1308PD - Preliminary efficacy and safety of lorlatinib in patients (Pts) with ROS1-positive non-small cell lung cancer (NSCLC)

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Background: Most pts with ROS1-rearranged NSCLC achieve initial benefit with crizotinib but subsequently develop resistance, and further treatment options are limited. In Phase 1 of this study, lorlatinib, a potent and brain-penetrant TKI, was associated with a response rate of 50% in ROS1-positive NSCLC pts, most of whom had central nervous system (CNS) metastases (mets) and a majority of whom had received prior crizotinib. Antitumor activity and safety were explored at the recommended Phase 2 dose. Methods: In this ongoing, Phase 2 study (NCT01970865), pts with ROS1+ NSCLC, ± asymptomatic untreated or treated CNS mets were enrolled with no restriction on the type or number of prior lines of therapy. Pts received lorlatinib 100 mg QD. The primary objective was overall and intracranial (IC) antitumor activity, measured as overall and IC response by independent central review. Results: 23 pts with ROS1+ NSCLC were treated; 12 had CNS involvement, 16 had received prior crizotinib and 1 had received prior crizotinib and ceritinib. The overall response rate (ORR) by investigator assessment for this cohort was 8/23 (34.8%; 95% CI: 16.4, 57.3). The best overall response was SD in 11 pts (47.8%) and progressive disease (PD) in 2 pts (8.7%). The disease control rate at 12 weeks was 17/23 (73.9%; 95% CI: 51.6, 89.8). Of 8 pts with a confirmed response, 3 have progressed (after a range of 3.5–7.0 mos) and the remainder are in follow-up (range: 5.6–8.3 mos). The IC-ORR was 3/12 (25%) (95% CI: 5.5, 57.2). The most commonly reported treatment-related adverse events (TRAEs) were hypercholesterolemia (95.7%) and hypertriglyceridemia (69.6%) both managed with statins or other lipid lowering agents. Additional TRAEs included peripheral edema (34.8%) and cognitive effects (30.4%). Treatment-related dose interruptions and dose reductions occurred in 26.1% and 17.4% of pts, respectively; there were no treatment-related discontinuations or deaths. Most pts remain on treatment. Conclusions: Lorlatinib has shown clinical activity in ROS1+ NSCLC pts, a majority of whom had CNS involvement and most of whom had received prior crizotinib. Overall, lorlatinib was well-tolerated with lipid elevations being the most common TRAEs. Clinical trial identification: NCT01970865 Legal entity responsible for the study: Pfizer Funding: Pfizer Disclosure: B. Besse: Corporate sponsored research: Pfizer. A.T. Shaw: Advisory board or board of directors: Blueprint medicines, KSQ Therapeutics (scientific advisory board). Consulting/Honoria Pfizer, Novartis, Ariad, Genentech/Roche, Ignyta, Daiichi-sankyo, Taiho, LOXO, Blueprint medicines, EMD Serono, Foundation Medicine. B.J. Solomon: Membership of an advisory board or board of directors: Advisory Boards: Pfizer, Novartis, Roche-Genentech, AstraZeneca, Merck, Bristol Myers Squibb. M. Satouchi: Corporate sponsored research: Pfizer Honoraria: Pfizer. J.S. Clancy: Employed by inVentiv clinical but under contract position with Pfizer. L.P. James, A. Abbattista: Employee and stock owner of Pfizer. E. Felip Font: Advisory boards: Eli Lilly, Pfizer, Roche, MSD, Boehringer Ingelheim Speaker's bureau/lectures fees: AstraZeneca, BMS, Novartis. All other authors have declared no conflicts of interest.