OA 05.06 Phase 2 Study of Lorlatinib in Patients with Advanced ALK+/ROS1+ Non-Small-Cell Lung Cancer

Abstract

Background: Brigatinib, a next-generation ALK inhibitor, recently received accelerated approval in the United States for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. We report updated data from the randomized phase 2 trial (ALTA; NCT02094573), which was designed to investigate the efficacy and safety of 2 brigatinib regimens in patients with crizotinib-refractory, advanced ALK+ NSCLC. Method: Patients were stratified by presence of brain metastases at baseline and best response to prior crizotinib and randomized 1:1 to receive brigatinib at 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). Investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1 was the primary endpoint. Result: Among 222 patients (n¼112/ n¼110, arm A/B), median age was 51/57 years; 71%/67% had brain metastases. As of February 21, 2017, 17 full months since the last patient enrolled, median follow-up was 16.8/18.6 months and 32%/ 41% of patients continued to receive brigatinib in A/B. The table shows brigatinib efficacy. Per independent review committee, confirmed ORR was 51%/55% and median PFS was 9.2/16.7 months in A/B. Among patients with measurable baseline brain metastases (n¼26/n¼18, A/ B), confirmed intracranial ORR was 50%/67% as of January 24, 2017; median intracranial DoR was not reached/16.6 months. The most common treatment-emergent adverse events (TEAEs) were: nausea (38%/47%, A/B), diarrhea (28%/44%), cough (28%/40%), headache (30%/35%), and vomiting (36%/30%); the most common grade 3 TEAEs were: increased creatine phosphokinase (5%/13%), hypertension (6%/8%), pneumonia (4%/5%), and increased lipase (5%/4%). Dose reduction (9%/30%, A/B) or discontinuation (4%/11%) due to TEAEs was reported. Conclusion: In ALTA, brigatinib continues to show substantial efficacy and acceptable safety at both dose levels, with numerically longer PFS and higher intracranial ORR at the recommended dosing regimen of 180 mg qd (with lead-in) vs 90 mg qd.

ALK, ROS1 and EGFR next-generation tyrosine kinase inhibitors in advanced non-small-cell lung cancer

“…Objective intracranial responses in patients with CNS metastases ranged from 39% (three treatment lines ALK TKI ± chemotherapy) to 75% (crizotinib ± chemotherapy). The percentage of ORR was 90% in patients receiving lorlatinib as the first-line of treatment [5].…”

“…In 2017, during the 18 th World Conference on Lung Cancer, the results of the Phase II study were presented, in which 275 patients were included. The participants were divided into six cohorts depending on the previously applied therapy (Table 1) [5]. For five cohorts of 197 patients who previously received ALK inhibitors in different configurations, the percentage of ORR ranged from 33% (first line of treatment for ALK TKI other than crizotinib ± chemotherapy) to 74% (patients previously receiving only crizotinib).…”

“…In phase I clinical trials 46% of patients with measurable CNS metastases received an objective intracranial response to treatment [4]. The Phase II study showed high systemic and intracranial ORR (Table 1) in patients treated with the first line of treatment as well as in those receiving TKI ALK [5].…”

“…It appeared in patients receiving 200 mg of lorlatinib once a day -dose-limiting toxicity (DLT) [4]. In the phase II study, third-and fourth-degree adverse effects related to treatment were found, which included hypercholesterolaemia (16%) and hypertriglyceridaemia (16%) [5]. No treatment-related deaths were reported.…”

Personalized therapy for lung cancer: Striking a moving target

“…It demonstrated a response rate of approximately 70% and median PFS of 19 months in a nonrandomized study (31). For patients that develop acquired resistance to crizotinib, a recent study documented modest activity with a response rate of 56% for lorlatinib, a multi-kinase inhibitor (32). Entrectinib, a ROS1 and TRK inhibitor, has also demonstrated a 29-month median PFS in a recent study for patients with ROS1 fusion abnormality including those with brain metastases (33).…”