FDA Approves Lorlatinib for ALK+ NSCLC

The FDA has granted lorlatinib (Lorbrena) an accelerated approval for the treatment of patients with ALK-positive metastatic non—small cell lung cancer (NSCLC) who have progressed on 1 or more ALK tyrosine kinase inhibitors (TKIs).

Specifically, lorlatinib is approved for patients who have progressed on crizotinib (Xalkori) and at least 1 other ALK inhibitor for metastatic disease; alectinib (Alecensa) as the first ALK inhibitor therapy for metastatic disease; or ceritinib (Zykadia) as the first ALK inhibitor therapy for metastatic disease.

The approval is based on a nonrandomized, dose-ranging, multicohort, multicenter phase II study (B7461001) that included a subgroup of 215 patients with ALK-positive metastatic NSCLC previously treated with ≥1 ALK kinase inhibitors. The overall response rate with lorlatinib in these 215 patients was 48% (95% CI, 42-55), including a complete response rate of 4% and a partial response rate of 44%. The median duration of response was 12.5 months (95% CI, 8.4-23.7).

The FDA-recommended dose of lorlatinib is 100 mg orally once daily.

“The last decade has witnessed dramatic improvements in the treatment of metastatic ALK-positive non—small cell lung cancer due to earlier generation ALK biomarker-driven therapies. Yet almost all patients still relapse due to drug resistance, with a large proportion of patients developing new or worsening brain metastases,” Alice T. Shaw, MD, PhD, Professor of Medicine at Harvard Medical School, and Director of the Center for Thoracic Cancers at Massachusetts General Hospital, said in a press release.

“In a clinical study which included patients with or without brain metastases, Lorbrena demonstrated clinical activity in patients with metastatic ALK-positive non—small cell lung cancer who had failed other ALK biomarker-driven therapies," added Shaw.

In the 215-patient efficacy population, 29 patients had prior crizotinib and no prior chemotherapy, 35 patients had prior crizotinib and 1 to 2 lines of prior chemotherapy, 28 patients had a prior ALK inhibitor (not crizotinib) with or without prior chemotherapy, 75 patients had 2 prior prior ALK inhibitors with or without prior chemotherapy, and 48 patients had 3 prior ALK inhibitors with or without prior chemotherapy.

The median age was 53 years (range, 29-85), 59% were female% 51% were white, and 34% were Asian. Ninety-six percent of patients had a baseline ECOG performance status of 0 or 1 and 95% had adenocarcinoma.

Sixty-nine percent of the 215 patients had a history of brain metastases, and 60% (n = 89) of these patients had measurable disease. Among this subgroup with measurable disease the intracranial response rate was 60% (95% CI, 49%-70%), comprising a 21% CR rate and a 38% PR rate. The median duration of response was 19.5 months (95% CI, 12.4 — not reached).

The safety population the FDA evaluated from Study B7461001 included 295 patients with ALK-positive or ROS1-positive metastatic NSCLC who were treated with 100 mg of lorlatinib orally once daily. The median duration of treatment exposure was 12.5 months (range 1 day to 35 months), with 52% receiving the drug for at least 12 months.

The most common (≥20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea; the most common (≥20%) laboratory abnormalities were hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, increased lipase, and increased alkaline phosphatase.

Thirty-two percent of patient had serious AEs. The most common serious AEs were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). AEs resulting in death occurred in 2.7% of patients and included pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%).

AE-related discontinuations occurred in 8% of patients, 48% of patients needed dose interruptions, and 24% needed at least 1 dose reduction.

The accelerated approval of lorlatinib in this setting is contingent on the results of a confirmatory trial.

Lorlatinib prescribing information. FDA. Accessed November 2, 2018. https://bit.ly/2P6uini.