1. Dr Tudor Eliade CIULEANU Institute of Oncology “Prof. Dr. Ion Chiricuta” University of Medicine and Pharmacy “Iuliu Hatieganu” 3.07.2013 Bucuresti Dynamic changes in the management of lung cancer in the era of personalized therapy Tudor Eliade CIULEANU Bucharest, Feb 19 th 2016

2. Personalized therapy in advanced NSCLC – is it already old fashioned? What is ready for immediate use? First line metastatic setting: Treatment by histology: bevacizumab and pemetrexed (nonSq), necitumumab (Sq) Treatment by molecular profiling: EGFR-TKIs, ALK inhibitors Maintenance therapy Appropriate selection (PS, histology, response, EGFR mut) Second line therapy: Treatment by histology: pemetrexed for non-squamous Treatment by molecular profiling: EGFR TKIs, ALK inhibitors Immuno-oncology – anti PD1 agents better than docetaxel New generation doublets (dtx + ramucirumab, dtx+ nintedanib) > docetaxel What we need to expect / prepare for the future? Incorporate pharmacogenomics / molecular profiling/ immune therapy “the right therapy for each patient, each time” Is immune checkpoint modulation more valuable than personalized therapy?

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4. The moving reality of molecular therapy in the thoracic tumors 1. Non-oncogene driven cancers (Sq, 50% NonSq) 2. Oncogene-driven cancers (50% NonSq) “personalized therapy/ actionable targets” 3. Immune checkpoint modulation (Sq, NonSq)

5. The moving reality of molecular therapy in the thoracic tumors 1. Non-oncogene driven cancers (Sq, 50% NonSq) -chemotherapy -antiangiogenic agents (bevacizumab, nintedanib), -EGFR directed (necitumumab, erlotinib, afatinib) 2. Oncogene driven cancers (50% NonSq) “personalized therapy/ actionable targets” EGFR, ALK, MET, ROS1, RAF, RET, HER2, RAS, TRK, PIK3CA

6. NSCLC Treatment Algorithm 2016 Determine: PS, histology, driver mutations EGFR-TKI: Erlotinib, Gefitinib, Afatinib ALKi: Crizotinib EGFR-TKI: Erlotinib, Gefitinib, Afatinib ALKi: Crizotinib NSCLC advanced/ metastatic EGFR mut+, ALK rearr. Eligibility for Bevacizumab SQUAMOUS Chemotherapy EGFR Wild-Type / unknown NON-SQUAMOUS Platinum doublet + Bevacizumab Platinum doublet + Bevacizumab Nivolumab, Pembrolizumab (PD-L1+) Docetaxel + Ramucirumab (NSCLC) or Docetaxel + Nintedanib (AK) Pemetrexed (non-SQ) Erlotinib, Gefitinib (EGFR mut+), Afatinib (SQ), Osimertinib (T790M mut+) Crizotinib/ Ceritinib, Alectinib (ALK+) Nivolumab, Pembrolizumab (PD-L1+) Docetaxel + Ramucirumab (NSCLC) or Docetaxel + Nintedanib (AK) Pemetrexed (non-SQ) Erlotinib, Gefitinib (EGFR mut+), Afatinib (SQ), Osimertinib (T790M mut+) Crizotinib/ Ceritinib, Alectinib (ALK+) Pemetrexed, Erlotinib Pemetrexed, Erlotinib (Erlotinib) Platinum/ Gem + Necitumumab Platinum/ Tax Platinum/ Nvb Platinum/ Gem + Necitumumab Platinum/ Tax Platinum/ Nvb Platinum/ Pem Bevacizumab Adenocarcinoma & Others 1 st line PS 0-2 chemo PS 0-3 TKIs 1 st line PS 0-2 chemo PS 0-3 TKIs Maintenance PS 0-1 2 nd, 3 rd line PS 0-2 chemo PS 0-3 TKIs 2 nd, 3 rd line PS 0-2 chemo PS 0-3 TKIs

7. NSCLC Treatment Algorithm – Romania 19.02.2016 Determine: PS, histology, driver mutations (+/-) Erlotinib**** NSCLC advanced/ metastatic EGFR mut+ Eligibility for Bevacizumab SQUAMOUS Chemotherapy EGFR Wild-Type / unknown NON-SQUAMOUS Platinum doublet+ Bevacizumab**** Platinum doublet+ Bevacizumab**** Docetaxel Pemetrexed (non-SQ)**** Erlotinib**** Crizotinib (ALK+)**** NEW!!! Docetaxel Pemetrexed (non-SQ)**** Erlotinib**** Crizotinib (ALK+)**** NEW!!! Pemetrexed****, Erlotinib**** Pemetrexed****, Erlotinib**** (Erlotinib) **** Platinum doublet Platinum + Pemetrexed**** Bevacizumab**** Adenocarcinoma & Others 1 st line PS 0-2 chemo PS 0-3 TKIs 1 st line PS 0-2 chemo PS 0-3 TKIs Maintenance PS 0-1 2 nd, 3 rd line PS 0-2 chemo PS 0-3 TKIs 2 nd, 3 rd line PS 0-2 chemo PS 0-3 TKIs

8. Tissue is the Issue! Adenocarcinoma glandular pattern / mucin + (50%) IHC:CK7+ / TTF1+ (<100%) Squamous Cell Carcinoma cellular keratinization / intercellular bridges / keratin “pearl” formation IHC:CK5/6+ / P63+

9. The moving reality of molecular targeted therapy in NSCLC 1. Metastatic disease, 1 st line & maintenance 2. Metastatic disease, 2 nd line3. Targeted immunotherapy

10. Anti-VEGF (1 st line and maintenance)

11. Treatment by histology – Bevacizumab Overall Survival 1.0 0.8 0.6 0.4 0.2 0 Time (month) Bev 15 mg/kg + CP Carbo + Paclitaxel HR=0.79 (0.67–0.92) p=0.003 10.3 12.3 m E4599 33rd Congress of the European Society for Medical Oncology (ESMO) in Stockholm 2008

12. Restricting eligibility to non-squamous histology leads to a significant reduction in pulmonary haemorrhage Grade  3 pulmonary haemorrhage Percentage 10 8 6 4 2 0 AVF0757g Bevacizumab 7.5&15mg/kg + CP E4599 Bevacizumab 15mg/kg + CP Johnson, et al. JCO 2004 Sandler, et al. NEJM 2006 Squamous and non-squamous histology Non-squamous histology

13. Survival advantage for ALIMTA/cisplatin in the 1st line treatment of advanced NSCLC patients with adenocarcinoma 1,2 * Superiority p-value. 1. Scagliotti GV, et al. Oncologist. 2009;14:253-263. 2. ALIMTA [Summary of Product Characteristics]. Eli Lilly and Company, approved 21 Sept 2009. ALIMTA/Cisplatin (n=436) GEMZAR/Cisplatin (n=411) Median (95% CI) 12.6 mo (10.7-13.6) 10.9 mo (10.2-11.9) Adjusted HR (95% CI) 0.84 (0.71-0.99) p-value 0.033 *

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17. EGFR (1 st line & maintenance)

18. EGFR: molecular biology Extracellular domain Tyrosin-kinase domain Regulatory domain EGFR protein (170 kDa) Transmembrane domain Exons 1–16 Exons 18–24 Exons 25–28 EGFR transcription Exon 17 EGFR Chromosome 7

19. Riely, et al. Clin Cancer Res 2006 EGFR gene: identified mutations Confers sensitivity 18 19 20 21 Deletions L858R G719A/S L861Q Unclear Effect on sensitivity at EGFR TKIs P694X V700D E709X G735S V738F V742A T751I S752Y D761N A763V N765A S768I T783A L792P L798F G810S N826S L838V T847I I853T A859T E866K L833V H835L H850N V851X G863D A864T L730F P733L E746K L688P V689M I715S L718P S720X D761Y D770_N771 insNPG T790M Or resistence to EGFR TKIs Exons 1–16 Exons 18–24 Exons 25–28 EGFR transcription Exon 17

20. Activating EGFR mutations not restricted to specific subgroups Rosell, et al. NEJM 2009 Patients (%) Male Former smoker Non-adeno/BAC Spanish Lung Cancer Group (SLCG) study in advanced NSCLC with activating EGFR mutations (n=350) 30% 26% 9% FemaleNever smoker Adenocarcinoma GenderSmoking statusHistology 100 80 60 40 20 0 BAC = bronchioalveolar carcinoma

21. First-line gefitinib vs C/P in population enriched for mutations: IPASS study design Gefitinib (250 mg / day) Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m 2 ) 3 weekly # 1:1 randomisation * Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped  15 years ago and smoked  10 pack years; # limited to a maximum of 6 cycles Carboplatin / paclitaxel was offered to gefitinib patients upon progression PS, performance status; EGFR, epidermal growth factor receptor Patients Chemonaïve Age ≥18 years Adenocarcinoma histology Never or light ex-smokers* Life expectancy ≥12 weeks PS 0-2 Measurable stage IIIB / IV disease Primary Progression-free survival (non-inferiority) Secondary Objective response rate Overall survival Quality of life Disease-related symptoms Safety and tolerability Endpoints Mok et al NEJM 2009

22. IPASS: First-line Gefitinib vs CP in Advanced NSCLC: PFS Fukuoka M, et al. ASCO 2009. Abstract 8006, Mok et al 2009 Progression Free (%) Mos PFS: Mutated EGFRPFS: Wild-Type EGFR Median PFS Gefitinib (n = 132): 9.5 mos CP (n = 129): 6.3 mos Median PFS Gefitinib (n = 91): 1.6 mos CP (n = 85): 5.5 mos HR: 0.48 P <.0001 HR: 2.85 P <.0001 0 20 40 60 80 100 04812162024 0 20 40 60 80 100 04812162024  Treatment by EGFR mutation status interaction test, P <.0001

23. ORR in EGFR MUT+ and WT patients Odds ratio >1 implies greater chance of response on gefitinib ORR (%) 80 70 60 50 40 30 20 10 0 (n=132)(n=129) (n=91) (n=85) MUT+ patientsWT patients 71.2% 47.3% 1.1% 23.5% Gefitinib CP EGFR MUT+ odds ratio 2.75 (1.65–4.60), p=0.0001 EGFR WT odds ratio 0.04 (0.01–0.27), p=0.0013 Mok T, et al. N Engl J Med 2009

24. COX analysis with covariates. HR <1 implies a lower risk of death on gefitinib 0481216202428 1.0 0.8 0.6 0.4 0.2 0 Time (months) Probability GefitinibCP Median OS (months)18.617.3 6 months OS (%)8486 12 months OS (%)6864 IPASS: OS in ITT population Mok T, et al. N Engl J Med 2009 Gefitinib (n=609) CP (n=608) HR (95% CI) = 0.91 (0.75–1.10)

25. Randomised studies with first-line chemotherapy or gefitinib in patients with NSCLC harbouring EGFR mutations NEJ GSG 1 NEJ GSG = North East Japan Gefitinib Study Group; WJTOG = West Japan Thoracic Oncology Group; CD = carboplatin-docetaxel 1. Maemondo, et al NEJM 2010 2. Mitsudomi, et al. Lancet Oncol 2010 n Median OS (months 2 year survival (%) Gefitinib9828,461 CP10023,945 PFS probability Time (days) 1.0 0.8 0.6 0.4 0.2 0 0100200300400500 n Median PFS (months) Gefitinib9810,4 CP965,5 Log-rank test p<0.001 HR=0.79 (0.49–1.3) p=0.354 OS probability Time (days) 1.0 0.8 0.6 0.4 0.2 0 020040060080010001200 Time (months) 1.0 0.8 0.6 0.4 0.2 0 010203040 n Median PFS (months) Gefitinib869.2 CD866.3 HR=0.49 (0.34–0.71) p<0.001 WJTOG 3405 2 1.0 0.8 0.6 0.4 0.2 0 n Median PFS (months) Gefitinib8630.9 CD86N/R Time (months) 010203040 HR=1.638 (0.49–3.582) p=0211

26. EURTAC study design Primary endpoint Progression-free survival (PFS) –interim analysis planned at 88 events Secondary endpoints Objective response rate Overall survival (OS) Location of progression Safety EGFR mutation analysis in serum Quality of life ECOG = Eastern Cooperative Oncology Group; PS = performance status; PD = progressive disease *Cisplatin 75mg/m 2 d1 / docetaxel 75mg/m 2 d1; cisplatin 75mg/m 2 d1 / gemcitabine 1250mg/m 2 d1,8; carboplatin AUC6 d1 / docetaxel 75mg/m 2 d1; carboplatin AUC5 d1 / gemcitabine 1000mg/m 2 d1,8 Chemonaїve Stage IIIB/IV NSCLC EGFR exon 19 deletion or exon 21 L858R mutation ECOG PS 0–2 (n=174) R Platinum-based doublet chemotherapy q3wks x 4 cycles* PD Erlotinib 150mg/day PD Stratification Mutation type ECOG PS (0 vs 1 vs 2)

27. PFS in ITT population (updated analysis 26 Jan 2011) PFS probability Erlotinib (n=86) Chemotherapy (n=87) HR=0.37 (0.25–0.54) Log-rank p<0.0001 Time (months) 03691215182124273033 Patients at risk Erlotinib866354322117974220 Chemo 874920854310000 Data cut-off: 26 Jan 2011 1.0 0.8 0.6 0.4 0.2 0 9.75.2

30. First-line Treatment With EGFR TKI vs Chemotherapy in EGFR-Mutated Patients Presented By Martin Edelman at 2014 ASCO Annual Meeting

31. Combined OS Analysis: LUX-Lung 3, LUX-Lung 6: Key Findings Presented By Howard West at 2014 ASCO Annual Meeting

32. Study design Presented By Terufumi Kato at 2014 ASCO Annual Meeting Erlotinib +/- Bevacizumab

33. Primary endpoint: PFS by independent review Presented By Terufumi Kato at 2014 ASCO Annual Meeting

34. Cost Considerations with Erlotinib/Bev Combination Presented By Howard West at 2014 ASCO Annual Meeting

35. ALK (1 st line)

38. Other mutations: BRAF, MET, ROS1, RET,…

39. Further developments in other mutation subsets of adenocarcinoma Presented By Martin Edelman at 2014 ASCO Annual Meeting

40. Davies H, et al. Nature. 2002;417:949-954; Platz A, et al. Mol Oncol. 2008;1:395-405; Karasarides M, et al. Oncogene. 2004;23:6292-6298; Long, et al. N Engl J Med. 2014;371:1877; Gilmartin et al Clin Cancer Res 2011;17:989. Dabrafenib Inhibits BRAF V600 Kinase and Trametinib Inhibits Downstream MEK Signaling Dabrafenib mode of action Reversible, small molecule BRAF inhibitor ATP competitive BRAF V600E: IC 50 0.65 nM Trametinib mode of action Reversible, small molecule MEK1 and MEK2 allosteric inhibitor MEK1 and MEK2: IC 50 0.7 and 0.9 nM 40 PI3K/AKT/mTOR pathway Proliferation, Growth, Survival MEK p90RSKMSK1 BRAF CRAF BRAF V600 ERK1/2 RAS Dabrafenib Trametinib

41. Summary BRF 113928 study D + T demonstrated clinically meaningful anti-tumor activity with a higher ORR when compared indirectly with dabrafenib monotherapy in BRAF V600E mutated NSCLC –ORR = 63% and DCR = 88% for dabrafenib plus trametinib –ORR = 32% and DCR = 56% for dabrafenib as monotherapy 1 Safety profile is manageable and similar to previous studies in melanoma Cohort B has completed recruitment with 59 subjects A third cohort investigating D + T in previously untreated V600E mutant Stage IV NSCLC is actively recruiting 41 1. Planchard D, et al. Ann Oncol 2014;25 (suppl 4):abstract LBA38_PR.

42. Efficacy and safety of crizotinib in patients with advanced MET-amplified non-small-cell lung cancer (NSCLC) Presented By D. Camidge at 2014 ASCO Annual Meeting

43. Objective response ratea Presented By D. Camidge at 2014 ASCO Annual Meeting

45. Slide 33 Presented By Martin Edelman at 2014 ASCO Annual Meeting

46. Study Design Presented By Nick Thatcher at 2014 ASCO Annual Meeting SQUIRE Necitumumab (Anti EGFR MoAb)

47. Slide 9 Presented By Nick Thatcher at 2014 ASCO Annual Meeting

48. Historical approach to NSCLC treatment Diagnosis Tumour response or stable disease 1st-line Tx Pt Doublet (4–6 cycles) Observation PD 2nd-line Tx to PD Death How can we further improve patient outcomes in NSCLC?

49. Revised approach to NSCLC treatment Diagnosis Tumour response or stable disease 1st-line Tx Pt Doublet (4–6 cycles) Maintenance treatment PD 2nd-line Tx to PD Death Patients with non-PD receive maintenance therapy –deferring disease progression –deferring symptom deterioration –deferring death

50. Why maintenance therapy? Many patients do not receive second-line therapy 1. Brodowicz, et al. Lung Cancer 2006 2. Westeel, et al. JNCI 2005; 3. Fidias, et al. JCO 2009; 4. Ciuleanu, et al. Lancet 2009 5. Miller, et al. ASCO 2009; 6. Cappuzzo, et al. Lancet Oncol 2010; 7. Pérol, et al. ESMO 2010 Control arm Trial% 2L Tx Median PFS (months) Brodowicz 1 57%2.0 Westeel 2 NR3.0 Fidias 3 63%2.7 JMEN 4 67%2.0 ATLAS 5 56%3.8 SATURN 6 72%2.6 IFCT-GFPC 0502 7 91%1.9 Approximately 2/3 of patients received second-line therapy Limited PFS

51. Stinchcombe, et al. JTO 2007; NCCN guidelines v2, 2012 Continuation Continuation of the non-platinum agent Switch Initiation of a different agent Preserves all second-line options Patient already benefitting Patients receive an additional treatment Potential to overcome resistance  Potential for cumulative toxicity Unlikely to improve tumour response Loss of one second-line option at PD Maintenance therapy options

52. JMEN: Maintenance Therapy with Pemetrexed - Study Design  Stage IIIB/IV NSCLC  PS 0-1  4 prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD Randomization factors:  gender  PS  stage  best tumor response to induction  non-platinum induction drug  brain mets 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 2:1 Randomization Ciuleanu et al, The Lancet 2009 Time-to-event endpoints measured from time of randomization into the maintenance phase

53. Pemetrexed 9.9 mos Placebo 10.8 mos Squamous (n=182) HR=1.07 (95% CI: 0.77–1.50) p=0.678 Time (months) Non-squamous (n=481) Pemetrexed 15.5 mo Placebo 10.3 mo HR=0.70 (95% CI: 0.56-0.88) p=0.002 Survival Probability Time (months) 036912151821242730333639424548 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 036912151821242730333639424548 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Survival Probability Maintenance Therapy with Pemetrexed Overall Survival by Histology Ciuleanu et al, The Lancet, 2009

54. PARAMOUNT: Study Design Induction Therapy 4 cycles, q21d Continuation Maintenance Therapy q21d until PD Pemetrexed + BSC Placebo + BSC Pemetrexed + Cisplatin CR/PR/SD per RECIST R 2:1 Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD)  Randomized, placebo-controlled, double-blind phase III study  Pemetrexed 500 mg/m 2 ; Cisplatin 75 mg/m 2  Folic acid and vitamin B 12 administered to both arms Previously untreated PS 0/1 Stage IIIB-IV NS-NSCLC

55. PARAMOUNT: Final OS from Randomization Patients at Risk Pem + BSC35933327223520016613810579 43152 0 Placebo + BSC180169131103 78 65 49 35 23 12 83 0 Time from Randomization (Months) 0 3 6 9 12 15 18 21 24 27 30 33 36 Survival Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 PemPlacebo OS Median (mo) (95% CI) 13.9 (12.8-16.0) 11.0 (10.0-12.5) Log-rank P = 0.0195 Unadjusted HR: 0.78 (95% CI: 0.64–0.96) 1-year58 (53-63)45 (38-53) 2-year32 (27-37)21 (15-28)

56. Maintenance treatment - SATURN 1:1 Chemonaïve advanced NSCLC n=1,949 Non-PD n=889 4 cycles of first- line platinum doublet chemotherapy* Placebo PD Erlotinib 150mg/day PD Mandatory tumour sampling Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region Co-primary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumours Secondary endpoints: OS in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC– tumours; biomarker analyses; safety; time to symptom progression; QoL *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel

57. Cappuzzo F, WCLC 2009

58. INFORM – Gefitinib maintenance Progression-free survival (ITT population) HR=0.42; 95% CI 0.33-0.55; p<0.0001 median PFS Gefitinib 4.8 mo Placebo 2.6 mo L. Zang – Presented at ASCO 2011

59. The moving reality of molecular targeted therapy in NSCLC 1. Metastatic disease, 1 st line & maintenance 2. Metastatic disease, 2 nd line3. Targeted immunotherapy

60. EGFR (2 nd line & beyond)

61. Erlotinib significantly prolongs survival in relapsed advanced NSCLC 2004 Shepherd, et al. N Engl J Med 2005 051015202530 HR=0.73, p<0.001 Survival distribution function 1.00 0.75 0.50 0.25 0 Erlotinib Placebo Survival time (months) Second-line therapy BR.21

62. TITAN primary endpoint: OS with erlotinib versus chemotherapy 1.0 0.8 0.6 0.4 0.2 0 03691215182124273033363942454851 Time (months) OS probability No at risk Erlotinib203120765238292218151088543320 Chemo 2211448963402220149776432200 Erlotinib (n=203) Chemotherapy (n=221) 5.35.5 HR=0.96 (0.78–1.19) Log-rank p=0.7299 Ciuleanu TE et al., Lancet Oncol, 2012

63. Sequist L et al. Sci Transl Med 2011;3:75ra26-75ra26 Causes of EGFR TKI Resistance in 37 EGFR mutated NSCLC patients

69. FLAURA Study Design Presented By Suresh Ramalingam at 2015 ASCO Annual Meeting

72. ALK (2 nd line & beyond)

73. ALK rearrangements PROFILE 1007: Study design a ALK status determined using standard ALK break-apart FISH assay b Stratification factors: ECOG PS (0/1 vs 2), brain metastases (present/absent), and prior EGFR TKI (yes/no) BID, twice daily; DCR, disease control rate; ECOG PS, Eastern Cooperative Group Performance Status; EGFR, epidermal growth factor receptor; EORTC QLQ, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; IV, intravenous; OS, overall survival; PO, by mouth; RECIST, Response Evaluation Criteria in Solid Tumors; TKI, tyrosine kinase inhibitor Shaw AT, et al. N Engl J Med 2013;368:2385–94 Key entry criteria ●ALK+ by central FISH testing a ●Stage IIIB/IV NSCLC ●1 prior chemotherapy (platinum-based) ●ECOG PS 0−2 ●Measurable disease ●Treated brain metastases allowed N=318 NCT00932893 Endpoints ●Primary –PFS (RECIST 1.1, independent radiology review) ●Secondary –ORR, DCR, DR –OS –Safety –Patient reported outcomes (EORTC QLQ- C30, LC13) RANDOMIZERANDOMIZE CROSSOVER TO CRIZOTINIB ON PROFILE 1005 b Crizotinib 250 mg BID PO, 21-day cycle (n=173) Pemetrexed 500 mg/m 2 or Docetaxel 75 mg/m 2 IV, day 1, 21-day cycle (n=174)

74. Crizotinib (n=172 a ) Pemetrexed (n=99 a ) Docetaxel (n=72 a ) Events, n (%)100 (58)72 (73)54 (75) Median, mo7.74.22.6 HR b (95% CI)0.59 (0.43–0.80)0.30 (0.21–0.43) P0.001<0.001 PFS of crizotinib vs pemetrexed or docetaxel 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 crizotinibShaw AT, et al. N Engl J Med 2013;368:2385–94 Probability of survival without progression (%) 100 80 60 40 20 0 0510152025 Time (months) 17293381120 99362310 7213310 No. at risk Crizotinib Pemetrexed Docetaxel

75. Overall Response Rate in ALK+ NSCLC Patients Treated with Ceritinib (750 mg daily) Presented By Dong-Wan Kim at 2014 ASCO Annual Meeting

76. Progression-Free Survival in Patients with ALK+ NSCLC Presented By Dong-Wan Kim at 2014 ASCO Annual Meeting

77. Abstract 8008 Efficacy and safety of the ALK inhibitor alectinib in ALK+ non-small-cell lung cancer (NSCLC) patients who have failed prior crizotinib: an open-label, single-arm, global phase 2 study (NP28673) Presented By Sai-Hong Ou at 2015 ASCO Annual Meeting

78. Long median progression-free survival in crizotinib-resistant ALK+ NSCLC patients Presented By Sai-Hong Ou at 2015 ASCO Annual Meeting

79. ALEX phase III study design Presented By Sai-Hong Ou at 2015 ASCO Annual Meeting

80. Anti-VEGFR (2 nd line and beyond) -ramucirumab -nintedanib

81. REVEL: Study Design Presented By Maurice Perol at 2014 ASCO Annual Meeting

82. Overall Survival ITT Population Presented By Maurice Perol at 2014 ASCO Annual Meeting

83. Nintedanib – LUME-LUNG 1 (docetaxel + nintedanib vs docetaxel + placebo)

84. The moving reality of molecular targeted therapy in NSCLC 1. Metastatic disease, 1 st line & maintenance 2. Metastatic disease, 2 nd line3. Targeted immunotherapy

85. Lung Cancer Immunotherapy Presented By Alexander Spira at 2015 ASCO Annual Meeting

106. CheckMate 017 (NCT01642004) - Study Design Presented By David Spigel at 2015 ASCO Annual Meeting

107. Overall Survival Presented By David Spigel at 2015 ASCO Annual Meeting

108. Progression-Free Survival Presented By David Spigel at 2015 ASCO Annual Meeting

109. Objective Response Rate Presented By David Spigel at 2015 ASCO Annual Meeting

110. OS and PFS by PD-L1 Expression Presented By David Spigel at 2015 ASCO Annual Meeting

111. Phase III, Randomized Trial (CheckMate 057) of Nivolumab versus Docetaxel in Advanced Non-squamous (non-SQ) Cell Non-small Cell Lung Cancer (NSCLC) Presented By Luis Paz-Ares at 2015 ASCO Annual Meeting

112. CheckMate 057 (NCT01673867) Study Design Presented By Luis Paz-Ares at 2015 ASCO Annual Meeting

113. Overall Survival Presented By Luis Paz-Ares at 2015 ASCO Annual Meeting

114. Progression-free Survival Presented By Luis Paz-Ares at 2015 ASCO Annual Meeting

115. Objective Response Rate Presented By Luis Paz-Ares at 2015 ASCO Annual Meeting

116. OS and PFS Hazard Ratios by Baseline PD-L1 Expression Presented By Luis Paz-Ares at 2015 ASCO Annual Meeting

117. NSCLC – patients, pathways, progress ●The registration of the newest targeted drugs “represents a paradigm shift in NSCLC treatment, where we're moving away from a one-size-fits- all approach to biomarker-based treatment decisions” (Paul Bunn). ●Another paradigm shift is represented by the use of immune checkpoint inhibitors, that hold the promise of a sustained immunological response.