The Evolving Management

Transcription

1 The Evolving Management of Advanced Lung Cancer CAGPO October 19th, 2013 M. Vincent Professor MB ChB, FRCPC, MRCP(UK) (Senate Stream) Dept. of Oncology Staff Medical Oncologist Thoracic & GI MDT London Regional Cancer Program 1

2 CONFLICT OF INTEREST CEO: Sarissa, Inc. Scientific Advisory Boards: YM BioSciences Critical Outcomes Technology Inc. Capital Royalty, Inc. Board of Directors: Lorus Therapeutics Inc. Speaker s Bureau Bristol Myers Squibb Eli Lilly, Inc. Honoraria: Amgen Astra Zeneca Bristol Myers Squibb Eli Lilly Inc. Hoffman La Roche Sanofi-Aventis Boehringer-Ingleheim Research Funding: Hoffman La Roche 2

3 OBJECTIVES Clear overview of both A-NSCLC and SCLC Explore areas of research and interest in Small Cell Lung Cancer Emphasize biomarker testing & R x decision impact Intro online A-NSCLC R x guide Case Study 3

4 4

5 5

6 Lung Cancer: Histology Small-cell carcinoma 10% to 15% Adenocarcinoma Large-cell carcinoma 10% to 15% 40% 25% to 30% American Cancer Society. Lung cancer (non-small-cell) Squamous cell carcinoma 6

7 Sensitivity...87% Specificity...98% Sensitivity...93%...94% Specificity...87%...97% Histopathology, 61:1017 7

8 8

9 Lung Cancer: Biomarkers in Adenocarcinoma 9

10 EGFR Mutations Associated with Sensitivity to EGFR-TKIs Nat Rev Cancer. 2007; 7:

11 GEFITINIB a Simplified illustration of signal transduction through the epidermal growth factor receptor (EGFR). Ligand binding causes receptor dimerization. This leads to receptor autophosphorylation, which is inhibited by gefitinib. b Structure of gefitinib and its in vitro inhibitory activity against various tyrosine kinases. Gefitinib was originally identified from structure activity studies based around a 4-anilinoquinazoline lead series MAPK 11

12 CASE REPORT: Response to an EGFR-TKI A RARE EVENT IN AN UNSELECTED CAUCASIAN 2003, June , Nov. 28 This was at a time before the mutation was recognised 12

13 13

14 14

15 Rapid Response to Crizotinib Pre-Treatment Crizotinib x 12 weeks 15

16 SO, HOW DO WE RECONCILE HISTOLOGY WITH MOLECULAR BIOMARKERS? 16

17 First, we need an approach to histopathology A-NSCLC Squamous AdenoCa Large Nested Sets Signet Cribri- BAC BAC Pap- Micro- Acinar Solid Ring form Muc Non- illary pap Muc Non- Squamous Non- N-E Neuroendocrine 17

18 Acinar Adenoca Papillary Adenoca (±13% EGFR mt) (±35% EGFR mt) Cribriform 80% ALK + Micropapillary (? 35% EGFR mt+) Solid Adenoca with Mucin (Never EGFR mt+) Signet Ring 65% ALK + Bronchioloalveolar Adenoca, Bronchioloalveolar Adenoca, Non-mucinous Mucinous (50% EGFR mt+) (Never EGFR mt+) 18

19 A-NSCLC: Algorithm Scaffold Non-Squamous Squamous NOS Adenoca Large 1L 1LM 2L 3L EGFR M+ ALK+ WT/WT UNKNOWN 19

20 A-NSCLC: Algorithm Scaffold Non-Squamous Squamous NOS Adenoca Large EGFR M+ ALK+ WT/WT UNKNOWN 1L 1L M 2L 3L 20

21 Adenocarcinoma Estimated Genomic Probabilities of KRAS and EGFR Mutations East Asia West (Japan, Korea, Taiwan, HK) (USA, Australia) 6 studies 2 studies n = 814 n = 116 Neversmokers EGFR mt KRAS mt neither Ever-smokers EGFR mt KRAS mt neither 70% 1% 29% 29% 17% 54% 37% 0% 63% 8% 41% 51% Shigematsu, Sakema, Takema, Bae, Tam 21

22 IPASS Study design Patients Age 18 years Life expectancy 12 weeks Adenocarcinoma histology Never smokers or light ex-smokers* PS 0-2 Stage IIIB/IV Measurable disease Gefitinib 250 mg/day 1:1 randomization Carboplatin AUC 5 or 6 and Paclitaxel 200mg/m 2 3 wkly Endpoints Primary Progression free survival (non-inferiority) Secondary Objective response rate Quality of life Disease related symptoms Overall survival Safety and tolerability Exploratory Biomarkers EGFR mutation EGFR gene copy number EGFR protein expression *Never smokers:<100 cigarettes in lifetime; light ex-smokers: stopped 15 years ago and smoked 10 pack yrs Carboplatin/paclitaxel was offered to gefitinib patients upon progression 22 PS, performance status; EGFR, epidermal growth factor receptor 22

23 Objective response rate in EGFR mutation positive and negative patients 71.2% Gefitinib Carboplatin / paclitaxel Overall response rate (%) 47.3% EGFR M+ odds ratio (95% CI) = 2.75 (1.65, 4.60), p= EGFR M- odds ratio (95% CI) = (0.01, ), p= % 1.1% (n=132) (n=129) (n=91) (n=85) Odds ratio >1 implies greater chance of response on gefitinib Mok et al, Chicago

24 Progression-free survival in EGFR mutation positive and negative patients EGFR mutation positive Gefitinib (n=132) Carboplatin / paclitaxel(n=129) 1. HR (95% CI) = 0.48 (0.36, ) 0. p< At risk : Months Gefitinib C / P rogression-free vival Probability of pr surv rogression-free vival Probability of pr surv EGFR mutation negative Gefitinib ib( (n=91) Carboplatin / paclitaxel (n=85) HR (95% CI) = 2.85 (2.05, 3.98) p< Months Treatment by subgroup interaction test, p< ITT population Cox analysis with covariates Mok et al, Chicago

25 Overall Survival in EGFR mutation positive and negative patients Fukuoka et al. JCO

26 26

27 27

28 EURTAC: 1L CHEMO vs ERLOTINIB 28

29 EURTAC: 1L CHEMO vs ERLOTINIB 29

30 30

31 31

32 32

33 33

34 EGFR M+ Iressa IPASS 1L + 1LM or Tarceva EURTAC or Tomtovok LUX-Lung 3 34

35 A-NSCLC Non-Squamous Squamous NOS Adenoca Large EGFR M+ ALK+ WT/WT UNKNOWN 1L + 1LM 2L 3L Iressa or Tarceva or Tomtovok Platinum doublet Alimta TKI rechallenge? 35

36 TKI Re-Challenge: May be a realistic option Chemotherapy Alimta-based 36

37 A-NSCLC: Algorithm Scaffold Non-Squamous Squamous NOS Adenoca Large 1L 1LM 2L 3L EGFR M+ ALK+ WT/WT UNKNOWN 37

38 38

39 ALK + 1L + 1LM Xalkori (crizotinib) US FDA 26/8/11 39

40 PROFILE 1007:PFS of 2L Crizotinib vs Pemetrexed or Docetaxel t Probability of survival without prog ression (%) No. at risk Crizotinib Pemetrexed Docetaxel Crizotinib Pemetrexed Docetaxel (n=172 a ) (n=99 a ) (n=72 a ) Events, n (%) 100 (58) 72 (73) 54 (75) Median, mo HR b (95% CI) 0.59 (0.43 to 0.80) 0.30 (0.21 to 0.43) P < Time (months) a As-treated population: excludes 1 patient in crizotinib arm who did not receive study treatment and 3 patients in chemotherapy arm who did not receive study treatment; b vs crizotinib 40

41 ORR a by Independent Radiologic Review ORR ratio: 3.4 (95% CI: 2.5 to 4.7); P< Crizotinib (n=173 b ) Crizotinib (n=172 c ) Chemotherapy (n=174 b ) Pemetrexed (n=99 c ) Docetaxel (n=72 c ) ORR (%) Treatment 0 Treatment a RECIST v1.1; b ITT population; c as-treated population 41

42 A-NSCLC: alternative schema for ALK + Non-Squamous Squamous NOS Adenoca Large EGFR M+ ALK+ WT/WT UNKNOWN 1L 1LM Platinum doublet X 4 Alimta PD 2L Xalkori PD and beyond? 42

43 A-NSCLC: Algorithm Scaffold Non-Squamous Squamous NOS Adenoca Large EGFR M+ ALK+ WT/WT UNKNOWN 1L 1LM 2L 3L 43

44 NON-SMALL CELL LUNG CANCER 1 st generation 2 nd generation 3 rd generation Cyclophosphamide Ifosphamide Paclitaxel Docetaxel Doxorubicin Mitomycin C Gemcitabine Cisplatin (low dose) Cisplatin (high dose) Oxaliplatin Carboplatin Vincristine Vinblastine Vindesine Vinorelbine Methotrexate Etoposide Irinotecan 44

45 BMJ Meta-Analysis (1995) No evidence existed that any group of patients specified by histological type benefited more or less from chemotherapy. 45

46 NON-SMALL CELL LUNG CANCER 1 st generation 2 nd generation 3 rd generation Cyclophosphamide Ifosphamide Paclitaxel Docetaxel Doxorubicin Mitomycin C Gemcitabine Cisplatin (low dose) Cisplatin (high dose) Oxaliplatin Carboplatin Vincristine Vinblastine Vindesine Vinorelbine Methotrexate Etoposide Irinotecan 46

47 Hitting the Wall First-line chemotherapy options in NSCLC (E1594): comparable efficacy with platinum doublets 1.0 Therapeutic plateau: overall survival <12 months survival Probability of Cisplatin/paclitaxel Cisplatin/gemcitabine Cisplatin/docetaxel Carboplatin/paclitaxel Time (months) NSCLC = non-small cell lung cancer Schiller, et al. NEJM

48 ECOG 1594: Efficacies by Histology Log-rank test for comparing OS and PFS distributions among different histology groups Survival in each histology group for different chemotherapy regimen Results: No difference in OS and PFS between the four histology groups No survival difference between the four chemotherapy regimens in each histology group Regardless of histology types, OS and PFS were similar in chemonaive NSCLC patients treated with standard platin-based doublets involving paclitaxel, docetaxel, or gemcitabine! WCLC 2009 Hoang et al, Abstract # PD

49 JMDB: Cis/Pem vs. Cis/Gem in First-Line NSCLC: Study Design Randomization Factors Stage Performance status (PS) (0 vs 1) Gender Histologic vs cytologic diagnosis History of brain metastases R Cisplatin 75 mg/m 2 day 1 + Pemetrexed 500 mg/m 2 day 1 Each cycle repeated every 3 weeks up to 6 cycles Cisplatin 75 mg/m 2 day 1 + Gemcitabine 1250 mg/m 2 days 1 & 8 Vitamin B 12, folate, and dexamethasone given in both arms Cis/Pem, cisplatin/pemetrexed; Cis/Gem, cisplatin/gemcitabine Scagliotti et al. J Clin Oncol 2008 (In Press). 49

50 Ov verall Survival Proba ability Cis/Pem vs. Cis/Gem in First-line NSCLC: Overall Survival in Squamous Cell Carcinoma and Adenocarcinoma / Large Cell 1.0 OS Median (95% CI) 0.9 Cis/Pem in Ad or La (N=512) 11.8 mos (10.4, 13.2) 0.8 Cis/Gem in Ad or La (N=488) 10.4 mos (9.6, 11.2) Cis/Pem in Sq (N=244) 9.4 mos (8.4,10.2) 0.7 Cis/Gem in Sq (N=229) 10.8 mos (9.5, 12.1) Overall Survival Time (months) in Squamous Patients 50

51 Figure 1. Kaplan Meier overall survival curves for the pemetrexed versus docetaxel study for each of the histologic. Subgroups:adenocarcinoma, large cell carcinoma, squamous cell carcinoma, and other NSCLC/NOS histologies. Scagliotti, The Oncologist 2009; 14:

52 A-NSCLC: Algorithm Scaffold Non-Squamous Squamous NOS Adenoca Large EGFR M+ ALK+ WT/WT UNKNOWN 1L 1LM 2L 3L 52

53 Adenoca/NOS/Large Cell: UNKNOWN, WT/WT Platinum doublet x 4-6: 1L Cisplatin/gemcitabine Cisplatin/docetaxel Carboplatin/paclitaxel Carboplatin/gemcitabine But also consider Cisplatin/pemetrexed 53

54 JMEN: Study Design Double-blind, Placebo-controlled, Multicenter, Phase III Trial Stage IIIB/IV NSCLC ECOG PS prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD Randomization factors: gender PS stage best tumor response non-platinum drug brain mets 2:1 Randomization Pemetrexed 500 mg/m 2 (d1,q21d) + BSC (N=441)* Primary Endpoint = PFS Placebo (d1, q21d) + BSC (N=222)* *B 12, folate, and dexamethasone given in both arms 54

55 Progression-free Survival by Histology Pro ogression-free Probability Non-squamous HR=0.47 (95% CI: ) 1.0 P < Pemetrexed 4.4 mos Placebo mos Time (months) Squamous HR=1.03 (95% CI: ) 1.0 P = Pemetrexed 2.4 mos Placebo mos Time (months) 55

56 Overall Survival by Histology Non-squamous (n=481) Squamous (n=182) Survival Probab bility HR=0.70 (95% CI: ) P =0.002 Placebo 10.3 mos Pemetrexed 15.5 mos Time (months) HR=1.07 (95% CI: ) P =0.678 Placebo 10.8 mos Pemetrexed 9.9 mos Time (months) 56

57 Treatment-related Toxicities* Pemetrexed (N = 441) Placebo (N = 222) % % Grade 3/4 Grade 3/4 Neutropenia 3 0 Anemia 3 1 Leukopenia 2 1 Fatigue 5 1 Anorexia 2 0 Infection 1 0 Diarrhea 1 0 Nausea 1 1 Vomiting <1 0 Sensory neuropathy 1 0 Mucositis/Stomatitis 1 0 *NCI CTC version 3.0 P <0.05 for grade 3/4 rates of neutropenia and fatigue 57

58 Tarceva maintenance therapy after first-line chemotherapy treatment SATURN Tumour samples EGFR protein expression (IHC) results Tarceva 150mg/day PD Off study Stage IIIb/IV NSCLC (n=1,700*) 4 cycles of a first-line standard platinumbased doublet Non-PD (n = 850) 1:1 Placebo PD Off study PD TITAN or Off study *planned; PD = progressive disease 58

59 OS in patients with non-squamous disease OS probab bility HR=0.79 ( ) Log-rank p= Erlotinib (n=272) Placebo (n=257) Time (months) Cappuzzo et al. ESMO

60 OS according to response to first-line chemotherapy (ITT population) SD CR/PR OS proba bility HR=0.72 ( ) Log-rank p= Erlotinib (n=252) Placebo (n=235) HR=0.94 ( ) Log-rank p= Erlotinib (n=184) Placebo (n=210) Time (months) Time (months) Multivariate HR for OS in SD population 0.71, p= Measured from time of randomisation into the maintenance phase 60

61 OS in patients with SD on first-line chemotherapy according to histology 1.0 Squamous-cell Non-squamous HR=0.67 ( ) Log-rank p= HR=0.76 ( ) Log-rank p= OS probab bility Erlotinib (n=97) Placebo (n=93) Erlotinib (n=155) Placebo (n=142) Time (months) Time (months) Measured from time of randomisation into the maintenance phase 61

62 A-NSCLC Non-Squamous Squamous NOS Adenoca Large EGFR M+ ALK+ WT/WT/WT UNKNOWN 1L Platinum doublet x 4 1LM Pemetrexed (or erlotinib) 2L 62

63 A-NSCLC: Algorithm Scaffold Non-Squamous Squamous NOS Adenoca Large EGFR M+ ALK+ WT/WT UNKNOWN 1L 1LM Platinum Doublet (non-pemetrexed) Surveillance (erlotinib) 2L 3L 63

64 Survival TAX 317B Docetaxel 75mg/m 2 vs BSC: Superior in 2 nd Line robability Cumulative P Doc75 (n=55) BSC75 (n=49) Median 7.5 mo vs. 4.6 mo Log-rank p = year 37% vs. 12% Chi-square p = Survival Time (months) 64

65 100 BR.21: Erlotinib vs Placebo in 2/3L Overall Survival g Erlotinib Placebo *HR 0.71, p < % 20 22% Months Shepherd, F. et al. N Engl J Med 2005;353:

66 Analysis of Survival Shepherd, F. et al. N Engl J Med 2005;353:

67 BR21: A large subgroup benefit in pts with zero EGFR mutations Clark GM et al. Clin Lung Cancer

68 A-NSCLC Non-Squamous Squamous NOS Adenoca Large EGFR M+ ALK+ WT/WT/WT UNKNOWN 1L Platinum doublet x 4 1LM 2L Alimta (or erlotinib) (Or Surveillance) Erlotinib (docetaxel not funded, no data) 68

69 A-NSCLC: Algorithm Scaffold Non-Squamous Squamous NOS Adenoca Large EGFR M+ ALK+ WT/WT UNKNOWN 1L 1LM 2L 3L Platinum Doublet (non-pemetrexed) Surveillance (erlotinib) Erlotinib Or Docetaxel Docetaxel Or Erlotinib 69

70 A-NSCLC Non-Squamous Squamous NOS Adenoca Large EGFR M+ ALK+ WT/WT/WT UNKNOWN 1L 1LM Gefitinib or Erlotinib or Afatinib Platinum doublet x 4 Pemetrexed Platinum doublet x 4 Pemetrexed (or erlotinib) Platinum Doublet (nonpemetrexed) Surveillance Or erlotinib 2L 3L Platinum doublet X 4 pemetrexed TKI rechallenge Crizotinib Erlotinib Erlotinib Or docetaxel Erlotinib Palliative RT, BSC or clinical trial Docetaxel or erlotinib 70

71 71

72 72

73 73

74 Met plays an important role in normal cellular physiology Met (c-met, HGFR) is a cell surface RTK that functions as a dimer 1 HGF Met (HGFR) Binding of HGF (scatter factor) causes receptor dimerisation 1 3 Grb2 Sos Gab1 Dimerisation activates multiple cell signalling cascades leading to Cell proliferation, survival, motility, invasion and migration 4,5 Rac1 Cdc42 Ras Shp2 Crk PI3K Raf C36 AKT Pak ERK/MAPK Rap1 Ets1 AP1 Motility Proliferation Migration/Invasion Survival Adapted from Birchmeier C, et al. Nat Rev Mol Cell Biol 2003;4: HGFR= hepatocyte growth factor receptor; RTK = receptor tyrosine kinase; HGF = hepatocyte growth factor 1. Kong-Beltran M, et al. Cancer Cell 2004;6:75 84; 2. Schmidt C, et al. Nature 1995;373: ; 3. Uehara Y, et al. Nature 1995;373:702 5; 4. Bladt F, et al. Nature 1995;376:768 71; 5. Birchmeier C, et al. Nat Rev Mol Cell Biol 2003;4:

75 The Met Pathway in Lung Cancer In non small cell lung cancer (NSCLC) studies 1 6 Met overexpression was detected in up to 67% of patient samples MET gene amplification has been observed in 1 7% of NSCLC patients samples surveyed Mutations in MET have been identified in patient samples and NSCLC cell lines Met activation has been reported in up to 5 20% of patients with EGFR tyrosine kinase inhibitor (TKI)-resistant NSCLC 1, 7 9 In preclinical studies, inhibition of Met signaling was capable of restoring sensitivity to treatment in EGFR TKI-resistant NSCLC cells 1. Lawrence R, Salgia R. Cell Adh Migr 2010; 4: Christensen J, et al. Cancer Lett 2005; 225: Cappuzzo F, et al. J Clin Oncol 2009; 27: Toschi L, Cappuzzo F. Future Oncol 2010; 6: Kris M, et al. J Clin Oncol 2011; 29(18 suppl.): Abstract CRA Kong-Beltran M, et al. Cancer Res 2006; 66: Engelman J, et al. Science 2007; 316: Sequist L, et al. J Clin Oncol 2008; 26: Sequist L, et al. Sci Transl Med 2011; 3:75ra26. 75

76 Prognostic value of Met High Met expression is linked with lower OS in NSCLC Retrospective study; 88 NSCLC tumours assessed by IHC* Adenocarcinoma (n=46) Squamous cell carcinoma (n=29) Large-cell carcinoma (n=13) 36/88 were intratumoural Met positive (40.9%) Intratumoural Met expression was a significant prognostic factor RR=2.642; p= OS = overall survival; NSCLC = non-small-cell lung cancer OS rate (% %) p= year survival rate(%) Met negative 63.2 Met positive 33.8 Intratumoural Met negative Intratumoural Met positive Months after surgery *IHC: rabbit polyclonal anti-met antibody (sc10), Santa Cruz Biotechnology 5-year survival rate, based on 52 Met negative tumours and 36 Met positive tumours Masuya D, et al. Br J Cancer 2004;90:

77 MET IHC as a companion diagnostic in NSCLC MET Positive was defined as majority ( 50%) of tumor cells with moderate or strong staining intensity Negative Weak 1000 MET Negative MET Positive Moderate Strong NA (2 -Dct ) MET mr Ventana s CONFIRM (SP44 mab clone) 0 MET IHC score MET diagnostic status was assessed after randomization and prior to unblinding 93% of patients had adequate tissue for evaluation of MET by IHC 52% patients with evaluable tissue were MET Positive IHC: immunohistochemistry Roche data on file 77

78 One-Armed (Monovalent) antibody binds MET, but does not lead to dimerization and activation Two-armed MET antibody Onartuzumab MET MET Onartuzumab prevents HGF binding and avoids MET homodimerization and activation Martens T, et al. Clin Cancer Res 2006;12:

79 Cross-talk between Met and EGFR pathways Scientific rationale for dual inhibition of Met and EGFR ERLOTINIB THERAPY Erlotinib is a small molecule inhibitor (SMI) of EGFR used to treat NSCLC and pancreatic cancer 1 SMI RESISTANCE VIA MET EGFR CROSS-TALK Tumour resistance to EGFR SMIs can occur via multiple mechanisms including crosstalk between Met and EGFR 2,3 Evidence of Met amplification is seen in ~20 22% of EGFR mutant NSCLC tumours 4 DUAL INHIBITION Dual inhibition of Met and EGFR may overcome tumour resistance 5 Onartuzumab EGF EGFR Erlotinib Erlotinib Met Erlotinib No activity Motility, invasion, survival, migration, proliferation No activity EGFR = epidermal growth factor receptor 1. Tarceva SmPC; 2. Engelman JA, et al. Science 2007;316: ; 3. Stommel JM, et al. Science 2007;318:287 90; 4. Bean J, et al. PNAS 2007;104: ; 5. Karamouzis MV, et al. Lancet Oncol 2009;10:

80 Key eligibility: Stage IIIB/IV NSCLC 2 nd /3 rd -line NSCLC Tissue required PS 0 2 Phase II: Erlotinib +/- MetMAb in 2 nd/ 3 rd -line NSCLC R A N D O M I Z MetMAb Arm A (15 mg/kg IV Q3W) 1:1 + n=69 Stratification factors: Tobacco history erlotinib Performance status (150 mg daily) Histology A T I O N Placebo (IV Q3W) n=137* + n=68 Arm B erlotinib (150 mg daily) Co-primary objectives: PFS in Met Diagnostic Positive patients (est. 50%) PFS in overall ITT population Other key objectives: OS in Met Diagnostic Positive pts OS in overall ITT patients Overall response rate Safety/tolerability PD Add MetMAb Must be eligible to be treated with MetMAb n=27 *128 NSCLC patients enrolled from 3/2009 to 3/2010 plus 9 SCC patients enrolled through 8/2010 Data presented includes >5 additional months of follow-up 5 80

81 MetMAb plus erlotinib in Met Dx+ patients PFS: HR=0.53 OS: HR=0.37 Pr robability of progress sion free Median (mo) HR (95% CI) Log-rank p-value No. of events Placebo + erlotinib MetMAb + erlotinib ( ) Probability of surv vival Median (mo) HR (95% CI) Log-rank p-value No. of events Placebo + erlotinib MetMAb + erlotinib ( ) Time to progression (months) Overall survival (months) 9 81

82 MetLung(OAM4971g): A RANDOMIZED, PHASE III, MULTICENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY EVALUATING ONARTUZUMAB IN COMBINATION WITH ERLOTINIB IN PATIENTS WITH MET DIAGNOSTIC POSITIVE mnsclc WHO AFTER STANDARD CHEMOTHERAPY 2L/3L NSCLC Met-positive (1 prior platinum-based line of therapy) Central testing for: Met status EGFR mutation status (N=490) Erlotinib: 150mg p.o. qd Onartuzumab/placebo: 15mg/kg i.v. q3w Randomise 1:1 Erlotinib + onartuzumab Erlotinib + placebo Treat until PD No crossover tx Survival follow-up Stratification criteria EGFR mutation status Met 2+ or 3+ score Number of prior lines of therapy Histology Key eligibility criteria Stage IIIb or IV Met+ NSCLC 1 2 prior lines of treatment No prior EGFR inhibitor ECOG PS 0 or 1 Primary endpoint: OS Secondary endpoints: PFS ORR Quality of life Safety ECOG = Eastern Cooperative Oncology Group; PFS = progression-free survival; ITT = intent-to-treat; OS = overall survival; ORR = overall response rate; PD = progressive disease 82

83 SMALL CELL LUNG CANCER C : ALGORITHM Limited Disease Extensive Disease 1L Cisplatin/Etoposide Carboplatin/Etoposide x 4-6 cycles x 4-6 cycles Concurrent thoracic RT ± Palliative RT Prophylactic Cranial RT Prophylactic Cranial RT 1LM Surveillance Surveillance 2L Re-challenge with Carboplatin/Etoposide or Topotecan single-agent 83

84 Group No. of trials Comparison Survival HR Group 1 1 ± Cisplatin (no etoposide) Group 2 17 ± Etoposide (no cisplatin) 0.72 Group 3 9 Cis/Etop vs Other 0.57 Group 4 9 Cis/Etop vs Etop/other

85 It was decided to remove the reference that Etoposide-carboplatin was biologically equivalent to etoposide-cisplatin..and to discuss the limited amount of data on this issue. 85

86 86

87 87

88 Compared to patients in arm III patients treated in arms I and II survived longer with median survivals of 336 days (95% CI ), 340 days (95% CI ), and 293 days (95% a ), respectively. The overall survival difference between the three arms was statistically significant (P = 0.04, Figure 1). Pairwise i comparison by the logrank test showed that the difference in survival between arm II and III was statistically significant (P , logrank test), while the P-value of the difference between arm I and arm III was

89 89

90 J Clin Oncol 1999 Similar survival, superior symptom, p y p relief, slightly better response rates; but more anemia,thrombocytopenia on topotecan. 90

91 15 pts re-challenged; 10 responses (67%) MST 5 months However, we have identified seven studies (192 patients altogether) employing so-called non-cross-resistant chemotherapy in clearly distinguishable relapsed patients... Their response rates (CR + PR)...range from 6% to 31%, and the median survival of responding patients was usually only 3-4 months. Thus, results with re-challenge chemotherapy, although poor, appear to be no worse than with alternative second-line chemotherapy. THERE IS NO STANDARD 2 ND LINE: CAV OR TOPOTECAN PROBABLY NOT SUPERIOR TO RE-CHALLENGE WITH PLATINUM AND ETOPOSIDE CONSIDER G-CSF TO PREVENT FN & MAINTAIN DOSE INTENSITY 91

92 PCI in ED-SCLC: Cumulative Incidence of Symptomatic Brain Metastases Slotman B et al. N Engl J Med 2007;357:

93 PCI in ED-SCLC: Overall Survival Slotman B et al. N Engl J Med 2007;357:

94 Bone Metastases: Zoledronate vs Placebo 94

95 95

96 96

97 97

98 98

99 99

100 100

101 101

102 102

103 103

104 104

105 105

106 EXPERIMENTAL TARGETS IN SMAL CEL LUNG CANCER Teicher B. Biochemical Pharmacology

107 107

108 Home page 108

109 Signing up 109

110 Logging in 110

111 Premise behind the website 111

112 Resources available to view without signing in or logging in 112

113 Resources include a link to the actual trial, granted the computer you are working from has access ie. hospital 113

114 User Guide tab 114

115 New patient (can be saved) vs sample patient (teaching or review opportunity) 115

116 Overview field 116

117 Overview 117

118 Entering patient characteristics allows for a personalized treatment guide 118

119 Patient Characteristics 119

120 Medical details 120

121 Prior therapy considerations 121

122 Specific notes that pertain to patient characteristics 122

123 Drug details 123

124 Warning symbols 124

125 Choosing a drug eliminates subsequent choices in later lines 125

126 Comment Boxes 126

127 CASE REPORT (1) An overview: Current systemic therapies for advanced d non-small cell lung cancer Ong M and Vincent M. Lung Cancer, In Press 127

128 CASE REPORT (cont) (2) 54 yr Caucasian male Never-smoker Dyspnea, large pleural effusion FNA: adenocarcinoma lung Chest tube drainage, pleurodhesis EGFR inconclusive (scant 6x material) 6 cycles carbo/paclitaxel minor response Relapsed within 3/12 Refractory to 3 cycles cles pemetrexeded Multiple brain mets, 0 2 dependent Whole brain RT 128

129 CASE REPORT (cont) (3) Rx erlotinib 150 mg po od 129

130 Disease burden before (Panels A, B, C) and 8 months after (Panels D, E, F) initiation of third-line erlotinib for metastatic A-NSCLC. 130

131 CASE REPORT (cont) (4) Eventual PD on erlotinib (± 1 year remission) Unresponsive to trial of afatinib Dies rapidly of respiratory failure EGFR? But almost certainly M+ 131

132 THE END 132

133 133

134 134

135 135

136 136

137 137