Kazuhisa TAKAHASHI, MD, PhD

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Society of Respirology (APSR) 1992 Ph.D.

1 Kazuhisa TAKAHASHI, MD, PhD Professor and Chairman, Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine Deputy Secretary and Educational Committee Member of The Asian Pacific Society of Respirology (APSR) 1992 Ph.D. (Doctor of Medical Science) Awarded from Juntendo University 1994~1997 Post-doctoral fellow, Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, USA

17th MIDYEAR CONVENTION State of the Art Pulmonology: Convergence of Practice An Educational Seminar of the Asian Pacific Society of Respirology (ESAP) Plenary lecture 2 Advances in Lung Cancer

2 17th MIDYEAR CONVENTION State of the Art Pulmonology: Convergence of Practice An Educational Seminar of the Asian Pacific Society of Respirology (ESAP) Plenary lecture 2 Advances in Lung Cancer Treatment: 2013 Updates Kazuhisa Takahashi, M.D., Ph.D. Department of Respiratory Medicine Juntendo University Graduate School of Medicine August 6, 2014 Crowne Plaza Manila Galleria, Ortigas Center, Quezon City. Philippine 2

Survival (%) Prognosis for pts with advanced NSCLC is improving Stage IV PS:0-1 Chemonaive patients 100 90 80 70 04-05: MST 16M

3 Survival (%) Prognosis for pts with advanced NSCLC is improving Stage IV PS:0-1 Chemonaive patients : MST 16M 生存率 : MST 11.8M 06-09: MST 20M : MST 8.2M 生存期間 Year ( 年 ) MST: median survival time 3

Frequency of driver mutations in Japanese

adenocarcinoma are positive for EGFR activating

Unknown 22% KRAS 15% EGFR 50% 5% of Japanese pts with

4 Frequency of driver mutations in Japanese adenocarcinoma of lung 40-50% of Japanese pts with lung adenocarcinoma are positive for EGFR activating mutation RET 1% ROS-1 1% BRAF 1% HER2 3% MET 4% ALK 5% Unknown 22% KRAS 15% EGFR 50% 5% of Japanese pts with lung adenocarcinoma are positive for ALK fusion gene Mitsudomi T 2013 ;40:

5 Patients harboring driver mutations who received targeted therapy survived longer than those who did not receive (retrospective study) Kris MG et al. JAMA. 2014;311(19):

6 Current status of EGFR-TKI Today s menu Comparison of EGFR-TKIs (efficacy toxicity) Combined therapy with EGFR-TKI and Chemo or Bevacizumab Future perspectives of EGFR-TKI Resistance to TKI Potential mechanism for TKI resistance 3 rd generation of EGFR-TKI 6

7 Molecular Targeted agents Gefitinib (Iressa ) Erlotinib (Tarceva ) Afatinib (Gilotrif ) EGFR-TKI Bevasizumab (Avastin ) Crizotnib(Xalkori ) Denosmab (Lanmark )

8 Current status of EGFR-TKI Today s menu Comparison of EGFR-TKIs (efficacy toxicity) Combined therapy using EGFR-TK(Chemo, Bevacizumab) Future perspectives of EGFR-TKI Resistance to TKI Potential mechanism 3 rd generation of EGFR-TKI 8

9 EGFR-TKI for non-small cell lung cancer (Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors) Gefitinib Iressa erlotinib tarceva R afatinib Gilotrif R Structure Target EGFR-TKI EGFR-TKI EGFR-TKI ERBB2-TKI mechanism reversible reversible irreversible approved July, 2002 October, 2007 April, 2014 T 1/2 48 hrs 32 hrs 33.9 hrs MTD 700mg 150mg 55mg RD 250mg 150mg 40mg

10 Which EGFR-TKI is the most effective? All EGFR-TKI prolonged PFS compared with chemotherapy What is the best EGFR-TKI? TKI which prolongs Overall Survival (OS)? TKI whose toxicity is the least? Direct comparison is necessary to answer these questions. 10

11 Current status of EGFR-TKI Today s menu Comparison of EGFR-TKIs (efficacy toxicity) Combined therapy with EGFR-TKI and Chemo or Bevacizumab Future perspectives of EGFR-TKI Resistance to TKI Potential mechanism for TKI resistance 3 rd generation of EGFR-TKI 11

12 Phase III trials comparing EGFR-TKI with chemotherapy for NSCLC pts with EGFR mutation Study Treatment arm n PFS Overall Survival IPASS* NEJ002 WJTOG3405 First-SIGNAL* OPTIMAL EURTAC Gefitinib CBDCA+PTX Gefitinib CBDCA+PTX Gefitinib CDDP+DTX Gefitinib CDDP+GEM Erlotinib CBDCA+GEM Erlotinib Platinum-based m 6.3m 10.8m 5.4m 9.2m 6.3m 8.4m 6.7m 13.7m 4.6m 9.7m 5.2m HR :0.48 p< HR: P< HR: 0.49 P< HR: 0613 P=0.84 HR: p< HR: 0.37 P< HR:1.00 ( ) HR: ( ) HR: ( ) HR: ( ) HR: 1.04 ( ) HR: 0.80 ( ) *subgroup analysis for EGFR mutation 12

13 PFS for pts with NSCLC favoring with EGFR mutation (19del/L858R) Chemo Gefitinib Erlotinib Afatinib

14 Phase III trials comparing EGFR-TKI with chemotherapy for NSCLC pts with EGFR mutation 試験治療症例数 PFS Overall Survival IPASS* NEJ002 WJTOG3405 First-SIGNAL* OPTIMAL EURTAC Gefitinib CBDCA+PTX Gefitinib CBDCA+PTX Gefitinib CDDP+DTX Gefitinib CDDP+GEM Erlotinib CBDCA+GEM Erlotinib Platinum-based m 6.3m 10.8m 5.4m 9.2m 6.3m 8.4m 6.7m 13.7m 4.6m 9.7m 5.2m HR :0.48 p< HR: P< HR: 0.49 P< HR: 0613 P=0.84 HR: p< HR: 0.37 P< HR:1.00 ( ) HR: ( ) HR: ( ) HR: ( ) HR: 1.04 ( ) HR: 0.80 ( ) *subgroup analysis for EGFR mutation 14

15 Overall survival in patients with advanced NSCLC harboring common (Del19/L858R) EGFR mutations: analysis of two large, open-label phase III studies of afatinib vs chemotherapy, LUX-Lung 3 and LUX-Lung 6 J. C.-H. Yang, L. V. Sequist, M. Schuler, T. Mok, N. Yamamoto, K. O Byrne, V. Hirsh, S. Geater, C. Zhou, D. Massey, V. Zazulina, Y.-L. Wu on behalf of LUX-Lung 3 and LUX-Lung 6 investigators

16 Presented by: James Chih-Hsin Yang LUX-Lung 3 and 6: design Stage IIIB/IV adenocarcinoma of the lung Presence of EGFR mutation in the tumor tissue* No prior treatment with chemotherapy for advanced/metastatic disease or EGFR inhibitors ECOG PS 0 or 1 Afatinib 40 mg orally once daily Randomization 2:1 Stratification by EGFR mutation type: Del19/L858R/other and by race (LUX-Lung 3 only): Asian/non-Asian Primary endpoint: PFS (independent review) Secondary end points: ORR, DCR, OS, PRO, safety LUX-Lung 3 1 : Cisplatin + pemetrexed up to 6 cycles LUX-Lung 6 2 : Cisplatin + gemcitabine up to 6 cycles *EGFR29: 19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I. 1. Sequist et al. J Clin Oncol. 2013;31:3327; 2. Wu et al. Lancet Oncol. 2014;15:213.

17 LUX-Lung 3 and 6: populations LUX-Lung 3 LUX-Lung 6 Afatinib n=230 Pem/Cis n=115 Afatinib n=242 Gem/Cis n=122 Gender Male 83 (36) 38 (33) 87 (36) 39 (32) Female 147 (64) 77 (67) 155 (64) 83 (68) Age median (range) 62 (28 86) 61 (31 83) 58 (29 79) 58 (27 76) Race Non-Asian 64 (28) 32 (28) Stage of disease Asian 166 (72) 83 (72) 242 (100) 122 (100) IIIB (wet) 20 (9) 17 (15) 16 (7) 6 (5) IV 210 (91) 98 (85) 226 (93) 116 (95) ECOG status 0 92 (40) 41 (36) 48 (20) 41 (34) (60) 74 (64)* 194 (80) 81 (66) EGFR mutation Common mutations 203 (88) 104 (90) 216 (89) 108 (89) categories Del (49) 57 (50) 124 (51) 62 (51) L858R 91 (40) 47 (41) 92 (38) 46 (38) Uncommon mutations 27 (12) 11 (10) 26 (11) 14 (11) *Includes one patient with ECOG 2. May not total 100% due to rounding. Presented by: James Chih-Hsin Yang

18 LUX-Lung 3 and 6: reported results Significant improvement over chemotherapy in PFS (primary endpoint) 1,2 Common mutations (Del19/L858R) LUX-Lung 3 (n=307) LUX-Lung 6 (n=324) Afatinib Pem/Cis Afatinib Gem/Cis Median PFS, mo HR, p-value HR=0.47, p< HR=0.25, p< Activity in some types of uncommon mutations (L861Q, G719X, S768I) 3 Improved symptom control and delay in worsening of cancer-related cough and dyspnea 4 1. Sequist et al. J Clin Oncol. 2013;31:3327; 2. Wu et al. Lancet Oncol. 2014;15:213; 3. Yang et al. J Thorac Oncol. 2013;8:suppl 2 (O03.05); 4. Sequist et al. J Thorac Oncol. 2013;8:suppl 2 (P ). Presented by: James Chih-Hsin Yang

19 Estimated OS probability Estimated OS probability LUX-Lung 3 and 6: OS in common mutations LUX-Lung 3 LUX-Lung Median, months Afatinib n=203 Pem/Cis n= Median, months Afatinib n=216 Gem/Cis n= HR (95%CI), p-value 0.78 ( ), p= HR (95%CI), p-value 0.83 ( ), p= No of patients Afatinib Pem/Cis Time (months) Time (months) No of patients Afatinib Gem/Cis Presented by: James Chih-Hsin Yang

20 Estimated OS probability Combined OS analysis: common mutations (n=631) Afatinib n=419 Chemo n=212 Median, months HR (95%CI), p-value 0.81 ( ), p= No of patients Afatinib Chemo Time (months) Presented by: James Chih-Hsin Yang

21 Estimated OS probability Estimated OS probability Combined OS analysis: mutation categories Del19 L858R 1.0 Afatinib n=236 Chemo n=119 Median, months Afatinib n=183 Chemo n=93 Median, months HR (95%CI), p-value 0.59 ( ), p= HR (95%CI), p-value 1.25 ( ), p= Time (months) Time (months) No of patients No of patients Afatinib Afatinib Chemo Chemo Presented by: James Chih-Hsin Yang

22 Treatment beyond 1st line in patients with common mutations Afatinib (n=203) LUX-Lung 3 LUX-Lung 6 Pem/Cis (n=104) Afatinib (n=216) Gem/Cis (n=108) Discontinued treatment, n (%) 184 (100) 104 (100) 194 (100) 108 (100) Subsequent systemic therapy, n (%) 144 (78) 88 (85) 123 (63) 70 (65) Chemotherapy, n (%) 131 (71) 49 (47) 114 (59) 29 (27) EGFR TKI therapy, n (%) 81 (44) 78 (75) 50 (26) 61 (56) Erlotinib Gefitinib Afatinib AZD9291 Dacomitinib Icotinib EGFR TKI combinations 61 (33) 28 (15) 2 (1) 2 (1) 5 (3) 46 (42) 44 (42) 7 (7) 1 (1) 1 (1) 9 (9) 21 (11) 19 (10) 11 (6) 5 (3) 22 (20) 39 (36) 3 (3) 3 (3) Other systemic therapy ±, n (%) 5 (3) 2 (2) 3 (2) 4 (4) Radiotherapy, n (%) 32 (17) 21 (20) 4 (2) 0 (0) Collection of data on subsequent therapies still ongoing. ± include investigational agents, monoclonal antibodies, non-egfr targeting protein kinase inhibitors etc Presented by: James Chih-Hsin Yang

23 Impact of subsequent EGFR TKIs on OS: exploratory analyses by category of EGFR TKI reimbursement policy in country of residence* Population Combined LL3/6 population (n=631) Countries with universal reimbursement policies** (n=219) Countries without universal reimbursement policies*** (n=412) Japan (n=77) % received TKI after 1 st line chemo HR (95% CI) Common mutations 66% 0.81 ( ) 91% 0.71 ( ) 52% 0.85 ( ) 100% 0.57 ( ) HR (95% CI) Del ( ) 0.50 ( ) 0.59 ( ) 0.34 ( ) HR (95% CI) L858R 1.25 ( ) 1.14 ( ) 1.32 ( ) 1.13 ( ) *Determined by presence or absence of a national reimbursement policy in effect throughout the period of trial conduct: **Main countries contributing : Japan, Taiwan, Korea, Germany, France, Australia, UK, Belgium, Ireland ***Main countries contributing : China, Thailand, Russia, the Philippines, Malaysia Presented by: James Chih-Hsin Yang

24 Conclusions Del19 and L858R patients are two distinct populations and should be studied separately in the future An OS benefit with afatinib in patients with common mutations (Del19/L858R) in the exploratory combined analysis First-line afatinib should be the standard of care for EGFR Del19 patients and remains a treatment option for EGFR L858R patients Presented by: James Chih-Hsin Yang

25 Current status of EGFR-TKI Today s menu Comparison of EGFR-TKIs (efficacy toxicity) Combined therapy with EGFR-TKI and Chemo or Bevacizumab Future perspectives of EGFR-TKI Resistance to TKI Potential mechanism for TKI resistance 3 rd generation of EGFR-TKI 25

26 NEJ002 WJTOG3405 JO22903 LUX-LUNG3 NEJ002 WJTOG3405 JO22903 LUX-LUNG3 NEJ002 WJTOG3405 JO22903 LUX-LUNG3 NEJ002 WJTOG3405 JO22903 LUX-LUNG3 NEJ002 WJTOG3405 JO22903 LUX-LUNG3 NEJ002 WJTOG3405 JO22903 LUX-LUNG3 Not reported Not reported Not reported Toxicities derived from EGFR-TKI for pts with EGFR mutations (1 st line) (%) Grade 1.2 Grade Rash paronychia dry skin diarrhea Liver dysfunction ILD NEJ002:gefitinib WJTOG3405:gefitinib JO22903:erlotinib LUX-Lung3:afatinib Data for Japanese pts except for LUX-LUNG3 Maemondo M. NEJM 2010, Mitsudomi T. Lancet Oncol. 2010, Goto K. Lung Cancer 2013, Sequist LV. JCO 2013

27 AE:ILD/TRD drug study line ILD TRD IPASS 2.6% 3/607 gefitinib NEJ % 1/115 WJTOG % 1/87 erlotinib afatinib gefitinib EURTAC 1.0% 1/84 1 st OPTIMAL 0.0% 0/83 LUX-Lung3 1.3% 4/229 LUX-Lung3 ( 日本人 ) ISEL* 3.7% 0/54 1.0% - V-15-32* After 2 nd 5.7% 3/244 INTEREST* line 1.0% - erlotinib BR % 1/485 afatinib LUX-Lung1 LUX-Lung4 ( 日本人 ) After 3 rd line 1.0% 2/ % 0/62 *All comers 27

28 Which EGFR-TKI is the most effective? All EGFR-TKI prolonged PFS compared with chemotherapy What is the best EGFR-TKI? TKI which prolongs Overall Survival (OS)? TKI whose toxicity is the least? Direct comparison is necessary to answer these questions. 28

WJOG5108L: Head to head trial of erlotinib and gefitinib (PIII) IIIB/IV NSCLC 2 nd line Adenocarcinoma, PS0-2 Non-ILD R A N D O M I Z E Gefitinib 250mg (n=280) Primary endpoint: PFS Secondary

29 WJOG5108L: Head to head trial of erlotinib and gefitinib (PIII) IIIB/IV NSCLC 2 nd line Adenocarcinoma, PS0-2 Non-ILD R A N D O M I Z E Gefitinib 250mg (n=280) Primary endpoint: PFS Secondary endopoint: ORR, OS, DCR etc. Erlotinib 150mg (n=280) Gender, stage, PS, smoking History, EGFR mutation status Site, Number of Chemo regimen Control arm is Erlotinib Non-inferiority Noninferiority was to be concluded if the upper CI limit for PFS is less than

30 Results

32 32

33 Conclusions Non-inferiority in PFS between erlotinib and gefitinib was not demonstrated according to predifined criteria There was no statistically significant difference in ORR, PFS and OS 33

34 LUX-LUNG 7 A Phase IIb Trial of Afatinib(BIBW2992) Versus Gefitinib for the Treatment of 1st Line EGFR Mutation Positive Adenocarcinoma of the Lung This is a randomised, open-label, phase IIb trial of afatinib to compare to gefitinib in first-line treatment setting with patients who are having epidermal growth factor receptor mutation positive advanced adenocarcinoma of the lung. Primary Outcome Measures: Progression-free survival (PFS) Time to Treatment Failure (TTF) Overall survival (OS)

35 Current status of EGFR-TKI Today s menu Comparison of EGFR-TKIs (efficacy toxicity) Combined therapy with EGFR-TKI and Chemo or Bevacizumab Future perspectives of EGFR-TKI Resistance to TKI Potential mechanism for TKI resistance 3 rd generation of EGFR-TKI 35

36 NEJ005/TCOG

37 Efficacy (A: PFS, B: OS) 37

38 STUDY SCHEMA OF NEJ009 **Stratified with gender, clinical stage, type of mutation, and smoking history Gefitinib (250 mg/day) for both arms CBDCA (AUC 5) and PEM (500 mg/m 2 ) for experimental arm 38

39 Current status of EGFR-TKI Today s menu Comparison of EGFR-TKIs (efficacy toxicity) Combined therapy with EGFR-TKI and Chemo or Bevacizumab Future perspectives of EGFR-TKI Resistance to TKI Potential mechanism for TKI resistance 3 rd generation of EGFR-TKI 39

40 Erlotinib plus bevacizumab versus erlotinib alone as first-line treatment for advanced EGFR mutation-positive non-squamous non-small-cell lung cancer: an open-label, randomized trial Terufumi KATO, Takashi SETO, Makoto NISHIO, Koichi GOTO Shinji ATAGI, Yukio HOSOMI, Noboru YAMAMOTO, Toyoaki HIDA Makoto MAEMONDO, Kazuhiko NAKAGAWA, Seisuke NAGASE Isamu OKAMOTO, Takeharu YAMANAKA Ryosuke HARADA, Masahiro FUKUOKA and Nobuyuki YAMAMOTO for the JO25567 study group

Study design Chemotherapy-naïve Stage IIIB/IV or postoperative recurrence Non-squamous NSCLC Activating EGFR mutations* Exon 19 deletion Exon 21 L858R Age 20 years PS 0 1 No brain metastasis

41 Study design Chemotherapy-naïve Stage IIIB/IV or postoperative recurrence Non-squamous NSCLC Activating EGFR mutations* Exon 19 deletion Exon 21 L858R Age 20 years PS 0 1 No brain metastasis Stratification factors: sex, smoking status, clinical stage, EGFR mutation type *T790M excluded R 1:1 Primary endpoint: Secondary endpoints: PFS (RECIST v1.1, independent review) OS, tumor response, QoL, safety Exploratory endpoint: EB combination Erlotinib 150mg qd + bevacizumab 15mg/kg q3w (n = 75) E monotherapy Erlotinib 150mg qd (n = 75) biomarker assessment PD PD Presented by: Terufumi Kato

42 Baseline characteristics Age Sex Smoking status PS Histology Stage at screening EGFR mutation type EB (n = 75) E (n = 77) Median (years) <75 years 63 (84%) 62 (81%) 75 years 12 (16%) 15 (19%) Male 30 (40%) 26 (34%) Female 45 (60%) 51 (66%) Never smoker 42 (56%) 45 (59%) Former light smoker 9 (12%) 6 (8%) Current smoker 24 (32%) 26 (33%) 0 43 (57%) 41 (53%) 1 32 (43%) 36 (47%) Adenocarcinoma 74 (99%) 76 (99%) Other 1 (1%) 1 (1%) IIIB 1 (1%) 0 (0%) IV 60 (80%) 62 (81%) Postoperative recurrence 14 (19%) 15 (19%) Exon 19 deletion 40 (53%) 40 (52%) Exon 21 L858R 35 (47%) 37 (48%) Presented by: Terufumi Kato

43 PFS probability Primary endpoint: PFS by independent review EB E Median (months) HR 0.54 (95% CI: ) P value* EB E *log-rank test, two-sided Number at risk Time (months) EB E Presented by: Terufumi Kato

44 PFS probability PFS probability PFS by EGFR mutation type 1.0 Exon 19 deletion EB E Median (months) HR 0.41 (95% CI: ) 1.0 Exon 21 L858R EB E Median (months) HR 0.67 (95% CI: ) Number at risk EB E EB E Time (months) E 0.2 Number at risk EB EB E Time (months) Presented by: Terufumi Kato

45 AEs (incidence >20%) All grades Grade 3 EB (75) E (77) EB (75) E (77) Rash 74 (99%) 76 (99%) 19 (25%) 15 (20%) Diarrhea 61 (81%) 60 (78%) 1 (1%) 1 (1%) Hypertension 57 (76%) 10 (13%) 45 (60%) 8 (10%) Paronychia 57 (76%) 50 (65%) 2 (3%) 3 (4%) Dry skin 56 (75%) 45 (59%) 2 (3%) 0 (0%) Hemorrhagic event 54 (72%) 22 (29%) 2 (3%) 0 (0%) Stomatitis 47 (63%) 46 (60%) 1 (1%) 2 (3%) Proteinuria 39 (52%) 3 (4%) 6 (8%) 0 (0%) Pruritus 34 (45%) 32 (42%) 1 (1%) 0 (0%) Hepatic dysfunction 33 (44%) 39 (51%) 6 (8%) 14 (18%) Decreased weight 33 (44%) 19 (25%) 0 (0%) 0 (0%) Decreased appetite 26 (35%) 26 (34%) 1 (1%) 1 (1%) Dysgeusia 20 (27%) 17 (22%) 0 (0%) 0 (0%) Nasopharyngitis 20 (27%) 15 (20%) 0 (0%) 0 (0%) Constipation 17 (23%) 15 (20%) 0 (0%) 1 (1%) Presented by: Terufumi Kato

46 Summary JO25567 is the first prospective randomized trial to investigate erlotinib plus bevacizumab as first-line treatment in patients with EGFR mutation-positive NSCLC Bevacizumab added to erlotinib demonstrated a significant, clinically relevant prolongation of median PFS to 16.0 months compared to 9.7 months with erlotinib alone ORR was 69% and DCR was 99% in the combination arm No new safety signals were identified Addition of bevacizumab did not significantly impact QoL OS data are still immature Presented by: Terufumi Kato

47 EGFR-TKIs EGFR-TKI monotherapy Exon19del, PS0,1, <75 y.o. : afatinib, however more toxic (skin rash, diarrhea) L858R: gefitinib Exon19del+ brain metastasis: erlotinib Elderly, poor PS with Common mutation+: gefitinib Combined therapy using EGFR-TKI Combination therapies using EGFR-TKI with chemotherapy or bevacizumab are expected 47

48 Algorithm for treatment for advanced NSCLC Cited by guideline for lung cancer treatment (Japan Lung Cancer Society) Non-sq EGFR mutation analysis EGFR mutation negative sq EGFR mutation positive EML4-ALK- EML4-ALK+ PS3 or 4 PS0-2 PS0-2 PS3 or 4 1 st line gefitinib 1 st line EGFR-TKIs 2nd line Non-sq: PC+bev or CDDP+Pem Sq: Pt doublet *PC or Platina doublet QOL Patient s choice ILD risk PD 1 st line Chemo No-sq: PC*+bev or CDDP+Pem Sq: Pt doublet PD 2nd line No-sq: gefitinib Sq: erlotinib PD Crizotinib Non-PD Maintenace Non-sq only Bev alone or Pem alone Non-sq Bev:OK 1 st line PC*+bev PD 2nd line Pem or erlotinib Non-PD sq Bev:No 1 st line CDDP/Pem Maintenace Non-sq only Bev alone or Pem alone PD BSC 2nd line DOC or erlotinib 1 st line Pt doublet PD EML4-ALK+ Crizotinib Sq: squamous, bev: bevacizmab, Doce: docetaxel PC:CBDCA+paclitaxel, Pem: pemetrexed, Pt: platina 48

49 Current status of EGFR-TKI Today s menu Comparison of EGFR-TKIs (efficacy toxicity) Combined therapy with EGFR-TKI and Chemo or Bevacizumab Future perspectives of EGFR-TKI Resistance to TKI Potential mechanism for TKI resistance 3 rd generation of EGFR-TKI 49

50 25 months later 4tmonts later before treatmnet Administration of erlotinib Potential mechanisms for acquired resistance to EGFR-TKI EGFR M+ CR Resistance toerlotinib Sequist L V, Sci Transl Med Pao W, PLoS Med.2005

51 Current status of EGFR-TKI Today s menu Comparison of EGFR-TKIs (efficacy toxicity) Combined therapy with EGFR-TKI and Chemo or Bevacizumab Future perspectives of EGFR-TKI Resistance to TKI Potential mechanism for TKI resistance 3 rd generation of EGFR-TKI 51

52 T790M specific EGFR-TKIs (3 rd generation) CO1686 AZD9291 HM

53 Phase I Study of CO-1686 in Patients with EGFR Mutated Recurrent, Advanced NSCLC 53

54 Phase I Study of AZD9291 in Patients with EGFR Mutated Recurrent, Advanced NSCLC 54

55 Oncology Research Group Juntendo University Acknowledgement Dr Fumiyuki Takahashi Dr Fariz Nurwidya Dr. Shinsaku Togo Dr Isao Kobayashi Dr Motoyasu Kato Dr Hario Baskoro Dr Takehito Shukuya Dr Naoko Shimada Dr Ken Tajima

56 Spheres of PC9-GRP Red: CD133 Blue: DAPI Juntendo University

Overall survival with afatinib versus chemotherapy in patients with NSCLC harboring common EGFR

Overall survival with afatinib versus chemotherapy in patients with NSCLC harboring common EGFR mutations: subgroup analyses by race/ethnicity in LUX-Lung 3 and LUX-Lung 6 Yi-Long Wu, 1 Lecia V Sequist,