Abemaciclib (abema), a cyclin D kinase 4 & 6 inhibitor, has single-agent activity and an acceptable safety profile when dosed continuously in patients with previously treated metastatic NSCLC (NCT01394016). In tumor models, CDK inhibition induces an escape pathway involving PI3kinase (PI3K) and abema induces synergistic immune activation with checkpoint inhibitors. We report on activity and safety of abema plus LY3023414 (LY), a PI3K/mTOR dual inhibitor, and abema plus pembrolizumab (pembro), an anti-PD-1 antibody, in an ongoing Phase 1b open-label, 3 + 3 multicenter trial of previously treated advanced NSCLC (NCT02079636).
For escalation, Abema [100, 150 mg, or 200 mg (cohort D only)] was given orally on a continuous schedule every 12 hours (q12h) with LY at 100, 150, or 200 mg q12h (cohort D) or with pembro at 200 mg I.V. infusion q3 weeks (cohort E). Confirmatory cohorts were given 150 mg abema with 150 mg LY or 200 mg pembro. Pts were treated until progression or other discontinuation criteria were met. Responses were evaluated with RECIST v1.1. Safety assessments followed the NCI-CTCAE v4.0.
As of 01-Mar-2017, cohort D (n = 29) had 62.1% males, 37.9% ≥65 years of age, median # prior systemic therapies=3; 86.2% stage IV; 72.4% adenocarcinoma; 62.1% ECOG PS = 1. 9 pts (31%) had stable disease (SD), 3 pts had progressive disease (PD), and the status for the remaining 17 pts was unknown or under evaluation. There were 3 deaths unrelated to study drug (2 disease related and 1 stroke). 24/29 pts had a treatment emergent, related AE (TRAE), 10/24 had a Grade 3/4 TRAE. Any grade TRAEs (>30% pts) were nausea (51.7%), diarrhea (51.7%), vomiting (41.4%), and decreased appetite (31%). Cohort E had 19 pts entered (42.1% male, 42.1% ≥65 years of age, median # prior systemic therapies=2; 52.6% stage IV; 89.5% adenocarcinoma; 57.9% ECOG PS = 1). 8 pts (42.1%) had SD, 1 had PD, and the status for the remaining 10 pts was unknown or under evaluation. There were 3 disease related deaths. 15/19 pts had a TRAE, 5/15 had a G3/4 TRAE. Any grade TRAEs (>30% pts) were fatigue (n = 47.4%) and diarrhea (36.8%).
To date, stable disease as best response and acceptable safety have been observed using combinations of abema and either LY or pembro in advanced NSCLC.
Clinical trial identification
Legal entity responsible for the study
Eli Lilly and Company
Eli Lilly and Company
P. Garrido Lopez: Advisor/Board member: MSD, Pfizer, BMS, Novartis, Roche, BI, Guardant Speakers Bureau: MSD, Pfizer, BMS, Novartis, Roche Honorarium recipient: BI J. Goldman: Research grant from Eli Lilly and company Eli Lilly and Company\'s Scientific Advisory Board member. K. Kelly: Attended a Lilly advisory board in Feb 2017 that discussed Abemaciclib. E.S. Kim: Celgene - Consultant Boehringer Ingelheim - Consultant Eli Lilly - Consultant AstraZeneca – Consultant. Z. Yang, L. Amstutz, W.J. John: Full time employee of Eli Lilly and Company. K-J. Ingram: Stock ownership in Eli Lilly and Company. Employee of Eli Lilly and company. M. Provencio Pulla: Corporate-sponsored research (investigator): GI Therapeutics, Eli Lilly and Company. All other authors have declared no conflicts of interest.