5 November 2018 - - The US Food and Drug Administration has approved Lorbrena [lor-BREN-ah] (lorlatinib), a third-generation anaplastic lymphoma kinase tyrosine kinase inhibitor for patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease; or whose disease has progressed on alectinib or ceritinib as the first ALK inhibitor therapy for metastatic disease, US-based Pfizer Inc. (NYSE: PFE) said.

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. This represents the third FDA approval Pfizer has received for an oncology treatment, including two lung cancer medicines, within two months.

Since Pfizer introduced XALKORI (crizotinib) as the first TKI for the treatment of ALK-positive metastatic NSCLC in 2011, the availability of these medicines has created an opportunity to provide patients with treatment options other than chemotherapy. However, lung cancer remains the leading cause of cancer-related death around the world.

While many ALK-positive metastatic NSCLC patients respond to initial TKI therapy, they typically experience tumor progression.

Additionally, options for patients who progress after treatment with second-generation ALK TKIs, alectinib, brigatinib and ceritinib, are limited.

The approval of Lorbrena represents a new option for patients who have progressed on a second-generation ALK TKI, providing an opportunity to remain on oral therapy.

The approval was based on a non-randomized, dose-ranging and activity-estimating, multi-cohort, multicenter Phase 1/2 study, B7461001, evaluating Lorbrena for the treatment of patients with ALK-positive metastatic NSCLC, who were previously treated with one or more ALK TKIs.

A total of 215 patients with ALK-positive metastatic NSCLC were enrolled across various subgroups based on prior treatment.

Among these patients, overall response rate was 48% (95% CI: 42%, 55%) and importantly, 57 % had previous treatment with more than one ALK TKI.

In the trial, 69 % of patients had a history of brain metastases and intracranial response rate was 60 % (95% CI: 49%, 70%).

Among 295 ALK-positive or ROS1-positive metastatic NSCLC patients who received Lorbrena 100 mg once daily in study B7461001, the most common (≥ 20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea.

The most common laboratory abnormalities were hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, increased lipase, and increased alkaline phosphatase. Serious adverse reactions occurred in 32% of the 295 patients.

The most frequent serious adverse reactions reported were pneumonia, dyspnea, pyrexia, mental status changes, and respiratory failure.

Fatal adverse reactions occurred in 2.7% of patients and included pneumonia, myocardial infarction, acute pulmonary edema, embolism, peripheral artery occlusion, and respiratory distress.

Permanent discontinuation of Lorbrena for adverse reactions occurred in 8% of patients; approximately 48% of patients required dose interruptions and 24% required at least one dose reduction.