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Phase I/II Study Results with Lorlatinib in ROS1-positive Advanced NSCLC

Clinical activity observed even in patients with CNS metastases and those previously treated with crizotinib
30 Oct 2019
Anticancer agents & Biologic therapy;  Lung and other thoracic tumours;  Personalised medicine

Results from a phase I/II study conducted in patients with ROS1-positive advanced non-small cell lung cancer (NSCLC) show clinical activity of lorlatinib, a third-generation tyrosine kinase inhibitor (TKI), even in patients with central nervous system (CNS) metastases and those previously treated with crizotinib. The results are published on 25 October 2019 in The Lancet Oncology.

The authors wrote in study background that ROS1 rearrangements are identified in approximately 1–2% of patients with NSCLC and define a distinct molecular subset with sensitivity to ROS1 inhibition. ALK TKIs are also active against ROS1, but most patients relapse because of resistance. Although acquired resistance is a major cause of crizotinib failures, relapses are also common in the CNS. Several ROS1-targeted agents are evaluated in clinical trials.

Lorlatinib is a potent, brain-penetrant, third-generation TKI that targets ALK and ROS1 with preclinical activity against most known resistance mutations in ALK and ROS1.

In this open-label, single-arm, ongoing phase I/II trial, the study team led by Prof. Alice T Shaw of the Massachusetts General Hospital in Boston, USA investigated the anti-tumour activity and safety of lorlatinib in ROS1-positive advanced NSCLC. They enrolled patients from 12 countries aged at least 18 years with histologically or cytologically confirmed advanced NSCLC with ROS1 rearrangement, with or without CNS metastases, and performance status 2 or less according Eastern Cooperative Oncology Group scale.

ROS1 positivity was established by fluorescence in situ hybridisation, RT-PCR, or next-generation sequencing via a local laboratory developed test.

Lorlatinib was administered orally in continuous 21-day cycles at escalating doses 10 mg once daily to 100 mg twice daily in phase I, and at a starting dose of 100 mg once daily in phase II study. Treatment continued until investigator-determined disease progression, unacceptable toxicity, withdrawal of consent, or death. Treatment could be continued after progression if the patient was still experiencing clinical benefit, at the discretion of the investigator.

The primary endpoint was overall and intracranial tumour response, assessed by independent central review. Activity endpoints were assessed in patients who received at least one dose of lorlatinib.

The study team assessed 364 patients between January 2014 and October 2016; among those 69 patients with ROS1-positive advanced NSCLC have been enrolled. In the study 21 of 69 patients (30%) were TKI-naive, 40 patients (58%) had previously received crizotinib as their only TKI, and 8 patients (12%) had previously received one non-crizotinib ROS1 TKI or two or more ROS1 TKIs. The estimated median duration of follow-up for response was 21.1 months.

In total 13 of 21 (62%) TKI-naive patients and 14 of 40 (35%) patients previously treated with crizotinib as their only TKI had an objective response. Intracranial responses were achieved in 7 of 11 (64%) TKI-naive patients and 12 of 24 (50%) previous crizotinib-only treated patients.

The most common grade 3–4 treatment-related adverse events were hypertriglyceridaemia (19%) and hypercholesterolaemia (14%). Serious treatment-related adverse events occurred in 7%. No treatment-related deaths were reported.

The authors concluded that lorlatinib shows clinical activity in patients with ROS1-positive advanced NSCLC who are ROS1 TKI-naive or who have previously received crizotinib. Marked intracranial activity was also observed in both TKI-naive and crizotinib-pretreated patients. Lorlatinib was well tolerated, with no new safety signals reported. Lorlatinib might represent an important next-line targeted agent in patients with ROS1-positive advanced NSCLC, including those with CNS metastases.

The study was funded byPfizer.



Shaw AT, Solomon BJ, Chiari R, et al. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1–2 trial. Lancet Oncology; Published 25 October 2019. DOI: https://doi.org/10.1016/S1470-2045(19)30655-2

Last update: 30 Oct 2019

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