FDA Approves Lorlatinib for ALK+ NSCLC

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Silas Inman

The FDA has granted an accelerated approval to lorlatinib as a treatment for patients with ALK-positive metastatic non–small cell lung cancer following progression on 1 or more prior ALK-targeted TKI.

The FDA has granted an accelerated approval to lorlatinib as a treatment for patients withALK-positive metastatic non—small cell lung cancer (NSCLC) following progression on 1 or more prior ALK-targeted TKI.

The approval was based on findings from a phase II study, which was updated at the 2018 ASCO Annual Meeting. In the study, the objective response rate (ORR) with lorlatinib was 72.9% in patients pretreated with crizotinib (Xalkori) with or without chemotherapy. In patients receiving a prior non-crizotinib, second-generation ALK inhibitor, the ORR was 42.9% for lorlatinib, and in patients receiving ≥2 prior ALK inhibitors the ORR was 39.6%.

The phase I/II study enrolled 275 patients, of which 198 hadALK+ metastatic NSCLC and had received 1 or more ALK-directed TKIs. The median age of patients was 53.6 years, and the majority were female (57.1%). The most common ECOG performance score was 0 (43.3%) or 1 (53.1%), with 3.6% having a score of 2. More than half of patients (59.6%) had brain metastases at baseline.

Overall, 59 patients had received only prior crizotinib. Second-generation TKIs received prior to lorlatinib included alectinib (n = 62; Alecensa), ceritinib (n = 47; Zykadia), and brigatinib (n = 8; Alunbrig). Lorlatinib was administered at 100 mg once daily in a 21-day cycle.

In those receiving prior crizotinib, the median duration of response (DOR) was not yet reached and the median progression-free survival (PFS) was 11.1 months. In those receiving a prior second-generation ALK inhibitor, the median DOR was 5.6 months and the median PFS was 5.5 months. In patients receiving ≥2 prior ALK inhibitors, the median DOR was 9.9 months (95% CI, 5.7-24.4) and the median PFS was 6.8 months (95% CI, 5.4-9.5).

In 37 patients with central nervous system (CNS) involvement treated with prior crizotinib, the intracranial ORR was 70.3% (95% CI, 53.0%-84.1%). In those treated with a prior second-generation TKI with CNS involvement (n = 13), the intracranial ORR was 46.2% (95% CI, 19.2%-74.9%). In those receiving ≥2 prior TKIs with CNS involvement (n = 81), the intracranial ORR was 48.1% (95% CI, 36.9%-59.5%).

Higher responses were noted in patients with ≥1 measurable CNS lesion at baseline. In this group, those treated with prior crizotinib (n = 24) had an intracranial ORR of 87.5%. In the second-generation TKI group (n = 9), the intracranial ORR was 66.7%, and in the ≥2 prior TKI arm (n = 48), the intracranial ORR was 52.1%.

In patients receiving prior alectinib, the ORR with lorlatinib was 40.3% (95% CI, 28.1%-53.6%). The median DOR was 5.6 months and the median PFS was 5.5 months (95% CI, 4.1-7.1). The intracranial ORR was 40.5%, with a median DOR of 11.6 months in this group. Patients treated with prior ceritinib had an ORR of 42.6% (95% CI, 28.3%-57.8%), with a DOR of 6.9 months and a median PFS of 7.3 months (95% CI, 5.5-11.1). The intracranial ORR was 54.3% with a median DOR that was not yet reached. The ORR with prior brigatinib was 37.5%. The median PFS and DOR were not calculable.

Of those initially enrolled, 30 had untreatedALK+ NSCLC, with 8 of these patients having CNS involvement. In this group, lorlatinib demonstrated an ORR of 90% (95% CI, 73.5%-97.9%) and an intracranial ORR of 75% (95% CI, 34.9%-96.8%).

Of the full 275 patients treated with lorlatinib, 95.3% experienced a treatment-related adverse event (TRAE), with 46% having a grade 3 or 4 event. The most common TRAEs were hypercholesterolemia (83.6%) and hypertriglyceridemia (66.5%), with 16.4% and 16.7% of patients having a grade 3/4 event, respectively.

Other common TRAEs, which were mostly grade 1/2 in severity, included edema (44%), peripheral neuropathy (33.8%), cognitive effects (23.3%), weight increase (22.5%), mood effects (16%), fatigue (15.3%), diarrhea (13.1%), increased AST (12%), arthralgia (10.9%), and increased ALT (10.2%).

TRAEs led to dose interruptions for 34% of patients and to dose reductions for 25%. The most common TRAEs leading to these events were hypertriglyceridemia and edema. Overall, 3.3% of patients discontinued lorlatinib due to a TRAE. There were no treatment-related deaths in the trial.

The accelerated approval for lorlatinib is contingent upon findings from a phase III study. The open-label CROWN trial is currently exploring lorlatinib in combination with crizotinib as a frontline therapy for patients with metastaticALK+ NSCLC. The primary endpoint of the study is PFS with secondary endpoints focused on overall survival and response. The targeted enrollment for the trial is 280 patients, and the estimated primary completion date is in February 2020 (NCT03052608).

Besse B, Solomon BJ, Felip E, et al. Lorlatinib in patients (Pts) with previously treated ALK+ advanced non-small cell lung cancer (NSCLC): Updated efficacy and safety. J Clin Oncol.2018; 36 (suppl; abstr 9032).