ALINA Trial

[Slide 1] 16:30 - 18:15 Presidential 1 CHAIRS JEAN-YVES BLAY, SOLANGE PETERS ALINA study design* Resected Stage IB (≥4cm)-IIIA ALK+ NSCLC Alectinib per UICC/AJCC 7th edition 600 mg BID Recurrence Other key eligibility criteria: 2 years Further ECOG PS 0-1 treatments at IESMO egress Eligible to receive platinum-based R investigator's chemotherapy 1:1 choice and Adequate end-organ function survival No prior systemic cancer therapy Platinum-based follow-up chemotherapy+ Recurrence Ben Solomon Stratification factors: N=257 Q3W; 4 cycles Stage: IB (2 4cm) VS II vs IIIA ALINA: Efficacy and safety of Race: Asian vs non-Asian adjuvant alectinib versus chemotherapy in patients with early-stage ALK+ non-small cell Primary endpoint Other endpoints lung cancer (NSCLC) Disease assessments (including brain DFS per investigator, tested hierarchically: CNS disease-free survival MRI)$ were conducted at baseline, Stage II-IIIA ITT (Stage IB-IIIA) OS every 12 weeks for year 1-2, every 24 weeks for year 3-5, then annually Safety congress Data cut-off: 26 June 2023; CNS central nervous system; DFS, disease-free survival; ITT. intention to treat MADRID 2023 ESMO "Superiority trial: Cisplatin pemetrexed, cisplatin vinorebine or cisplatin gemcitabine; cisplatin could be switched to carboplatin in case of intolerability FDFS defined as the time from randomisation to the first documented recurrence of disease or new primary NSCLC as determined by the investigator, or death from any cause, whichever occurs first; Assessment by CT scan where MRI not available; NCT03456076 congress MADRID 2023 ESMO Madrid Auditorium - Hall 6 MADRID SPAIN 20-24 OCTOBER 2023 --- [Slide 2] 16:30 - 18:15 Presidential 1 CHAIRS JEAN-YVES BLAY, SOLANGE PETERS Disease-free survival: stage II-IIIA* 100 93.8% Alectinib Chemotherapy 88.3% (N=116) (N=115) 80 Alectinib Patients with event 14 (12%) 45 (39%) Death 0 1 Disease-free survival (%) 63.0% Recurrence 14 44 IESMO 60 53.3% Chemotherapy Median DFS, Not reached 44.4 months (95% CI) (27 NE) 40 DFS HR 0.24 (0.13, 0.45) Ben Solomon (95% CI) pt<0.0001 ALINA: Efficacy and safety of 20 adjuvant alectinib versus chemotherapy in patients with 0 0 6 12 18 24 30 36 42 48 54 early-stage ALK+ non-small cell Time (months) lung cancer (NSCLC) No. at risk Alectinib 116 111 111 107 67 49 35 21 10 3 Chemo 115 102 88 79 48 35 23 17 10 2 Median survival follow up: alectinib, 27.9 months; chemotherapy, 27.8 months MADRID 2023 ESMO congress Data cut-off: 26 June 2023; Time from last patient in to data cut off was 18 months "Per UICC/AJCC 7th edition; Stratified log rank; DFS defined as the time from randomisation to the first documented recurrence of disease or new primary NSCLC as determined by the investigator, or death from any cause, whichever occurs first MADRID congress 2023 ESMO Madrid Auditorium - Hall 6 MADRID SPAIN 20-24 OCTOBER 2023 --- [Slide 3] 16:30 18:15 Presidential 1 CHAIRS JEAN-YVES BLAY, SOLANGE PETERS Disease-free survival by stage* 100 Alectinib Stage IB 2-year DFS rate, % Stage IB Stage II Stage IIIA 80 (95% CI) (n=26) (n=92) (n=139) Disease-free survival (%) no Alectinib 92.3 95.6 92.7 (77.8, 100.0) (89.5, 100.0) (86.4,98.9) 40* 71.6 66.3 60.7 Chemotherapy Chemotherapy (44.2,99.0) (51.7,81.0) (47.9,73.5) 20* IESMO I HR 0.21 0.24 0.25 0. (95% CI) (0.02.1.84) (0.09.0.65) (0.12,0.53) 0 6 12 15 24 30 36 42 48 54 No. at risk Time (months) Address 11 : M NP Chemo 12 10 10 10 1 NE Ben Solomon 100 100 Stage II Stage IIIA ALINA: Efficacy and safety of Alectinib 80 60 Alectinib adjuvant alectinib versus Disease-free survival (%) Disease-free survival (%) chemotherapy in patients with 00 $ early-stage ALK+ non-small cell Chemotherapy 40 40 Chemotherapy lung cancer (NSCLC) 20 20 0 0 0 6 12 18 24 30 36 42 48 54 0 6 12 18 24 30 36 42 48 54 No at risk Time (months) No. Time (months) Neclab 47 44 - 43 20 18 : 12 " Alectinic 58 KY 17 64 35 27 10 Chamo 11 #1 " 30 21 If a NE Chemo 70 61 55 17 17 18 14 9 : congress MADRID ESMO Data cut-off 26 June 2023 2023 Per UICC/AJCC 7th edition; Unstratified analysis congress MADRID 2023 ESMO Madrid Auditorium - Hall 6 MADRID SPAIN 20-24 OCTOBER 2023 --- [Slide 4] 16:30 - 18:15 Presidential 1 CHAIRS JEAN-YVES BLAY, SOLANGE PETERS Disease-free survival subgroup analysis (ITT) Subgroup No. of events / patients DFS HR (95% CI) All patients 65 257 0.24 (0.14-0.43) Age <65 43 196 0.26 (0.13-0.52) a65 22 61 0.24 (0.08-0.71) Sex Male 35 123 0.26 (0.11-0.60) Female 30 134 0.22 (0.10-0.50) ESMO Race Asian 31 143 0.36 (0.17-0.79) Non-Asian 34/114 0.16 (0.06-0.38) ECOG PS at 0 32 137 0.20 (0.09-0.46) baseline 1 33 120 0.31 (0.14-0.69) Ben Solomon Tobacco use Never 37 154 0.27 (0.13-0.55) Current 0 8 NE ALINA: Efficacy and safety of history Previous 28 95 0.22 (0.08-0.57) adjuvant alectinib versus Stage* Stage IB 6 26 0.21 (0.02-1.84) chemotherapy in patients with Stage II 22 92 0.24 (0.09-0.65) 37 139 early-stage ALK+ non-small cell Stage IIIA 0.25 (0.12-0.53) lung cancer (NSCLC) Regional lymph NO 11 39 0.19 (0.04-0.88) node status N1 20 88 0.34 (0.13-0.89) N2 34 130 0.21 (0.09-0.47) 0.1 0.3 1.0 3.0 Alectinib better Chemotherapy better MADRID ESMO congress Data cut-off 26 June 2023 2023 Altows indicate lower bound of the CHO 1; "Per UICC/AJCC yrs edition MADRID congress 2023 ESMO Madrid Auditorium - Hall 6 MADRID SPAIN 20-24 OCTOBER 2023

[Slide 1] Disease-free survival: stage II-IIIA* 100 Alectinib Chemotherapy (N=116) (N=115) 80 Alectinib Patients with event 14 (12%) 45 (39%) Death 0 1 Disease-free survival (%) Recurrence 14 44 60 Chemotherapy Median DFS, Not reached 44.4 months (95% CI) (27.8, NE) 40 DFS HR 0.24 (0.13, 0.45) (95% CI) pt<0.0001 20 0 0 6 12 18 24 30 36 42 48 54 Time (months) No. at risk Alectinib 116 111 111 107 67 49 35 21 10 3 Chemo 115 102 88 79 48 35 23 17 10 2 Median survival follow up: alectinib, 27.9 months; chemotherapy, 27.8 months MADRID congress ESMO Data cut-off: 26 June 2023; Time from last patient in to data cut off was -18 months 2023 *Per UICC/AJCC 7th edition; Stratified log rank; DFS defined as the time from randomisation to the first documented recurrence of disease or new primary NSCLC as determined by the investigator, or death from any cause, whichever occurs first --- [Slide 2] Disease-free survival: ITT (stage IB-IIIA)* 100 Alectinib Chemotherapy (N=130) (N=127) 80 Alectinib Patients with event 15 (12%) 50 (39%) Death 0 1 Disease-free survival (%) Recurrence 15 49 60 Chemotherapy Median DFS, Not reached 41.3 months (95% CI) (28.5, NE) 40 DFS HR 0.24 (0.13, 0.43) (95% CI) pt<0.0001 20 0 0 6 12 18 24 30 36 42 48 54 Time (months) No. at risk Alectinib 130 123 123 118 74 55 39 22 10 3 Chemo 127 112 98 89 55 41 27 18 11 2 Median survival follow up: alectinib, 27.8 months; chemotherapy, 28.4 months congress Data cut-off: 26 June 2023; Time from last patient in to data cut off was -18 months MADRID 2023 ESMO *Per UICC/AJCC 7th edition; Stratified log rank; :2 events in the alectinib arm, 4 events in the chemo arm; one additional patient in the chemo arm died but was censored due to incomplete date of death recorded. DFS defined as the time from randomisation to the first documented recurrence of disease or new primary NSCLC as determined by the investigator, or death from any cause, whichever occurs first --- [Slide 3] Sites of disease recurrence (ITT) 100% No disease No disease Site(s) of distant Alectinib Chemotherapy 90% recurrence recurrence recurrence* (n=130) (n=127) (n=115) (n=77) 80% Brain 4 14 70% Bone 1 8 60% Adrenal gland 0 3 Patients Lymph node 0 2 50% Kidney 0 1 40% Local/regional New primary + distant (n=5) Peritoneum 0 1 30% lung cancer Distant (n=1) (n=22) Other 1 0 20% Local/regional + distant (n=2) Local/regional 10% (n=22) Local/regional (n=9) Distant (n=3) 0% Alectinib Chemotherapyt congress Data cut-off: 26 June 2023; *At disease assessment where first recurrence detected; patients may have MADRID 2023 ESMO multiple sites of disease recurrence counted; One patient died without a recurrence event reported --- [Slide 4] Post-recurrence subsequent therapy Number of patients with disease recurrence, n (%) Alectinib Chemotherapy (n=15) (n=49) Patients with any subsequent therapy 13 (87) 43 (88) Systemic therapy 13 (87) 38 (78) ALK TKI 7 (47) 37 (76) Alectinib 4 (27) 29 (59) Brigatinib 4 (27) 4 (8) Crizotinib 0 4 (8) Lorlatinib 0 2 (4) Ceritinib 0 1 (2) Chemotherapy 6 (40) 2 (4) Immunotherapy 1 (7) 1 (2) Other anti-cancer therapy 1 (7) 1 (2) Radiotherapy 5 (33) 9 (18) Surgery 1 (7) 3 (6) congress Data cut-off: 26 June 2023 MADRID ESMO Includes any subsequent therapy reported on or after date of earliest contributing event to disease recurrence; 2023 Patients may have received more than one subsequent anticancer therapy

[Slide 1] OF NEW 1928 1812 3828 ENGLAND The NEW ENGLAND JOURANT JOURNAL of MEDICINE SPECIALTIES TOPICS MULTIMEDIA CURRENT ISSUE LEARNING/CME AUTHOR CENTER PUBLICATIONS ORIGINAL ARTICLE f X in Alectinib in Resected ALK-Positive Non-Small- Cell Lung Cancer Authors: Yi-Long Wu, M.D. ID , Rafal Dziadziuszko, M.D., Ph.D., Jin Seok Ahn, M.D., Ph.D., Fabrice Barlesi, M.D., Ph.D., Makoto Nishio, M.D., Ph.D., Dae Ho Lee, M.D., Ph.D., Jong-Seok Lee, M.D., Ph.D., Wenzhao Zhong, M.D., Ph.D., Hidehito Horinouchi, M.D., Ph.D., Weimin Mao, M.D., Ph.D., Maximilian Hochmair, M.D., Filippo de Marinis, M.D., M. Rita Migliorino, M.D., Igor Bondarenko, M.D., Ph.D., Shun Lu, M.D., Qun Wang, M.D., Tania Ochi Lohmann, Ph.D., Tingting Xu, M.D., Andres Cardona, M.Sc., Thorsten Ruf, M.D., Johannes Noe, Ph.D., and Benjamin J. Solomon, M.B., B.S., Ph.D., for the ALINA Investigators* -15 Author Info & Affiliations Published April 10, 2024 I N Engl I Med 2024;390:1265-1276 I DOI: 10.1056/NEJMoa2310532

[Slide 1] Disease-free survival subgroup analysis (ITT) Subgroup No. of events / patients DFS HR (95% All patients 65 / 257 0.24 (0.14-0 Age <65 43 / 196 0.26 (0.13-C 265 22 / 61 0.24 (0.08-C Sex Male 35 / 123 0.26 (0.11-0 Female 30 / 134 0.22 (0.10-0 Race Asian 31 / 143 0.36 (0.17- Non-Asian 34 / 114 0.16 (0.06-0 ECOG PS at 0 32 / 137 0.20 (0.09- baseline 1 33 / 120 0.31 (0.14- Tobacco use Never 37 / 154 0.27 (0.13- history Current 0 / 8 NE Previous 28 / 95 0.22 (0.08- Stage IB 6 / 26 Stage* 0.21 (0.02- Stage II 22 / 92 0.24 (0.09- Stage IIIA 37 / 139 0.25 (0.12- Regional lymph NO 11 / 39 0.19 (0.04- node status N1 20 / 88 0.34 (0.13- N2 34 / 130 0.21 (0.09- 0.1 0.3 1.0 3.0 Alectinib better Chemotherapy better congress MADRID 2023 ESMO Arrows indicate lower bound of th

[Slide 1] j congre 3 DRID ESMO ongress --- [Slide 2] Should we treat also patients with Stage II? YES! Study or Subgroup Perioperative Immunothery Placebo Hazard Ratio Events Total Events Total Exp [(O-E)/V], Fixed, 95% CI 77T 22 81 26 81 0.81 [0.46, 1.43] Aegean 21 104 27 110 0.76 [0.43, 1.34] Keynote671 37 118 62 121 0.59 [0.40, 0.88] Total (95% CI) 303 312 0.68 [0.51, 0.90] Total events 80 115 Heterogeneity: Chi2 = 1.01, df = 2 (P = 0.60); 12 = 0% 0,1 0,2 0.5 1 2 5 10 Test for overall effect: Z = 2.70 (P = 0.007) Perioperative Control MADRIO ESMO congress Marina Chiara Garassino @marinagarassino Content of this presentation is copyright and responsibility of the author. Permission is required for re-use. --- [Slide 3] Should we treat also when PD-L1 is negative? YES! Study or Subgroup Placebo Hazard Ratio Events Total Events Total Exp [(O-E)/V], Fixed, 95% CI 77T 33 93 44 93 0.73 [0.47, 1.14] Aegean 35 122 46 125 0.76 [0.49, 1.17] Keynote 671 58 138 77 151 0.75 [0.54, 1.05] Neotorch 17 69 30 70 0.59 [0.33, 1.04] Total (95% CI) 422 439 *0.72 [0.58- 0.89] Total events 143 197 Heterogeneity: Chi² = 0.59, df = 3 (P = 0.90); 12 = 0% 0.05 0.2 1 5 20 Test for overall effect: Z = 2.99 (P = 0.003) Perioperative immuno Placebo congress I Marina Chiara Garassino @marinagarassino Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.

[Slide 1] The NEW ENGLAND JOURNAL of MEDICINE RESEARCH SUMMARY Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer Wu Y-L et al. DOI: 10.1056/NEJMoa2310532 CLINICAL PROBLEM ALK-positive ALINA Trial non-small-cell Although platinum-based chemotherapy is currently the lung cancer Alectinib Chemotherapy recommended adjuvant treatment for resected ALK-posi- N=130 N=127 tive non-small-cell lung cancer (NSCLC), it is associated with only modestly improved survival and a high risk of adverse events. Alectinib, a potent oral tyrosine kinase inhibitor, may improve patient outcomes and reduce Alectinib disease recurrence, but data comparing alectinib against standard chemotherapy are lacking. 600 mg Twice daily for 24 mo Four 21-day cycles CLINICAL TRIAL Design: A global, phase 3, open-label, randomized trial assessed the efficacy and safety of alectinib as adjuvant Disease Recurrence or Death therapy in resected ALK-positive NSCLC. HR, 0.24 (95% CI, 0.13-0.43); P<0.001 Intervention: 257 adults with completely resected, ALK- 100 Alectinib positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA 90 80 were randomly assigned to receive oral alectinib (600 mg twice daily) for 24 months or four 21-day cycles of intra- point was disease-free survival. Percentage of Patients Alive and Free from Disease 70 60 venous platinum-based chemotherapy. The primary end 50 40 30 Chemotherapy 20 10 RESULTS 0 0 6 12 18 24 30 36 42 48 54 Efficacy: During a median follow-up of 27.8 months Months since Randomization (27.8 months in the alectinib group and 28.4 months in the chemotherapy group), alectinib therapy was associ- ated with a 76% lower risk of disease recurrence or death Adverse Events than chemotherapy. Alectinib (N=128) Chemotherapy (N=120) Safety: Adverse events were common, most were low 100 98.4 93.3 grade, and few led to treatment discontinuation. No 90 LIMITATIONS AND REMAINING QUESTIONS Estimated Percentage of Patients 80 new safety issues arose. 70 60 50 40 30 29.7 30.8 Black patients were underrepresented in the trial 20 population. 10 0 Longer follow-up is needed to better understand the Any Adverse Event Grade 3 or 4 Adverse Events effect of adjuvant alectinib on overall survival. The trial did not address the potential usefulness of CONCLUSIONS adding chemotherapy to alectinib, which could allow therapy intensification in selected patient groups. In patients with resected ALK-positive NSCLC, adjuvant alectinib showed a significant benefit with respect to The appropriate treatment duration of adjuvant targeted therapies in resectable NSCLC is still unclear. disease-free survival as compared with adjuvant platinum- based chemotherapy, as well as a low-grade safety profile with few discontinuations due to adverse events. Links: Full Article NEJM Quick Take Editorial

[Slide 1] E SNINKER MIASON SVR AUTHAR and

[Slide 1] STATES YORK BE