Lorlatinib Is Active in ROS1-Positive Non–Small Cell Lung Cancer

In approximately 1% to 2% of patients with non–small cell lung cancer (NSCLC), chromosomal rearrangements of the ROS1 locus (encoding the tyrosine kinase ROS1) are present. These patients may respond to ALK tyrosine kinase inhibitors (TKI), such as crizotinib, but most develop resistance. In a multicenter, open-label, single-arm, phase I/II clinical trial, Shaw and colleagues tested the safety and efficacy of the third-generation oral TKI lorlatinib in 69 patients with advanced, ROS1-positive NSCLC. Among the participants, 21 (30%) were TKI-naïve, 40 (58%) had previously been administered crizotinib, and 8 (12%) had previously received other TKIs. Overall, 28 patients (41%) had objective responses. The most favorable response rate was seen in the 21 TKI-naïve patients, among whom 13 patients (62%) had objective responses, including two patients (10%) who experienced complete responses and 11 patients (52%) who experienced partial responses. Further, five of the 11 patients (45%) in the TKI-naïve group who had brain metastases at baseline experienced objective responses, whereas eight of the 10 patients (80%) in the TKI-naïve group who did not have brain metastases at baseline experienced objective responses. Consistent with lorlatinib's ability to cross the blood–brain barrier, seven of the 11 patients (64%) in the TKI-naïve group who had brain metastases at baseline experienced intracranial objective responses. Among all 21 TKI-naïve patients, the median duration of response was 25.3 months. Of all 69 patients, 66 (96%) experienced at least one treatment-related adverse effect (most commonly hypercholesterolemia, hypertriglyceridemia, or edema), with serious treatment-related adverse effects occurring in five patients (7%). One patient (1%) permanently discontinued treatment due to adverse effects; however, no deaths deemed to be due to treatment occurred. Some limitations of the study include its small size and single-arm design. Although recruitment of ROS1-positive patients for future trials of lorlatinib may be challenging due to the small patient population, this trial indicates that further study of the drug is warranted, perhaps especially in TKI-naïve patients.

Shaw AT, Solomon BJ, Chiari R, Riely GJ, Besse B, Soo RA, 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;20:1691–701.

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