Câncer de Pulmão. Benefício e emprego das novas drogas. XIV Congresso da Sociedade Brasileira de Radioterapia

+ Câncer de Pulmão Benefício e emprego das novas drogas XIV Congresso da Sociedade Brasileira de Radioterapia Maikol Kurahashi, MD. Oncologia Clínica Hospital Santa Casa de Curitiba

Declaração de conflitos de interesse Categorias de Potencial Conflito de Interesse Patrocínio de transporte e/ou hospedagem em Congressos Patrocínio em estudos clínicos e/ou experimentais subvencionados pela indústria Ser conferencista/palestrante em eventos patrocinados pela indústria Participar de comitês normativos de estudos científicos patrocinados pela indústria Indústria(s) Novartis, Pfizer, Roche, GSK, Merck Serono, Lilly Roche, Pierre- Fabre, Morphotek Pfizer, Roche, Novartis Não Receber apoio institucional da indústria Não Preparo de textos científicos em periódicos patrocinados pela indústria Não Ter ações da indústria Não CFM n 1.595/00 de 18/05/2000

+ Principal causa de morte por câncer em todo mundo 1.200.000 óbitos anualmente EUA em 2010: 222.520 casos novos e 157.300 óbitos Brasil em 2010: 27.630 casos novos

SCLC NSCLC + Adenocarcinoma Carcinoma Epidermóide Carcinoma de grandes células

+ Incidence of NSCLC Histologic Subtypes 15% 20% 40% Adenocarcinoma Squamous-cell carcinoma Large-cell carcinoma NOS 30% American Cancer Society.

+ The role of chemoteraphy Surgery, Radiotherapy, Chemotherapy vs. BSC 9387 patients (7151 deaths) from 52 randomised clinical trials C vs. NoC:11 trials (1190 patients and 1144 deaths) Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ1995;311:899 909.

+ Chemotherapy vs Best Supportive Care in Advanced NSCLC: Meta-Analysis Meta-analysis of 8 trials (778 patients) using cisplatin-based chemotherapy [1] Absolute improvement in survival of 10% at 1 yr [1] Median survival, BSC vs chemo: 4 vs 8+ mos, respectively Median survival now 12+ mos in more recent trials VEGF-targeted therapy plus platinum doublet [2] Quality-of-life benefit from chemotherapy [3] 1. NSCLC Collaborative Group, et al. BMJ. 1995;311:899-909. 2. Herbst R, et al. Clin Lung Cancer. 2009;10:20-27 3. Klastersky J, et al. Lung Cancer. 2001;34(suppl 4):S95-S101.

+ One Size Fits All

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+ A histologia faz a diferença Adenocarcinoma Carcinoma Epidermóide Carcinoma de grandes células

+ CONSORT: Phase III Gemcitabine or Pemetrexed + Cisplatin as First-line Therapy Advanced-stage, previously untreated NSCLC patients (N = 1725) Stratified by: ECOG PS (0 vs 1) Cisplatin 75 mg/m 2 on Day 1 Gemcitabine 1250 mg/m 2 on Days 1 and 8 Six 3-wk cycles Cisplatin 75 mg/m 2 on Day 1 Pemetrexed 500 mg/m 2 on Day 1 Six 3-wk cycles Disease stage (IIIB vs IV) Brain metastases (yes vs no) Sex (male vs female) Pathologic diagnosis (histologic vs cytologic) Treatment center Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.

+ JMDB Trial: Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine in Advanced NSCLC No difference in OS or PFS between study arms Cis/pem improves OS over cis/gem in non-scca (HR: 0.81; P =.005) Cis/gem improves OS over cis/pem in SCCA (HR: 1.23; P =.05) Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551. Survival Probability Survival Probability Survival Probability 1.0 0.8 CP CG 0.6 CP vs CG 0.4 0.2 0 0 6 12 18 24 30 Survival Time (Mos) in All Patients 1.0 0.8 CP CG 0.6 CP vs CG 0.4 0.2 0 0 6 12 18 24 30 Survival Time (Mos) in Patients With Nonsquamous Histology 1.0 0.8 CP CG 0.6 CP vs CG 0.4 0.2 0 0 6 12 18 24 30 Survival Time (Mos) in Patients With Squamous Histology Median (95% CI) 10.3 (9.8-11.2) 10.3 (9.6-10.9) Adjusted HR (95% CI) 0.94 (0.84-1.05) Median (95% CI) 11.8 (10.4-13.2) 10.4 (9.6-11.2) Adjusted HR (95% CI) 0.81 (0.70-0.94) Median (95% CI) 9.4 (8.4-10.2) 10.8 (9.5-12.1) Adjusted HR (95% CI) 1.23 (1.00-1.51)

+ CONSORT: Efficacy Survival Pemetrexed + Cisplatin (n = 862) Gemcitabin e + Cisplatin (n = 863) HR (95% CI) P Value Median OS, mos 10.3 10.3 0.94 (0.84-1.05) Noninferi or Adenocarcinoma (N = 847) 12.6 10.9 0.84 (0.71-0.99).03 Large-cell carcinoma (N = 153) 10.4 6.7 0.67 (0.48-0.96).03 Squamous cell carcinoma (N = 473) 9.4 10.8 1.23 (1.00-1.51).05 Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.

+ Cancer Paradigm 2012 Tumors Genes Targets Drugs

Lung Cancer Mutation Consortium Incidence of Single Driver Mutations

+ Algorithm for Therapy of Advanced Stage NSCLC: 2012 Proposed treatment algorithm EGFR mutation positive or ALK fusion positive Molecular Good PS Clinical (PS) Poor PS Erlotinib or Crizotinib Nonsquamous Histologic Squamous Single-agent chemotherapy Bevacizumab eligible Platinum/pemetrexed (or other*) ± bevacizumab Clinica l Bevacizumab ineligible Platinum/pemetrexed (or other*) Platinum doublet plus cetuximab? First line Progression Chemotherapy by algorithm Bevacizumab or erlotinib or pemetrexed Based on prior therapy End of first-line chemotherapy Pemetrexed or erlotinib Based on prior therapy Erlotinib? Based on prior therapy Based on prior therapy Maintenance Second line *Docetaxel, paclitaxel, or vinorelbine. Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

+ Mabs Tkis Bevacizumab Cetuximab Erlotinib Gefitinib Crizotinib

VEGF: Targeted Approaches - Antibody Bevacizumab Anti-receptor blocking antibodies Tyrosine kinase inhibitors Antiligand blocking antibodies Adapted from Noonberg and Benz. Drugs. 2000;59:753.

Bevacizumab in Advanced NSCLC Phase III ECOG 4599 878 patients: Carboplatin/Paclitaxel +/- Bevacizumab PFS 6.2 vs 4.5 mo, response 35% vs 15% OS 12.3 mo (10.3 mo control) Phase III AVAiL 1043 patients: Cisplatin/Gemcitabine +/- Bevacizumab PFS HR 0.75, p.003 at 7.5 mg/kg 0.85, p.046 at 15 mg/kg RR 32% vs 20% OS 13.6m (7.5); 13.4m (15); 13.1m (plac), NS Johnson. JCO. 22:184-91, 2004, Sandler. NEJM. 355: 3542-52, 2006, Manegold. ASCO. 2007, abstr LBA 7514.

E4599: Phase III Carbo/Paclitaxel +/- Bevacizumab Patients with recurrent or advanced stage IIIb/IV NSCLC and no previous chemotherapy Paclitaxel 200 mg/m 2 + Carboplatin AUC 6 (PC) q3w 6 (no crossover permitted) (N = 878) Bevacizumab + 15 mg/kg q3w + PC 6 Bevacizumab until PD or unacceptable toxicity (n = 215; 53%) Of the 407 patients starting treatment with paclitaxel and carboplatin plus bevacizumab for whom we had adequate data on the duration of treatment, 215 patients (53%) continued with bevacizumab monotherapy, and of these, 107 (50%) received more than 5 cycles of monotherapy Sandler A, et al. N Engl J Med. 2006;355:2542-2550.

E4599: Carboplatin/Paclitaxel ± Bevacizumab Carboplatin/paclitaxel Carboplatin/paclitaxel + bevacizumab 100 PFS 100 OS PFS (%) 80 60 40 P <.001; HR: 0.66 Median PFS: 6.2 vs 4.5 mos OS (%) 80 60 40 P =.003; HR: 0.79 Median OS: 12.3 vs 10.3 mos 20 20 0 0 6 12 18 24 30 36 0 0 6 12 18 24 30 36 Mos Mos Sandler A, et al. N Engl J Med. 2006;355:2542-2550.

Bevacizumab in Advanced NSCLC Phase III ECOG 4599 878 patients: Carboplatin/Paclitaxel +/- Bevacizumab PFS 6.2 vs 4.5 mo, response 35% vs 15% OS 12.3 mo (10.3 mo control) Phase III AVAiL 1043 patients: Cisplatin/Gemcitabine +/- Bevacizumab PFS HR 0.75, p.003 at 7.5 mg/kg 0.85, p.046 at 15 mg/kg RR 32% vs 20% OS 13.6m (7.5); 13.4m (15); 13.1m (plac), NS Johnson. JCO. 22:184-91, 2004, Sandler. NEJM. 355: 3542-52, 2006, Manegold. ASCO. 2007, abstr LBA 7514.

Possibility of PFS (%) 1.0 0.8 0.6 0.4 0.2 PFS Endpoint CG + Placebo AVAiL: Efficacy Results 0 0 3 6 9 12 15 18 Mos CG + Bevacizumab (7.5 mg/kg) CG + Bevacizumab (15 mg/kg) PFS, HR (95% CI; P value) NA 0.75 (0.62-0.91;.0026) 0.82 (0.68-0.98;.0301) RR, % (P value) 20 34 (<.0001) 30 (<.017) Median survival, mos HR (P value) CG + placebo CG + bevacizumab 7.5 mg/kg 13.1 (-) 1. Reck M, et al. J Clin Oncol. 2009;27:1227-1234. 2. Reck M, et al. Ann Oncol. 2010;21:1804-1809. 1.0 0.8 0.6 0.4 0.2 PFS 13.6 0.92 (.3664) CG + placebo CG + bevacizumab 15 mg/kg 0 0 3 6 9 12 15 18 Mos 13.4 1.02 (.8420)

Bevacizumab in Special Populations: Summary Caution with elderly patients; ongoing trials Hemoptysis remains an issue, but anticoagulation can be considered cautiously Safe in patients with treated brain metastases Squamous histology still a major bleeding risk

Cetuximab Background Monoclonal anti-egfr IgG1 antibody Inhibits EGFR signaling Effective across several solid tumors, improving overall survival in mcrc (Van Cutsem E. J Clin Oncol, 2011) SCCHN (Bonner JA. N Engl J Med, 2006 and Lancet Oncol, 2009; Vermorken J. N Engl J Med, 2008) Advanced NSCLC (Pirker R. Lancet, 2009) In first-line treatment of advanced NSCLC, cetuximab significantly increased OS when added to cisplatin/vinorelbine (phase III FLEX) (Pirker R. Lancet, 2009) EGFR = epidermal growth factor receptor; ADCC = antibody-dependent cell-mediated cytotoxicity; mcrc = metastatic colorectal cancer; SCCHN = squamous cell carcinoma of the head and neck; NSCLC = non-small cell lung cancer

FLEX: Chemotherapy ± Cetuximab in First-line Therapy of Advanced NSCLC Stage IIIB or IV EGFR positive R Cetuximab + Cisplatin + Vinorelbine (n = 557) Survival Cisplatin + Vinorelbine (n = 568) Eligibility criteria: EGFR-expressing, advanced-stage NSCLC; no previous CT Primary endpoint: median OS (845 events needed) Secondary endpoints: survival rate (1 and 2 yrs), PFS rate (6 and 12 mos), response rate, safety, QoL Sample size: 1125 in 155 centers in EU, Latin America, Asia Pirker R, et al. Lancet. 2009;373:1525-1531.

Rationale for EGFR Expression Analysis as Continuous Variable: Results from FLEX: ITT Analysis of OS Overall Survival (%) 10.1 mo CT + Cetuximab (n = 557) CT (n = 568) 11.3 mo HR = 0.871 (95% CI 0.762 0.996) P = 0.044 1-year OS: 47% vs 42% Pirker (months) No at risk CT 568 383 225 134 48 0 CT + Cetuximab 557 383 251 155 53 3 Pirker R, et al. Lancet, 2009 P value = stratified log-rank test (2-sided)

FLEX: Response Rate by EGFR Expression Levels (IHC Score) Low EGFR Expression (< 200) (n = 776) (69%) High EGFR Expression ( 200) (n = 345) (31%) 50 50 44.4 Response Rate (%) 40 30 20 10 29.6 32.6 Response Rate (%) 40 30 20 10 28.1 0 0 P =.36 P =.002 CT + cetuximab CT Treatment interaction test p =.040 O Byrne K, et al. JTO. 2010;12(suppl): S558 (LBOA1).

Predictive Value of High EGFR for Survival Benefit With CT + Cetuximab OS (%) 100 90 80 70 60 50 40 30 20 10 0 Low EGFR 0 6 12 18 24 30 Mos Interaction P =.044 High EGFR HR: 0.99 (95% CI: 0.84-1.16) HR: 0.73 (95% CI: 0.58-0.93) OS (%) 100 90 80 70 60 50 40 30 20 10 0 CT + cetuximab CT 0 6 12 18 24 30 Mos Pirker R, et al. IASLC WCLC 2011. Abstract O01.06

+ Epidermal Growth Factor Receptor Mutations

+ Início do uso de TKIs Gefitinib Descoberta do alvo Biomarcador Mutação do EGFR

+ First-line treatment of EGFR-mutant NSCLC EGFR mutant EGFR TKI 1. Is EGFR TKI monotherapy better than chemo? 2. What about combinations of TKI and chemo? 3. Are all the mutants the same? 4. Why are responses to EGFR TKIs heterogenous? 5. What pathways are driving (relative) resistance?

+ IPASS: Gefitinib vs Carboplatin/Paclitaxel in Select Patients With Advanced NSCLC Randomized from March 2006 to October 2007 Up to six 3-wk cycles Previously untreated patients with stage IIIB/IV NSCLC; never or light ex-smokers; PS 0-2 (N = 1217) Gefitinib 250 mg/day PO (n = 609) Paclitaxel 200 mg/m 2 IV on Day 1 + Carboplatin AUC 5-6 mg/ml/min IV on Day 1 (n = 608) Primary endpoint: PFS (noninferiority) Secondary endpoints: ORR, OS, QoL, safety, disease-related symptoms Exploratory endpoints: EGFR mutation, EGFR gene copy number, EGFR protein expression Mok TS, et al. N Engl J Med. 2009;361:247-257.

+ IPASS: Results in ITT Population 1.0 PFS 1.0 OS* Probability of PFS 0.8 0.6 0.4 0.2 0 0 4 8 12 16 20 24 Mos G C/P n 609 608 Median PFS, mos Gefitinib Carboplatin/paclitaxel 5.7 5.8 HR: 0.74; P <.001 12-mo PFS, % 25 7 Mok TS, et al. N Engl J Med. 2009;361:947-957. Probability of Survival 0.8 0.6 0.4 0.2 0 0 4 8 12 16 20 24 28 Mos G C/P ORR, % 43.0 32.2 Median OS, mos Gefitinib Carboplatin/paclitaxel *Follow-up ongoing. 18.6 17.3 HR: 0.91; P = NR 12-mo OS, % 68 64

+ IPASS: PFS in EGFR Mutation Probability of PFS Positive vs Negative Patients EGFR Mutation Positive Gefitinib (n = 132) Carboplatin/paclitaxel (n = 129) HR: 0.48 (95% CI: 0.36-0.64) P <.001 No. events gefitinib,: 97 (73.5%) No. events C/P,: 111 (86.0%) 0 0 4 8 12 16 20 24 Mos At risk: Gefitinib 132 108 71 31 11 3 0 C/P 1.0 0.8 0.6 0.4 0.2 129 103 37 7 2 1 0 Treatment by subgroup interaction test, P <.001 Incidence of EGFR mutation on IPASS participants: 261/437 (59.7%) Mok TS, et al. N Engl J Med. 2009;361:947-957. Probability of PFS 1.0 0.8 0.6 0.4 0.2 EGFR Mutation Negative Gefitinib (n = 91) Carboplatin/paclitaxel (n = 85) HR: 2.85 (95% CI: 2.05-3.98) P <.001 No. events gefitinib: 88 (96.7%) No. events C/P: 70 (82.4%) 0 0 4 8 12 16 20 24 Mos 91 21 4 2 1 0 0 85 58 14 1 0 0 0

+ OPTIMAL study design Phase III study initiated by Tongji University, Shanghai, China Recruitment ongoing in China Chemo-naїve advanced NSCLC (N~150) EGFR mutation positive (exon 19 or 21) ECOG PS 0 2 Primary endpoint R 1:1 Erlotinib 150 mg/day until PD Gemcitabine + carboplatin (1,000 mg/m 2 d1, 8; AUC5 d1) q3w, up to 4 cycles PFS Secondary endpoints OS, ORR, QoL and safety

+ OPTIMAL: 1 st -line erlotinib is associated with longer PFS vs GC in EGFR-mutant NSCLC Zhou, You, Lancet Oncology 2011

+ EURTAC study design Phase III study initiated by the Spanish Lung Cancer Group (GECP) Recruitment ongoing in Spain, Italy and France Chemo-naїve advanced NSCLC EGFR mutation positive (exon 19 or L858R) ECOG PS 0 2 (n~150) R 1:1 Erlotinib 150 mg/day until PD Platinum-based doublet chemotherapy Primary endpoint PFS Secondary endpoints ORR, 1-year survival, OS, safety, QoL, localization of PD

+ EURTAC: First-line Erlotinib vs Chemo in European Patients With EGFR Mutations 174 patients Trial run in Europe (lead by Spanish group) Outcome CT Erlotinib HR P Value Response rate, % 15 58 - NR Median PFS, mos 5.2 9.7 0.37 <.0001 Median OS, mos NR NR 0.80.42 Most common toxicities, % ALT elevation: 72 Anemia: 46 Neutropenia: 36 ALT elevation: 80 Rash: 80 Diarrhea: 57 Rosell R, et al. ASCO 2011. Abstract 7503.

+ EURTAC: PFS in ITT Population PFS Probability 1.0 0.8 0.6 0.4 0.2 Patients at Risk, n Erlotinib Chemo 86 87 63 49 5.2 9.7 Erlotinib (n = 86) Chemotherapy (n = 87) HR: 0.37 (95% CI: 0.25-0.54; log-rank P <.0001) 0 0 3 6 9 12 15 18 21 24 27 30 33 Mos 54 20 32 8 21 5 17 4 9 3 7 1 4 0 2 0 2 0 0 0 Rosell R, et al. ASCO 2011. Abstract 7503.

+ EURTAC vs Asian Trials in EGFR Mutated NSCLC: RR and PFS Study Response Rate, % PFS, Mos (HR) EURTAC 58.0 vs 14.9 9.7 vs 5.2 (0.37) OPTIMAL 83 vs 36 13.1 vs 4.6 (0.16) NEJ 002 74 vs 31 10.8 vs 5.4 (0.30) WJTOG 3405 62 vs 31 9.2 vs 6.3 (0.49) None of the EGFR-TKI vs chemo as first-line therapy trials in EGFR mut NSCLC have shown a significant OS benefit Rosell R, et al. J Clin Oncol. 2011;29(suppl). Abstract 7503.

+ Summary: First-line treatment of EGFRmutant NSCLC Which mutant? EGFR mutant T790M? Other markers? 1. EGFR monotherapy is a standard. PFS for TKI is better than chemo. Addition of chemo not beneficial thus far. 2. All mutants are not the same. 3. We may be missing baseline T790M should we be using combinations for these patients at onset? Or different TKIs? 4. In the future, other markers (e.g. IGF-1R) may predict worse outcome combination Rx?

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EML4-ALK Translocations in NSCLC EML4 1 HELP 496 981 Basic WD EML4-ALK frequency: ~ 4% (64/1709) EML4-ALK variant 1 1 1 496 1059 1058 1620 Primarily in adenocarcinoma More common in younger patients ALK TM Kinase More common in never-smokers

Crizotinib: First-in-human ALK Inhibitor Potent and selective ATP competitive oral inhibitor of ALK and MET tyrosine kinases and their oncogenic variants Crizotinib (PF- 02341066) Safety and activity of crizotinib examined in an expanded cohort of patients with advanced ALK-positive NSCLC 1 Crizotinib administered at the MTD of 250 mg PO twice daily 1 Kwak et al. NEJM 2010;363:1693-703 Shaw ASCO 2011, Lancet Oncology 12:1004, 2011

+ Tumor Responses to Crizotinib for Maximum change in tumor size (%) Patients with ALK-positive NSCLC 60 40 20 0 20 40 60 80 30% Progressive disease Stable disease Confirmed partial response Confirmed complete response 100 * Bang ASCO plenary 2010, Kwak NEJM 2010 N= 76

Crizotinib Summary Crizotinib highly effective in pts w/ ALK FISH+ NSCLC Better diagnostics under development Survival benefit demonstrated Role as 1 st line therapy under investigation Currently in NCCN guidelines Resistance in < 1 yr a major issue Mechanisms, 2 nd mutations, growth of other clones

+ c-met as a Therapeutic Target in NSCLC HGF/MET axis is associated with invasiveness and is regulated in part by the HIF and EGFR pathways MET amplifications are associated with EGFR inhibitor resistance HGF/MET may promote resistance to VEGF inhibitors Xu L, et al. Oncogene. 2010;29:2616-2627. Engelman JA, et al. Science. 2007;316:1039-1043. Cascone, et al. ASCO 2010.

+ c-met receptor tyrosine kinase inhibitors promising therapeutic target in NSCLC ARQ-197, a novel and selective non-atp competitive inhibitor of c-met ARQ 209 enrolled 167 advanced NSCLC patients Randomized, placebo-controlled, double-blind clinical trial NSCLC Inoperable locally adv/metastatic dz. 1 prior chemo (no prior EGFR TKI) Endpoints Primary: PFS Secondary: ORR, OS Subset analyses Crossover: ORR R A N D O M I Z E 33 sites in 6 countries Erlotinib 150 mg PO QD + ARQ 197 360 mg PO BID 28-day cycle Erlotinib 150 mg PO QD + Placebo 28-day cycle Study accrual over 11 months (10/08 9/09) PD Randomization stratified by prognostic factors including sex, age, smoking, histology, performance status, prior therapy, best response, and geography (US vs ex-us) Schiller JH, et al. J Clin Oncol 2010;28:18s (abstr LBA7502 and oral presentation)

+ ARQ-197 plus erlotinib was associated with improvements in PFS and OS compared with erlotinib alone PFS (ITT population) Overall survival (ITT population) *Cox regression model. Schiller JH, et al. J Clin Oncol 2010;28:18s (abstr LBA7502 and oral presentation)

+ EPIC: Prospective Validation of ERCC1, RRM1, TS 2:1 Randomization Individualized arm Control arm EGFR mut + Squamous cell carcinoma Treatment based on investigators preference Yes Yes No EGFR mut + Yes Off study ERCC1 low RRM1 high ERCC1 high RRM1 low ERCC1 low RRM1 low ERCC1 high RRM1 high No Carboplatin Gemcitabine Carbo/gem Taxane ERCC1 low TS high ERCC1 high TS low ERCC1 low TS low ERCC1 high TS high Carboplatin Pemetrexed Carbo/pem PIs : G. Simon & G. Scagliotti University of South Carolina (Hollings Cancer Center) & University of Torino RRM1 low Gemcitabine RRM1 high Taxane

Figure 6 Source: Cell, Volume 144, Issue 5, Pages 646-674 (DOI:10.1016/j.cell.2011.02.013) Copyright 2011 Elsevier Inc. Terms and Conditions

Riess JW, Wakelee HA. Clinical Advances in Hematology & Oncology Volume 10, Issue 4 April 2012

+ History of Therapy in Advanced NSCLC: FDA Approval Dates First line Second line Third line Maintenance Not approved *Label does not include NSCLC-specific indication Cisplatin* 1978 ~ 2-4 Standard therapies Carboplatin* 1989 Vinorelbine 1994 1970 1980 1990 2000 ~ 6 Docetaxel 1999 Paclitaxel Gemcitabine 1998 Docetaxel 2002 BSC Single-agent platinum Doublets ~ 8-10 Gefitinib 2003 Erlotinib Pemetrexed 2004 Bevacizumab 2006 12+ Pemetrexed 2008/2009 Median OS (mos) IPASS: 18.8m Bevacizumab + PC Histology-directed therapy 1. FDA Web site. 2. NCCN. Clinical practice guidelines in oncology. v.3.2011. 3. Schrump, et al. Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.