28673 : étude de phase II de l’alectinib chez les patients ALK+ prétraités par crizotinib (1) CBNPC ALK+ [FISH test]; ≥ 18 ans Localement avancé ou métastatique  Progression sous crizotinib ou intolérance Alectinib 600 mg x 2/j p.o. Traitement à progression, décès, toxicité Objectif principal : RO par revue indépendante RECIST1.1 Objectifs secondaires RO investigateurs Durée de réponse Réponse cérébrale SSP Taux de contrôle Progression SNC SG Tolérance 8008 - Efficacy and safety of the ALK inhibitor alectinib in ALK+ non-small-cell lung cancer (NSCLC) patients who have failed prior crizotinib: An open-label, single-arm, global phase 2 study (NP28673).   Session: Lung Cancer—Non-Small Cell Metastatic Type: Oral Abstract Session Time: Sunday May 31, 8:00 AM to 11:00 AM Location: N Hall B1 Citation: Background: The ALK inhibitor crizotinib is approved for patients (pts) with ALK-rearranged (ALK+) NSCLC, but most pts progress within a year and CNS progression is common. The NP28673 study (NCT01801111) investigated the efficacy and safety of alectinib, a highly selective, CNS-active ALK inhibitor, in ALK+ NSCLC pts who had progressed on crizotinib.Methods: Eligible pts ( ≥ 18 yrs; locally advanced or metastatic ALK+ NSCLC [by FDA-approved FISH test]; failed on/intolerant to crizotinib) received alectinib 600mg p.o. BID until progression, death or withdrawal. Crizotinib was the only prior ALK inhibitor permitted. Primary endpoint was objective response rate (ORR) by independent review committee (IRC) using RECIST v1.1. Secondary endpoints included ORR by investigator; duration of response (DOR); CNS ORR and DOR; progression-free survival (PFS); disease control rate (DCR), CNS progression rate, overall survival, and safety. Results: 138 pts from 16 countries were enrolled by the 18 Aug 2014 cut-off. Median age 52 yrs; 80% had prior chemo; 60% had baseline CNS mets (60/83 treated). Median follow-up was 30 wks. In the response-evaluable population assessed by IRC (122 pts with measurable disease at baseline), ORR was 49.2% (95% CI 40.0–58.4; all PRs); DCR was 79.5% (95% CI 71.3–86.3). For patients with prior chemo and crizotinib (n = 96), ORR was 43.8% (95% CI 33.6–54.3); DCR was 78.1% (95% CI 68.5–85.9). For patients with baseline measurable CNS disease (n = 34), IRC-assessed CNS ORR was 55.9% (95% CI 37.9–72.8), including five CRs. Updated ORR, DOR and PFS data will be presented. Overall, 27.5% of pts had grade 3–5 adverse events (AEs), most commonly dyspnea (3.6%) and pulmonary embolism (2.2%); low rates of dose interruptions (19.6%), reductions (8.7%), and withdrawals (8.0%) due to AEs were seen. Conclusions: Alectinib was well tolerated and achieved a robust treatment response, including excellent intracranial activity, in ALK+ NSCLC pts who had progressed on crizotinib; most had also failed prior chemo and had CNS mets. A phase 3 trial of first-line alectinib vs crizotinib and an expanded access program are ongoing. Clinical trial information: NCT01801111 ASCO® 2015 - D’après Ou SHI et al., abstr. 8008, actualisé

28673 : étude de phase II de l’alectinib chez les patients ALK+ prétraités par crizotinib (2) Alectinib (n = 138) Âge (ans) Mediane (min-max) 52 (22–79) Sexe, n (%) Masculin 61 (44) Féminin 77 (56) Ethnie, n (%) Caucasien 93 (67) Asiatique 36 (26) Autre 9 (7) ECOG PS, n (%) 44 (32) 1 81 (59) 2 13 (9) Tabagisme, n (%) Jamais fumeur 96 (70) Ancien fumeur 42 (30) Histologie, n (%) Adénocarcinome 133 (96) 5 (4) Métastase cérébrale à l’inclusion, n (%) Oui 84 (61) Non 54 (39) Chimiothérapie antérieure, n (%) Toutes lignes 110 (80) 1 ligne 52 (47) 2 lignes 16 (12) > 2 lignes ASCO® 2015 - D’après Ou SHI et al., abstr. 8008, actualisé

Sum of longest diameter, Max decrease from BI (%) 28673 : étude de phase II de l’alectinib chez les patients ALK+ prétraités par crizotinib (3) Protocole : NP28673 Population : réponse évaluable (IRC) 140 120 BOR systémique PD (n = 22) SD (n = 35) RP (n = 61) NE (n = 1) Manquant (n = 3) 100 80 60 40 Sum of longest diameter, Max decrease from BI (%) 20 -20 -40 -60 -80 Patient -100 Population évaluable (n = 122) Prétraitée par CT (n = 96) Chimionaïve (n = 26) RO (%) 61 (50,0) 43 (44,8) 18 (69,2) Taux de contrôle (%) 96 (78,7) 74 (77,1) 22 (84,6) ASCO® 2015 - D’après O SHI et al., abstr. 8008, actualisé

Survie sans progression (%) 28673 : étude de phase II de l’alectinib chez les patients ALK+ prétraités par crizotinib (4) 100 80 60 Survie sans progression (%) 40 20 Alectinib 600 mg BID SE (n = 138) Alectinib 600 mg BID RE2 (n = 112) Alectinib 600 mg Chimiothérapie antérieure (n = 96) Alectinib 600 mg BID Chimionaïf (n = 26) J1 M3 M6 M9 M12 M15 M18 Alectinib 600 mg BID SE Alectinib 600 mg BID RE2 Alectinib 600 mg CT antérieure Alectinib 600 mg BID Chimionaïfs 138 122 96 26 109 95 73 22 76 68 53 15 65 57 44 13 17 16 13 3 1 ASCO® 2015 - D’après Ou SHI et al., abstr. 8008, actualisé

28673 : étude de phase II de l’alectinib chez les patients ALK+ prétraités par crizotinib (5) Réponse cérébrale à l’alectinib 80 Irradiation cérébrale Oui (n = 24) Non (n = 11) 60 40 20 Réduction de taille tumorale (%) –20 –40 –60 –80 Patient –100 Irradiation antérieure (n = 61) Pas d’irradiation (n = 23) Réponse cérébrale, n (%) RO (%) 24 (39,3) 12 (52,2) Taux de contrôle 86,9 % 73,9 % ASCO® 2015 - D’après OU SHI et al., abstr. 8008, actualisé