General Information

Lorbrena (lorlatinib) is next-generation ALK/ROS1 tyrosine kinase inhibitor.

Lorbrena is specifically indicated for the the following:

patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on 1) crizotinib and at least one other ALK inhibitor for metastatic disease; or 2) alectinib as the first ALK inhibitor therapy for metastatic disease; or 3) ceritinib as the first ALK inhibitor therapy for metastatic disease;

the first-line treatment of patients with ALK-positive NSCLC

Lorbrena is supplied as a tablet for oral administration. The recommended dosage is 100 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Tablets should be swallowed whole. They should not be chewed, crushed or split out. Tablets should not be ingested if they are broken, cracked, or otherwise not intact. Lorbrena should administered at the same time each day. If a dose is missed, then take the missed dose unless the next dose is due within 4 hours. Do not take two doses at the same time to make up for a missed dose. Do not take an additional dose if vomiting occurs after Lorbrena but continue with the next scheduled dose.

Clinical Results

The FDA approval of Lorbrena for previously treated patients was based on a subgroup of 215 patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) previously treated with one or more ALK kinase inhibitors who were enrolled in a non-randomized, dose-ranging and activity-estimating, multi-cohort, multicenter study. The patients received 100 mg of Lorbrena orally once daily. Among patients with ALK-positive metastatic NSCLC, the overall response rate (ORR) with lorlatinib was 48 percent, with 4% of patients achieving complete responses and 44% achieving a partial response. The median duration of response was 12.5 months. The intracranial ORR in 89 patients with measurable lesions in the CNS according to RECIST 1.1 was 60%, with 21% complete and 38% partial responses. The estimated median response duration was 19.5 months.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The FDA approval of Lorbrena for the first-line treatment of ALK-positive NSCLC was based on results from the pivotal Phase 3 CROWN trial. The randomized, open-label, parallel 2-arm trial enrolled 296 patients with previously untreated advanced ALK-positive NSCLC who were randomized 1:1 to receive Lorbrena monotherapy (n=149) or Xalkori monotherapy (n=147). Treatment with Lorbrena resulted in a 72% reduction in risk of progression or death vs. Xalkori (crizotinib) in a previously untreated patient population as assessed by blinded independent central review (BICR). Central nervous system (CNS) involvement was assessed in all patients. There were 17 patients in the Lorbrena arm and 13 in the Xalkori arm with measurable brain metastases based on baseline brain imaging. A prespecified exploratory analysis showed that among these patients, the intracranial objective response rate (IC-ORR), as assessed by BICR, was 82% in the Lorbrena arm and 23% in the Xalkori arm. The intracranial duration of response (IC-DOR) was 12 months or longer in 79% (n=11) and 0% of patients in the Lorbrena and Xalkori arms, respectively.

Side Effects

Adverse effects associated with the use of Lorbrena may include, but are not limited to, the following:

edema

peripheral neuropathy

cognitive effects

dyspnea

fatigue

weight gain

arthralgia

mood effects

diarrhea

laboratory abnormalities may include hypercholesterolemia and hypertriglyceridemia

Mechanism of Action

Lorbrena (lorlatinib) is next-generation ALK/ROS1 tyrosine kinase inhibitor that has been shown to be highly active in preclinical lung cancer models harboring chromosomal rearrangements of both ALK and ROS1. Lorlatinib was specifically designed to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood brain barrier.