By Ben Solomon, MBBS, PhD, FRACP
Posted: August 21, 2020
ROS1 rearrangements are found in 1% to 2% of patients with NSCLC. They tend to occur in never smokers and those with adenocarcinoma histology, but molecular testing guidelines recommend testing all patients with non-squamous NSCLC for ROS1 rearrangements regardless of smoking history. Crizotinib was the first U.S. Food and Drug Administration (FDA)–approved agent, with an objective response rate of 72%, median PFS of 19.3 months, and median OS of 51.4 months.1,2 However, additional treatment options are required for patients with ROS1-positive NSCLC who develop disease progression on crizotinib, including progression in the central nervous system (CNS). ROS1 tyrosine kinase inhibitors (TKIs) with increased CNS activity—including entrectinib, lorlatinib, and repotrectinib—have been developed and evaluated in clinical trials.
Lorlatinib is a novel macrocyclic inhibitor of both the ALK and ROS1 kinases. The overall and intracranial activity of lorlatinib in patients with ALK-positive NSCLC has been reported3,4 and led to the FDA approval of lorlatinib for patients with previously treated ALK-positive NSCLC. In this study, published in December 2019 in The Lancet Oncology, Shaw et al.5 reported the efficacy of lorlatinib in patients with advanced ROS1-positive NSCLC.
Sixty-nine patients with ROS1-positive NSCLC were enrolled in the trial and received treatment with lorlatinib at a starting dose of 100 mg daily. Twentyone (30%) were ROS1 TKI–naive, whereas 40 (58%) had received only crizotinib, and eight (12%) had received one non-crizotinib TKI or two or more TKIs. Brain metastases were present at baseline in 39 patients (57%), of whom 19 had received prior radiotherapy. Sixty-two percent (13/21) of patients who were TKI naive had an objective response, including two (10%) complete responses. The median duration of response was 25.3 months. Median PFS was 21.0 months. In patients who had received prior crizotinib, 35% (14/40) had objective responses with a median duration of response of 13.8 months and median PFS of 8.5 months. No responses were seen in patients with G2032R mutations. Importantly, lorlatinib demonstrated CNS activity with intracranial responses in seven of 11 patients who were TKI naive (64%) and in 12 of 24 (50%) patients who had received only crizotinib. Toxicity was consistent with that previously reported: treatment-related grade 3 or 4 adverse events occurred in 49% of patients; the most common were hypertriglyceridemia (19%) and hypercholesterolemia (14%).
These results indicate that lorlatinib represents an effective treatment option both for crizotinib-treated and crizotinib-naive patients and, significantly, also for patients with brain metastases. Notably, entrectinib, another agent with CNS activity, was recently approved for ROS1-positive NSCLC.6 This agent, however, does not have reported activity in patients whose disease has progressed on crizotinib outside the brain. Trials are ongoing with repotrectinib (TPX005), a novel ROS1 and TRK inhibitor that works as a CNS penetrant compound with activity against mutations, including G2032R, that confer resistance to crizotinib. ✦
About the Author: Prof. Solomon is a medical oncologist in the Lung Service and group leader of the Molecular Therapeutics and Biomarkers Laboratory in the Research Division at Peter MacCallum Cancer Centre, Australia, and was an investigator on the phase I/II clinical trial with lorlatinib.
1. Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-Rearranged Non-Small-Cell Lung Cancer. N Engl J Med. 2014;371(21):1963-1971.
2. Shaw AT, Riely GJ, Bang YJ, et al. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann Oncol. 2019;30(7):1121-1126.
3. Shaw AT, Felip E, Bauer TM, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017;18(12):1590-1599.
4. Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018;19(12):1654-1667.
5. 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 Oncol. 2019;20(12):1691- 1701.
6. Drilon A, Siena S, Dziadziuszko R, et al. Entrectinib in ROS1 fusion-positive non-smallcell lung cancer: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):261-270.