Treatment of ALK Positive Advanced NSCLC Fiona Blackhall PhD FRCP Medical Oncologist Manchester, UK

Treatment of ALK Positive Advanced NSCLC Fiona Blackhall PhD FRCP Medical Oncologist Manchester, UK ESMO The Christie Preceptorship in Lung Cancer March 2017

2017 : Similar incidence in women & men ADC SQ cell Ca Small cell 2017 : ADC > SQCC > small cell 2017 : at least half of new cases present with metastatic disease for which average survival is less than one year Possible aetiology in 1927? Damp climate Dust inhaled from grooming horses No mention of tobacco smoke exposure!

Learning Objectives Molecular basis & diagnosis of ALK positive NSCLC Current treatment strategy : - Role for 1 st generation & 1 st in class ALK inhibitor, crizotinib - Role for 2 nd & 3 rd generation ALK inhibitors Major challenges - intracranial metastases - mechanisms of resistance Patient cases March 2017 ESMO Christie Preceptorship Lung Cancer 3

The EML4-ALK Fusion Gene First identified in NSCLC cells in 2007 Small inversion within chromosome 2p results in fusion of the EML4 & ALK genes Fusion results in redistribution of the ALK kinase domain from the cell membrane to cytoplasm Ligand dependent activation & transforming activity Multiple EML4-ALK fusion variants have been identified due to truncations of EML4 at different exons Soda M et al. Nature 2007;448:561 567

Transforming Activity of ALK Fusion Gene Hallberg & Palmer Ann Oncol Supp 3 2016

ALK gene fusion in NSCLC Incidence ~ 2-7% non-squamous NSCLC Associated with never-smoker/light former smoking history & younger age ESMO guidance - Screen all non squamous cases - Other histological subtypes depending on clinical characteristics 6

Diagnosis of ALK gene rearrangement FISH, PCR, IHC Schematic diagram of EML4- ALK fusion Kerr & Lopez-Rios Ann Oncol supp 3 2016

Timeline of Rapid Progress made in treatment of ALK + NSCLC since the 2007 discovery of EML4-ALK Fusions Only 4 years between the discovery of EML4-ALK and the FDA approval of the 1 st in class ALK inhibitor, crizotinib in 2011 Solomon & Soria, Ann Oncol Vol 27 Supp 3 2016

Crizotinib: First-in-human ALK inhibitor Potent and selective ATP competitive oral inhibitor of ALK and MET tyrosine kinases and their oncogenic variants administered at the MTD of 250 mg PO twice daily FDA accelerated approval was based on phase I data for the safety and activity of crizotinib in an expanded cohort of patients with advanced ALK-positive NSCLC 1 Baseline CTscan 2 weeks post CZT initiation Crizotinib (PF-02341066) 1 Kwak et al. NEJM 2010;363:1693-703

WATERFALL PLOT OF BEST PERCENTAGE CHANGE IN TUMOUR LESIONS FROM BASELINE IN PATIENTS WITH ALK POSITIVE NSCLC & MEASURABLE DISEASE TREATED WITH CRIZOTINIB IN THE PHASE 1 PROFILE 1001 STUDY N=133 Response rate = 61% Median duration of response = 49 weeks Camidge et al. Lancet Oncology 2012 10

Phase III PROFILE 1007 & PROFILE 1014 Trials of Crizotinib vs. Chemotherapy PROFILE 1007 Shaw et al. NEJM 2013 (2 nd line) Response Rate 65 vs 20% PROFILE 1014 Solomon et al NEJM 2014 (1 st line) Response Rate 74 vs 45% Blackhall & Cappuzzo Ann Oncol Supp 3 2016

Clinical efficacy of Crizotinib for ALK+ NSCLC PROFILE Study Phase Pa ents NSCLC ALK+ ORR (%) PFS (months) Author 1001 Phase I N: 149 60.8 (95% CI, 52.3-68.9) 9.7 (95% CI, 7.7-12.8) Camidge 2012 1005 Phase II N: 261 60 (95% CI, 53.6-65.9) 8.1 (95% CI, 6.8-9.7) Kim 2012 1007 Phase III (CZT vs. C/D) N: 346 65 vs. 19.5 P<0.0001 7.7 vs. 3.0 P<0.0001 Shaw 2013 1014 Phase III (CZT vs. C + P) N: 343 74 vs. 45 P<0.001 10.9 vs. 7.0 P<0.001 Solomon 2014 ORR, objec ve response rate; PFS, progression free survival; CZT, crizo nib; P, pemetrexed; D, docetaxel; C, cispla n or carbopla n. 12

ESMO MAGNITUDE OF CLINICAL BENEFIT SCALE Cherny NI, Sullivan R, Dafni U et al. Ann Oncol 26:1547-1573, 2015

PROFILE 1014 Trial Common AEs of any cause in 25% of patients with 5% difference between groups Crizotinib (n=171), n (%) Chemotherapy (n=169), n (%) b AE Any grade Grade 3/4 Any grade Grade 3/4 Higher frequency ( 5% absolute difference) in crizotinib arm Vision disorder c 122 (71) 1 (1) 24 (14) 0 Diarrhoea 105 (61) 4 (2) 29 (17) 1 (1) Oedema c 83 (49) 1 (1) 22 (13) 1 (1) Vomiting 78 (46) 3 (2) 68 (40) 6 (4) Constipation 74 (43) 3 (2) 53 (31) 0 Elevated transaminases c 61 (36) 24 (14) 22 (13) 4 (2) Upper respiratory infection c 55 (32) 0 21 (12) 1 (1) Abdominal pain c 45 (26) 0 20 (12) 0 Dysgeusia 45 (26) 0 11 (7) 0 Higher frequency ( 5% absolute difference) in chemotherapy arm Nausea 95 (56) 2 (1) 103 (61) 3 (2) Decreased appetite 51 (30) 4 (2) 59 (35) 1 (1) Fatigue 49 (29) 5 (3) 65 (38) 4 (2) Neutropenia c 36 (21) 19 (11) 51 (30) 26 (15) Asthenia 22 (13) 0 42 (25) 2 (1) Anemia c 15 (9) 0 54 (32) 15 (9) 14

Toxicities associated with crizotinib in Ph I & II Trials n=255 Common % Vision 62 Nausea 53 Diarrhoea 43 Vomiting 40 Constipation 27 Oedema 28 Fatigue 20 ALT 13 Rash 10 Camidge & Doebele, Nature Reviews 2012; *Weickhardt et al. Cancer 2012 Common mainly G1/2 Visual : light trails, flashes, image persistence at edge of visual field (light adaptation) Other less common Renal cysts Pneumonitis Asymptomatic bradycardia Low testosterone (? common)(16/16 crizotinib; 6/19 metastatic NSCLC)

PROFILE 1014 Solomon et al. NEJM 16

PROFILE 1014 Solomon et al NEJM 17

Patterns of Progression & Mechanisms of Resistance to Crizotinib Dagogo-Jack & Shaw Ann Oncol Supp 3 2016

Chemistry of ALK Tyrosine Kinase Inhibitors TAE684 Ceritinib Crizotini b Alectinib Lorlatinib Brigatini b Models show variation in contact sites between different TKI molecules with the ATP-binding pocket of the wild-type ALK kinase domain Figure adapted from Hallberg & Palmer Ann Oncol 2016 Ceritinib has 20 fold more binding affinity for wild type ALK than crizotinib Central Nervous System Penetration > for 2 nd & 3 rd generation ALK inhibitors 2 nd & 3 rd generation ALK inhibitors are active against crizotinib resistance mutations 19

Clinical efficacy of 2 nd generation ALK inhibitors in crizotinib resistant patients Response rates : 38 to 71% Median PFS : 5.7 to 13.4 months 20

Manchester Patient Case 1 : 49 yr old male, 10 pack year smoking history MRI brain July 2014 July 2013: T2N1M1b ALK + ADC lung, bone & lung mets Cis/pem 4 cycles : PR Mar 2014 : PD lung & brain (headaches) April 2014 : WBRT May 2014 to July 2015 : crizotinib 14 cycles : SD [AE low testosterone & bradycardia] Aug 2015 Progressive Disease (liver, brain, bone ) : commenced on brigatinib on clinical trial October 2015 : Response in all disease sites Feb 2017 : Remains on trial with excellent quality of life : recent travel & holiday to Japan 21

ALK inhibitors (ALKi) Approved Crizotinib Ceritinib Alectinib Breakthrough Therapy Brigatinib Investigational Lorlatinib Ensartinib Entrectinib Current Treatment Algorithm for ALK+ NSCLC 1st generation ALKi Progressive disease 2 nd generation ALKi Solomon & Soria, Annals of Oncology 2016 Soria ESMO 2016

ASCEND-4 Soria et al. NEJM 2017 PROFILE 1014 Solomon et al. NEJM 2014 ASCEND-4 PFS [95% CI] HR (95%CI) ORR ceritinib 16.6 (12.6,27.2) 72.5% chemot 8.1 (5.8,11.1) 0.55(0.42,0.73) 26.7% PROFILE PFS [95% CI] HR (95%CI) ORR crizotinib 10.9 (8.3,13.9) 74 % chemot 7.0 (6.8,8.2) 0.45(0.35,0.60) 45% 23

How does ASCEND-4 compare with PROFILE 1014? Are there differences in study design clinical demographics toxicity intracranial efficacy 24

Study Design ASCEND-4 Soria et al. NEJM 2017 PROFILE 1014 Solomon et al. NEJM 2014 1:1 randomisation Chemotherapy (ChemoT) Platinum/pemetrexed Platinum/pemetrexed Maintenance pemetrexed Crossover on progression Stage IIIB/IV ALK+ by ALK+ by central FISH ALK+ by central IHC Stratification for Brain metastases PS 0-2 Prior treatment

Clinical Demographics (%) ASCEND-4 Soria et al. NEJM 2017 PROFILE 1014 Solomon et al NEJM 2014 Ceritinib ChemoT Crizotinib ChemoT Median Age (years) 55 54 52 54 Female 54 61 60 63 Performance Status 2 6.9 5.9 6 5 Never smoker 57.1 65.2 62 65 Ex-smoker 34.9 26.7 33 32 Current smoker 7.9 8.0 6 3 Caucasian 55 52.4 53 50 Asian 40.2 43.9 45 47 Brain Metastases present 31.2 33.2 26 27

Toxicity% : All Grades (G3/4) ASCEND-4 Soria et al NEJM 2017 PROFILE 1014 Solomon et al NEJM 2014 Ceritinib Chemo Crizotinib Chemo Vision Disorder - - 71 (1) 9 (0) Diarrhea 84.7 (5.3) 10.9 (1.1) 61 (2) 13 (1) Edema - - 49 (1) 12 (1) Vomiting 66.1 (5.3) 36 (5.7) 46 (2) 36 (3) Nausea 68.8 (2.6) 55.4 (5.1) 56 (1) 59 (2) Fatigue 29.1 (4.2) 29.7 (2.9) 29 (3) 38 (2) Elevated transaminases [ALT for ASCEND-4] 60.3 (30.7) 21.7 (2.9) 36 (14) 13 (2) Discontinuation due to AEs (study drug) % 11.1 (5.3) 16.6 (11.4) 12 (5) 14 (8) 27

STUDY (n) Intracranial Efficacy ASCEND-4 (n=376) Soria et al. NEJM 2017 PROFILE 1014 (n=343) Solomon et al JCO 2016 Ceritinib ChemoT Crizotinib ChemoT PFS (mths) overall population 16.6 8.1 10.9 7.0 Brain metastases (BM) present N=61 N=60 N=39 N=40 Prior brain radiotherapy number (%) 24 (40%) 24 (40%) Treated* Treated* PFS in BM subgroup (mths) [95%CI] PFS in no BM subgroup (mths) [95% CI] 10.7 [8.1,16.4] 26.3 [15.4,27.7] 6.7 [4.1,10.6] 8.3 [6.0,13.7] 9 [6.8,15] 11.1 [8.3,14] 4 [1.5,6.8] 7.2 [6.9,8.3] Intracranial response rate 73% (22) 27.3% (22) NE NE Intracranial DCR at 24 weeks 86% 50% 56% 25% Intracranial Progression number (%) NR NR 25 (15%) 26 (15%) DCR : Disease control rate (CR,PR,SD), NE : Not evaluated, NR : Not reported *details of prior radiotherapy not known 28

ASCEND-4 challenges the current treatment algorithm of using a next generation ALKi for treatment after progression on crizotinib No prospective, randomised data for a sequential 1 st generation then 2 nd /3 rd generation ALKi versus 2 nd /3 rd generation ALKi first line In a retrospective analysis of 73 patients treated sequentially with crizotinib then ceritinib - combined median PFS of 17.4 (15.5,19.4) months - comparable with median PFS of 16.6 (12.6,27.2) months in ASCEND-4 In 23 patients evaluable there was no difference in PFS on ceritinib between those with or without ALK resistance mutations to crizotinib (median PFS 5.8 vs 6.5 months; P = 0.510) Swimmer plot showing PFS for 73 patients treated sequentially with ceritinib after progression on crizotinib Gainor et al CCR 2015 29

ASCEND-4 challenges the current treatment algorithm of using a next generation ALKi for treatment after progression on crizotinib No prospective, randomised data for a sequential 1 st generation then 2 nd /3 rd generation ALKi versus 2 nd /3 rd generation ALKi first line In a retrospective analysis of 73 patients treated sequentially with crizotinib then ceritinib - combined median PFS of 17.4 (15.5,19.4) months - comparable with median PFS of 16.6 (12.6,27.2) months in ASCEND-4 In 23 patients evaluable there was no difference in PFS on ceritinib between those with or without ALK resistance mutations to crizotinib (median PFS 5.8 vs 6.5 months; P = 0.510) Swimmer plot showing PFS for 73 patients treated sequentially with ceritinib after progression on crizotinib Gainor et al CCR 2015 30

Progression-free survival rate (%) First Line Head to Head trials of ALK inhibitors The J-ALEX trial demonstrated superior survival for the 2 nd generation ALKi alectinib compared with crizotinib The AE profile for alectinib demonstrated all grade rates of diarrhea, nausea, vomiting, transaminase elevation < 11% J-ALEX TRIAL Nokihara et al. ASCO 2016 Primary Endpoint: PFS by IRF (ITT Population) 100 80 60 40 20 Alectinib (N=103) Crizotinib (N=104) Events, n (%) 25 (24.3%) 58 (55.8%) Median, mo [95% CI] NR [20.3 - NR] 10.2 [8.2-12.0] P-value <0.0001 HR [99.6826% CI] 0.34 [0.17-0.71] NR Results awaited & ongoing trials - Global ALEX trial of alectinib vs crizotinib - crizotinib vs brigatinib (ALTA trial) - crizotinib vs lorlatinib 0 10.2 months 0 1 3 6 9 12 15 18 21 24 27 No. of patients at risk Alectinib 103 103 93 76 49 36 27 9 1 Time (months) Crizotinib 104 102 86 65 40 21 14 4 Presented by: Hiroshi Nokihara 14 J-ALEX PFS [95% CI] HR (95%CI) ORR alectinib NR (20.3,NR) 91.6% crizotinib 10.2 (8.2,12.0) 0.34(0.17,0.71) 78.9% 31

Subgroup Analysis of PFS by IRF Alectinib (N=103) Crizotinib (N=104) Subgroup n Events n Events HR [95% CI] Overall 103 25 104 58 0.34 [ 0.21-0.54 ] ECOG performance 0/1 101 24 102 57 0.33 [ 0.20-0.53 ] status 2 2 1 2 1 1.41 [ 0.08-23.57 ] Prior chemotherapy 0 66 15 67 35 0.30 [ 0.17-0.56 ] 1 37 10 37 23 0.39 [ 0.18-0.83 ] Clinical stage Postoperative recurrence 24 6 26 13 0.49 [ 0.18-1.30 ] Stage IIIB/IV 79 19 78 45 0.31 [ 0.18-0.52 ] Age group 75 12 3 10 5 0.28 [ 0.06-1.19 ] <75 91 22 94 53 0.34 [ 0.21-0.56 ] Smoking status Never smoker 56 18 61 33 0.50 [ 0.28-0.89 ] Past or Current smoker 47 7 43 25 0.18 [ 0.08-0.42 ] Brain metastases Yes 14 1 29 16 0.08 [ 0.01-0.61 ] at baseline No 89 24 75 42 0.39 [ 0.23-0.64 ] ALK testing method IHC and FISH 96 21 94 52 0.30 [ 0.18-0.50 ] RT-PCR 7 4 10 6 0.80 [ 0.22-2.90 ] Sex Female 62 16 63 37 0.31 [ 0.17-0.57 ] Male 41 9 41 21 0.35 [ 0.16-0.77 ] Multiple stratified Cox regression using prognostic factors including brain metastases showed consistent treatment effect (HR = 0.34) 0.01 0.1 1 10 100 Favors Alectinib Favors Crizotinib Presented by: Hiroshi Nokihara 32

Safety Overview Alectinib (N=103) Crizotinib (N=104) Any AEs 100 (97.1%) 104 (100.0%) Grade 3/4 AEs 27 (26.2%) 54 (51.9%) Treatment-related deaths 0 0 Serious AEs 15 (14.6%) 27 (26.0%) Discontinuation of study drug due to AEs 9 (8.7%) 21 (20.2%) Dose interruptions due to AEs 30 (29.1%) 77 (74.0%) Presented by: Hiroshi Nokihara 33

Common AEs, 20% of Patients in Either Arm Alectinib (N=103) All Grade Grade 3/4 Crizotinib (N=104) Alectinib (N=103) Crizotinib (N=104) Constipation 36 (35.0%) 46 (44.2%) 1 (1.0%) 1 (1.0%) Nausea 11 (10.7%) 77 (74.0%) 0 2 (1.9%) Diarrhea 9 (8.7%) 76 (73.1%) 0 2 (1.9%) Vomiting 6 (5.8%) 60 (57.7%) 0 2 (1.9%) Aspartate aminotransferase increased 11 (10.7%) 32 (30.8%) 1 (1.0%) 5 (4.8%) Alanine aminotransferase increased 9 (8.7%) 33 (31.7%) 1 (1.0%) 13 (12.5%) Visual disturbance 1 (1.0%) 57 (54.8%) 0 0 Nasopharyngitis 21 (20.4%) 24 (23.1%) 0 0 Dysgeusia 19 (18.4%) 54 (51.9%) 0 0 Pyrexia 10 (9.7%) 21 (20.2%) 1 (1.0%) 0 Decreased appetite 1 (1.0%) 21 (20.2%) 1 (1.0%) 1 (1.0%) Presented by: Hiroshi Nokihara 34

Will the choice of 1 st Line ALKi impact on patterns of progression & mechanisms of resistance? Figures from Gainor et al. Cancer Discovery 2016 The spectrum of ALK resistance mutations varies according to ALK inhibitor Some mutations confer resistance to ceritinib but not alectinib and vice versa Some mutations are only sensitive to the 3 rd generation ALK TKI lorlatinib Majority are resistant to crizotinib

The Art of Precision Medicine Shaw et al. NEJM 2016 36

Manchester Patient Case 2 : How would you treat? 40 yr old lady 5 pack year smoking history Stage IV ALK + NSCLC who received platinum/pemetrexed CT with minor response then on progression 1 year later commenced crizotinib After 15 cycles she develops symptomatic brain metastases ; extracranial disease remains stable What would you do? Would you switch ALK inhibitor, treat with WBRT or both? 37

Manchester Patient Case 2 : How would you treat? She receives WBRT & continues on crizotinib for 15 months She then develops intracranial progression with a dominant lesion causing mass effect and midline shift What would you do? June 2015 temporal lobe lesion causing mass effect and midline shift 38

Manchester Patient Case 2 : How would you treat? The neurosurgeons agree to resect! 2 months later PD with new bone & liver mets Commenced on a clinical trial of brigatinib 2 months later response in liver, bone and residual brain metastases 16 months later remains stable June 2015 temporal lobe lesion causing mass effect, midline shift & deterioration in symptoms / PS 39

Take Home Message New targeted therapy treatment paradigms continue to evolve for patients with ALK gene fusion positive NSCLC with several trials ongoing in the 1 st line setting Opportunity to combine pragmatism with precision? - Crizotinib may be a better tolerated 1st line option in patients where the GI toxicities of ceritinib may be detrimental e.g poor PS, comorbid conditions, very elderly groups underrepresented in trials to date - Serial tumor tissue biopsy & concomitant evaluation of serial liquid biopsy (mutations in circulating tumor DNA) look set to become routine for precise matching of ALK resistance mechanism to select optimal therapy after failure of first line ALKi treatment 40

Thank you for joining us in Manchester ESMO The Christie Preceptorship in Lung Cancer March 2017