Agenda. 6:30pm 7:00pm. Dinner. 7:00pm 7:15pm. NSCLC Treatment in 2014: Focus on Use of 2nd Generation TKIs in Clinical Practice.

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2 Agenda 6:30pm 7:00pm Dinner 7:00pm 7:15pm Welcome and Introductions Natasha Leighl, MD 7:15pm 7:50pm 7:50pm 8:00pm NSCLC Treatment in 2014: Focus on Use of 2nd Generation TKIs in Clinical Practice Questions Tony Mok, MD 8:00pm 9:00pm Closing Remarks/Interactive Discussion Natasha Leighl, MD & Tony Mok, MD

3 Welcome and Introductions Natasha Leighl, MD, FRCP(C) Princess Margaret Hospital Associate Professor, Department of Medicine University of Toronto

4 Welcome & Introductions The CARE (Community Academic Research Education) Faculty is a Pan-Canadian group of medical oncologists from across Canada who meet and discuss various topics from key conferences. The vision of the CARE Lung Cancer Faculty is to share opinions and update Canadian specialists with key news and developments from key conferences framed in a Canadian perspective. The mission of the CARE Lung Cancer Faculty is to enhance medical education with the explicit goal of improving patient outcomes. The CARE Lung Cancer Faculty is proud to host globally recognized lung cancer specialist Dr. Tony Mok. He previously spoke in Vancouver, Montreal and Toronto in January of this year, as part of a three-day CARE Lung Cancer Speaker Tour.

5 NSCLC Treatment in 2014: Focus on Use of 2nd Gen TKIs in Clinical Practice Tony Mok, MD, FRCP(C) Professor, Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital President, IASLC

6 Optimal Strategy in EGFR Inhibition: 2014 Professor Tony Mok Li Shu Fun Medical Foundation Professor of Clinical Oncology The Chinese University of Hong Kong

7 Optimal Strategies Finding the EGFR Mutation Choosing a EGFR TKI Stopping the EGFR TKI Treating the resistance Adding to EGFR TKI

8 Optimal Strategies Finding the EGFR Mutation How good are we?

9 Mutation testing in Asia 2011 Country (N diagnosed with NSCLC * ) Proportion tested for EGFR mutations % (95% CI ) Proportion of males/females, smokers and non-smokers, and histological subtypes that were tested for EGFR mutations Gender Smoking status Histology ADC / Males / Females Current + ex-smoker All non-adc / Only (%) / Never smoker (%) SCC (%) Total (22,193) 31.8 ( ) 26.9 / / / 12.5 / 12.5 China (12,086 ) 18.3 ( ) 15.2 / 25.3 N.D / 8.0 / 9.4 Hong Kong (795) 42.0 ( ) 36.2 / / / 9.0 / 6.4 Japan (2,379) 64.8 ( ) 63.6 / / / 55.0 / 50.3 Korea (3,794) 33.5 ( ) 26.1 / / / 9.8 / 8.3 Taiwan (2,890) 54.3 ( ) 47.1 / / / 15.5 / 8.5 Thailand (249 ) 57.8 ( ) 51.6 / / / 7.1 / 6.9

10 Sequencing was used in 40% of tumor tissue Methods of Testing

11 Optimal strategy 1wk 2wk 3wk Circulating 4wk Free Plasma DNA (cfplasma DNA) Core needle biopsy Pathologic diagnosis of adeno carcinoma EGFR or ALK testing Circulating Tumor Cell (CTC)

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13 Targeting EGFR mutation -cobas 4800 Blood test -COLD PCR -Digital PCR

14 cobas EGFR _ blood Test _ Kit Components Utilizing most of the reagents in the cobas EGFR_FFPET test and requiring additional reagents and the blood-specific data analysis software Blood ctdna Preparation Kit Cobas EGFR_Blood ctdna SP 2 ml Plasma cobas cell-free DNA Preparation Kit (To be used for other blood based assays) cobas EGFR _ blood Test cobas 4800 v 2.0 cobas EGFR _ Blood HPEA x25 PK x2 PBB x6 Additional reagents added to cobas DNA preparation Kit Tube FAM HEX JA270 1 EX 19Del S768I 2 L858R T790M 3 G719X L861Q* EX 20Ins *New primer and probe for L861Q Blood-specific cutoffs; Blood-specific data analysis software Mok et al ASCO 2013

15 FASTACT 2: Tumor versus plasma DNA for EGFR Mutation Analysis TISSUE SAMPLES 397 (88%) patients consented 301 (66.7%) samples available PLASMA SAMPLES 241 (53.4%) samples analyzable 224 patients with matched tumor and plasma samples 451 (100%) patients consented 427 (94.6%) samples available 427 (94.6%) samples analyzable

16 Concordance between tumor and plasma samples Total of 224 patients had both tumor and baseline plasma samples with available EGFR mutation analysis results (Table 3) Sensitivity: 77% (69/90) Specificity: 96% (129/134) Positive predictive value: 93% (69/74) Negative predictive value: 86% (129/150) Overall concordance: 88% (198/224) EGFR Activating Mutations p-egfr Mut+ (Plasma) p-egfr Mut- (Plasma) Total t-egfr Mut+ (Tumor) t-egfr Mut- (Tumor) Total

17 Droplet digital PCR (ddpcr) Hindson et al. Analytical chemistry 2011

18 Positive result on exon 19 deletion assay Plasma sample 214 Mutant concentration:72 copies/ml plasma Fraction concentration : 3.2%

19 Negative result on exon 19 deletion assay

20 Analyzing plasma and tumor sample from ASPIRATION study and matched control (n=197) Tumor sample: COBAS EGFR Mutation Test Plasma sample: Droplet digital PCR Lee et al WCLC 2013

21 Diagnostic utility of digital PCR for detection of EGFR mutation POS in plasma NEG in plasma POS in tumor NEG in tumor Droplet digital PCR Sensitivity 81% Specificity 100% Positive Predictive Value 100% Concordance 86%

22 Blood-based molecular analysis may optimize the timing and coverage

23 First line TKI Finding the EGFR Mutation Choosing a EGFR TKI

24 Where we are? Author Study N (EGFR mut +) RR Median PFS Mok et al IPASS % vs vs 6.4 months Lee et al First-SIGNAL % vs 37.5% 8.4 vs 6.7 months Mitsudomi et al WJTOG % vs 32.2% 9.2 vs 6.3 months Maemondo et al NEJGSG % vs 30.7% 10.8 vs 5.4 months Zhou et al OPTIMAL % vs 36% 13.1 vs 4.6 months Rosell et al EURTAC % vs 18% 9.2 vs 4.8 months Yang et al LUX Lung % vs 22% 11.1 vs 6.9 months Wu et al LUX Lung % vs 23% 11.0 vs 5.6 months Mok et al NEJM 2009, Lee et al WCLC 2009, Mitsudomi et al Lancet Oncology 2010, Maemondo NEJM 2010 Zhou et al Lancet Oncol 2010; Yang et al JCO epub; Wu et al Lancet Oncol: In Press

25 Katakami et al ASCO 2014 ASCO 2014: WJOG5108 Study Register Randomize Lung adenoca. Evaluable 2nd line & latter Age > 20 y.o PS 0-2 Stage III, IV, recurrence No interstitial lung disease R Stratify gender PS stage smoking history mutation status institution prior regimen A Erlotinib 150mg/day B Gefitinib 250mg/day PD

26 EGFR mutation (+) % PFS 95% CI p E mo mo G 8.90 mo mo EGFR mutation (-) % PFS 95% CI p E 2.10 mo mo G 2.07 mo mo E G EGFR mutation unknown % PFS 95% CI p E 2.53 mo mo G 3.61 mo mo 26

27 LUX Lung 3 Stage IIIB (wet)/iv lung adenocarcinoma (AJCC version 6) EGFR mutation in tumor (central lab testing; Therascreen EGFR29* RGQ PCR) Randomization 2:1 stratified by EGFR mutation (Del19/L858R/other) and race (Asian/non-Asian) Afatinib 40 mg/day Cisplatin + Pemetrexed 75 mg/m mg/m 2 i.v. q21days, up to 6 cycles Primary endpoint: PFS (RECIST 1.1, independent review) Secondary endpoints: ORR, DCR, DoR, tumor shrinkage, OS, PRO, safety, PK Primary PFS analysis (independent review) Sample size: 217 independent events needed to detect HR of 0.64 (or median increase in PFS from 7 to 11 months) at two-sided 5% significance level with 90% power Yang JC, et al. Yang et al JCO 2013

28 Progression-free survival (probability) Primary endpoint: PFS Independent review all randomized patients Afatinib n=230 Cis/pem n=115 PFS event, n (%) 152 (66) 69 (60) Median PFS (months) Hazard ratio (95% confidence interval) 0.58 ( ) p= % % Number at risk Progression-free survival (months) Afatinib Cis/Pem

29 Progression-free survival (probability) Common mutations: PFS Independent review patients with Del19/L858R (n=308) LUX lung 2: PFS 13.7m Afatinib n=204 Cis/pem n=104 PFS event, n (%) 130 (64) 61 (59) Median PFS (months) Hazard ratio (95% confidence interval) 0.47 ( ) p< % % Number at risk Progression-free survival (months) Afatinib Cis/Pem

30 LUX Lung 6 Asian patients (China, South Korea, Thailand) Stage IIIB (wet)/iv lung adenocarcinoma EGFR mutation in the tumor* No prior treatment for advanced disease, no prior EGFR TKI ECOG PS 0 or 1 Randomization Stratified by mutation (Del19/L858R/other) 2:1 Afatinib 40 mg/day Gemcitabine + Cisplatin 1000 mg/m 2 D1, D mg/m 2 i.v. q21 days, up to 6 cycles Primary endpoint: PFS (RECIST 1.1, independent review) Secondary endpoints: ORR, DCR, DoR, tumor shrinkage, OS, PRO, safety *Central lab testing; Therascreen EGFR29 RGQ PCR detecting 19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I. Dose escalated to 50 mg if limited AE observed in cycle 1. Dose reduced by 10 mg decrements in case of related G3 or prolonged G2 AE. Tumor assessments: q6 weeks until Week 48 and q12 weeks thereafter until progression/start of new therapy. Patient-reported outcomes: EQ-5D, EORTC QLQ-C30 and QLQ-LC13 at randomization and q3 weeks until progression or new anti-cancer therapy. Presented by: WU YL et al ASCO 2013

31 Primary endpoint PFS by independent review Presented by:

32 Study 1017: Clinical Activity of Dacomitinib (PF ) in First-line Advanced NSCLC with an EGFR-activating Mutation Cohort A: Non- or former light-smoker or EGFR-mutation (1 st -line) n=89 (fully enrolled) Dacomitinib 45 mg QD (amended to 30 mg for selected patients b ) Until progression Cohort B: HER2 mutation or HER2 amplification a Target n=25 (still recruiting) Optional biopsy on progression a [gene]/[centromere of chromosome 17] ratio >2 b Starting dose changed to 30 mg QD with dose escalation to 45 mg QD after 8 weeks of treatment in absence of grade >1 toxicity for 1 month for 30 patients in Cohort A, and patients in Cohort B who had no prior lines of therapy Janne and Mok et al Lancet Oncology In Press

33 Change from baseline (%) Waterfall Plot for Patients with EGFR-mutant Lung Cancers with Exon 19 and Exon 21 Mutations (N=45) PR Exon 19 Exon 21 RR=76%

34 From PFS to OS

35 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= Time (months) No of patients Afatinib Pem/Cis Time (months) No of patients Afatinib Gem/Cis Presented by: James Chih-Hsin Yang

36 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= Time (months) No of patients Afatinib Chemo Presented by: James Chih-Hsin Yang

37 Estimated OS probability Estimated OS probability Two subgroups of LUX Lung 3 and 6 OS analysis Del19 L858R 1.0 Median, months Afatinib n=236 Chemo n= Median, months Afatinib n=183 Chemo n= HR (95%CI), p-value 0.59 ( ), p= HR (95%CI), p-value 1.25 ( ), p= Time (months) No of patients Afatinib Chemo Time (months) No of patients Afatinib Chemo Exon 19 Exon 21

38 Why???

39 Estimated OS probability Estimated OS probability Afatinib: OS in Del19 subgroup Median, months HR (95%CI), p-value LUX-Lung 3 Afatinib n=112 Pem/Cis n= ( ), p= Median, months HR (95%CI), p-value LUX-Lung 6 Afatinib n=124 Gem/Cis n= ( ), p= Time (months) No of patients Afatinib Pem/Cis Time (months) No of patients Afatinib Gem/Cis Presented by: James Chih-Hsin Yang

40 Treatment beyond 1st line in patients with common mutations LUX-Lung 3 LUX-Lung 6 Afatinib (n=203) 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, 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. Presented by: James Chih-Hsin Yang 419/419 pt had exposure to first line TKI plus 131/419 had further TKI 131/212 pt had exposure to TKI

41 More TKI exposure during the course of illness may be associated with longer survival 419/419 pt had exposure to first line TKI plus 131/419 had further TKI 131/212 pt had exposure to TKI

42 Median progression-free survival (months) Exon 21: a weaker cousin? Mok et al. N Engl J Med. 2009;361:947; 2. Maemondo et al. N Engl J Med. 2010;362:2380; 3. Mitsudomi et al. Lancet Oncol. 2010;11:121; 4. Rosell et al. Lancet Oncol. 2012;13:239; 5. Wu et al. J Thorac Oncol. 2013;8:suppl 2 (P ); 6. Zhou et al. Lancet Oncol. 2011;12:735; 7. Sequist et al. J Clin Oncol. 2013;31:3327; 8. Wu et al. Lancet Oncol. 2014;15:213. Presented by: James Chih-Hsin Yang

43 Direct comparison: LUX Lung 7 Randomized IIb Study Is Afatinib better than Gefitinib in patients with EGFR mutation? Advanced NSCLC Adenocarcinoma EGFR mut+ First-line treatment PS 0-1 N= 264 patients R A N D O M I Z E 1 1 Afatinib 40mg qd Gefitinib 250mg qd PFS 13.7 vs 10 months HR 0.73 Sample size increased to 319

44 Direct comparison: LUX Lung 7 Randomized IIb Study Is Afatinib better than Gefitinib in patients with EGFR mutation? Advanced NSCLC Adenocarcinoma EGFR mut+ First-line treatment PS 0-1 N= 264 patients R A N 1 D Aug O M I 1 Z E Complete accrual on Afatinib 40mg qd Gefitinib 250mg qd PFS 13.7 vs 10 months HR 0.73 Sample size increased to 319

45 ARCHER 1050: Randomized Phase III Study Dacomitinib vs Gefitinib Advanced NSCLC Adenocarcinoma EGFR exon 19/21 mut+ First-line treatment PS 0-1 R A N D O M I Z E 1 1 Dacomitinib 45mg qd Gefitinib 250mg qd Primary endpoint in PFS 14.8 vs 9.5 months N= 440 patients Stratification -Race -Exon 19 v 21

46 ARCHER 1050: Randomized Phase III Study Dacomitinib vs Gefitinib Advanced NSCLC Adenocarcinoma EGFR exon 19/21 mut+ First-line treatment PS 0-1 N= 440 patients R A N D O M I Z E accrued in Sept Stratification -Race -Exon 19 v 21 Dacomitinib 45mg qd Gefitinib 250mg qd Primary endpoint in PFS 14.8 vs 9.5 months

47 Second generation TKI may optimize the PFS and possibly the OS (for exon19 deletion)

48 Optimal Strategy Finding the EGFR Mutation Choosing a EGFR TKI Stopping the EGFR TKI

49 Options at RECIST progression RECIST PD to first line TKI Continue with TKI Change to doublet chemo Add doublet chemo and continue TKI

50 Options at RECIST progression RECIST PD to first line TKI Continue with TKI ASPIRATION ESMO Abst 5892 Sept.27 at 15:45

51 ASPIRATION: Study design Patients 18 years with stage IV, EGFR mut+ NSCLC Erlotinib PFS 1 PD by RECIST Erlotinib PD by physician assessment PFS 2 Inclusion criteria: patients 18 years with confirmed stage IV or recurrent NSCLC with exon mutations (except T790M) with measurable disease and ECOG PS 0 2 Exclusion criteria: T790M mutations, prior chemotherapy, prior treatment with anti-her agents, uncontrolled systemic conditions, pre-existing lung conditions, warfarin use Primary endpoint: PFS1 (time to RECIST PD or death) Secondary endpoints: PFS2 (time to off-erlotinib PD if erlotinib was extended beyond RECIST PD) PFS1 in exon 19 deletion/l858r subsets OS ORR/DCR/BOR safety ESMO 2014 Park et al

52 Survival probability PFS1 (time to RECIST PD or death) PFS1 assessed by investigator 1.0 N=176 PFS events months (95% CI ) Progression-free survival time (months) Secondary endpoints, ITT population ORR : 66.2% DCR : 82.6% median OS: 31.0 months (95% CI 27.3 not reached) CI = confidence interval Data cut-off 14 Feb 2014

53 Erlotinib continuation post-pd Screened n=359 Enrolled n=208 ITT n=207 Safety n=207 Per protocol * n=148 ITT n=207 Patients with PFS1 RECIST PD event n=171 Patients not receiving post-pd erlotinib n=78 Patients receiving post-pd erlotinib n=93 Patients with PFS1 event of death n=5 Patients without PFS1 (still receiving firstline treatment) n=21 Patients withdrawn without PFS1 n=10 AE n=2 Withdrew consent n=6 Refused treatment n=2 Patients still on post-pd treatment n=14 Patients with PFS2 event n=70 Patients withdrawn n=9 AE n=1 Withdrew consent n=3 Other n=5 *Per-Protocol (PP) population is defined as those patients who have EGFR mutations confirmed by study designated central laboratory. Data cut-off 14 Feb 2014

54 Baseline characteristics according to post-pd erlotinib Characteristic Continued erlotinib beyond PD N=93 Did not continue erlotinib beyond PD * N=78 * Median age, years (range) 60.5 (36 83) 59.9 (31 89) Gender, n (%) Male Female 33 (35.5) 60 (64.5) 35 (44.9) 43 (55.1) Smoking status, n (%) Never smoker Former smoker Current smoker 68 (73.1) 16 (17.2) 9 (9.7) 54 (69.2) 15 (19.3) 9 (11.5) EGFR mutation Exon 19 deletion Exon 21 L858R Other (exon 18/21) 52 (55.9) 36 (38.7) 13 (14.0) 36 (46.2) 38 (48.7) 16 (20.5) Histology, n (%) Adenocarcinoma Squamous-cell Other 90 (96.8) 0 (0.0) 3 (3.2) 76 (97.4) 1 (1.3) 1 (1.3) Disease stage ECOG PS baseline Recurrent Stage IV 15 (16.1) 78 (83.9) 15 (16.1) 73 (78.5) 5 (5.4) 3 (3.8) 75 (96.2) 14 (17.9) 54 (69.2) 10 (12.8) * only consider patients who had a PD event; n=9 in each group (n=93 and n=78) were evaluated by cytology not histology Data cut-off 14 Feb 2014

55 Survival probability PFS2 (time to off-erlotinib PD if erlotinib was extended beyond RECIST PD) Median PFS2 (n=93; 79 PD events): 14.1 months (95% CI ) months (95% CI ) Progression-free survival time (months) Data cut-off 14 Feb 2014

56 Survival probability Continuation of erlotinib post-pd extended PFS In patients receiving post-pd erlotinib (n=93) PFS1 was 11.0 months the difference between PFS1 and PFS2 was an additional 3.1 months PFS1 PFS months 14.1 months Progression-free survival time (months)

57 Options at RECIST progression RECIST PD to first line TKI IMPRESS ESMO LBA6544 Presidential Symposium 1 Sept 28 16:00 Change to doublet chemo Add doublet chemo and continue TKI

58 IMPRESS: Study Design Enrollment period: March 2012-December 2013 Patients Age 18 years ( 20 years in Japan) WHO PS 0-1 Histologically confirmed stage IIIB / IV EGFR mutationpositive advanced NSCLC Chemotherapy naive Achieved CR/PR 4 months or SD >6 months with first-line gefitinib Disease progression (RECIST) <4 weeks prior to study randomisation Cisplatin 75 mg/m 2 + Pemetrexed 500 mg/m 2 ( 6 cycles) + Gefitinib 250 mg 1:1 randomisation Cisplatin 75 mg/m 2 IV + Pemetrexed 500 mg/m 2 IV ( 6 cycles) + Placebo 250 mg Objectives Endpoints Primary Progression-free survival Secondary Overall survival Objective response rate Disease control rate Safety and tolerability Health-related quality of life b Mok et al EMSO 2014

59 Patient demographics (ITT) Demographic characteristic Gefitinib (n=133) Placebo (n=132) 65 years 32% 26% Mean age, years (range) 59 (33-79) 57 (35-79) Female 65% 64% PS 0, 1 41%, 59% 40%, 60% Never-smoker 66% 69% Adenocarcinoma histology 95% 99% Metastatic (baseline) 93% 90% Brain metastases (baseline) 33% 23% CR or PR/SD to first-line gefitinib 68% / 32% 76% / 24% Time to progression after initial gefitinib treatment 10 months >10 months 39% 61% 44% 56% Exon 19 deletion, exon 21 L858R 64%, 30% 65%, 32%

60 ORR (%) DCR (%) ORR and DCR (ITT population) Odds ratio (95% CI) = 0.92 (0.55, 1.55); p=0.760 Odds ratio (95% CI) = 1.39 (0.74, 2.62); p=0.308 (n=133) (n=132) (n=133) (n=132) Odds ratio >1 favours gefitinib Odds ratio and p-value from logistic regression with covariates CI, confidence interval

61 Probability of PFS PFS (primary endpoint; ITT) Gefitinib (n=133) Placebo (n=132) Gefitinib (n=133) Patients at risk: Time of randomisation (months) Gefitinib Placebo Placebo (n=132) Median PFS, months Number of events, n (%) 98 (73.7) 107 (81.1) HR a (95% CI) = 0.86 (0.65, 1.13); p=0.273 a Primary cox analysis with covariates A HR <1 implies a lower risk of progression with gefitinib

62 Probability of OS OS (ITT; 33% of events) Gefitinib (n=133) Placebo (n=132) Gefitinib (n=133) Placebo (n=132) Median OS, months Number of events, n (%) 50 (37.6) 37 (28.0) HR a (95% CI) = 1.62 (1.05, 2.52); p= Patients at risk: Time of randomisation (months) Gefitinib Placebo a Primary cox analysis with covariates A HR <1 implies a lower risk of death with gefitinib

63 Post-discontinuation therapy (ITT) Anti-cancer therapy Gefitinib (n=133) ITT population Placebo (n=132) Any, n (%) 61 (45.9) 72 (54.5) Platinum alone, a n (%) 0 (0) 2 (1.5) Platinum-based regimen (doublet or triplet), n (%) Single-agent cytotoxic, b n (%) 5 (3.8) 17 (12.9) 27 (20.3) 27 (20.5) EGFR TKI, c n (%) 30 (22.6) 44 (33.3) Others, n (%) 16 (12.0) 14 (10.6) a Platinum: carboplatin, cisplatin, nedaplatin b Single agent: docetaxel, paclitaxel, pemetrexed, gemcitabine, vinorelbine c EGFR TKI (gefitinib, erlotinib, AZD9291 [n=2 gefitinib arm; n=3 placebo arm])

64 Optimal Strategy TKI Chemo 2 nd /3 rd line therapy Death TKI Treatment beyond progression (RECIST)

65 Optimal Strategy TKI Chemo 2 nd /3 rd line therapy Death TKI Treatment beyond progression (RECIST)

66 Optimal Strategies Finding the EGFR Mutation Choosing a EGFR TKI Adding to EGFR TKI Stopping the EGFR TKI

67 Optimal Strategies Finding the EGFR Mutation Choosing a EGFR TKI Adding to EGFR TKI Stopping the EGFR TKI

68 FASTACT-2 (MO22201; CTONG0902) study design Screening Study treatment Maintenance phase Previously untreated stage IIIB/IV NSCLC, PS 0/1 (n=451) Primary endpoint: PFS with IRC confirmation R Gemcitabine 1,250mg/m 2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m 2 (d1) + erlotinib 150mg/day (d15 28); q4wks x 6 cycles GC-erlotinib (n=226) 1:1; stratified by stage, histology, smoking status and chemo regimen Gemcitabine 1,250mg/m 2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m 2 (d1) + placebo (d15 28); q4wks x 6 cycles GC-placebo (n=225) Erlotinib 150mg/day Placebo Secondary endpoints: subgroup analyses, OS in all patients and subgroups, ORR, duration of response, TTP, NPR at 16 weeks, safety, QoL PD PD Erlotinib 150mg/day Wu and Mok Lancet Oncology 2013

69 Improved overall survival outcomes Wu and Mok Lancet Oncology 2013

70 PFS benefit confined to patients with EGFR mutations EGFR Mutation EGFR Wild type Wu and Mok Lancet Oncology 2013

71 OS benefit confined to patients with EGFR mutations EGFR Mutation EGFR Wild type Wu and Mok Lancet Oncology 2013

72 OS benefit confined to patients with EGFR mutations Need confirmation with FASTACT 3 using EGFR TKI as control arm EGFR Mutation EGFR Wild type Wu and Mok Lancet Oncology 2013

73 JO25567: Randomized phase II study on erlotinib + bevacizumab Assessed for eligibility Randomized (n = 154) EB combination (n = 77) E monotherapy (n = 77) Withdrew before treatment started Thrombosis: 1 Pleural effusion: 1 Received EB and eligible for analysis (n = 75) Received E and eligible for analysis (n = 77) Kato et al ASCO 2014

74 Tumor volume change from baseline (%) Tumor volume change from baseline (%) Objective tumor response EB (n = 75) E (n = 77) *P value CR 3 (4%) 1 (1%) PR 49 (65%) 48 (62%) SD 22 (29%) 19 (25%) PD 0 (0%) 6 (8%) NE 1 (1%) 3 (4%) ORR 69% 64% DCR 99% 88% *Fisher s exact test EB combination E monotherapy Responder (CR or PR) Non-responder (SD, PD or NE) Median duration of response: 13.3 months with EB vs 9.3 months with E Presented by: Terufumi Kato

75 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

76 PFS probability PFS probability 1.0 PFS by EGFR mutation type 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

77 PFS probability PFS probability 1.0 PFS by EGFR mutation type 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: ) Chance of a phase III study is remote Number at risk EB E EB E Time (months) E 0.2 Number at risk EB EB E Time (months) Presented by: Terufumi Kato

78 Addition of chemotherapy or bevacizumab to TKI may prolong PFS but need to be validated by phase III study

79 Optimal Strategies Finding the EGFR Mutation Choosing a EGFR TKI Stopping the EGFR TKI Treating the resistance Adding to EGFR TKI

80 What we know about the mechanism of resistance? Oxnard et al CCR 17:5530, 2011

81 Gatekeeper Mutation: T790M Acquired point mutation resulting in threonine-tomethioine amino acid change at positive 790 Kobayashi S NEJM 352:786, 2006

82 SLCG: Implication of de-novo T790M Rosell et al ASCO 2010

83 Implication of acquired T790M Median T790M pos = 19 months Median T790M neg = 12 months Median T790M pos = 39 months Median T790M neg = 26 months Oxnard et al CCR 17:1616, 2011

84 Targeting T790M T790M

85 Third generation EGFR TKI targeting the resistant T790M mutation Erlotinib Gefitinib CO1686 WZ4002

86 In vitro and In vivo activity of AZD9291 AZD9291 is a potent oral, irreversible inhibitor of EGFR that contains EGFR-TKI-sensitising (EGFR+) and resistance mutations (T790M) Updated long-term dosing of H1975 (L858R/T790M) xenograft with indicated doses of AZD9291 Good potency and high selectivity demonstrated in enzymatic and cellular in vitro assays 1 Model AZD9291 phospho- EGFR IC 50 nm Wildtype LoVo cells EGFR+ PC9 cells EGFR+/ T790M H1975 cells Cross et al. Abstract A109, AACR-EORTC-NCI conference, Boston, 2013 Profound regression in EGFR-mutant tumour models, showing sustainable complete macroscopic tumour response out to at least 200 days Ranson et al WCLC 2013

87 Phase I/II study on AZ9291 Phase I, open-label, multicenter study of AZD9291 administered once daily in Asian and Western patients with advanced NSCLC who have documented radiological progression while on prior therapy with an EGFR-TKI (AURA; NCT ) Objectives Primary: safety and tolerability in EGFR-TKI-refractory patients Secondary include: define maximum tolerated dose, pharmacokinetics, preliminary efficacy Escalation Not preselected by T790M status Cohort 1 20 mg Cohort 2 40 mg Rolling six design Cohort 3 80 mg Cohort mg Cohort mg Expansion Enrollment by local testing followed by central laboratory confirmation* of T790M status or by central laboratory testing alone T790M+ T790M+ T790M- T790M+ T790M- 1st-line EGFRm+ T790M+ T790M- 1st-line EGFRm+ T790M+ Biopsy Biopsy *cobas EGFR Mutation Test (Roche Molecular Systems) Janne ASCO 2014 Tablet

88 Response rate* in overall population ####### Best percentage change from baseline in target lesion: all evaluable patients, escalation and expansion (N=205) Complete response Partial response* Non-response First patient dosed Mar 6, 2013 Longest response >9 months ongoing at time of data cutoff ORR* = 53% (109/205; 95% CI 46%, 60%); no difference in ORR by race Overall disease control rate (CR+PR+SD) = 83% (171/205; 95% CI 78%, 88%) 20 mg 40 mg 80 mg 160 mg 240 mg N (205) ORR 55% 44% 54% 58% 67% *Includes confirmed responses and responses awaiting confirmation; # represents imputed values. Population: all dosed patients with a baseline RECIST assessment and an evaluable response (CR, PR, SD or PD), N=205 (from 232 dosed patients, 27 patients with a current nonevaluable response are not included). CI, confidence interval; CR, confirmed complete response; ORR, overall response rate; PR, confirmed partial response; PD, progressive disease; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease Presented by: Pasi A. Jänne

89 40 20 # # D D Response rate* in central T790M+ Best percentage change Best from percentage baseline in change target lesion: from baseline all evaluable in target T790M+ lesion: patients, Part B T790M+ evaluable patients, expansion cohorts only (N=107) 0-20 D D D D D D D D D mg QD 40 mg QD 80 mg QD 160 mg QD 240 mg QD D D D D D D D D D D D D -100 ORR* = 64% (69/107; 95% Cl 55%, 73%) in patients with EGFR T790M+ NSCLC Overall disease control rate (CR+PR+SD) = 94% (101/107; 95% CI 88%, 98%) 20 mg 40 mg 80 mg 160 mg 240 mg N (107) ORR 50% 62% 68% 64% 83% *Includes confirmed responses and responses awaiting confirmation; # represents imputed values. Population: all dosed central T790M+ patients with a baseline RECIST assessment and an evaluable response (CR/PR, SD or PD), N=107 (from 120 T790M+ patients, 13 patients with a current non-evaluable response are not included). QD, once daily; central T790M+, T790M positive by central laboratory testing Presented by: Pasi A. Jänne

90 CO-1686 Phase I Study: Dose Levels Presented By Lecia Sequist at 2014 ASCO Annual Meeting

91 CO-1686 Phase I patient characteristics Presented By Lecia Sequist at 2014 ASCO Annual Meeting

92 Adverse events Presented By Lecia Sequist at 2014 ASCO Annual Meeting

93 Best response in Phase 1 and early <br />Phase 2 expansion cohort patients Presented By Lecia Sequist at 2014 ASCO Annual Meeting

94 Sum of target lesions over time Presented By Lecia Sequist at 2014 ASCO Annual Meeting

95 Both AZ9291 and CO1686 are on fast track approval by FDA TIGER 2 study: Single arm phase II study of CO1686 for patient with T790M resistant mutation after first TKI failure AURA 2 study: Single arm phase II study of AZ 9291 for patient with T790M resistant mutation after first line TKI failure

96 AURA 3 Study Design Randomise ~610 patients 2:1 Central testing of ~ 1540 biopsy samples T790M+ (n=610) AZD9291 (80 mg p.o. qd) (n=407) Platinum-based doublet chemotherapy* every 3 weeks (n=203) Primary endpoint: PFS T790M- Not eligible for enrolment *Pemetrexed 500 mg/m 2 + carboplatin AUC5 or Pemetrexed 500 mg/m 2 + cisplatin 75 mg/m 2 P PI: T Mok YL Wu AUC5, area under the plasma concentration time curve 5 mg/ml 1 per minute; EGFRm+, EGFR mutation-positive; EGFR-TKI, EGFR tyrosine kinase inhibitor; NSCLC, non-small cell lung cancer; p.o., orally; qd, once daily; T790M+, T790M mutation-positive; T790M-, T790M mutation-negative

97 Summary Advanced stage NSCLC (2014) EGFR mut Gefitinib or Erlotinib or Afatinib PD Chemo +/- Bev

98 Summary Advanced stage NSCLC EGFR mut (by tissue or blood) Gefitinib or Erlotinib or Afatinib or Dacomitinib Continue TKI beyond RECIST PD T790m+ AZ9291/ CO1686 PD T790m- Chemo +/- Bev Chemo +/- Bev

99 Optimal shape

100 Questions

101 CARE Lung Cancer Faculty The CARE (Community Academic Research Education) Faculty is a Pan-Canadian group of medical oncologists from across Canada who meet and discuss various topics from key conferences. The CARE Lung Cancer Faculty is comprised of leading medical oncologists from across Canada and includes Drs. Barbara Melosky (BC), Anil A. Joy (AB), Denis Soulieres (QC), Natasha Leighl (ON), Sunil Verma (ON) & Ron Burkes (ON)

102 Canadian Perspectives & Interactive Discussion

103 Thank You!