IN A GLOBAL phase II study reported in The Lancet Oncology, Benjamin J. Solomon, MBBS, of Peter MacCallum Cancer Centre, Melbourne, and colleagues found that lorlatinib showed high overall and intracranial activity in patients with advanced ALK-positive non–small cell lung cancer (NSCLC) who were treatment-naive or who had received crizotinib or other ALK inhibitors.¹ These study findings support the recent approval of lorlatinib as second- or third-line treatment of ALK-positive metastatic disease.

Benjamin J. Solomon, MBBS

Study Details

IN THE STUDY, 276 patients with ALK-positive or ROS1-positive disease with or without central nervous system (CNS) metastases were enrolled between September 2015 and October 2016. Patients were enrolled into six different expansion cohorts (EXP1- 6) on the basis of ALK and ROS1 status and previous therapy. All patients were treated with oral lorlatinib at 100 mg once daily continuously in 21-day cycles. The primary endpoint was overall and intracranial tumor response on an independent central review assessed in pooled subgroups of ALK-positive patients. Patients with measurable CNS metastases at baseline on an independent central review were included in the intracranial response analysis.

The 6 cohorts included 5 cohorts of ALK-positive patients: 30 were treatment-naive (EXP1); 59 received previous crizotinib without (n = 27; EXP2) or with (n = 32; EXP3A) previous chemotherapy; 28 received a previous ALK tyrosine kinase inhibitor (not crizotinib) with or without chemotherapy (EXP3B); and 112 received 2 (n = 66; EXP4) or 3 (n = 46; EXP5) previous ALK tyrosine kinase inhibitors with or without chemotherapy. The sixth cohort, which is not included in the current efficacy analysis, consisted of 47 patients who had ROS-positive disease and had received any previous treatment (EXP6). Safety data are from all six cohorts.

Responses in ALK-Positive Cohorts

IN TREATMENT-NAIVE patients (EXP1), objective response was achieved in 27 of 30 patients (90.0%); intracranial response occurred in 2 of 3 patients (66.7%) with measurable baseline CNS lesions.

In patients who had received at least 1 previous ALK tyrosine kinase inhibitor (EXP2–5), objective response was achieved in 93 of 198 patients (47%), and objective intracranial response was observed in 51 of 81 patients (63%) with measurable CNS lesions. Objective response was achieved in 41 of 59 patients (69.5%) who had received previous crizotinib alone (EXP2–3A), 9 of 28 patients (32.1%) who had received one previous ALK tyrosine kinase inhibitor (not crizotinib; EXP3B), and 43 of 111 patients (38.7%) who had received 2 or more ALK tyrosine kinase inhibitors (EXP4–5). Among patients with measurable CNS lesions, objective intracranial response was observed in 20 of 23 patients (87.0%) in EXP2–3A, 5 of 9 patients (55.6%) in EXP3B, and 26 of 49 patients (53.1%) in EXP4 and EXP5.

Among the 198 patients in cohorts EXP2–5, overall complete response was observed in 2% of patients, partial response was noted in 45%, and stable disease was reported in 29%. With the median duration of follow-up ranging from 6.9 to 7.2 months, the median duration of response had not been reached overall or in any cohort. Among the 30 patients in the treatment-naive cohort (EXP1), overall complete response was observed in 3%, partial response was noted in 87%, and stable disease was reported in 7%. With a median follow-up of 6.9 months, the median duration of response had not been reached.

“Lorlatinib could represent an effective treatment option for patients with <em>ALK</em>-positive NSCLC in first-line or subsequent therapy.”

— Benjamin J. Solomon, MBBS, and colleagues

Tweet this quote

Among the 81 patients with measurable CNS disease in cohorts EXP2–5, complete intracranial response was observd in 20%, partial response was noted in 43%, and stable disease was reported in 25%. The median duration of intracranial response was 14.5 months, including 14.5 months in cohort EXP4–5 (≥ 2 prior tyrosine kinase inhibitors) and not reached in cohorts EXP2–3A and EXP3B. Among the three patients in the treatment-naive cohort (EXP1) with measurable disease, partial response was observed in two and stable disease, in one. The median duration of response was not reached.

Adverse Events

THE MOST COMMON treatment-related adverse events of any grade and of grade ≥ 3 among all 275 patients were hypercholesterolemia (81%; 16% grade 3 or 4) and hypertriglyceridemia (60%; 16% grade 3 or 4). The next most common adverse events of any grade were edema (43%), peripheral neuropathy (30%), increased weight (18%), and cognitive effects (18%). The next most common treatment related grade ≥ 3 adverse event was increased lipase (3%), with no other individual adverse events occurring in more than 2% of patients. Serious treatment-related adverse events occurred in 7% of patients. Treatment-related adverse events led to treatment discontinuation in 3%. No treatment-related deaths were reported.

The investigators concluded: “Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive NSCLC and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive NSCLC in first-line or subsequent therapy.” ■

DISCLOSURE: The study was funded by Pfizer. For full disclosures of the study authors, visit www.thelancet.com.

REFERENCE

1. Solomon BJ, Besse B, Bauer TM, et al: Lorlatinib in patients with ALK-positive non-small-cell lung cancer: Results from a global phase 2 study. Lancet Oncol 19:1654-1667, 2018.