Lorlatinib in Tyrosine Kinase Inhibitor-Naive Advanced ROS1-Positive Non-Small Cell Lung Cancer: A Phase 2
Beung Chul Ahn1, Yu Jung Kim2, Youngjoo Lee1
1Center for Lung Cancer, Division of Hematology and Oncology, Department of Internal Medicine, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
Importance:
ROS1 rearrangement is rare but is an attractive therapeutic target in advanced non-small cell lung cancer (NSCLC). Crizotinib, entrectinib, and repotrectinib have been approved by the US Food and Drug Administration for treatment of ROS1-positive NSCLC. Lorlatinib, a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI), targets ROS1 and ALK; however, its efficacy and safety for patients with advanced ROS1-positive remains unknown.
Objective:
To evaluate the efficacy and safety of lorlatinib for patients with advanced ROS1-positive NSCLC never treated with any TKI.
Design, Setting, And Participants:
This multicenter phase 2 nonrandomized clinical trial enrolled patients with advanced ROS1-positive NSCLC who were TKI-naive with an Eastern Cooperative Oncology Group performance status of 2 or less, and 1 or no prior platinum-based chemotherapy. Participants were recruited from June 2019 to April 2023 and followed up through August 2024. Data analysis was performed from April 5 to August 30, 2025.
Interventions:
Lorlatinib, 100 mg daily, was administered until disease progression, toxic effects, consent withdrawal, or death.
Main Outcomes And Measures:
Objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival, and safety.
Results:
The analysis included 32 patients (mean [IQR] age, 59 [11] years; 20 female [63%] and 12 male [37%] individuals), all of whom had adenocarcinoma histologic findings. There were 21 patients (66%) who were treatment-naive, and 11 (34%) who had prior chemotherapy. The median (SD) follow-up duration was 22.1 (15.4-46.8) months; ORR was 73% (95% CI, 56%-86%; 22 of 30 patients), and disease control rate was 90% (95% CI, 74%-97%; 27 of 30 patients). Median (IQR) PFS was 53.6 (95% CI, 27.8-79.5) months, and overall survival was not reached. For treatment-naive vs previously treated patients, the ORR was 90% vs 60%, and PFS was not reached vs 35.8 months. Grade 3 to 4 adverse effects were hypertriglyceridemia (5 patients [16%]) and hypercholesterolemia (8 patients [25%]). No treatment-related deaths occurred.
Conclusions And Relevance:
In this nonrandomized clinical trial, lorlatinib demonstrated durable efficacy and manageable safety in TKI-naive advanced ROS1-positive NSCLC, supporting the potential for using lorlatinib in earlier treatment settings.
Trial Registration:
ClinicalTrials.gov Identifier: NCT03612154.
Insights
Lorlatinib shows durable efficacy and manageable safety in patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) who have not previously received tyrosine kinase inhibitors (TKIs). This suggests lorlatinib could be used earlier in NSCLC treatment.
Area of Science:
- Oncology
- Pharmacology
Background:
- ROS1 rearrangement is a rare but actionable target in advanced non-small cell lung cancer (NSCLC).
- Approved therapies for ROS1-positive NSCLC include crizotinib, entrectinib, and repotrectinib.
- Lorlatinib, a third-generation tyrosine kinase inhibitor (TKI), targets ROS1 and ALK, but its efficacy in TKI-naive ROS1-positive NSCLC was unknown.
Purpose of the Study:
- To evaluate the efficacy and safety of lorlatinib in patients with advanced ROS1-positive NSCLC who have never been treated with any TKI.
- To assess lorlatinib's potential for earlier use in the treatment of ROS1-positive NSCLC.
Main Methods:
- A multicenter, phase 2, nonrandomized clinical trial (NCT03612154) enrolled TKI-naive patients with advanced ROS1-positive NSCLC.
- Patients received lorlatinib 100 mg daily until disease progression, unacceptable toxicity, or other discontinuation criteria were met.
- Objective response rate (ORR) was the primary endpoint, with progression-free survival (PFS) and safety as secondary endpoints.
Main Results:
- The study included 32 patients, with a median follow-up of 22.1 months. The ORR was 73% (22/30), and the disease control rate was 90% (27/30).
- Median PFS was 53.6 months. In TKI-naive patients, ORR was 90% and PFS was not reached; in previously treated patients, ORR was 60% and PFS was 35.8 months.
- Grade 3-4 adverse events included hypertriglyceridemia (16%) and hypercholesterolemia (25%). No treatment-related deaths occurred.
Conclusions:
- Lorlatinib demonstrated durable efficacy and manageable safety in TKI-naive advanced ROS1-positive NSCLC.
- These findings support the potential use of lorlatinib in earlier treatment settings for this patient population.
- Lorlatinib represents a promising therapeutic option for advanced ROS1-positive NSCLC, particularly in treatment-naive individuals.
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