1478OResults of the ASCEND-7 phase II study evaluating ALK inhibitor (ALKi) ceritinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) metastatic to the brain

• Published in: Annals of oncology Vol. 30; no. Supplement_5
• Main Authors: Chow, L Q, Barlesi, F, Bertino, E M, van den Bent, M J, Wakelee, H, Wen, P Y, Chiu, C-H, Orlov, S, Majem, M, Chiari, R, McKeage, M, Yu, C-J, Hurtado, F K, Arratia, P Cazorla, Song, Y, Branle, F, Shi, M, Kim, D-W
• Format: Journal Article
• Language: English
• Published: Oxford University Press 01.10.2019
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdz260

Abstract Background Ceritinib is approved for the treatment of pts with metastatic ALK+ NSCLC. In previous studies (ASCEND-1 to 5), ceritinib was highly active in ALK+ NSCLC pts with reported intracranial responses in pts with measurable baseline brain lesions. ASCEND-7 (NCT02336451) was designed to specifically study intracranial effects of ceritinib and we report here efficacy and safety in pts with ALK+ NSCLC metastatic to the brain (Arms 1-4). Methods Eligible pts had, WHO performance status 0-2, ALK + (FISH) NSCLC, with active brain metastases (BM) either newly diagnosed or progressive, and ≥1 extracranial measurable lesion using RECIST v1.1. Pts may have been pretreated with chemotherapy and/or crizotinib (ALK inhibitor [ALKi]). Pts were assigned to arms 1 to 4 depending on prior treatment (refer to below table). Primary endpoint was investigator assessed whole body overall response rate (CR or PR) and key secondary endpoint was investigator assessed disease control rate (CR or PR or SD). Intracranial responses and extracranial responses were assessed using modified RECIST 1.1 and RECIST 1.1, respectively. Results As of 6-Feb-2019, 138 pts were treated in Arms 1-4 (Arm 1: 42; Arm 2: 40; Arm 3: 12; Arm 4: 44), and all the pts discontinued the treatment. Median follow-up for whole body progression free survival was 5.49 months across Arm 1-4. Efficacy endpoints by investigator assessment are reported in the below Table. Most common AEs (>50% all grades in any of the Arms 1-4) regardless of causality were diarrhoea, nausea, ALT increased, vomiting, AST increased, decreased appetite. Majority of these AEs was grade 1/2. Table:1478O Overall efficacyArm 1 (prior brain radiotherapy and prior ALKi) N = 42Arm 2 (no prior brain radiotherapy and prior ALKi) N = 40Arm 3 (prior brain radiotherapy and no prior ALKi) N = 12Arm 4 (no prior brain radiotherapy and no prior ALKi) N = 44Whole body efficacy (RECIST v1.1) ORR, % [95% CI] DCR, % [95% CI] 35.7 [21.6, 52.0] 66.7 [50.5, 80.4] 30.0 [16.6, 46.5] 82.5 [67.2, 92.7] 50.0 [21.1, 78.9] 66.7 [34.9, 90.1] 59.1 [43.2, 73.7] 70.5 [54.8, 83.2]Whole body efficacy (RECIST v1.1) Median DOR, months [95% CI] Estimated 6-month event-free probability, % [95% CI]L‡ = 15 10. 8 [4.1, NE] 64.6 [34.7, 83.5]L‡ = 12 12.8 [3.7, 17.3] 74.1 [39.1, 90.9]L‡ = 6 NE [11.7, NE] 100 [100, 100]L‡ = 26 9.2 [7.3, 23.9] 72.7 [51.1, 86.0]Whole body efficacy (RECIST v1.1) Median PFS, months [95% CI] Estimated 6-month event-free probability, % [95% CI] 7.2 [3.3, 10.9] 58.7 (41.6, 72.4) 5.6 [3.6, 9.2] 44.7 [28.5, 59.5] NE [1.0, NE] 66.7 [33.7, 86.0] 7.9 [5.5, 9.4] 63.4 [46.8, 76.1]Intracranial response* (modified RECIST v1.1†) ORR, % [95% CI] DCR, % [95% CI]M = 28 39.3 [21.5, 59.4] 75.0 [55.1, 89.3]M = 29 27.6 [12.7, 47.2] 82.8 [64.2, 94.2]M = 7 28.6 [3.7, 71.0] 85.7 [42.1, 99.6]M = 33 51.5 [33.5, 69.2] 75.8 [57.7, 88.9]Intracranial response* (modified RECIST v1.1†) Median DOR, months [95% CI] Estimated 6-month event-free probability, % (95% CI)L‡ = 11 9.2 [3.7, NE] 66.7 [28.2, 87.8]L‡ = 8 10.1 [3.8, 17.3] 62.5 [22.9, 86.1]L‡ = 2 NE 100 [100, 100]L‡ = 17 7.5 [5.6, 11.2] 70.6 [43.1, 86.6]Extracranial response (RECIST v1.1) ORR, % [95% CI] DCR, % [95% CI] 31.0 [17.6, 47.1] 69.0 [52.9, 82.4] 42.5 [27.0, 59.1] 92.5 [79.6, 98.4] 41.7 [15.2, 72.3] 66.7 [34.9, 90.1] 61.4 [45.5, 75.6] 72.7 [57.2, 85.0]Median OS, months [95% CI] Estimated 12-month event-free probability, % [95% CI]24.0 [12.6, NE] 67.4 [50.4, 79.6]NE [16.2, NE] 72.9 [55.5, 84.5]NE [1.0, NE] 75.0 [40.8, 91.2]NE [26.5, NE] 77.9 [61.8, 87.9]*In patients with measurable brain metastases at baseline. †The usual criteria to select target lesions will be used but a maximum five target lesions located in the brain can be selected at baseline and evaluated at each assessment time point. ‡L is the number of patients included in the duration of response analysis. M, number of patients with measurable brain metastases at baseline DCR, disease control rate; DOR, duration of response; NE, not estimable ORR, overall response rate; OS, overall survival; PFS, progression free survival; RECIST, Response Evaluation Criteria in Solid Tumors Conclusions Efficacy of ceritinib, either in pts with or without a prior exposure to crizotinib, as reported in other studies, is confirmed in this study where only pts with active brain metastases were eligible. Safety profile of ceritinib in these pts remain consistent to what was reported earlier. Clinical trial identification NCT02336451. Editorial acknowledgement Shiva Krishna Rachamadugu, Novartis Healthcare Pvt Ltd, Hyderabad, India. Legal entity responsible for the study Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals Corporation. Disclosure L.Q. Chow: Advisory / Consultancy, Consultation Honoraria/Review panel: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Lilly/Imclone; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune ; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Incyte; Advisory / Consultancy: Takeda; Research grant / Funding (institution): VentiRx; Advisory / Consultancy: Sanofi-Genzyme; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Dynavax; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy: Synthorx; Research grant / Funding (institution): Alkermes. F. Barlesi: Honoraria (self), Research grant / Funding (institution): AstraZeneca, Bayer; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Boehringer–Ingelheim; Honoraria (self), Research grant / Funding (institution): Eli Lilly Oncology; Honoraria (self), Research grant / Funding (institution): F. Hoffmann–La Roche Ltd; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Merck; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Pierre Fabre; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Takeda; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): ACEA; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): MedImmune and Sanofi-Aventis; Non-remunerated activity/ies: Principal Investigator for AstraZeneca, BMS, Merck, Pierre Fabre and F. Hoffmann-La Roche, Ltd, sponsored trials (or ISR). E.M. Bertino: Advisory / Consultancy: Takeda; Speaker Bureau / Expert testimony: Pfizer. M.J. van den Bent: Honoraria (self): Celgene, Agios, Boehringer, BMS, AbbVie ; Research grant / Funding (institution): AbbVie. H. Wakelee: Honoraria (self): Novartis, AstraZeneca; Advisory / Consultancy, NOT compensated: Merck, Takeda, Genentech/Roche: AstraZeneca, Xcovery, Janssen; Research grant / Funding (institution): ACEA Biosciences, Arrys Therapeutics, AstraZeneca/MedImmune, Bayer (under Suki and not me), BMS, Celgene, Clovis Oncology, Exelixis, Genentech/Roche, Gilead, Lilly, Merck, Novartis, Pfizer, Pharmacyclics, Xcovery; Travel / Accommodation / Expenses: AstraZeneca; Officer / Board of Directors: International Association for the Study of Lung Cancer (IASLC). P.Y. Wen: Advisory / Consultancy: Agios, AstraZeneca, Beigene, Eli Lilly, Genentech/Roche, Karyopharm, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Sanofi-Aventis, VBI Vaccines, Tocagen; Speaker Bureau / Expert testimony: Merck, Prime Oncology; Research grant / Funding (institution): Agios, AstraZeneca, Beigene, Eli Lilly, Genentech/Roche, Karyopharm, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Sanofi-Aventis, VBI Vaccines. C. Chiu: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche, and Takeda. M. Majem: Advisory / Consultancy: Roche, MSD, AstraZeneca, Boehringer, Tesaro, Takeda, Pierre Fabre; Speaker Bureau / Expert testimony: Roche, BMS, MSD, AstraZeneca, Boehringer Hellsin, Pierre Fabre, Amgen; Research grant / Funding (self): BMS; Travel / Accommodation / Expenses: BMS, MSD, AstraZeneca, Lilly. R. Chiari: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Pfizer, Roche, and Takeda. M. McKeage: Advisory / Consultancy: Novartis, Pfizer; Research grant / Funding (institution): Novartis, Pfizer, Roche. C. Yu: Honoraria (self): Roche, AstraZeneca, Ono pharma, Boehringer Ingelheim ; Advisory / Consultancy: Roche, AstraZeneca, Ono pharma, Boehringer Ingelheim. F.K. Hurtado: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. P. Cazorla Arratia: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. Y. Song: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. F. Branle: Honoraria (self), Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. M. Shi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. D. Kim: Research grant / Funding (institution): Alpha Biopharma, AstraZeneca/MedImmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, and Yuhan. All other authors have declared no conflicts of