INNOVATION IN LUNG CANCER MANAGEMENT. Federico Cappuzzo Department of Oncology-Hematology, AUSL della Romagna, Ravenna, Italy

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1 INNOVATION IN LUNG CANCER MANAGEMENT Federico Cappuzzo Department of Oncology-Hematology, AUSL della Romagna, Ravenna, Italy

2 FIRST-LINE THERAPY FOR METASTATIC NSCLC IN 216 Stratification for EGFR, ALK and histology EGFRm ALK+ EGFR WT/ALKnon-squamous EGFR WT/ALKsquamous EGFR TKI Crizotinib Platinum doublet + bevacizumab OR platinum + pemetrexed +/- bevacizumab Platinum-based doublet Novello S, et al., Ann Oncol 216 ; NSCLC, NCCN guidelines 216

3 OPTIONS FOR METASTATIC NSCLC IN 218 5% 3% 2% EGFR WT/ALK - / ROS1 - /PD-L1 - EGFR WT/ALK - / ROS1 - /PD-L1 high (>5%) EGFR + ALK + ROS1 + BRAF V6E 1 st Platinum-based chemotherapy PD-1 inhibitor Pembrolizumab EGFR-TKIs Erlotinib Afatinib Gefitinib ALK inhibitor Alectinib Crizotinib Ceritinib ALK/ROS1 inhibitor Crizotinib Dabrafenib + trametinib 2 nd Immune checkpoint inhibitors Nivolumab or atezolizumab Platinum-based chemotherapy EGFR TKIs Osimertinib Platinum-based Chemotherapy ALK inhibitor Brigatinib Chemotherapy Systemic therapy Chemotherpy Immune checkpoint inhibitors* Clinical trials Department of Oncology-Hematology, AUSL della Romagna, Ravenna, Italy.

4 O S, % KEYNOTE 24 study design IMMUNOTHERAPY SUPERIOR TO PLATINUM-BASED CHEMOTHERAPY In patients with high levels of PD-L1 expression Key eligibility criteria Untreated stage IV NSCLC PD-L1 TPS 5% ECOG PS -1 No activating EGFR mutation or ALK translocation No untreated brain metastases No active autoimmune disease requiring systemic therapy Pembrolizumab 2 mg IV Q3W (2 years) R 1:1 N=35 Platinum-doublet chemotherapy (4-6 cycles) Key endpoints Primary: PFS (RECIST v1.1 per blinded, independent central review) Secondary: OS, ORR, and safety Exploratory: DOR PD a Pembrolizumab 2 mg IV Q3W (2 years) Overall survival % 54.8% Events, n HR (95% CI) Pembrolizumab Chemotherapy % 34.5% (.47.86) P =.2 a Median (95% CI) 3. mo (18.3 mo NR) 14.2 mo (9.8 mo 19. mo) N o. a t ris k T im e, m o n th s P em bro C h e m o a To be eligible for crossover, progressive disease (PD) had to be confirmed by blinded, independent central radiology review and all safety criteria had to be met. From The New England Journal of Medicine, Reck M, et al., Pembrolizumab versus Chemotherapy for PD-L1 Positive Non Small-Cell Lung Cancer, 375 (19), Copyright 216 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

5 OS (%) IMMUNOTHERAPY NOT SUPERIOR TO PLATINUM-BASED CHEMOTHERAPY In patients with low levels of PD-L1 expression Key eligibility criteria: Stage IV or recurrent NSCLC No prior systemic therapy for advanced disease No EGFR/ALK mutations sensitive to available targeted inhibitor therapy 1% PD-L1 expression a CNS metastases permitted if adequately treated at least 2 weeks prior to randomization Randomize 1:1 Nivolumab 3 mg/kg IV Q2W n = 271 Chemotherapy (histology dependent) b Maximum of 6 cycles n = 27 Tumor scans Q6W until wk 48 then Q12W Disease progression Disease progression or unacceptable toxicity Crossover nivolumab c (optional) Stratification factors at randomization: PD-L1 expression (<5% vs 5%) a Histology (squamous vs non-squamous) Primary endpoint: PFS ( 5% PD-L1+) d Secondary endpoints: PFS ( 1% PD-L1+) d OS ORR d OS ( 5% PD-L1+) CheckMate 26: Nivolumab vs Chemotherapy in First-line NSCLC Median OS, months (95% CI) Nivolumab n = (11.7, 17.4) Chemotherapy n = (1.7, 17.1) 1-year OS rate, % HR = 1.2 (95% CI:.8, 1.3) % in the chemotherapy arm had subsequent nivolumab therapy 43.6% in the nivolumab arm had subsequent systemic therapy Chemotherapy Nivolumab No. of patients at risk: Nivolumab Months Chemotherapy Socinski M, et al., Ann Oncol 216;27 suppl_6, LBA7_PR. Courtesy of Dr Mark Socinski All randomized patients ( 1% PD-L1+): HR = 1.7 (95% CI:.86, 1.33) SocinskiM et al. ESMO 216

6 OVERVIEW OF PHASE III STUDIES OF ANTI-PD1/PDL1 THERAPY In previously treated NSCLC Study arms CheckMate 17 1 CheckMate 57 1 KEYNOTE-1 2 OAK 3 Nivolumab vs. docetaxel Nivolumab vs. docetaxel Pembrolizumab 2 or 1 mg/kg vs docetaxel Atezolizumab vs. docetaxel Phase of study III III II/III III PD-L1 selected No No Yes (TPS* 1%) No Study size, n 272 (135 vs. 137) 582 (292 vs. 29) 133 (344 vs. 346 vs. 343) 85 in primary analysis (425 vs. 425) Histology, % Non-squamous Squamous Other/unknown Line of therapy, % 2L 3L >3L Other/unknown < < Minimum follow-up of latest data ~24 months ~24 months ~19 months ~19 months *Tumour proportion score (TPS) is the proportion of viable tumour cells showing partial or complete membrane PD-L1 expression; 1225 patients enrolled in total 1. Barlesi F, et al., ESMO 216; 2. Herbst, et al., ESMO 216; 3. Barlesi F, et al., ESMO 216

7 OS (%) OS (%) PHASE III STUDIES OF NIVOLUMAB IN PREVIOUSLY TREATED NSCLC OS (3 YEARS MINIMUM FOLLOW-UP) CheckMate 17 (SQ NSCLC) CheckMate 57 (non-sq NSCLC) 1 8 Nivolumab (n=135) Docetaxel (n=137) HR (95% CI):.62 (.48,.8) 1 8 Nivolumab (n=292) Docetaxel (n=29) HR (95% CI):.73 (.62,.88) y OS = 42% 4 Δ18% 2-y OS = 23% 2 1-y OS = 24% 3-y OS = 16% Δ15% Δ1% 2-y OS = 8% 3-y OS = 6% Months 4 2 Δ12% 1-y OS = 39% 1-y OS = 51% 2-y OS = 16% 2-y OS = 29% Δ13% 3-y OS = 9% 3-y OS = 18% Δ9% Months No. of patients at risk Nivolumab No. of patients at risk Nivolumab Docetaxel Docetaxel Felip E, et al., Presented at ESMO 217; poster 131PD. With permission from Prof Enriqueta Felip

8 PEMBROLIZUMAB VERSUS DOCETAXEL In pretreated NSCLC with PD-L1 expression: Survival results of the KEYNOTE 1 trial PD-L1 score 5% or greater PD-L1 score 5% or greater Study population Study population Reprinted from The Lancet, 216; 387(127), Herbst RS, et al., Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-1): a randomised controlled trial; 154-5, Copyright 216, with permission from Elsevier.

9 Overall Survival (%) ATEZOLIZUMAB VERSUS DOCETAXEL IN NSCLC: OAK TRIAL Overall survival, ITT (n = 85) Overall survival, ITT (n=85) Atezolizumab Docetaxel 12-mo OS 55% 41% 18-mo OS 4% HR,.73 a (95% CI,.62,.87) P =.3 Minimum follow up = 19 months Median 13.8 mo (95% CI, 11.8, 15.7) Median 9.6 mo (95% CI, 8.6, 11.2) 27% Months a Stratified HR. a Stratified HR. Reprinted from The Lancet, 389, Rittmeyer A, et al., Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial, Copyright 217, with permission from Elsevier.

10 Overall Survival (%) HIGH LEVELS OF PD-L1 EXPRESSION PREDICTS HIGHER OS BENEFIT WITH IMMUNOTHERAPY Atezolizumab in PD-L Pembrolizumab PD-L1 score 5% in PD-L1 or greater score 5% or higher 2 HR,.41 a (95% CI,.27,.64) P <.1 b Minimum follow up = 19 months Atezolizumab Docetaxel Median 8.9 mo (95% CI, 5.6, 11.6) Median 2.5 mo (95% CI, 17.5, NE) Months 1. Reprinted from The Lancet, 389, Rittmeyer A, et al., Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, openlabel, multicentre randomised controlled trial, Copyright 217, with permission from Elsevier. 2. Reprinted from The Lancet, 216; 387(127), Herbst RS, et al., Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-1): a randomised controlled trial; 154-5, Copyright 216, with permission from Elsevier.

11 EVIDENCE OF SURVIVAL BENEFIT IN PD-L1 NEGATIVE: OAK TRIAL RESULTS 16% 31% On-study Prevalence 55% 45% Subgroup TC3 or IC3 TC2/3 or IC2/3 TC1/2/3 or IC1/2/3 a TC and IC Median OS, mo Atezolizumab Docetaxel n = 425 n = % 2% 4% 6% 8% 1% 1% ITT a Significant benefit in PD-L1 negative with squamous and non-squamous histology Hazard Ratio a In favour of atezolizumab In favour of docetaxel a Stratified HR for ITT and TC1/2/3 or IC1/2/3. Unstratified HR for subgroups. TC, tumour cells; IC, tumour-infiltrating immune cells; OS, overall survival. Barlesi F, et al., Presented at ESMO 216; Abstract LBA44_PR

12 2-YEAR OS RATES OVERALL AND BY PD-L1 EXPRESSION LEVEL IN CHECKMATE 57 (NON-SQ NSCLC) Marginal benefit Relevant benefit In CheckMate 57, consistent with the primary analysis,2 PD-L1 expression level was associated with the magnitude of OS benefit at 2 years starting at the lowest level studied (1%) a Kaplan Meier estimates, with error bars indicating 95% Cls b For the comparison of the full Kaplan Meier survival curves for each treatment group Borghaei H, et al., Presented at ASCO 216; poster 925. Courtesy of Dr Hossein Borghaei

13 OS (%) NIVOLUMAB IMPROVES SURVIVAL OVER DOCETAXEL Irrespective of PD-L1 expression in squamous-cell lung carcinoma 1% PD-L1 Expression level 5% PD-L1 Expression level 1% PD-L1 Expression level mos (mo) mos (mo) mos (mo) Nivolumab Docetaxel Nivolumab Docetaxel Nivolumab Docetaxel 1 9 PD-L1 1% PD-L1 <1% PD-L1 5% PD-L1 <5% PD-L1 1% PD-L1 <1% Time (months) Time (months) Time (months) Nivolumab PD-L1+ Nivolumab PD-L1 Docetaxel PD-L1+ Docetaxel PD-L1 From N Engl J Med, Brahmer J, et al., Nivolumab versus Docetaxel in Advanced Squamous-Cell Non Small-Cell Lung Cancer, 373(2): Copyright 215 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

14 WHICH PATIENTS ARE NOT CANDIDATE FOR SECOND-LINE IMMUNOTHERAPY? Meta-analysis of trials with checkpoint inhibitors in patients with EGFR mutations Study Weight Hazard Ratio (95%CI) Hazard Ratio EGFR wild-type Checkmate %.66 (.51,.86) Keynote 1 52.%.66 (.55,.8) POPLAR 11.%.7 (.47, 1.4) Subtotal (95% CI) 89.%.66 (.58,.76) EGFR mutant Checkmate 57 6.% 1.18 (.69, 2.) Keynote 1 3.8%.88 (.45, 1.7) POPLAR 1.1%.99 (.29, 3.4) Subtotal (95% CI) 11.% 1.5 (.7, 1.55) Total (95% CI) 1.%.7 (.61,.8) Favours PD1/PDL1 inhibitor Favours docetaxel Reprinted from Journal of Thoracic Oncology, 12(2), Lee CK, et al., Checkpoint Inhibitors in Metastatic EGFR-Mutated Non Small Cell Lung Cancer A Meta-Analysis, 43-7, Copyright 217, with permission from Elsevier.

15 Patients with factor in OS subgroup (%) WHICH PATIENTS ARE NOT CANDIDATE FOR SECOND-LINE IMMUNOTHERAPY? Combination of clinical factors and PD-L1 expression in Checkmate OS 3 months OS >3 months <3 mo from last TX PD best resp. No maint. TX >5 sites with lesions Bone mets Liver mets Current/ former Never 1 <1% 1% 5% 1% Prior therapy Baseline disease site Smoking status ECOG PS PD-L1 expression a EGFR mut.-pos. Post-hoc, exploratory multivariate analysis suggested that nivolumab-treated patients with poorer prognostic features and/or aggressive disease when combined with lower or no tumour PD-L1 expression may be at higher risk of death within the first 3 months These included the following known prognostic factors: <3 months since last treatment, PD as best response to prior treatment, and ECOG PS=1 Peters S, et al., Presented ar WCLC 216. Abstract OA3. With permission from Dr Federico Cappuzzo

16 EGFR TKIS VERSUS CHEMOTHERAPY IN EGFR MUT+ NSCLC Study # Treatment RR % mpfs (mos) PFS HR P-value mos (mos) OS HR P-value IPASS * (Mok TS, et al. N Engl J Med 29;361:947 57) Gefitinib CBDCA + TXL < First SIGNAL * (Lee JS, et al. J Thor Oncol 29; 4(Suppl):PRS.4) Gefitinib CDDP+ GEM NR WJTOG 345 (Mitsudomi T, et al. Lancet Oncol 21;11:121 8) Gefitinib CDDP + TXT < NR NEJ 2 (Maemondo M, et al. N Engl J Med 21;362:238 8) Gefitinib CBDCA + TXL < OPTIMAL (Zhou C, et al. Lancet Oncol. 211; 12:735 42) Erlotinib CBDCA + GEM < EURTAC (Rosell R, et al. Lancet Oncol 212;13:239 46) Erlotinib Platinum Doublet < ENSURE (Wu Y-L, et al. J Thor Oncol 8:s63 Suppl. 2) Erlotinib CDDP + GEM <.1 NR NR NR NR LUX Lung 3 (Sequist LV, et al. J Clin Oncol 213;31: ) Afatinib CDDP + PEM LUX Lung 6 (Wu Y-L, et al. Lancet Oncol 214;15:213 22) Afatinib CDDP + GEM < *Shown data are restricted to EGFR mut+ population

17 ERLOTINIB VERSUS ERLOTINIB+BEVACIZUMAB As first-line therapy in EGFR mut+ NSCLC: Phase IIR study Chemotherapy-naive stage IIIB-IV or postoperative recurrence Non-squamous NSCLC Activating EGFR mutations Exon 19 deletion Exon 21 L858R Age 2 years PS -1 No brain metastasis R 1:1 Erlotinib 15 mg/day + Bevacizumab 15 mg/kg q3w (N=77) Erlotinib 15 mg/day (N=75) PD PD Primary endpoint: PFS Secondary endpoints: OS, ORR, QoL, symptoms improvement FACT-L scale and safety Seto T, et al., Lancet Oncol 214;15(11):

18 ERLOTINIB VERSUS ERLOTINIB+BEVACIZUMAB As first-line therapy in EGFR mut+ NSCLC: PFS Reprinted from The Lancet Oncology, 15(11),Seto T, et al., Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study, , Copyright 214, with permission from Elsevier.

19 Probability of progression-free survival OSIMERTINIB THE NEW STANDARD OF CARE IN PRETREATED EGFR T79M+ AURA 3 trial design Key eligibility criteria 18 years ( 2 years in Japan) Locally advanced or metastatic NSCLC Evidence of disease progression following first-line EGFR-TKI therapy Documented EGFRm and central confirmation of tumour EGFR T79M mutation from a tissue biopsy taken after disease progression on first line EGFR-TKI treatment WHO performance status of or 1 No more than one prior line of treatment for advanced NSCLC No prior neo-adjuvant or adjuvant chemotherapy treatment within 6 months prior to starting first EGFR-TKI treatment Stable* asymptomatic CNS metastases allowed PFS in the study population R a n d o m i s e 2:1 Osimertinib Platinum-pemetrexed Osimertinib 8 mg orally (n=279) Platinum-pemetrexed (n=14) Pemetrexed 5 mg/m 2 + carboplatin AUC5 or cisplatin 75 mg/m 2 q3w for up to 6 cycles + optional maintenance pemetrexed # Median PFS, months (95% CI) HR (95% CI) 1.1 (8.3, 12.3).3 (.23,.41) 4.4 (4.2, 5.6) p<.1 Primary endpoint PFS by investigator assessment (RECIST 1.1) Secondary and exploratory endpoints Overall survival Objective response rate Duration of response Disease control rate Tumour shrinkage BICR-assessed PFS Patient reported outcomes Safety and tolerability Optional crossover Protocol amendment allowed patients on chemotherapy to begin post-bicr confirmed progression open-label osimertinib treatment No. at risk Osimertinib Platinum-pemetrexed Months Analysis of PFS by BICR was consistent with the investigator-based analysis: HR.28 (95% CI.2,.38), p<.1; median PFS 11. vs 4.2 months. From The N Engl J Med, Mok T, et al., 376: Copyright 217. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

20 OSIMERTINIB THE NEW STANDARD OF CARE IN FIRST-LINE EGFRM+ NSCLC: FLAURA TRIAL DESIGN Primary endpoint: PFS based on investigator assessment (according to RECIST 1.1) Patients with locally advanced or metastatic NSCLC Key inclusion criteria 18 years* WHO performance status /1 Exon 19 deletion / L858R (enrolment by local # or central EGFR testing) No prior systemic anticancer / EGFR-TKI therapy Stable CNS metastases allowed Stratification by mutation status (Exon 19 deletion / L858R) and race (Asian / non-asian) Osimertinib 8 mg p.o. qd (n=279) Randomised 1:1 EGFR-TKI SoC ; Gefitinib 25 mg p.o. qd or Erlotinib 15 mg p.o. qd (n=277) The study had a 9% power to detect a hazard ratio of.71 (representing an improvement in median PFS from 1 months to 14.1 months) at a two-sided alpha-level of 5% Secondary endpoints: objective response rate, duration of response, disease control rate, depth of response, overall survival, patient reported outcomes, safety RECIST 1.1 assessment every 6 weeks until objective progressive disease Crossover was allowed for patients in the SoC arm, who could receive openlabel osimertinib upon central confirmation of progression and T79M positivity Soria JC, et al., N Engl J Med 218;378(2):113 25

21 FLAURA: PFS AND OS From N Engl J Med, Soria JC, et al., Osimertinib in Untreated EGFR-Mutated Advanced Non Small-Cell Lung Cancer, 378: Copyright 218 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

22 FLAURA: PFS IN PATIENTS WITH AND WITHOUT BMS AT STUDY ENTRY With CNS metastases (n=116) Without CNS metastases (n=44) CNS progression events occurred in 17 (6%) vs. 42 (15%) patients receiving osimertinib vs. SoC (all patients) Ramalingam S, et al., Presented at ESMO 217. Abstract LBA2_PR. Courtesy of Dr Suresh S. Ramalingam.

23 PFS probability (%) CRIZOTINIB FIRST-LINE STANDARD OF CARE UP TO 217 IN ALK+ NSCLC PROFILE 114 study design Multicenter, randomised open-label Phase III study Key entry criteria ALK-positive by central FISH testing a Locally advanced, recurrent, or metastatic nonsquamous NSCLC No prior systemic treatment for advanced disease ECOG PS 2 Measurable disease Treated brain metastases allowed R a n d o m i s e 1:1 N=334 Crizotinib 25 mg bid po, continuous dosing (N=167) Pemetrexed 5 mg/m 2 + cisplatin 75 mg/m 2 OR carboplatin AUC 5 6 q3w for 6 cycles (N=167) Crizotinib continued after PD if ongoing clinical benefit Crossover to crizotinib permitted after PD b Randomised stratified by: ECOG PS (/1, 2) Race (Asian, non-asian) Brain metastases (present, absent) a ALK status determined using standard ALK break-apart FISH assay; b Assessed by independent radiologic review. PFS by independent radiologic review (all patients) PFS by Independent Radiologic Review (All Patients) At risk (ALL) Crizotinib Chemotherapy a 1-sided stratified log-rank test Crizotinib (N=172) All patients Chemo. (N=171) Events, n (%) 1 (58) 137 (8) Median, mo HR (95% CI).45 (.35.6) P a < Time (months) a 1-sided stratified log-rank test. From N Engl J Med, Solomon B,et al., First-line crizotinib versus chemotherapy in ALK-positive lung cancer, 371, Copyright 214 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

24 J-ALEX Phase III study comparing alectinib versus crizotinib in ALK+ NSCLC Key entry criteria Stage IIIB/IV or recurrent ALK+ NSCLC ALK centralised testing (IHC and FISH or RT-PCR) ECOG PS -2 1 measurable lesion assessed by investigator Treated /asymptomatic brain metastases allowed 1 prior chemotherapy R 1:1 Alectinib 3 mg BID PO, 28-day cycle (N=1) Crizotinib 25 mg BID PO, 28-day cycle (N=1) Primary endpoint: PFS assessed by IFR* Secondary endpoints: OS, ORR, PK, QoL, CNS PFS, and safety Nokihara H, et al., J Clin Oncol 34, 216 (suppl; abstr 98) Presented at ASCO 216

25 PFS estimate J-ALEX PRIMARY ENDPOINT: PFS BY IRF (ITT) 1..8 Alectinib (n=13) Crizotinib (n=14) HR=.34 (.17.71) p<.1.6 NR (2.3 NR) ( ) Time (months) Reprinted from Lancet 217; 39 (189), Hida T, et al., Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an openlabel, randomised phase 3 trial, Copyright 217, with permission from Elsevier.

26 ALECTINIB IS SUPERIOR TO CRIZOTINIB IN ALK+ NSCLC PFS in ALEX trial Key eligibility Advanced or metastatic ALK+ NSCLC ALK+ by central IHC testing Treatment-naïve ECOG PS -2 Measurable disease Asymptomatic brain metastases allowed R a n d o m i s e N=286 Alectinib 6 mg bid po Primary endpoint NO CROSSOVER PFS by IRC per protocol Time to CNS progression ORR, DOR Crizotinib OS 25 mg bid po Safety and tolerability Stratification factors: Patient-reported outcomes ECOG PS (/1 vs. 2) Race (Asian, non-asian) Brain metastases (present vs. absent) PFS (RECIST 1.1), by investigator review Secondary endpoints HR=.47 P<.1 From N Engl J Med, Peters S, et al., Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer, 377: Copyright 217 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

27 ASCEND 4 CERITINIB VERSUS PLATIN-PEMETREXED As first-line therapy in ALK+ NSCLC Inclusion criteria Stage IIIB/IV ALK+ NSCLC by Ventana IHC test (central) Treatment-naive (no prior chemotherapy or ALK inhibitor) WHO PS -2 Neurologically stable brain metastases (symptomatic or not) R 1:1 Stratified randomisation: WHO PS Brain metastases Prior neoadjuvant/adjuvant chemotherapy Ceritinib 75 mg/day Daily oral dosing in fasted state Chemotherapy (Induction Investigator choice)*: Four cycles Pemetrexed 5 mg/m 2 + cisplatin 75 mg/m 2 or Pemetrexed 5 mg/m 2 + carboplatin AUC 5 6 CR, PR, SD Pemetrexed maintenance 5 mg/m 2 q21d PD (BIRC confirmed) Optional Ceritinib 75 mg PD (BIRC confirmed) Optional crossover to extension treatment *At the time when ASCEND-4 was designed and initiated, pemetrexed-platinum chemotherapy followed by pemetrexed maintenance was the standard of care in patients with non-squamous advanced NSCLC One cycle = 21 days BIRC, Blinded Independent Review Committee; CR, complete response; IHC, immunohistochemistry; PD, progressive disease; PR; partial response; PS, performance status; SD, stable disease; WHO, World Health Organization. Soria JC, et al., Lancet 217;389(172):

28 PFS probability (%) ASCEND 4 PRIMARY ENDPOINT: PFS BY BIRC Ceritinib demonstrated an estimated 45% risk reduction vs. chemotherapy Ceritinib (N=189) Chemotherapy (N=187) Events, n (%) 89 (47.1) 113 (6.4) Median (95% CI), months 16.6 (12.6, 27.2) 8.1 (5.8, 11.1) Hazard ratio (95% CI) =.55 (.42,.73) Stratified Log-rank p-value < Time (months) No. at risk Ceritinib Chemotherapy Reprinted from The Lancet, 389 (172), Soria JC, et al., First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study, Copyright 217, with permission from Elsevier.

29 CNS INVOLVEMENT IN NSCLC Higher incidence in EGFR mut+ or ALK+ All-comers incidence of BM 1,2 EGFR+ patients treated with first-generation TKI 3 5 ALK+ patients treated with crizotinib 6,7 BM 3% (25 4%) BM 4% (3 6%) BM 5% Incidence of BM is higher: Different tumour biology Lack of drug penetration Longer survival ALK, anaplastic lymphoma kinase; BM, brain metastases; CNS, central nervous system; EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor. 1. Sørensen JB, et al., J Clin Oncol 1988;6:1474 8; 2. Dempke W, et al. Anticancer Res 215;35: ; 3. Omuro AMP, et al., Cancer 25;13:2344 8; 4. Heon S, et al. Clin Cancer Res 21;16: ; 5. Lee YJ, et al., Cancer 21:116; ; 6. Shaw AT, et al. Lancet Oncol 211;12:14 12; 7. Camidge DR, et al., Nat Rev Clin Oncol 214;11:473 81; data presented at ASCO 215, by Soria J-C.

30 Proportion surviving PROGNOSTIC IMPACT OF EGFR MUTATION AND/OR ALK REARRANGEMENTS IN BMS Molecularly unselected NSCLC 1 Molecularly selected lung ADC GPA (n=65) GPA (n=455) GPA (n=664) GPA 1 (n=337) Time from start of BM treatment (months) Median survival in overall population 7 mos Median survival in EGFR mut+ /ALK + NSCLC 46 mos Clinical factors: Age, KPS, extracranial disease, number of BMs Clinical factors + EGFR mut+ and/or ALK + 1. Sperduto PW, et al., J Clin Oncol, 3(4), 212: ; Reprinted with permission American Society of Clinical Oncology. All rights reserved. 2. Sperduto PW, et al., JAMA Oncol 217;3(6):

31 CNS ACTIVITY OF 2 ND 3 RD GENERATION ALK-IS IN CRIZOTINIB-RESISTANT ALK+ NSCLCs Ceritinib, ASCEND 2 1 Alectinib, pooled analysis 2 NP28761/NP28673 RR 45% RR 64% Brigatinib, ALTA trial 3 9 mg once daily 18 mg once daily with 7-day lead-in at 9 mg Lorlatinib, Phase 1/2 4 RR 46% RR 67% RR 56% *Includes patients with active brain metastases at baseline (9 mg qd, n=16; 18 mg qd [with lead-in], n=14) 1. Crinò L, et al., J Clin Oncol 34(24), 216: Reprinted with permission American Society of Clinical Oncology. All rights reserved. 2. Gadgeel S, et al., J Clin Oncol 34(34), 216: ; Reprinted with permission American Society of Clinical Oncology. All rights reserved. 3. Kim DW, et al., J Clin Oncol, 35(22), 217: Reprinted with permission.217. American Society of Clinical Oncology. All rights reserved. 4. Solomon BJ, et al., J Clin Oncol 34, 216 (suppl; abstr 99). Presented at ASCO 216. By permission of Dr Solomon.

32 Appearance-free rate (%) Probability of progression-free survival NEW TARGETED THERAPIES ARE EFFECTIVE AGAINST BM Alectinib more effective than crizotinib in preventing BM 1 OsimertinibWith more CNS effective metastases than chemotherapy in presence of BM Time to appearance of CNS disease in patients without CNS mets at baseline Time to appearance of CNS disease in patients without CNS mets at baseline HR=.17 (.5.6) p= Osimertinib (n=93) Platinum-pemetrexed (n=51) Median PFS, months (95% CI) 8.5 (6.8, 12.3) 4.2 (4.1, 5.4) HR.32 (95% CI.21,.49) Alectinib (n=89; 3.4% with event) Crizotinib (n=75; 14.7% with event) Time (months).2 No. at risk Osimertinib Plat-pemetrexed Months Kim YH, et al.,presented at WCLC 216; MA7.3; 2. From The N Engl J Med, Mok T, et al., 376: Copyright 217. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

33 CONCLUSIONS Landscape of NSCLC therapy is rapidly evolving Immunotherapy is replacing chemotherapy in first-line setting in PD-L1 expressing NSCLC Immunotherapy is the new standard for EGFR wt, ALK wt NSCLC in second line irrespective of PD-L1 expression Gefitinib, erlotinib or afatinib seem equivalent in terms of efficacy irrespective of type of mutation Combination of erlotinib and bevacizumab is more effective than erlotinib alone Osimertinib is the best option in patients with EGFRT 79M+ NSCLC Alectinib is replacing crizotinib in first-line therapy for ALK rearranged NSCLC New EGFR or ALK inhibitors cross blood brain barrier extending patient survival impacting on treatment of patients with brain metastases

34 THANK YOU!