ALK +ive Lung Cancer: First line and Resistance Disease

Transcription

1 ALK +ive Lung Cancer: First line and Resistance Disease Professor Tony Mok Li Shu Fan Medical Foundation Professor of Clinical Oncology Dept of Clinical Oncology The Chinese University of Hong Kong

2 Disclosures Affiliation/Financial Interest Grant/Research Support from: Lecture fees: Honoraria/Honorarium from: Major Stock Shareholder in: Advisory Board for: Board of Directors: Name of Organisation(s) AstraZeneca, BI, BMS, Clovis Oncology, MSD, Novartis, Pfizer, Roche, SFJ, XCovery AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, MSD, Novartis, BMS, Taiho, Takeda Oncology, PrIME Oncology, Amoy Diagnostics Co., LTD. AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, Merck Serono, MSD, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Inc., Vertex Pharmaceuticals, BMS, OncoGenex Pharmaceuticals, Inc., Celgene, Ignyta, Inc., Fishawack Facilitate Ltd, Takeda Oncology, Janssen, Hutchison Chi-Med, OrigiMed, Hengrui Therapeutics Inc., Sanofi-Aventis R&D, Yuhan Corporation, PrIME Oncology, Amoy Diagnostics Co., LTD., Loxo-Oncology Sanomics Ltd., Hutchison Chi-Med AstraZeneca, BI, Roche/Genentech, Pfizer, Eli Lilly, Merck Serono, MSD, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Inc., Vertex Pharmaceuticals, BMS, genedecode Co., Ltd., OncoGenex Technologies Inc., Celgene, Ignyta, Inc., Cirina, Fishawack Facilitate Ltd., Janssen, Takeda, Hutchison Chi-Med, OrigiMed, Hengrui Therapeutics Inc., Sanofi-Aventis R&D, Yuhan Corporation, Loxo- Oncology IASLC, ASCO, Hutchison Chi-Med, Chinese Lung Cancer Research Foundation Ltd., Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Therapy Society (HKCTS), Asian Thoracic Oncology Research Group (ATORG), St. Stephen s College & Prep. School

3 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 3 5 Centromere t(2;5) ALK gene breakpoint region p12 q12.1 q12.3 q14.1 q14.3 q21.2 q22.1 q22.2 q23.2 q24.1 q24.3 p12 q12.1 q12.3 q14.1 q14.3 q21.2 q22.1 q22.2 q23.2 q24.1 q24.3 ~250 kb ~300 kb Break-apart FISH assay for ALK-fusion genes 1 q31.3 q31.3 q32.1 q32.1 q32.3 q32.3 q33.2 q34 q36.1 q36.3 q37.2 q33.2 q34 q36.1 q36.3 q37.2 Split signal Non-split signal ALK break-apart 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 >15% cells 1 Shaw AT et al. J Clin Oncol 2009;27:

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5 Concordance between FISH and IHC Yatabe et al JTO 2015

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7 Which biomarker to use? FISH +ive IHC +ive IHC +ive ALK TKI ALK TKI FISH +ive What happens to the IHC+/FISH- ive patient? ALK TKI

8 ALEX study: Biomarker analysis Patient with ALK-positive NSCLC will benefit from first line ALK targeted therapies Current definition of ALK-positive is based on either FISH or IHC Discrepancy between FISH and IHC occurs, and clinical outcomes on the discrepant cases are not available. The ALEX trial provides a unique dataset to assess ALK IHC- and FISH-based assays regarding clinical outcome for alectinib and crizotinib, particularly for the subset of patients with IHC-positive/FISH-negative (n=39) NSCLC ALK status by IHC and FISH test in ALEX Result, n (%) IHC FISH Total, n Positive 303 (100) 203 (67) Negative -Alectinib -Crizotinib 0 39 (12.9) Uninformative FISH result 0 33 (10.9) 33 Not done* 0 28 (9.2) 28 *Not enough adequate tissue/no tissue available for FISH test Mok et al WCLC 2017

9 ALK IHC positive, FISH negative - outcomes *Investigator-assessed; NR, not reached Crizotinib (n=18) Alectinib (n=21) Patients with event, n (%) 11 (61.1) 14 (66.7) Median PFS,* months (95% CI) HR (95% CI), P value 12-month event free rate, % (95% CI) Difference, % (95% CI), P value 7.4 (2.7 NR) 3.8 (1.9 NR) 1.45 ( ), ( ) 35.0 ( ) 7.1 ( ), Responders, % (95% CI) 44 (22 69) 29 (11 52) CR, % 0 5 PR, % SD, % 28 24

10 First line therapy

11 PROFILE 1014 Study Design Key entry criteria ALK-positive by central FISH testing a Locally advanced, recurrent, or metastatic non-squamous NSCLC No prior systemic treatment for advanced disease ECOG PS 0 2 Measurable disease Stable treated brain metastases allowed R A N D O M I Z E b N=343 Crizotinib 250 mg BID PO, continuous dosing (n=172) Pemetrexed 500 mg/m 2 + cisplatin 75 mg/m 2 or carboplatin AUC 5 6 q3w for 6 cycles (n=171) Endpoints Primary PFS (RECIST 1.1, independent radiologic review [IRR]) Secondary ORR OS Safety Patient-reported outcomes (EORTC QLQ-C30, LC13) CROSSOVER TO CRIZOTINIB PERMITTED AFTER PROGRESSION c a ALK status determined using standard ALK break-apart FISH assay b Stratification factors: ECOG PS (0/1 vs. 2), Asian vs. non-asian race, and brain metastases (present vs. absent) c Assessed by IRR Solomon & Mok (co-first) et al NEJM Dec 2014

12 RN1 PROFILE 1014

13 Slide 12 RN1 Can you confirm this reference is Solomon & Mok (co-first) et al NEJM Dec 2014? Rebecca Nunn, 01/09/2017

14 Intracranial DCR by IRR in Patients with Brain Metastases at Baseline Solomon et al JCO 2016

15 Final Primary OS Analysis (ITT Population) Overall Survival (%) Median follow-up ~46 months in both arms Crizotinib (N=172) HR (95%CI: ); a P= Chemotherapy (N=171) Deaths, n (%) 71 (41.3) 81 (47.4) Median OS (95% CI), months NR (45.8 NR) 47.5 (32.2 NR) + Censored No. at risk Crizotinib Chemotherapy Months a 1-sided stratified log-rank test. P value <0.05 is not statistically significant as it was 1-sided Mok et al ESMO 2017

16 Impact of Subsequent Therapy on OS: ALK TKI versus Treatment Other Than ALK TKI Subsequent treatment, n (%) Any ALK tyrosine kinase inhibitor (TKI) Crizotinib (N=172) Chemotherapy (N=171) Number of patients 57 (33.1) 145 (84.8) Deaths, n (%) 11 (19.3) 66 (45.5) Median OS, months (95% CI) NR (NR, NR) 49.5 (41.0, NR) 1 2 Treatment other than ALK TKI Number of patients 37 (21.5) 3 (1.8) Deaths, n (%) 25 (67.6) 2 (66.7) Median OS, months (95% CI) 20.8 (14.4, 31.8) 12.1 (2.2, NR) 3 4 NR, not reached 15

17 Impact of Subsequent Therapy on OS: ALK TKI versus Treatment Other Than ALK TKI Censored Overall Survival (%) No. at risk Crizotinib followed by any ALK TKI Crizotinib followed by any follow-up therapy other than ALK TKI Chemotherapy followed by any ALK TKI Chemotherapy followed by any followup therapy other than ALK TKI Months

18 Second generation TKI

19 Defining second generation: selectivity Alectinib Crizotinib IC 50 (nm) ALK RET INSR KDR ROS1 ABL EGFR FGFR2 HER2 IGF1R JAK1 KIT MET PDFGRβ RON SRC AKT1 AuroraA CDK1 CDK2 MEK1 PKA PKCα PKCβ1 PKCβ2 Raf ALK RET INSR KDR ROS1 ABL EGFR FGFR2 HER2 IGF1R JAK1 KIT MET PDFGRβ RON SRC AKT1 AuroraA CDK1 CDK2 MEK1 PKA PKCα PKCβ1 PKCβ2 Raf-1 Cell-free kinase inhibition assay ROS1 MET RON

20 Defining second generation: Potency Mok et al Can Treat Report 2017

21 Ceritinib: Higher potency Fribouler et al Cancer Discovery 2014

22 Defining second generation: Targeting resistant mutations Alectinib on resistant mutation 1151T insertion affects ATP affinity L1196M gatekeeper mutation to prevent access of crizotinib into the binding pocket G1202R solvent front mutation altering crizotinib binding C1156Y, L1152R, G1296A, F1174L other mutations reported in the literature

23 Ceritinib on resistant gene Mok et al Can Treat Report 2017

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25 The pump P-glycoproteins are ATP-driven pumps drugs out of the cells. Presence of P-gp in brain endothelial cell restrict permeability of hydrophobic compound. Prevent neurotransmitters from entering the brain (low lipid solubility and lack of specific transport carriers)

26 Defining second generation: Better CNS penetration Alectinib is a lesseffective substrate for drug efflux proteins such as Able to achieve higher intra-csf drug levels One report up to 87% of CNS penetration rate Baik et al JTO 2015

27 Ceritinib

28 ASCEND 4 Eligibility criteria: ALK-positive locally advanced/metastat ic non-squamous NSCLC No prior treatment for advanced disease R A N D O M I S E Ceritinib 750mg (n=174) Pemetrexed/cisplatin OR pemetrexed/carboplati n q3w (n=174) Pemetrexed q3w Primary endpoint = PFS Soria et al Lancet 2017

29 ASCEND 4 Soria et al Lancet 2017

30 ASCEND 8: Randomized PK study on lower dose with food Cho et al JTO 2017

31 ASCEND 8 Cho et al JTO 2017

32 DOR and PFS by BIRC Assessment DOR Ceritinib 450 mg fed (N = 32) Ceritinib 600 mg fed (N = 30) Ceritinib 750 mg fasted (N = 28) Events, n (%) 6 (18.8) 6 (20.0) 11 (39.3) Patients censored, n (%) Ongoing without event or death Median duration of response, months (95% CI) Estimated 12-month DOR rate, % (95% CI) PFS 26 (81.2) 23 (71.9) 16.4 ( ) 74.6 ( ) Ceritinib 450 mg fed (N = 41) 24 (80) 22 (73.3) NE (6.9-NE) 72.5 ( ) Ceritinib 600 mg fed (N = 40) 17 (60.7) 17 (60.7) 10.4 (7.1-NE) 42.5 ( ) Ceritinib 750 mg fasted (N = 40) Events, n (%) 12 (29.3) 13 (32.5) 17 (42.5) Patients censored, n (%) Ongoing without event or death Median progression-free survival, months (95% CI) Estimated 15-month PFS rate, % (95% CI) 29 (70.7) 26 (63.4) 17.6 (8.5-NE) 66.4 ( ) 27 (67.5) 23 (57.5) NE (8.3-NE) 58.0 ( ) 23 (57.5) 21 (52.5) 10.9 (6.3-NE) 41.0 ( ) Δ Efficacy-analysis set Cho et al ESMO Asia 2017

33 Should we use Ceritinib 450mg daily with food as standard first line therapy?

34 Alectinib

35 J-ALEX Phase III Study Design Key Entry Criteria Stage IIIB/IV or recurrent ALK-positive NSCLC ALK centralized testing (IHC and FISH or RT-PCR) ECOG PS measurable lesion assessed by investigator Treated/asymptomatic brain metastases allowed 1 prior chemotherapy R 1:1 Alectinib 300 mg BID PO, 28-day cycle (N=100) Crizotinib 250 mg BID PO, 28-day cycle (N=100) Endpoints Primary - PFS assessed by IRF* Secondary - OS - ORR - PK - QOL - CNS PFS - Safety *IRF Independent Review Facility Stratification factors: Clinical stage (IIIB/IV vs. Recurrent) Prior chemotherapy (0 vs. 1) ECOG PS (0/1 vs. 2) JapicCTI Hiroshi Nokihara ASCO 2016

36 J-ALEX: PFS Alectinib (N=103) Crizotinib (N=104) Events, n (%) 25 (24.3%) 58 (55.8%) Median, mo [95% CI] NR [ NR] 10.2 [ ] P-value < HR [ % CI] 0.34 [ ] Hida et al Lancet 2017

37 Global ALEX study (with differences from J-ALEX) KEY ELIGIBILITY Advanced or metastatic ALK+ NSCLC ALK+ by central IHC testing Treatment-naïve ECOG PS 0 2 Measurable disease Asymptomatic brain metastases allowed R A N D O M I Z E N=286 Alectinib 600mg BID PO NO CROSSOVER per protocol Crizotinib 250mg BID PO ENDPOINTS Primary PFS (RECIST 1.1) by investigator review Secondary PFS by IRC Time to CNS progression ORR, DOR OS Safety and tolerability Patient-reported outcomes Randomized 1:1 Stratification factors: ECOG PS (0/1 vs 2) Race (Asian vs non-asian) Brain metastases (present vs absent) IHC, immunohistochemistry; ECOG PS, Eastern Cooperative Oncology Group performance status; PO, by mouth; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; IRC, independent review committee; ORR, objective response rate; DOR, duration of response; OS, overall survival Peter and Mok NEJM 2017

38 ALEX Study: PFS Peter and Mok NEJM 2017

39 ALEX: Toxicity profile Peter and Mok NEJM 2017

40 Highly effective systemic therapy for CNS disease Peter and Mok et al NEJM 2017

41 G-ALEX: PFS of alectinib vs crizotinib in patients with and without BM *investigator-assessed; All patients with CNS metastases at baseline, irrespective of radiotherapy Peter and Mok NEJM 2017

42 G-ALEX: Time to CNS progression by prior brain RT* Gadgeel et al. ESMO 2017;

43 ALESIA: STUDY DESIGN Stage IIIB/IV ALK+ NSCLC Asian patients Treatment naïve ECOG PS 0 2 Central ALK testing (Ventana IHC) Stratification ECOG PS (0 /1 vs 2) Baseline CNS metastases (yes vs no) N=187 1 Primary endpoint Key secondary endpoints Investigator-assessed PFS PFS by IRC Zhou et al ESMO 2018 R 2:1 Alectinib 600mg twice daily (n=125) Crizotinib 250mg twice daily (n=62) 2 CNS ORR Time to CNS progression (IRC RECIST v1.1) Investigator-assessed ORR and DoR OS Safety and tolerability Quality of life Pharmacokinetics No crossover permitted DoR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status IHC, immunohistochemistry; IRC, Independent Review Committee; ORR, objective response rate OS, overall survival; RECIST, Response Evaluation Criteria in Solid Tumors

44 PROGRESSION-FREE SURVIVAL (INVESTIGATOR) Primary endpoint 100 Alectinib (n=125) Crizotinib (n=62) Censored Progression-free survival, % NE months 0 Day Time (months) Alectinib (n=125) Crizotinib (n=62) Patients with event, n (%) 26 (20.8) 37 (59.7) Median PFS, months (95% CI) HR (95% CI) P-value (log-rank test) NE (20.3 NE) 0.22 ( ) P< ( ) Primary data cut-off: 31 May, 2018 Median duration of follow up (alectinib vs crizotinib): 16.2 vs 15.0 months The p-values presented for the efficacy endpoints are descriptive only NE, not estimable

45 TIME TO CNS PROGRESSION (IRC) A competing risk analysis with CNS progression, non-cns progression and death as competing events was conducted; for each patient, only the first event was counted 100 Cumulative incidence* (%) Alectinib (n=125) Crizotinib (n=62) 35.5% (95% CI ) 7.3% (95% CI ) Alectinib (n=125) Crizotinib (n=62) Patients with event, n (%) 12 (9.6) 22 (35.5) Cause-specific HR (95% CI) P-value (log-rank test) 0.14 ( ) P< Time (months) *Cumulative incidence of CNS progression without prior non-cns progression or death Primary data cut-off: 31 May, 2018; IRC by RECIST v1.1 The p-values presented for the efficacy endpoints are descriptive only

46 Three trials with differences in design J-ALEX Global ALEX ALESIA Sample size Age Stage IV 74% (+ 23% recurrence) 96% 91% Never smoker 56% 63% 69% Prior chemo 36% 0% 8.5% CNS met 16% 40% 36% Randomization 1 to 1 1 to 1 2 to 1 Race All Japanese 46% Asian All Asian Stratification Exclude CNS met Include CNS met Include CNS met Dose 300mg bd 600mg bd 600mg bd Prior RT to brain NA 15.5% 7% Primary endpoint PFS by IRC PFS by investigator PFS by investigator

47 No difference in key outcome J-ALEX (HR 0.34) Global ALEX (HR 0.47) Primary endpoint Progression-free survival, % ALESIA (HR 0.22) Alectinib (n=125) Crizotinib (n=62) Censored NE 11.1 months 0 Day Time (months)

48 I am better than you! I am better than you! I am better than you! You are very annoying Alectinib Crizotinib

49 ALTA-1L: Phase 3, Open-label, Randomized, Multicenter, Study (NCT ) Stage IIIB/IV ALK+ NSCLC Enrollment based on local ALK testing No prior ALK inhibitor 1 prior systemic therapy for locally advanced/metastatic NSCLC Randomized 1:1 Brigatinib 180 mg qd with 7-day lead-in at 90 mg Stratified by: Brain metastases at baseline (y/n) Prior chemotherapy for locally advanced or metastatic disease (y/n) Crizotinib 250 mg bid Disease assessment every 8 weeks, including brain MRI for all patients Primary endpoint: Blinded independent review committee (BIRC) assessed PFS per RECIST v1.1 BIRC-assessed PD* Intolerable toxicity Other reasons for discontinuation Key secondary endpoints: Confirmed ORR, confirmed intracranial ORR, intracranial PFS, OS, safety, and tolerability Statistical considerations: ~270 total patients (198 events); 135 in each arm to detect a 6-month improvement in PFS (HR=0.625), assuming: 10-month PFS in crizotinib arm 2 planned interim analyses at 99 (50%) and 149 (75%) total expected events Trial fully accrued in August 2017 (N=275) *Arm B crossover to brigatinib permitted at BIRC-assessed PD First interim analysis: A total of 99 PFS events are included According to the prespecified O Brien-Fleming Lan-DeMets alpha spending function, a 2-sided P value of was used to define the threshold for significance

50 Brigatinib met the prespecified threshold for statistical superiority vs crizotinib Primary Endpoint: BIRC-Assessed PFS Treatment No. (%) of Patients With Events Median PFS (95% CI) 1-Year PFS, % (95% CI) Brigatinib (n=137) 36 (26) NR (NR NR) 67 (56 75) Crizotinib (n=138) 63 (46) 9.8 months ( ) 43 (32 53) Investigator-assessed median PFS was NR (95% CI, NR NR) in the brigatinib arm and 9.2 months (95% CI, months) in the crizotinib arm (HR, 0.45 [95% CI, ]; log-rank P=0.0001) 1-year OS probability: brigatinib, 85% (95% CI, 76% 91%); crizotinib, 86% (77% 91%)

51 Intracranial PFS in Patients With Any Brain Metastases at Baseline Treatment Brigatinib (n=43) Crizotinib (n=47) Median Intracranial PFS (95% CI) 1-Year PFS Probability, % (95% CI) NR (11.0 NR) 67 (47 80) 5.6 months ( ) 21 (6 42)

52 Ongoing phase III studies Drug Ensartinib vs crizotinib Lorlatinib vs crizotinib Sample size Primary endpoint Study starting date 402 PFS June PFS April 2017 Clinical trial number NCT NCT

53 Resistance

54 Mechanisms of resistances ALK TKIs ALK resistance mutations Bypass pathways activation Histological transformation CNS metastasis

55 Preclinical TKI activity against ALK point mutants ALK Mutation Type And New ALK TKI Efficacy 1st gen 2nd gen 3rd gen Crizotinib Alectinib Brigatinib Ceritinib Lorlatinib G1123S Res Sens N/D Res N/D 1151Tins Res Sens Sens Res Sens L1152P/R Res Sens N/D Res Sens C1156Y/T Res Sens Sens Res Sens I1171T/N Res Res Sens Sens N/D F1174C/L/V Res Sens Sens Res Sens V1180L Res Res N/D Sens N/D L1196M Res Sens Sens Sens Sens L1198F Sens Res Res Res Res G1202R Res Res Sens Res Sens S1206C/Y Res Sens Res Sens Sens F1245C Res N/D Sens Sens N/D G1269A/S Res Sens Sens Sens Sens Adopted from Lovly, ELCC 2016; Friboulet Cancer Disc 2014, Gainor Cancer Disc 2016, Mologni, Oncotarget 2015

56 Spectrum of ALK resistance mutations detected from tumor or liquid biopsy in Lorlatinib phase 2 study (Shaw et al, AACR 2018) cfdna analysis: - 45/190 patients (24%) with 1 or more ALK kinase domain mutations - 75 mutations detected (used for the frequency denominator) 17 L1196M % 6 F1174C/L/V 14.7% G1202R/del 25.0% 139 C1156Y D1160H D1203N E1129V E1161D E1210K/Q F1174C/L/V a F1245C G1128A No Mutation 1 ALK G1202R/del Mutation >1 ALK I1171N/S/T Mutation Other G1269A L1122V L1196M b L1198F N1335K P1213H P1329S R1113Q R1192P T1151K T1151M V1180L Tumor tissue analysis (archival or de novo): - 40/191 (21%) patients with 1 or more ALK kinase domain mutations - 58 mutations detected (used for the frequency denominator) G1202R/del 27.6% F1174C/L/V 17.2% 124 No Mutation 1 ALK Mutation >1 ALK Mutation Other C1156Y D1160H D1203N E1129V E1161D E1210K/Q F1174C/L/V F1245C G1128A G1202R/del G1269A I1171N/S/T L1122V L1196M b L1198F N1335K P1213H P1329S R1113Q R1192P T1151K T1151M V1180L a No mutation includes samples with no cfdna was detected; b Other includes samples which failed analysis, were uninformative or not analyzed.

57 Bypass pathways reported in literature as resistance to ALK TKIs ALK TKI Bypass Pathway Reference Crizotinib EGFR Activation Katayama et al 2012 Doebele et al 2012 Sasaki et al 2011 ckit amplification Katayama et al 2012 IGF-1R Signaling Lovely et al 2014 SRC Signaling Crystal et al 2014 Crizotinib/Ceritinib MAPK Pathway Activation Doebele et al 2012 Crystal et al 2014 RAS Pathway Dardaei et al 2018 Alectinib MET amplification Gouji et al

58 ASCEND-9: phase II study, of ceritinib after alectinib (300 mg BID) in Japanese patients 100 Ceritinib 750mg (n=17) Ceritinib demonstrated clinical benefit in Japanese patients who progressed on alectinib (alectinib only [n=16]; alectinib and crizotinib [n=4]) Median PFS: 3.7 months Median DoR: 6.3 months ORR: 25% (5/20 patients) Best % change from baseline (measurable lesions) Prior therapies: ALECENSA ALECENSA + crizotinib Chemotherapy * * *% change in target lesion available but contradicted by overall lesion response = PD (contradicting assessment represents the only valid post-baseline assessment) Ceritinib is not licenced for use post-alecensa Horinouchi et al. WCLC 2017; Hida et al. Cancer Sci 2018

59 ALTA II Study Open-label, randomized, multicenter, international phase II study to prospectively assess brigatinib efficacy and safety at 90 mg once daily and 180 mg once daily (with lead-in) in patients with crizotinibrefractory advanced ALK-positive NSCLC. Primary Efficacy Endpoint: confirmed ORR per RECIST v1.1 (per investigator) Secondary endpoints: confirmed ORR (per central IRC)

60 Results response Efficacy Parameter Investigator Assessed 90 mg once daily (n = 112) 90 mg 180 mg once daily (n = 110) 90 mg once daily (n = 112) IRC Assessed a 90 mg 180 mg once daily (n = 110) Confirmed ORR, n (%) [97.5% CI] b or [95% CI], % 50 (45) 61 (55) 55 (49) [34-56] b [44-65] b [40-59] 59 (54) [44-63] Confirmed CR, n (%) 2 (2) 6 (5) 4 (4) 6 (5) Confirmed PR, n (%) 48 (43) 55 (50) 50 (45) 54 (49) DCR, n (%) [95% CI] 91 (81) [73-88] 95 (86) [79-92] 87 (78) [69-85] 92 (84) [75-90] Median DOR, months [95% CI] 12.0 [7.4-NR] 13.8 [9.2-NR] 13.8 [7.4-NR] 15.6 [9.7-NR] The IRC-assessed confirmed ORR was 49% in the 90-mg arm and 54% in the 90-mg 180-mg once daily arm The IRC-assessed median DOR was 13.8 months in the 90-mg once daily arm and 15.6 months in the 90-mg 180-mg once daily arm

61 PFS by Arm Probability of PFS (%) Median PFS exceeds 1 year (12.9 months) with 180 mg brigatinib Events / Total (%) 1-Year PFS Probability, % (95% CI) Median PFS (95% CI) Hazard Ratio (95% CI) 90 mg qd 50/112 (45) 180 mg qd* 31/110 (28) 39 (27 52) 54 (37 68) 9.2 months ( ) 12.9 months (11.1 not reached) 0.55 ( ) * 180 mg qd with 7-day lead-in at 90 mg Study was not designed to compare treatment arms statistically; however, post hoc comparisons were performed to support dose selection

62 Brigatinib CNS Antitumor Activity by Arm mg qd 180 mg qd 40 Best Change From Baseline in Target Lesions (%) * * * Progressive disease Stable disease ǁ Partial response Complete response Dotted line at 30% indicates threshold for partial response per RECIST v1.1 * Single response awaiting confirmation Includes patients with active brain metastases at baseline (90 mg qd, n=16; 180 mg qd, n=14) 180 mg qd with 7-day lead-in at 90 mg ǁ Category includes single responses that were not confirmed Last scan date: February 17, 2016 Brigatinib Pivotal Randomized Phase 2 Trial Presented by: Dr. Dong-Wan Kim

63 Brigantinib: a retrospective study of brigatinib in patients pretreated with alectinib Brigatinib demonstrated clinical activity in heavily pre-treated patients who had previously received ALECENSA (n=22) Collaboration among Massachusetts General hospital, University of California Irvine, and MSKCC Baseline characteristics Lines of systemic therapy before alectinib Intervening lines of therapy between alectinib and brigatinib Number of ALK TKIs prior to brigatinib All patients (N=22) 3 (14%) 12 (55%) 6 (27%) 1 (5%) 19 (86%) 2 (9%) 1 (6%) 5 (23%) 13 (59%) 4 (18%) Progression-free survival (%) Median PFS: 4.4 months Median DoR: 5.7 months ORR: 17% (3/18 patients*) Time (months) Number at risk *18 patients had measurable disease at baseline Lin et al, J ThoracOncol 2018; 13:

64 Brigatinib-2002: phase II study of brigatinib in patients pre-treated with alectinib or ceritinib Locally advanced Stage IIIB or Stage IV NSCLC ALK+ disease confirmed by IHC or FISH Progressive disease on prior treatment with alectinib or ceritinib Brigatinib 180mg QD 1 2 Primary endpoint Confirmed ORR Secondary endpoints DoR ORR PFS DCR TTR OS iorr Duration of intracranial response ipfs Safety PROs Clinicaltrials.gov (NCT )

65 54 patients (41 ALK positive, 13 ROS1) 72% with CNS met All had prior TKIs MTD not reached Shaw et al Lancet Oncology 2017

66 Response rate RR 46% for ITT RR 41% for 2 or more line of TKI

67 CNS response RR 31%

68 Schema of Lorlatinib Phase 2 design Solomon et al, Lancet Oncol 2018 in press

69 Efficacy in ALK+ Patients Previously Treated with 2G ALK TKIs (EXP3B and EXP4 5) Best Change From Baseline (%) Overall a,b Complete response Partial response Stable disease Progressive disease (PD) Indeterminate Off treatment or PD occurred EXP3B: 1 non-crizotinib TKI ± chemo (n=27) ORR, n/n (%) (95% CI) IC ORR, n/n (%) (95% CI) Median PFS, mo (95% CI) 9/27 (33) (16, 54) 5/12 (42) (15, 72) 5.5 (2.9, 9.0) Best Change From Baseline (%) Overall a,b Complete response Partial response Stable disease Progressive disease (PD) Indeterminate Off treatment or PD occurred EXP4 5: 2 prior ALK TKIs ± chemo (n=111) ORR, n/n (%) (95% CI) IC ORR, n/n (%) (95% CI) Median PFS, mo (95% CI) 43/111 (39) (30, 49) 40/83 (48) (37, 59) 6.9 (5.4, 9.5) Solomon BJ, et al. J Thorac Oncol:2017;12:abs1756 (Data cut-off: 15 Mar 2017). a Patients with at least one on-study target lesion assessment as per independent central review were included. If any procedure was different and not interchangeable from the procedure at screening, the percent change from baseline could not be calculated and is not displayed. b Complete response was defined as the disappearance of all target lesions; when nodal disease was included in target lesions, reversion to normal node size (<10 mm) prevented the percent change from baseline from reaching 100%. Some patients with a total change from baseline of 100% are shown as partial responses due to the inclusion of non-target lesions in the summary. 68

70 Cumulative incidence of CNS progression, non-cns progression, and death in patients with 1 prior 2nd-gen ALK TKI (EXP3B 5) In EXP3B and EXP4 5, IC-ORR* was 46% (95% CI 19 75) and 48% (95% CI 37 60), and median IC-DOR was NR (95% CI 4 mos NR) and 15 mos (95% CI 11 NR), respectively. Cumulative incidence function Patients with baseline CNS mets (n=94) CNS PD Non-CNS PD Death Time (months) Cumulative no. of events CND PD Non-CNS PD Death For patients with baseline CNS mets, the probabilities of non- CNS PD was higher than CNS PD (35% vs 23% at 12 months). Cumulative incidence function Patients without baseline CNS mets (n=45) CNS PD Non-CNS PD Death Time (months) Cumulative no. of events CNS PD Non-CNS PD Death Patients without baseline CNS mets had a higher probability of non-cns PD than CNS PD (55% vs 12% at 12 months). Bauer et al, WCLC 2018

71 First line Summary Both Alectinib and Brigatinib is superior to crizotinib in PFS and CNS control Phase III studies on other second/third generation TKI are ongoing Resistance Multiple mechanism of resistance Brigatinib: promising phase II data on Alectinib failure Loratinib: promising phase I /II data

72 Populated Landscape