III III SESSIONE: TUMORI TORACICI NUOVI DATI NSCLC. B. Di Cocco UOC Oncologia Osp S.M. Goretti ASL Latina

Transcription

1 III III SESSIONE: TUMORI TORACICI NUOVI DATI NSCLC B. Di Cocco UOC Oncologia Osp S.M. Goretti ASL Latina

2

3

4

5

6

7

8

9

10

11

12 CheckMate 153: Continuous vs 1-Year Nivolumab Study Design Key eligibility criteria Advanced/ metastatic NSCLC 1 prior systemic therapy a ECOG PS 0 2 Treated CNS metastases allowed Nivolumab 3 mg/kg IV Q2W Treatment for 1 year b R c Continuous nivolumab Stop nivolumab Nivolumab retreatment allowed at PD Exploratory endpoints d : safety/efficacy e with continuous vs 1-year treatment, efficacy, other (eg, biomarkers, PK) At database lock (May 15, 2017), minimum/median follow-up time post-randomization was 10.0/14.9 months a Conventional systemic therapies, excluding immuno-oncology therapies; b Treatment until PD, unacceptable toxicity, or withdrawal of consent; treatment beyond investigator-assessed PD permitted; c All patients on treatment at 1 year were randomized regardless of response status; d Primary endpoint was incidence of high-grade select treatment-related AEs 1,2 ; e Responses were investigator-assessed every 8 weeks ± 5 days from week 9 1. Hussein M, et al. Oral presentation at IASLC 16th World Conference on Lung Cancer; September 6 9, 2015; Denver, CO, USA. Abstract ORAL Waterhouse D, et al. Poster presentation at ASCO Annual Meeting; June 3 7, 2016; Chicago, IL, USA. Abstract

13 CheckMate 153: Continuous vs 1-Year Nivolumab Patient Flow and Analysis Populations Efficacy analyses Continuous nivolumab 76 had response or SD at randomization c 220 patients on 1,245 patients treated a treatment at 1 year R b Stop nivolumab 87 had response or SD at randomization d a Main US cohort; 1,025 patients discontinued prior to 1 year due to progression, death, study withdrawal, toxicity, or other reasons; b All 220 patients continuing on treatment at 1 year were randomized regardless of response status; 57 of these 220 patients had PD and were randomized as allowed per protocol; safety analyses were based on all 220 patients, 107 in the continuous arm and 113 in the stop arm; c 8 patients discontinued treatment due to patient request or withdrawal of consent; d 12 patients discontinued treatment due to patient request or withdrawal of consent 13

14 CheckMate 153: Continuous vs 1-Year Nivolumab Baseline Patient Characteristics (Efficacy Analyses) a Median age, years (range) 70 years, % Continuous treatment (n = 76) 1-year treatment b (n = 87) 67 (50 92) (49 86) 40 Female, % ECOG PS, c % Current or former/never smoker, % 96/4 97/3 Squamous histology, % PD-L1 status, d % Quantifiable <1% e 1% e 50% e Prior lines of therapy, f % CR or PR prior to randomization, g % a Patients who did not have PD at randomization; b With optional retreatment allowed at PD; c Not reported: continuous, n = 1; 1-year, n = 2; d Using Dako PD-L1 IHC 28-8 pharmdx assay; e Percentage of patients with quantifiable PD-L1 expression; f Not reported: continuous, n = 0; 1-year, n = 3; g CRs: continuous, n = 8; 1-year, n = 2 14

15 CheckMate 153: Continuous vs 1-Year Nivolumab PFS From Randomization a Median, months (95% CI) PFS rate, % 6-month 1-year Continuous tx NR (NR) year tx b 10.3 (6.4, 15.2) HR: 0.42 (95% CI: 0.25, 0.71) No. at risk Continuous tx 1-year tx Time post-randomization (months) a Patients who did not have PD at randomization; minimum/median follow-up time post-randomization, 10.0/14.9 months b With optional retreatment allowed at PD NR = not reached; tx = treatment 15

16 CheckMate 153: Continuous vs 1-Year Nivolumab PFS From Randomization by Response Status a CR/PR Continuous tx Median, months (95% CI) NR (NR) SD Continuous tx Median, months (95% CI) NR (5.6, NA) 1-year tx b,c 10.6 (4.8, NA) 1-year tx b 9.6 (4.5, 12.6) 100 HR: 0.45 (95% CI: 0.24, 0.85) 100 HR: 0.44 (95% CI: 0.17, 1.09) No. at risk Time post-randomization (months) Continuous tx year tx Time post-randomization (months) a Best overall response prior to randomization; minimum/median follow-up time post-randomization, 10.0/14.9 months; b With optional retreatment allowed at PD; c Two patients who stopped treatment had CR prior to randomization; both patients lost CR (6 and 13 months after stopping treatment) with progression due to new lesions; NA = not available 16

17 CheckMate 153: Continuous vs 1-Year Nivolumab PFS From Randomization by Subgroup a Overall (0.25, 0.71) <70 years 70 years n (0.13, 0.60) 0.66 (0.32, 1.37) ECOG PS 0 1 b (0.25, 0.73) Male Female (0.18, 0.74) 0.56 (0.25, 1.25) Former/current smoker c (0.25, 0.72) Squamous histology Non-squamous histology Second-line treatment Third-line treatment Fourth-/later-line treatment/unknown (0.18, 0.93) 0.46 (0.23, 0.92) 0.34 (0.14, 0.82) 0.65 (0.27, 1.56) 0.35 (0.13, 0.95) HR (95% CI) <1% PD-L1 expression 1% PD-L1 expression 50% PD-L1 expression PD-L1 not quantifiable/not reported (0.11, 1.17) 0.36 (0.15, 0.86) 0.15 (0.03, 0.76) 0.51 (0.23, 1.12) Favors continuous tx Favors stopping tx HR = 0.43 (95% CI: 0.25, 0.76) when adjusted for gender, histology, best overall response, and PD-L1 status using multivariate analysis a Patients who did not have PD at randomization; minimum/median follow-up time post-randomization, 10.0/14.9 months; b HR not calculated for patients with ECOG PS 2 due to small sample size (n = 8); 3 patients had unreported ECOG PS; c HR not calculated for never-smokers/patients with unknown smoking status due to small sample size (n = 6) 17

18 CheckMate 153: Continuous vs 1-Year Nivolumab OS From Randomization a Median, months (95% CI) OS rate, % 6-month 1-year Continuous tx NR (NR) year tx b 23.2 (23.2, NA) HR: 0.63 (95% CI: 0.33, 1.20) No. at risk Continuous tx 1-year tx Time post-randomization (months) a Patients who did not have PD at randomization; minimum/median follow-up time post-randomization, 10.0/14.9 months b With optional retreatment allowed at PD 18

19 CheckMate 153: Continuous vs 1-Year Nivolumab Retreatment in 1-Year Treatment Arm Efficacy analyses 1,245 patients treated a 220 patients on treatment at 1 year R b Continuous nivolumab c Stop nivolumab d 76 had response or SD at randomization 87 had response or SD at randomization 43 (49%) had PD after stopping nivolumab 34 (79%) were retreated with nivolumab Data at time of analysis (database lock May 15, 2017) a Main US cohort; 1,025 patients discontinued prior to 1 year due to progression, death, study withdrawal, toxicity, or other reasons; b All 220 patients continuing on treatment at 1 year were randomized regardless of response status; 57 of these 220 patients had PD and were randomized as allowed per protocol; safety analyses were based on all 220 patients, 107 in the continuous arm and 113 in the stop arm; c 8 patients discontinued treatment due to patient request or withdrawal of consent; d 12 patients discontinued treatment due to patient request or withdrawal of consent 19

20 CheckMate 153: Continuous vs 1-Year Nivolumab Tumor Burden Change of Target Lesions in Retreated Patients Tumor burden change in target lesions following retreatment a,b 100 Type of PD n (%) Target lesions only 12 (35) Non-target lesions only 1 (3) New lesions only 14 (41) Target lesions and new lesions 4 (12) Non-target lesions and new lesions 1 (3) Target lesions, non-target lesions, and new lesions 2 (6) Start of retreatment % change truncated to 100% Days since randomization a Patients with PD in target lesions only; b n = 11: 1 patient without further assessment after retreatment start was excluded 20

21 CheckMate 153: Continuous vs 1-Year Nivolumab Summary of Safety Post-Randomization a Continuous treatment (n = 107) 1-year treatment b (n = 113) Any grade, % Grade 3 4, % Any grade, % Grade 3 4, % Treatment-related AEs Treatment-related SAEs Select treatment-related AEs Treatment-related AEs leading to discontinuation Few new-onset events occurred after 1 year No treatment-related deaths were reported among randomized patients No new safety signals were observed a All randomized patients b AEs in this group include those during retreatment 21

22 CheckMate 153: Continuous vs 1-Year Nivolumab Summary CheckMate 153 is the first randomized study to evaluate duration of therapy with a PD-1/PD-L1 inhibitor Among patients still on nivolumab at 1 year, PFS was significantly improved for those treated continuously vs stopping: PFS HR = 0.42 (95% CI: 0.25, 0.71) OS HR = 0.63 (95% CI: 0.33, 1.20), showing a trend favoring continuous nivolumab; follow-up for OS is ongoing The frequency of treatment-related AEs was numerically higher with continuous vs 1-year treatment, but overall, few new-onset events occurred after 1 year 22

23 Three-Year Follow-up From CheckMate 017/057: Nivolumab Versus Docetaxel in Patients With Previously Treated Advanced Non-Small Cell Lung Cancer Enriqueta Felip, 1 Scott Gettinger, 2 Marco Angelo Burgio, 3 Scott J. Antonia, 4 Esther Holgado, 5 David Spigel, 6 Oscar Arrieta, 7 Manuel Domine, 8 Osvaldo Arén Frontera, 9 Julie Brahmer, 10 Laura Q. Chow, 11 Lucio Crinò, 3 Charles Butts, 12 Bruno Coudert, 13 Leora Horn, 14 Martin Steins, 15 William J. Geese, 16 Ang Li, 16 Diane Healey, 16 Everett E. Vokes 17 1 Hospital Universitari Vall d Hebron, Barcelona, Spain; 2 Yale Cancer Center, New Haven, CT, USA; 3 IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy; 4 H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA; 5 Hospital De Madrid, Norte Sanchinarro, Madrid, Spain; 6 Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA; 7 Instituto Nacional de Cancerología, Mexico City, Mexico; 8 Fundación Jiménez Díaz, Madrid, Spain; 9 Centro Internacional de Estudios Clinicos, Santiago, Chile; 10 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; 11 University of Washington, Seattle, WA, USA; 12 Cross Cancer Institute, Edmonton, AB, Canada; 13 Centre Georges François Leclerc, Dijon, France; 14 Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 15 Thoraxklinik, Heidelberg University Hospital, Heidelberg, Germany; 16 Bristol-Myers Squibb, Princeton, NJ, USA; 17 University of Chicago Medicine & Biological Sciences, Chicago, IL, USA

24 Background Nivolumab, an anti programmed death (PD)-1 antibody, is approved in many countries for the treatment of patients with advanced non-small cell lung cancer (NSCLC) and disease progression during or after platinum-based chemotherapy 1,2 Approval was based on data from 2 pivotal phase 3 trials in previously treated patients with squamous (SQ) NSCLC (CheckMate 017) or non-sq NSCLC (CheckMate 057), which showed nivolumab significantly prolonged overall survival (OS) and had a favorable safety profile compared with docetaxel 3,4 Treatment benefit was observed in patients with SQ or non-sq NSCLC, including those with <1% PD-1 ligand 1 (PD-L1) expression 3-6 ; higher levels of PD-L1 expression were associated with a greater magnitude of benefit in non- SQ NSCLC 4 Here, we present updated efficacy and safety data from CheckMate 017 and CheckMate 057 based on >3 years of follow-up

25 CheckMate 017 and 057 study designs CheckMate 017 (NCT ; N = 272) Key eligibility criteria Stage IIIB/IV SQ NSCLC ECOG PS prior platinum-based chemotherapy Pretreatment (archival or fresh) tumor samples required for PD-L1 analysis CheckMate 057 (NCT ; N = 582) Key eligibility criteria Stage IIIB/IV non-sq NSCLC ECOG PS prior platinum-based chemotherapy Pretreatment (archival or fresh) tumor samples required for PD-L1 analysis Prior maintenance therapy allowed Prior TKI therapy allowed for known ALK translocation or EGFR mutation Nivolumab 3 mg/kg IV Q2W until progressive disease or unacceptable toxicity (n = 135) Docetaxel 75 mg/m 2 IV Q3W until progressive disease or unacceptable toxicity b (n = 137) Nivolumab 3 mg/kg IV Q2W until progressive disease or unacceptable toxicity (n = 292) Docetaxel 75 mg/m 2 IV Q3W until progressive disease or unacceptable toxicity b (n = 290) Optional switch to flat dose nivolumab 480 mg Q4W allowed after September 2016 a Optional switch to flat dose nivolumab 480 mg Q4W allowed after September 2016 a Endpoints Primary OS Additional PFS ORR Efficacy by tumor PD-L1 expression Safety Quality of life (LCSS) a The protocols of both studies were amended in September 2016, when minimum follow-up was approximately 2.5 years, allowing patients to switch to nivolumab 480 mg Q4W starting 2 weeks after their last 3-mg/kg Q2W dose; b After completion of the primary analyses, 3,4 patients in the docetaxel arms who ended treatment at any time during the studies were allowed to cross over to nivolumab ALK = anaplastic lymphoma kinase; ECOG PS = Eastern Cooperative Oncology Group performance status; EGFR = epidermal growth factor receptor; IV = intravenous; LCSS = Lung Cancer Symptom Scale; ORR = objective response rate; PFS = progression-free survival; Q3W = every 3 weeks; TKI = tyrosine kinase inhibitor

26 OS (3 years minimum follow-up) CheckMate 017 (SQ NSCLC) CheckMate 057 (non-sq NSCLC) Months No. of patients at risk Nivolumab Docetaxel Nivolumab (n = 135) Docetaxel (n = 137) 1-y OS = 42% Δ18% 2-y OS = 23% 1-y OS = 24% 3-y OS = 16% Δ15% Δ10% 2-y OS = 8% 3-y OS = 6% CI = confidence interval; HR = hazard ratio HR (95% CI): 0.62 (0.48, 0.80) Months No. of patients at risk Nivolumab Docetaxel Nivolumab (n = 292) Docetaxel (n = 290) Δ12% 1-y OS = 39% 1-y OS = 51% Δ13% 2-y OS = 16% HR (95% CI): 0.73 (0.62, 0.88) 2-y OS = 29% Δ9% 3-y OS = 18% 3-y OS = 9% year OS rates nivolumab vs docetaxel CheckMate 017 were 16% versus 6% CheckMate 057 were 18% versus 9%

27 PFS a (3 years minimum follow-up) 100 CheckMate 017 (SQ NSCLC) Nivolumab (n = 135) Docetaxel (n = 137) 100 CheckMate 057 (non-sq NSCLC) Nivolumab (n = 292) Docetaxel (n = 290) HR (95% CI): 0.63 (0.48, 0.82) 60 HR (95% CI): 0.89 (0.74, 1.06) y PFS = 21% 20 2-y PFS = 16% 3-y PFS = 12% 1-y PFS = 7% 2-y PFS = NC 3-y PFS = NC y PFS = 19% 20 2-y PFS = 12% 3-y PFS = 10% 1-y PFS = 10% 2-y PFS = 2% 3-y PFS = <1% No. of patients at risk Nivolumab Docetaxel a Investigator-assessed NC = not calculable Months No. of patients at risk Nivolumab Docetaxel Months year PFS rates nivolumab and docetaxel CheckMate 017: 12% versus not calculable CheckMate 057 and 10% versus <1%

28 Tumor response (3 years minimum follow-up) CheckMate 017 (SQ NSCLC) CheckMate 057 (non-sq NSCLC) Nivolumab Docetaxel Nivolumab Docetaxel (n = 135) (n = 137) (n = 292) (n = 290) ORR, % (95% CI) 20 (14, 28) 9 (5, 15) 19 (15, 24) 12 (9, 17) Median DOR, months (95% CI) 25.2 (9.8, NE) 8.4 (3.6, 14.0) 18.3 (8.4, NE) 5.6 (4.4, 6.9) Response ongoing, n/n (%) 7/27 (26) 0/12 (0) 13/56 (23) 0/36 (0) DOR = duration of response; NE = not estimable Among responders, patients had longer median durations of response with nivolumab versus docetaxel

29 Subsequent therapy (all randomized patients), n (%) Subsequent systemic therapies CheckMate 017 (SQ NSCLC) Nivolumab (n = 135) Docetaxel (n = 137) a Patients may have received 1 subsequent therapy; b In CheckMate 017 and 057, 3 patients in each study received subsequent immunotherapy as part of a combination therapy; c In CheckMate 017 and 057, 40% (2/5 patients) and 20% (3/15 patients) received subsequent immunotherapy as the first therapy after discontinuing docetaxel, respectively; d Includes subsequent nivolumab poststudy; e Includes crossover to nivolumab in the extension phase of the study or subsequent nivolumab post-study CTLA-4 = cytotoxic T-lymphocyte antigen 4; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor CheckMate 057 (non-sq NSCLC) Nivolumab (n = 292) Docetaxel (n = 290) Any subsequent systemic therapy a 57 (42) 48 (35) 141 (48) 156 (54) Immunotherapy b 7 (5) 11 (8) c 10 (3) 32 (11) c Nivolumab 5 (4) d 6 (4) e 7 (2) d 24 (8) e Other anti PD-(L)1 0 3 (2) 0 4 (1) Anti CTLA (1) 0 3 (1) Investigational/unspecified 2 (1) 0 3 (1) 1 (<1) ALK/EGFR inhibitor 9 (7) 9 (7) 40 (14) 68 (23) VEGF/VEGFR inhibitor (4) 8 (3) Investigational agent/other 4 (3) 5 (4) 24 (8) 14 (5) Chemotherapy 52 (38) 35 (26) 120 (41) 115 (40) In the nivolumab and docetaxel arms, respectively, 42% and 35% of patients in CheckMate 017 and 48% and 54% of patients in CheckMate 057 received other systemic therapy subsequent to study treatment

30 Safety summary for nivolumab-treated patients in pooled CheckMate 017/057 (3 years minimum follow-up) a,b Pooled nivolumab (N = 418) Any grade Grade 3 4 Treatment-related select AEs in nivolumabtreated patients in pooled CheckMate 017/057 (3 years minimum follow-up) a,b Pooled nivolumab (N = 418) Any grade Grade 3 4 TRAEs, % Any AE 67.7 AE leading to discontinuation 6.0 Most frequent TRAEs, c % Fatigue Nausea Decreased appetite Asthenia Diarrhea Rash Pruritus Hypothyroidism Arthralgia Vomiting Overall, % Skin Gastrointestinal Endocrine Hepatic Pulmonary Renal Hypersensitivity/inf usion reaction a Select AEs are those with potential immunologic etiology that require frequent monitoring/intervention; b Includes events reported between first nivolumab dose and 30 days after last on-study nivolumab dose (3 mg/kg or 480 mg) Median (range) duration of therapy for patients treated with nivolumab was 2.8 ( ) months a Includes events reported between first nivolumab dose and 30 days after last nivolumab dose (3 mg/kg or 480 mg); b There were no grade 5 TRAEs; c Reported in 5% of patients Because no patient remained on docetaxel treatment for >2 years, updated safety data are presented in nivolumabtreated patients only Between 2 and 3 years minimum follow-up: 3 new grade 3 4 TRAEs (arthralgia, joint effusion, interstitial lung disease [select TRAE]) were reported

31 Authors Conclusions After 3 years minimum follow-up in the phase 3 CheckMate 017 and 057 studies: Nivolumab continued to demonstrate long-term OS and PFS benefit in patients with advanced SQ and non-sq NSCLC 3-year OS rates with nivolumab were 16% in CheckMate 017 and 18% in CheckMate 057 In CheckMate 017 and CheckMate 057, 26% and 23% of patients who responded to nivolumab, respectively, had ongoing tumor responses No new safety signals were identified for nivolumab and rates of TRAEs were similar to those seen at 2 years minimum follow-up

32 NSCLC: TARGET THERAPY

33

34

35

36

37

38

39

40

41

42

43

44

45 PROFILE 1014: Study Design 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 0 2 R A N D O M I Measurable disease Stable treated brain N=343 metastases allowed Z E b Accrual period: January 2011 July 2013 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 v1.1, by IRR) Secondary ORR OS Safety Patient-reported outcomes (EORTC QLQ-C30, QLQ- LC13, EQ-5D) Crossover to crizotinib permitted after progression c a ALK status determined centrally using Abbott's Vysis ALK break-apart FISH probe kit; b Stratification factors: ECOG PS (0/1 vs 2), Asian vs non-asian race, and brain metastases (present vs absent); c Assessed by IRR Median follow up: 46 months Solomon BJ, Mok TS, et al. N Engl J Med 2014;371:

46 PROFILE 1014: Background PROFILE 1014 (Solomon et al NEJM 2014) was published after approximately 17 months of followup (data cutoff date 30 Nov 2013). Primary efficacy endpoint (superiority of crizotinib versus chemotherapy in terms of progression-free survival by IRR) was met: HR (95% CI: 0.346, 0.596) and p-value <0.0001, Median PFS was 10.9 and 7.0 months for crizotinib and chemotherapy treatment, respectively ORR was significantly higher with crizotinib than with chemotherapy. 74% vs 45%, p<0.001 With only 26% of all-cause deaths at data cutoff, median OS was not reached in either group at the time of first report. Here we report OS and safety of an additional 3 years of follow-up (LSLV 30 Nov 2016). Solomon BJ, Mok TS, et al. N Engl J Med 2014;371:

47

48

49

50

51 Conclusions With a median follow-up of approximately 46 months in both arms, this study has reported one of the highest 4 year survival rate to date for any study of TKIs in patients with Stage IV metastatic NSCLC. The difference in OS between crizotinib and chemotherapy arm (HR: [95% CI: 0.548, 1.053]) did not reach statistical significance. After hypothetical adjustment for crossover (84.2% in chemotherapy arm and 19.2% in crizotinib arm), OS in the crizotinib arm could be significantly longer than in the chemotherapy arm (HR [95% bootstrap CI: 0.081, 0.718] log-rank test approach). Patients who received crizotinib followed by another ALK-TKI had the longest OS while patients randomized to chemotherapy followed by no ALK-TKI or other treatment had the worst OS. No unexpected toxicities were revealed with long-term crizotinib treatment.

52 ALECTINIB VS CRIZOTINIB IN TREATMENT-NAÏVE ALK+ NSCLC: CNS EFFICACY RESULTS FROM THE ALEX STUDY 1 Shirish Gadgeel, 2 Solange Peters, 3 Tony Mok, 4 Alice T. Shaw, 5 Dong-Wan Kim, 6 Sai-Hong Ignatius Ou, 7 Maurice Pérol, 8 Rafal Dziadziuszko, 9 Jin Seok Ahn, 10 Rafael Rosell, 11 Ali Zeaiter, 11 Emmanuel Mitry, 11 Eveline Nueesch, 11 Bogdana Balas, 12 D. Ross Camidge 1 University of Michigan, Ann Arbor, MI, USA; 2 Lausanne University Hospital, Lausanne, Switzerland; 3 State Key Laboratory of South China, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; 4 Massachusetts General Hospital, Boston, MA, USA; 5 Seoul National University Hospital, Seoul, South Korea; 6 Chao Family Comprehensive Cancer Center, University of California, Irvine School of Medicine, Orange, CA, USA; 7 Department of Medical Oncology, Léon Bérard Cancer Center, Lyon, France; 8 Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland; 9 Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 10 Catalan Institute of Oncology, Barcelona, Spain; 11 F. Hoffmann-La Roche Ltd, Basel, Switzerland; 12 University of Colorado, Denver, CO, USA 52 52

53 ALEX STUDY DESIGN Stage IIIB/IV NSCLC ALK+ disease according to IHC test Treatment naïve ECOG PS 0 2 Brain metastases permitted if asymptomatic (n=303) R 1:1 Alectinib 600mg BID (n=152) All patients underwent restaging chest/abdominal CT scans and brain imaging every 8 weeks Crizotinib 250mg BID (n=151) Until PD*, toxicity, withdrawal or death Subsequent therapy and survival follow-up Primary endpoint Secondary endpoints Stratification factors Investigator-assessed PFS in the ITT population Time to CNS progression, CNS ORR, CNS DoR (CNS endpoints were assessed by IRC) ECOG PS (0/1 vs 2); Ethnicity (Asian vs non- Asian); CNS metastases at baseline (presence vs absence) The primary endpoint of the study was met: HR 0.47 (95% CI ) P<0.001 Median PFS with alectinib was not reached compared with 11.1 months with crizotinib Median duration of follow-up: crizotinib arm 17.6 months (range: ); alectinib arm 18.6 months (range: ) Primary data cut-off: 9 February 2017 CNS follow-up was conducted for all patients Lesions were documented by computed tomography scans, colour photography and MRI, brain scans, using RECIST v1.1 * Isolated asymptomatic CNS progression, treatment until systemic or symptomatic CNS PD allowed BID = twice daily; DoR = duration of response; ECOG = Eastern Cooperative Oncology Group Performance Status; HR =hazard ratio; IHC = Immunohistochemistry; ORR = objective response rate; PD = disease progression; PFS = progression-free survival. Peters, et al. NEJM

54

55

56

57

58

59

60 CONCLUSIONS Alectinib showed significantly superior CNS activity versus crizotinib in patients with CNS disease both with/without prior CNS RT across multiple CNS endpoints in previously untreated advanced ALK+ NSCLC alectinib significantly prolonged PFS in patients with and without CNS disease at baseline (HR 0.40, 95% CI ; p< and HR 0.51, 95% CI ; p=0.0024, respectively) compared with crizotinib alectinib significantly improved intracranial ORR compared with crizotinib, irrespective of RT (alectinib: 85.7% versus crizotinib: 71.4% and alectinib: 78.6% versus crizotinib: 40.0%) duration of CNS response with alectinib was longer in all patient subgroups than with crizotinib At 12 months, 31.3% of crizotinib vs 4.6% of alectinib patients had CNS metastases at the time of first progression suggesting alectinib is protective against the development of CNS progression Overall, these CNS results along with the systemic results consolidate alectinib as the new standard of care for patients with previously untreated, advanced ALK+ NSCLC

61

62

63

64

65

66

67

68 ACKNOWLEDGMENTS A special thanks to: POMPERRA BELLINA CHEBORA ESMO 2017 (in alph. order: A.B., B.D.C., A.F.,T.F., L.P.,D.S., N.S., V.S. ET AL) Il Cremonese Jessica grazie per l attenzione!