Standard therapy for advanced anaplastic lymphoma kinase (ALK)+ NSCLC consists of first-line crizotinib, followed by 2nd-generation ALK tyrosine kinase inhibitors (TKIs) such as ceritinib, alectinib, or brigatinib. While pts can achieve some clinical benefit from these agents, most will subsequently develop resistance. Lorlatinib, a brain-penetrant next-generation ALK TKI, is active against most known resistance mutations that can develop during treatment with 1st- and 2nd-generation TKIs. Here, we explore the antitumor activity and safety of lorlatinib in pts with ALK+ NSCLC treated with ≥1 prior 2nd-generation TKI.
In this ongoing phase 2 study (NCT01970865), pts with ALK+ or ROS1+ NSCLC, ± asymptomatic untreated or treated central nervous system (CNS) metastases, were enrolled into 1 of 5 ALK+ cohorts dependent on the number of prior TKIs received, and 1 ROS1+ cohort with no restriction on the extent of previous therapy. Pts received lorlatinib 100 mg QD. The primary objective was overall and intracranial (IC) antitumor activity, measured as confirmed overall and IC response by independent central review (ICR).
At the data cutoff (15 Aug 2016), 65 pts with ALK+ NSCLC were treated with ≥1 prior 2nd-generation TKI (alectinib, ceritinib, brigatinib, or other). Of these pts, 41 had CNS metastases at baseline. The table shows the confirmed overall and IC responses (complete response + partial response) by ICR. The most common treatment-related adverse events (TRAEs) of any grade in pts who received prior ALK TKIs were hypercholesterolemia, hypertriglyceridemia, and peripheral neuropathy. Hyperlipidemia was successfully managed by appropriate medical treatment.Table:
|Type of 2nd-Generation TKI||Overall||Intracranial|
|Na||Confirmed Responses, n (%)||Na||Confirmed Responses, n (%)|
|Alectinib||33||9 (27)||16||8 (50)|
|Ceritinib||29||9 (31)||23||11 (48)|
|Brigatinib||6||1 (17)||3||0 (0)|
|Other||5b||2 (40)||4||2 (50)|
Patients in each group of prior TKI; a patient could have received more than one type of prior TKI.b
Other TKIs included entrectinib (n = 3) and ensartinib (n = 2).
Lorlatinib has shown clinical activity in pts with ALK+ NSCLC who had received ≥1 prior 2nd-generation TKI.
Clinical trial identification
Legal entity responsible for the study
E. Felip Font: Advisory boards: Eli Lilly, Pfizer, Roche, MSD, Boehringer Ingelheim. Speaker\'s bureau/lectures fees: AstraZeneca, BMS, Novartis. 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: Advisory Boards: Pfizer, Novartis, Roche-Genentech, AstraZeneca, Merck, Bristol Myers Squibb. S-H.I. Ou: Membership of an advisory board or board of directors: Genentech/Roche, Ariad, Pfizer, Novartis, Astra Zeneca. S. Gadgeel: Membership of an advisory board or board of directors: Genentech/Roche, Ariad, Pfizer, Novartis. R.A. Soo: Membership of an advisory board or board of directors: AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Merck, Novartis, Pfizer, Roche, Taiho Corporate sponsored research: AstraZeneca. T. Seto: Research funding from Eisai Co., Ltd., MSD, K.K., Nippon Boehringer Ingelheim Co., Ltd, Pfizer Japan Inc., AstraZeneca K.K., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., Merck Serono Co., Ltd., Novartis Pharma K.K., Pfizer Japan Inc. Honoraria from AstraZeneca K.K., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Kissei Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co., Ltd., MSD K.K., Nippon Boehringer Ingelheim Co., Ltd, Nippon Kayaku Co., Ltd., Ono Pharmaceutical Co. Ltd., Pfizer Japan Inc. Roche Singapore Pte Ltd, Taiho Pharmaceutical Co., Ltd., YakultHonsha Co., Ltd. J.S. Clancy: Employed by inVentiv Clinical but under contract position with Pfizer. L.P. James, A. Abbattista: Employee and stock owner of Pfizer. B. Besse: Corporate sponsored research: Pfizer. All other authors have declared no conflicts of interest.