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Background Most patients with ALK- or ROS1-rearranged non-small cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the central nervous system (CNS). This study aimed to determine the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK/ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK- or ROS1-positive NSCLC. Methods In this ongoing, multicenter phase 1 study, eligible patients had advanced ALK- or ROS1-positive NSCLC. Lorlatinib was orally administered at doses ranging from 10–200 mg once daily or 35–100 mg twice daily. For some patients, tumor biopsy was performed before lorlatinib treatment to identify ALK resistance mutations. Safety was evaluated in patients who received ≥1 treatment; efficacy was evaluated in the intention-to-treat population (patients who received ≥1 dose of study treatment and were positive for either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities (DLTs) during cycle 1; secondary endpoints included safety, pharmacokinetics, and overall response rate (ORR). This study is registered with ClinicalTrials.gov, NCT01970865. Findings Fifty-four patients were treated, including 41 with ALK-positive and 12 with ROS1-positive NSCLC. Twenty-eight patients had received ≥2 TKIs, and 39 patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolemia (39 [72%] of 54 patients), hypertriglyceridemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral edema (21 [39%] of 54 patients). One DLT occurred at 200 mg (failure to deliver at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, in this case grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected to be 100 mg daily. Among ALK-positive patients, the ORR was 19 (46%) of 41 patients (95% CI, 31–63%); among those who had received ≥2 TKIs, the ORR was 11 (42%) of 26 patients (95% CI, 23–63%). Among ROS1-positive patients, including seven crizotinib-pretreated patients, ORR was 6 (50%) of 12 patients (95% CI, 21–79%). Responses were observed in the CNS and in patients with tumors harboring resistance mutations such as ALK G1202R. Interpretation In this phase 1, dose-escalation study, lorlatinib demonstrated both systemic and intracranial activity in patients with advanced ALK- or ROS1-positive NSCLC, most of whom had CNS metastases and had failed ≥2 TKIs. Therefore, lorlatinib may represent an effective therapeutic strategy for patients who have become resistant to currently available TKIs, including second-generation ALK TKIs in ALK-positive NSCLC. Funding Pfizer

PURPOSE Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS1 tyrosine kinase inhibitor (TKI) with robust clinical activity in advanced ALK-positive non–small-cell lung cancer, including in patients who have failed prior ALK TKIs. Molecular determinants of response to lorlatinib have not been established, but preclinical data suggest that ALK resistance mutations may represent a biomarker of response in previously treated patients. PATIENTS AND METHODS Baseline plasma and tumor tissue samples were collected from 198 patients with ALK-positive non–small-cell lung cancer from the registrational phase II study of lorlatinib. We analyzed plasma DNA for ALK mutations using Guardant360. Tumor tissue DNA was analyzed using an ALK mutation–focused next-generation sequencing assay. Objective response rate, duration of response, and progression-free survival were evaluated according to ALK mutation status. RESULTS Approximately one quarter of patients had ALK mutations detected by plasma or tissue genotyping. In patients with crizotinib-resistant disease, the efficacy of lorlatinib was comparable among patients with and without ALK mutations using plasma or tissue genotyping. In contrast, in patients who had failed 1 or more second-generation ALK TKIs, objective response rate was higher among patients with ALK mutations (62% v 32% [plasma]; 69% v 27% [tissue]). Progression-free survival was similar in patients with and without ALK mutations on the basis of plasma genotyping (median, 7.3 months v 5.5 months; hazard ratio, 0.81) but significantly longer in patients with ALK mutations identified by tissue genotyping (median, 11.0 months v 5.4 months; hazard ratio, 0.47). CONCLUSION In patients who have failed 1 or more second-generation ALK TKIs, lorlatinib shows greater efficacy in patients with ALK mutations compared with patients without ALK mutations. Tumor genotyping for ALK mutations after failure of a second-generation TKI may identify patients who are more likely to derive clinical benefit from lorlatinib.

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The multipeak hazard curve suggests that the process resulting in overt clinical metastases may have discrete features. Primary tumor size could affect in different ways early and late metastases, while axillary node status should be related to the risk level, not to the risk pattern, and menopausal status does not seem to significantly affect the hazard distribution. Moreover, contralateral breast tumors, occurring at constant risk throughout the time, should be considered as second primary cancers. These findings could be reasonably explained by a tumor dormancy hypothesis, which assumes that micrometastases may be in different biological steady states, most of which do not imply tumor growth. Tumor or microenvironment changes could induce metastatic growth after given mean transition times from surgery and originate a discrete pattern of the hazard function.