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

Abstract

Background: Most patients with anaplastic lymphoma kinase (ALK)-rearranged or ROS proto-oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the CNS. This study aimed to analyse the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK-positive or ROS1-positive NSCLC.

Methods: In this international multicentre, open-label, single-arm, first-in-man phase 1 dose-escalation study, eligible patients had advanced ALK-positive or ROS1-positive NSCLC and were older than 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Lorlatinib was administered orally to patients at doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily, with a minimum of three patients receiving each dose. For some patients, tumour biopsy was done before lorlatinib treatment to identify ALK resistance mutations. Safety was assessed in patients who received at least one dose of lorlatinib; efficacy was assessed in the intention-to-treat population (patients who received at least one dose of study treatment and had either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities during cycle 1 according to investigator assessment; secondary endpoints included safety, pharmacokinetics, and overall response. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865.

Findings: Between Jan 22, 2014, and July 10, 2015, 54 patients received at least one dose of lorlatinib, including 41 (77%) with ALK-positive and 12 (23%) with ROS1-positive NSCLC; one patient had unconfirmed ALK and ROS1 status. 28 (52%) patients had received two or more TKIs, and 39 (72%) patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolaemia (39 [72%] of 54 patients), hypertriglyceridaemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral oedema (21 [39%] of 54 patients). One dose-limiting toxicity occurred at 200 mg (the patient did not take at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, which were 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 as 100 mg once daily. For ALK-positive patients, the proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31-63); for those who had received two or more TKIs, the proportion of patients with an objective response was 11 (42%) of 26 patients (23-63). In ROS1-positive patients, including seven crizotinib-pretreated patients, an objective response was achieved by six (50%) of 12 patients (95% CI 21-79).

Interpretation: In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK-positive or ROS1-positive NSCLC, most of whom had CNS metastases and had previously had two or more TKI treatments fail. Therefore, lorlatinib might be an effective therapeutic strategy for patients with ALK-positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs, and is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib (ClinicalTrials.gov, NCT03052608).

Funding: Pfizer.

Figure 1. Tumor responses to lorlatinib in ALK-positive NSCLC

(A) Best confirmed tumor responses of 41 ALK-positive patients treated with lorlatinib across all dose levels based on investigator assessment. The bars indicate best percent change in target tumor burden from baseline. The number above each bar indicates the number of different ALK TKIs each patient received prior to lorlatinib; 1+ indicates that the patient received one prior ALK TKI and that TKI was a second-generation TKI (not crizotinib). Filled circles indicate ongoing treatment. Data for three patients are not included: two with objective progression in whom not all target lesions were assessed and one who was not assessed on treatment. (B) Best intracranial tumor response of ALK-positive patients who had evaluable central nervous system metastases at baseline according to investigator assessment. The bars indicate best percent change in intracranial lesions from baseline. The numbers are as described above. Two patients who were not evaluable on treatment were not included. ALK=anaplastic lymphoma kinase; NSCLC=non-small cell lung cancer; TKI=tyrosine kinase inhibitor.

Figure 1. Tumor responses to lorlatinib in ALK-positive NSCLC

(A) Best confirmed tumor responses of 41 ALK-positive patients treated with lorlatinib across all dose levels based on investigator assessment. The bars indicate best percent change in target tumor burden from baseline. The number above each bar indicates the number of different ALK TKIs each patient received prior to lorlatinib; 1+ indicates that the patient received one prior ALK TKI and that TKI was a second-generation TKI (not crizotinib). Filled circles indicate ongoing treatment. Data for three patients are not included: two with objective progression in whom not all target lesions were assessed and one who was not assessed on treatment. (B) Best intracranial tumor response of ALK-positive patients who had evaluable central nervous system metastases at baseline according to investigator assessment. The bars indicate best percent change in intracranial lesions from baseline. The numbers are as described above. Two patients who were not evaluable on treatment were not included. ALK=anaplastic lymphoma kinase; NSCLC=non-small cell lung cancer; TKI=tyrosine kinase inhibitor.

Figure 2. Progression-free survival of patients with ALK-positive NSCLC

Shown are Kaplan-Meier estimates of progression-free survival in patients with advanced, ALK-positive NSCLC treated with lorlatinib. Among all 41 ALK-positive patients, median progression-free survival was 9·6 months (blue). In the subset of 14 patients who had received one prior ALK TKI, median progression-free survival was 13·5 months (orange). In the subset of 26 patients who had received two or more ALK TKIs (including at least one second-generation TKI), median progression-free survival was 9·2 months (yellow). One ALK-positive patient who had received no prior ALK TKIs is included in the total but is not shown separately. Vertical lines on the survival curves indicate censoring of data. ALK=anaplastic lymphoma kinase; NSCLC=non-small cell lung cancer; TKI=tyrosine kinase inhibitor.

Figure 3. Response to lorlatinib and correlation with ALK resistance mutations in patients treated with ≥2 ALK TKIs

(A) Waterfall plot of 12 ALK-positive patients who had received ≥2 prior ALK TKIs and who underwent repeat biopsy before study enrollment. These biopsies may have been collected as de novo samples for the study or may have been collected outside of this study. All biopsies were taken from extracranial sites of disease. For ten samples from Massachusetts General Hospital (MGH), sequencing was performed using local sequencing platforms and these data were stored, summarized, and validated by MGH; for the remaining two samples, next-generation sequencing was performed in a central laboratory and additionally summarized and validated by MGH (see Methods). For each patient, the ALK resistance mutation is shown above the bar corresponding to the patient’s best percent change in systemic (ie, extracranial) target lesions according to Response Evaluation Criteria in Solid Tumors v1·1. WT (wildtype) indicates that no ALK mutation was identified in the resistant specimen. One patient whose resistant tumor showed no ALK mutation on biopsy was not evaluable because of rapid progression and is not shown here. (B) The duration of treatment in days for the same group of ALK-positive patients. ALK mutation status is indicated to the left of each bar. Arrows indicate patients who were still receiving lorlatinib at the time of data cutoff. ALK=anaplastic lymphoma kinase; TKI=tyrosine kinase inhibitor.

Figure 3. Response to lorlatinib and correlation with ALK resistance mutations in patients treated with ≥2 ALK TKIs

(A) Waterfall plot of 12 ALK-positive patients who had received ≥2 prior ALK TKIs and who underwent repeat biopsy before study enrollment. These biopsies may have been collected as de novo samples for the study or may have been collected outside of this study. All biopsies were taken from extracranial sites of disease. For ten samples from Massachusetts General Hospital (MGH), sequencing was performed using local sequencing platforms and these data were stored, summarized, and validated by MGH; for the remaining two samples, next-generation sequencing was performed in a central laboratory and additionally summarized and validated by MGH (see Methods). For each patient, the ALK resistance mutation is shown above the bar corresponding to the patient’s best percent change in systemic (ie, extracranial) target lesions according to Response Evaluation Criteria in Solid Tumors v1·1. WT (wildtype) indicates that no ALK mutation was identified in the resistant specimen. One patient whose resistant tumor showed no ALK mutation on biopsy was not evaluable because of rapid progression and is not shown here. (B) The duration of treatment in days for the same group of ALK-positive patients. ALK mutation status is indicated to the left of each bar. Arrows indicate patients who were still receiving lorlatinib at the time of data cutoff. ALK=anaplastic lymphoma kinase; TKI=tyrosine kinase inhibitor.