390OEfficacy and safety of ceritinib in ALK-positive non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM): Results from the phase II, ASCEND-7 study

• Published in: Annals of oncology Vol. 30; no. Supplement_5
• Main Authors: Barlesi, F, Kim, D -W, Bertino, E M, van den Bent, M J, Wakelee, H, Wen, P Y, Garrido Lopez, P, Orlov, S, Majem, M, McKeage, M, Yu, C -J, Hurtado, F K, Cazorla Arratia, P, Song, Y, Branle, F, Shi, M, Chow, L Q
• Format: Journal Article
• Language: English
• Published: Oxford University Press 01-10-2019
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdz243

Abstract
Background
LM are seen in approximately 5% of ALK+ NSCLC patients (pts), and are associated with poor prognosis with standard treatment. Ceritinib is highly active in ALK+ NSCLC pts with previously reported intracranial/central nervous system activity. We report the efficacy and safety of ceritinib in ALK+ NSCLC pts with LM enrolled in the ASCEND-7 study (NCT02336451).
Methods
Pts with documented ALK + (FISH) NSCLC, CSF invasiveness with radiologically or cytologically confirmed LM, and ≥1 extracranial measurable lesion using RECIST v1.1 were eligible. The study objectives included evaluation of antitumor activity based on overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Data cut-off was Feb 6, 2019.
Results
Of the 18 LM pts enrolled, 14 pts (77.8%) also had brain metastases and 8 pts (44.4%) had measurable brain metastases at baseline. Majority of the pts (n = 16, 88.9%) had received prior crizotinib and 7 pts (38.9%) had received prior brain radiotherapy. Median duration of exposure to ceritinib was 18.1 weeks (range: 1.7–125.9). Whole body ORR by investigator assessment was 16.7% (95% CI: 3.6, 41.4) with median duration of response of 5.5 months (95% CI: 3.7, 9.9) and a clinically significant median PFS of 5.2 months (95% CI: 1.6, 7.2). Median duration of follow-up for PFS was 3.84 months (range: 0.5–13). Additional efficacy endpoints are included in the below Table. Adverse events (AEs, all grades, regardless of study drug relationship) were reported in all 18 pts. Grade 3/4 AEs occurring in ≥ 10% of pts were increased alanine aminotransferase (22.2%), hyperglycemia (16.7%), increased gammaglutamyltransferase (11.1%), pneumonia (11.1%), and increased lipase (11.1%). Table: Efficacy results
Table: 390OEndpoint per investigator assessmentArm 5 (ALK+ NSCLC pts with LM) N = 18Whole body Response (RECIST v1.1)ORR, % (95% CI)16.7 (3.6, 41.4)DCR, % (95% CI)66.7 (41.0, 86.7)Median DOR, (months) [95% CI]5.5 (3.7, 9.9)Median PFS, (months) [95% CI]5.2 (1.6, 7.2)Intracranial response* (modified RECIST v1.1)M = 8ORR, % (95% CI)12.5 (0.3, 52.7)DCR, % (95% CI)62.5 (24.5, 91.5)Extracranial response (RECIST v1.1)ORR, % (95% CI)22.2 (6.4, 47.6)DCR, % (95% CI)72.2 (46.5, 90.3)Median OS, months (95% CI)7.2 (1.6, 16.9)*In patients with measurable brain metastases 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
Ceritinib demonstrated a clinically meaningful efficacy and a safety profile similar to earlier reported results in this largest reported set of ALK+ NSCLC pts with LM.
Clinical trial identification
NCT02336451.
Editorial acknowledgement
Aarti Kamaraj, Novartis Healthcare Pvt Ltd (Hyderabad, India).
Legal entity responsible for the study
Novartis Pharmaceuticals.
Funding
Novartis Pharmaceuticals.
Disclosure
F. Barlesi: Honoraria (self): AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology; Honoraria (self): F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda; Research grant / Funding (institution): Abbvie, ACEA, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis; Non-remunerated activity/ies, Principal investigator: AstraZeneca, BMS, Merck, Pierre Fabre and F. Hoffmann-La Roche, Ltd, sponsored trials (or ISR); Research grant / Funding (institution): Takeda. 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. 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, AZ; Advisory / Consultancy, Compensated: AstraZeneca, Xcovery, Janssen; Advisory / Consultancy, Not compensated: Merck, Takeda, Genentech/Roche; 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 Lily, 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 Lily, Genentech/Roche, Karyopharm, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Sanofi-Aventis, VBI Vaccines. P. Garrido Lopez: Advisory / Consultancy: Roche, MSD, BMS, Boerhinger Ingelheim, Pfizer, Abbvie, Guardant Health, Novartis, Lilly, AstraZeneca, Jansen, Sysmex, Blueprint Medicines, Takeda; Speaker Bureau / Expert testimony: Roche, MSD, BMS, Pfizer, Novartis, Boerhinger Ingelheim, Rovi; Research grant / Funding (institution), Financial support for clinical trials: Roche, MSD, BMS, Takeda, Lilly, Pfizer, Novartis, Pharmamar, Celgene, Sanofi, GSK, Theradex Oncology, BluePrint Medicines; Research grant / Funding (institution), Financial support for contracted research: Guardant Health, Sysmex. 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. 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: Novartis Pharmaceuticals Corp.; Full / Part-time employment: Novartis Pharmaceuticals Corp. P. Cazorla Arratia: Shareholder / Stockholder / Stock options: Novartis Pharmaceuticals Corporation; Full / Part-time employment: Novartis Pharmaceuticals Corporation. Y. Song: Shareholder / Stockholder / Stock options, Restricted Stock Unit: Novartis Pharmaceutical Corporation; Full / Part-time employment: Novartis Pharmaceutical Corporation. F. Branle: Shareholder / Stockholder / Stock options: Novartis AG; Full / Part-time employment: Novartis AG. M. Shi: Shareholder / Stockholder / Stock options: Novartis; Full / Part-time employment: Novartis Pharmaceuticals Corporation. L.Q. Chow: Advisory / Consultancy: Bristol-Myers Squibb, Merck, Genentech, AstraZeneca/Medimmune, Pfizer, Seattle Genetics, Novartis, Dynavax Inc., Alkermes, Amgen, Sanofi-Genzyme, Takeda; Research grant / Funding (institution): Bristol-Myers Squibb, Merck, Genentech, AstraZeneca/Medimmune, Pfizer, Seattle Genetics, Novartis, Dynavax Inc. and Alkermes,Incyte, VentiRx and Lily/Imclone. All other authors have declared no conflicts of interest.