LOREALAUS: LOrlatinib REAL-World AUStralian Experience in Advanced ALK-Rearranged NSCLC

Abstract

Introduction: Over the past decade, ALK tyrosine kinase inhibitors have delivered unprecedented survival for individuals with ALK-positive (ALK+) lung cancers. Real-world data enhance the understanding of optimal drug sequencing and expectations for survival.

Methods: Multicenter real-world study of individuals with pretreated advanced ALK+ lung cancers managed on a lorlatinib access program between 2016 and 2020. Key outcomes were lorlatinib efficacy, tolerability, and treatment sequencing. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method among all individuals (PFSa and OSa), with at least 30 days (one-cycle) lorlatinib exposure (PFSb and OSb), and with good performance status (PFSc and OSc). Subgroups of interest were analyzed to assess signals of potential clinical applicability. Two OS index dates were analyzed, from lorlatinib initiation and advanced ALK+ diagnosis.

Results: The population (N = 38, 10 sites) was heavily pretreated (23 had ≥2 previous treatment lines) with a high disease burden (26 had 2-4 sites and 11 had >4 sites of metastatic disease, 19 had brain metastases). The overall response rate was 44% and the disease control rate was 81%. Lorlatinib dose reduction (18%), interruption (16%), and discontinuation (3%) were consistent with the trial experience. From advanced ALK+ diagnosis, the median OS for populations a, b, and c was 45.0 months, 69.9 months and 61.2 months respectively. From lorlatinib initiation, the median PFSa, PFSb and PFSc was 7.3 months, 13.2 months and 27.7 months and the median OSa, OSb and OSc was 19.9 months, 25.1 months and 27.7 months. The median PFSa with versus without brain metastases was 34.6 months versus 5.8 months (p = 0.09). The intracranial median PFS was 14.2 months. Previous good response versus poor response to the first ALK-directed therapy median PFSa was 27.7 months versus 4.7 months with a hazard ratio of 0.3 (p = 0.01).

Conclusions: Lorlatinib is a potent, highly active brain-penetrant third-generation ALK tyrosine kinase inhibitors with benefits for most individuals in the later-line setting in a real-world evaluation, consistent with clinical trial data.

Keywords: ALK; Anaplastic Lymphoma Kinase; Lorlatinib; NSCLC; Non–small cell lung cancer; Real-World.

Figure 1

Swimmer plot displaying treatment sequences from diagnosis of advanced or metastatic NSCLC, the best response to lorlatinib, duration of benefit on lorlatinib, and current mortality status, with time zero reflecting the initiation of lorlatinib on the drug access program. Patient 2 received lorlatinib initially on clinical trial before reexposure on the access program and their lorlatinib PFS has been included as their PFS2 on lorlatinib under the study protocol analyzing patients’ performance on lorlatinib under the compassionate access program. Chemo, nonplatinum cytotoxic chemotherapy; Chemo-Bev, bevacizumab/carboplatin/paclitaxel; Chemo-IO-Bev, atezolizumab/bevacizumab/carboplatin/paclitaxel, Chemo-Platinum, carboplatin with pemetrexed, paclitaxel or gemcitabine; IO, immunotherapy; CR, complete response; PR partial response; SD, stable disease; PD, progressive disease; NA, not assessed/not assessable; PFS, progression-free survival.

Figure 2

Real-world progression-free survival (A) and overall survival (B) from initiation of lorlatinib. ALKi, ALK-tyrosine kinase inhibitor.

Figure 3

Real-world progression-free survival (A) and overall survival (B) from initiation of lorlatinib according to previous exposure to ALKi. Treatment group classification according to ALKi only; patients may have received chemotherapy and/or immunotherapy. ALKi, ALK-tyrosine kinase inhibitor; G1, first-generation ALKi; G2, second-generation ALKi.

Figure 4

Real-world progression-free survival from initiation of lorlatinib according to previous responses to first ALKi among all comers (A), and among the subgroup who received only one second-generation ALKi before lorlatinib (B). Groups classified according to PFS to first ALK-directed therapy with individuals having PFS less than the median grouped as “poor responders” and greater than the median grouped as “good responders.” Figure A includes all patients regardless of first systemic treatment line (some individuals had chemotherapy and/or immunotherapy before first ALKi) and regardless of first ALKi generation (first or second-generation ALKi). Figure B includes the subgroup that received only first-line second-generation ALKi followed by second-line lorlatinib. ALKi, ALK-tyrosine kinase inhibitor; PFS, progression-free survival.

Figure 5

CNS outcomes. CNS progression-free survival from initiation of lorlatinib in the whole population (A) and progression-free survival (B) and overall survival (C) according to the presence of brain metastasis at the initiation of lorlatinib. CI, confidence interval; CNS, central nervous system; mets, metastasis; NR, not reported.

Figure 6

Overall survival from advanced ALK diagnosis.