Efficacy and safety of lorlatinib in patients with ALK- and ROS1-rearranged metastatic non-small cell lung cancer treated within the compassionate use program in Spain

BACKGROUND: Lorlatinib, a third-generation tyrosine kinase inhibitor (TKI), targets both ALK and ROS1 rearrangements in non-small cell lung cancer (NSCLC). It is approved for ALK-positive patients after progression on prior TKIs but lacks FDA or EMA approval for ROS1-positive NSCLC. This study evaluates lorlatinib's efficacy and safety in both ALK- and ROS1-positive patients through a compassionate use program in Spain. METHODS: We analyzed ALK-positive patients treated from November 2016 to February 2019 and ROS1-positive patients treated from November 2016 to March 2021. Eligible patients had Stage IV NSCLC with confirmed ALK or ROS1 rearrangements and prior TKI therapy. For ALK-positive patients, at least two prior TKIs were required if crizotinib was used first. For ROS1-positive patients, prior crizotinib was required. RESULTS: In 61 ALK-positive patients, 59 % had brain metastasis, and 85.2 % received at least two prior ALK TKIs. The overall response rate (ORR) was 32.8 %, with a median progression-free survival (PFS) of 11.2 months. Intracranial ORR was 47.6 %, with higher efficacy in patients with evaluable brain metastasis. In patients with 1, 2, or ≥3 lines of previous TKIs, we observed a median PFS of 15.1, 11.1 and 7.6 months, respectively. Among 42 ROS1-positive patients, 59 % had brain metastasis, and 61.9 % received ≥2 prior therapies. The confirmed ORR was 47.6 %, with 16.7 % complete responses. Median PFS was 10 months. Patients receiving crizotinib alone had a median PFS of 10 months, while those with two prior TKIs had a median PFS of 8.5 months. Intracranial response was 44.4 %, rising to 57.1 % in patients evaluable with brain metastasis. No new safety signals were observed. CONCLUSION: Lorlatinib demonstrated consistent efficacy and manageable safety in both ALK- and ROS1-positive NSCLC patients treated under the compassionate use program in Spain. These real-world findings support its use as an effective treatment option in heavily pretreated patients. MICROABSTRACT: We evaluated the efficacy and safety of lorlatinib in ALK- and ROS1-positive NSCLC patients within a compassionate use program in Spain. Among 61 ALK-positive patients, including 59 % with brain metastasis and 85.2 % treated with at least 2 prior ALK TKIs, lorlatinib achieved a confirmed overall response rate (ORR) of 32.8 % and a median progression-free survival (PFS) of 11.2 months. In 42 ROS1-positive patients previously treated with crizotinib, lorlatinib showed an ORR of 47.6 % and a median PFS of 10 months, confirming its clinical activity despite the lack of FDA or EMA approval for this indication.