EGFR gene mutations Ex 19 Ex 21 Paez et al, Science 2004

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1 Evolution of knowledge in NSCLC Pao and Girard, Lancet Oncology 2011

2 Fattori da considerare nella scelta terapeutica del NSCLC nel 2012 Stadio di malattia PS Età Comorbidità Compliance e desiderio del paziente Istologia (squamoso vs non-squamoso) Mutazioni di EGFR Riarrangiamento di ALK (EML-4ALK)

3 EGFR gene mutations Ex 19 Ex 21 Paez et al, Science 2004

4 EGFR gene mutations Activating mutations with ligand independent receptor activity 90% in exons 19 (deletion) and 21 (LB58R) Global incidence: 10% caucasians; ;30-40% Asiatic pts ++ never-smoker or light-smoker More frequent in female sex ++ adenocarcinoma (in particular BAC non mucinous) Predictive factor of EGFR-TKIs, gefitinib and erlotinib (in retrospective and prospective studies) Tiseo et al, Drug Des Devel Ther 2011

5 IPASS: Study design Patients Chemonaïve Age 18 years Adenocarcinoma histology Never or light exsmokers* Life expectancy 12 weeks PS 0-2 Measurable stage IIIB / IV disease Gefitinib (250 mg / day) 1:1 randomisation Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m 2 ) 3 weekly # Endpoints Primary Progression-free survival (non-inferiority) Secondary Objective response rate Overall survival Quality of life Disease-related symptoms Safety and tolerability Exploratory Biomarkers EGFR mutation EGFR-gene-copy number EGFR protein expression Mok et al, NEJM 2009

6 Progression-free survival in EGFR mutation positive and negative patients EGFR mutation positive EGFR mutation negative progression-free e survival Gefitinib (n=132) Carboplatin / paclitaxel (n=129) HR (95% CI) = 0.48 (0.36, 0.64) p< No. events gefitinib, 97 (73.5%) No. events C / P, 111 (86.0%) progression-free e survival Gefitinib (n=91) Carboplatin / paclitaxel (n=85) HR (95% CI) = 2.85 (2.05, 3.98) p< No. events gefitinib, 88 (96.7%) No. events C / P, 70 (82.4%) Probability of 0.2 At risk : Gefitinib C / P Months Probability of Months Treatment by subgroup interaction test, p< Mok et al, NEJM 2009

7 IPASS: Response Rates and Quality of life Mutation Positive ORR % Gefitinib Carboplatin/paclitaxel % M+ HR: 2.75; P= M HR: 0.04; P= % 1.1% N=132 N=129 N=91 N=85 Mutation Positive Mutation Negative Mok et al, NEJM 2009 Thongprasert et al, JTO 2011 Mutation Negative

8 Randomized studies of EGFR TKIs vs CT in first-line therapy Author Study N (EGFR +) RR, % (TKI vs CT) PFS, months (HR, 95%CI) OS, months Mok et al, 2009 IPASS CT vs Gefitinib vs vs ( ) 21.6 vs 21.9 Lee et al, First-SIGNAL vs vs vs PG vs Gefitinib 0.61 ( ) Mitsudomi et al, 2009 WJTOG vs vs vs 39 PD vs Gefitinib 049( ( ) (ASCO 12) Maemondo et al, 2010 NEJGSG002 CT vs Gefitinib vs vs ( ) 27.7 vs 26.6 Zhou et al, 2011 OPTIMAL CG vs Erlotinib vs vs ( ) 22.7 vs 28.6 (ASCO 12) Rosell et al, EURTAC vs vs vs P-bas vs Erlotinib 0.37 ( ) Yang et al, ASCO 2012 LUX-LUNG 8 PA vs Afatinib vs vs ( ) NR vs NR

9 Meccanismi di resistenza aegfrtkis EGFR-TKIs Sequist et al, Sci Transl Med. 2011

10 FISH Assay for ALK Rearrangement p25.2 p24.3 p24.1 p23.2 p22.3 p22.1 p16.3 p16.1 p14 p13.2 ALK 29.3 EML p25.2 p24.3 p24.1 p23.2 p22.3 p22.1 p16.3 p16.1 p14 p13.2 Telomere 2p23 region Centromere t(2;5) ALK gene breakpoint region 3 5 p12 q12.1 q12.3 q14.1 q14.3 q21.2 q22.1 q22.2 q23.22 q24.1 q24.3 p12 q12.1 q12.3 q14.1 q14.3 q21.2 q22.1 q22.2 q q24.1 q24.3 ~250 kb ~300 kb Break-apart FISH assay for ALK-fusion genes 1 q31.3 q31.3 q32.1 q32.3 q33.2 q34 q36.1 q36.3 q37.2 q32.1 q32.3 q33.2 q34 q36.1 q36.3 q37.2 Split signal Non-split signal ALK break-apart bea apa FISH assay [Courtesy John Iafrate, Massachusetts General Hospital] Assay is positive if rearrangements can be detected in 15% of cells FISH = fluorescence in situ hybridization Shaw AT et al. J Clin Oncol 2009

11 ALK rearrangements: clinico-pathologic characteristics Global incidence: ~ 5%; + EML4-ALK translocation Determination with FISH; ongoing studies with IHC ++ never-smoker or light-smoker; ++ young pts Similar incidence in Caucasians and Asiatic pts ++ adenocarcinoma with acinar o solid patterns (in particular signet ring-type cells) In general mutually exclusive with EGFR and K-ras mutations Factor of EGFR-TKI resistance; preliminary data of higher response to pemetrexed Tiseo et al, Expert Rev Anticancer Ther 2011

12 Tumor Responses to Crizotinib for Patients with ALK-positive p NSCLC Maxim mum chang ge in tumor size (%) % Progressive disease Stable disease Confirmed partial response Confirmed complete response No. prior regimens* ORR %(n/n) 0 80 (4/5) 1 52 (14/27) 2 67 (10/15) Objective response rate (ORR): 3 56 (19/34) 57% (95% CI: 46, 68%) * *Partial response patients with 100% change have non-target disease present Bang Y et al, NEJM 2010

13 Responses to Crizotinib: update PROFILE trial 1001 (149 pts) 133 pts with measurable disease 39 pts treated beyond PD RR: 60.8% DCR: 82.5% at week % at week 16 RR: similar regardless age, sex, PS, line PFS: 9.7 months ( months) I line 18.3 months II line or later 9.2 months mos: NR, 6-12 ms 87.9%-74.8% Camidge et al, Lancet Oncol 2012

14 Crizotinib PROFILE Program PROFILE 1007 (N=318) ALK positive by central laboratory 1 prior chemotherapy (platinum based) PROFILE 1005 (N=400) ALK positive by central laboratory 1 prior chemotherapy and not eligible for 1007 R A N D O M I S E Crizotinib 250 mg b.i.d. (n=159) [continuous] Pemetrexed 500 mg/m 2 or docetaxel 75 mg/m 2 (n=159) infused on day 1 of a 21 day cycle Crossover on PD Crizotinib 250 mg b.i.d. (N=400) [continuous] PROFILE 1014 (N=334) ALK positive locally advanced / metastatic nonsquamous NSCLC No prior treatment for advanced disease R A N D O M I S E Crizotinib 250 mg b.i.d. (n=167) [continuous] Crossover on PD Pemetrexed/cisplatin or pemetrexed/carboplatin (n=167) infused on day 1 of a 21 day cycle Clinicaltrials.gov

15 PROFILE 1007: PFS by independent radiological review (ITT)

16 PROFILE 1007: ORR by independent radiological review (ITT)

17 Doebele et al, Clin Cancer Res 2012 Resistenza a Crizotinib

18 EGFR e ALK e relativi inibitori a confronto Variable EGFR and TKI ALK and TKI notes Pts characteristics ADK, NS o Light-S ADK, NS o Light-S Ex 20 vs 35%, S 5% Prognostic factor Yes (good) Y/N RR and PFS 70% and 9-12 months 60% and 7-9 months Regardless line Resp and mutation type Toxicity and outcome > Del 19 than L858R < atypical mut Skin (60%), early outcome correlation Probably diff according to variants Visual (60%), early (14 days)? Flare at stop (%) Yes (23%) Yes (?) Res mechanisms 1 st T790M and others 1 st C1156Y, L1196M and others T790M intratorax PD Brain PD in Crizo Overcome Res Many strategies Many strategies Hsp90, Beyond PD and local therapy Resp to CT > than EGFR wt Resp to PEM > than ALK neg From target to therapy approved years 4 years