Months Sandler A, et al. J Clin Oncol 2005;23 (16S):2s (Abstract LBA4)

24 Phase III trial of Avastin in NSCLC Overall Survival Avastin + CP CP 12 mo. 24 mo. 51.9% 22.1% 43.7% 16.9% Probability Medians: 10.2 vs 12.5 HR: 0.77 (0.65, 0.93) P = Months Sandler A, et al. J Clin Oncol 2005;23 (16S):2s (Abstract LBA4)

25 Bevasizumab: treatment-related deaths Haemorrhage Haemoptysis Gastrointestinal bleed CP (n=427) 0 1 CP + Avastin (n=420) 5 2 Neutropenic fever 1 1 Total 2 8

26 Bevasizumab: questions to be answered Can be used: with other chemotherapy combinations? in patients with brain mets? in patients with gross hemoptysis history? in patients with recent surgery? in patients with unstable angina? in patients on anticoagulants? in squamous cell carcinomas?

27 The treatment algorithm for NSCLC (cont d) NSCLC Advanced (stage IIIb/IV) Suitable for chemotherapy? First-line No Elderly/ PS2 3? Yes Yes No (PS4, frail elderly) PT-based doublet Single agent BSC

28 Current treatment options in advanced NSCLC: approved second-line therapies Chemotherapy docetaxel pemetrexed HER1/EGFR tyrosine-kinase inhibitors Tarceva* BSC *Approved in the EU on 19 September, 2005

29 Docetaxel versus pemetrexed in second-line NSCLC: OS 1.00 Docetaxel (n=276) Pemetrexed (n=265) Survival distribution function Median survival (months) year survival (%) HR=0.99 (0.8, 1.2) Pemetrexed Docetaxel Months Hanna N, et al. J Clin Oncol 2004;22:

30 TYROSINE KINASE INHIBITORS compete with adenosine triphosphate binding Proliferation Invasion Metastasis P P Signalling Angiogenesis Prevent HER1 activation Adhesion Apoptosis Sensitivity to chemotherapy

31 TYROSINE KINASE INHIBITORS F CI H 3 C O O NH N O N O NH N H 3 C O O N O N Erlotinib Gefitinib K i = 0.4 nm 1 K i = 3 nm 1 Wood ER, et al. Cancer Res 2004;64:

32 INTACT 1: Survival Data Median survival, months 1-year survival rate, % Log rank vs placebo (p=0.4377) (p=0.3034) ZD mg/day ZD mg/day Placebo 0.2 At risk 0.0 Population: intention to treat Survival time (months)

33 INTACT 2: Survival Data Median survival, months 1-year survival rate, % Log rank vs placebo (p=0.6425) (p=0.6705) ZD mg/day ZD mg/day Placebo Survival time (months) At risk Population: intention to treat

34 ERLOTINIB: OVERALL SURVIVAL 42.5% improvement in median survival

35 QOL Response Erlotinib Placebo P-value Improve Stable Worsen Improve Stable Worsen Chi Squared DISEASE Pain Dyspnea Cough Fatigue

36 Efficacy in second-line setting Tarceva versus BSC 1,2 Docetaxel (75mg/m 2 ) versus pemetrexed 3 Docetaxel (75mg/m 2 ) versus BSC 4 T (n=488) BSC (n=243) D (n=288) P (n=283) D (n=55) BSC (n=100) PS (%) 0/1 2 3 Prior regimens (%) *Survival cannot be compared directly because of different patient populations n=156 (T) and 82 (BSC); n= Median survival (months)* year survival (%) Median survival in PS 0/1 patients with one prior regimen Tarceva product information; 2 OSI and Roche data on file 3 Pemetrexed product information; 4 Docetaxel product information 5 Hanna N, et al. J Clin Oncol 2004;22:

37 Summary: second-line treatments Agent Improved survival versus BSC Survival comparable to chemotherapy Less toxicity Symptom control Docetaxel Pemetrexed ( ) Tarceva

38 Erlotinib: which patients benefit the most? Gender Tarceva patients (%) (n=427) Female (146) 14.4 Male (281) 6.1 p value* Histology Adenocarcinoma (209) Other (218) <0.001 Ethnicity Asian (53) Other (374) Ever smoked Yes (311) 3.8 No (93) 24.7 <0.001 Unknown (23) 13.0

39 The treatment algorithm for NSCLC NSCLC Advanced (stage IIIb/IV) Suitable for chemotherapy? First-line No Elderly/ PS2 3? Yes Yes No (PS4, frail elderly) PT-based doublet Single agent BSC Relapse Second-/ third-line Chemotherapy docetaxel pemetrexed Tarceva

40 The treatment algorithm for NSCLC Early (stage I/II/IIIa) Surgery + chemotherapy Radiotherapy (if unfit for surgery) NSCLC First-line No Elderly/ PS2 3? Advanced (stage IIIb/IV) Suitable for chemotherapy? Yes Yes No (PS4, frail elderly) Locally advanced PT-based doublet Single agent Relapse BSC Chemotherapy (PT doublet) + concomitant radiotherapy Second-/ third-line Chemotherapy docetaxel pemetrexed Tarceva PS = performance status; PT = platinum; BSC = best supportive care

41 TREATMENT OPTIONS FOR A-NSCLC Clinical Practice at 2007 in GREECE 1 st st Line 1 st Cis Cis + Gemcitabine Carbo + Paclitaxel + Avastin Cis Cis + Vinorelbine Cis Cis + Docetaxel or BSC for for Unfit pts pts 2 nd 2 nd nd Line Pemetrexed Docetaxel Tarceva * * Pts unsuitable for CT and Selected pts (Non-Smoker, ADC or BAC, Women) 3 rd 3 rd rd Line Tarceva (if (ifct CT in in 2nd 2nd line) line) Pemetrexed (if (iftarceva in in 2nd 2nd line) line) in in pts ptswith withgood goodps PS

42 Targeted Therapies for Lung Cancer CURRENT STATUS

43 Targeted Therapies for Lung Cancer EXPECTED STATUS

44 NSCLC: A Chronic Disease