The US Food and Drug Administration (FDA) has approved another targeted agent for use in the treatment of patients with metastatic non–small cell lung cancer (NSCLC) whose tumors test positive for anaplastic lymphoma kinase (ALK+).
The new drug is lorlatinib (Lorbrena, Pfizer), described as a third-generation ALK inhibitor.
It is indicated for use in patients with ALK+ metastatic NSCLC whose disease has progressed on crizotinib (Xalkori, Pfizer) and at least one other ALK inhibitor for metastatic disease, or whose disease has progressed on alectinib (Alecensa, Genentech) and ceritinib (Zykadia, Novartis) as the first ALK inhibitor therapy for metastatic disease.
The agency granted an accelerated approval for this indication on the basis of 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 company noted in a press release.
“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, commented in a company press release.
“In a clinical study which included patients with or without brain metastases, Lorbrena demonstrated clinical activity in patients with metastatic ALK+ NSCLC who had failed other ALK biomarker-driven therapies,” she said.
The approval was based on a nonrandomized multicenter phase 1/2 study, known as B7461001, which involved 215 patients with ALK+ metastatic NSCLC who had previously been treated with other ALK-targeted drugs (57% had previously undergone treatment with more than one such drug).
Among these patients, the overall response rate was 48%.
In the trial, 69% of patients had a history of brain metastases. The intracranial response rate was 60%.
The most common (≥20%) adverse reactions reported with lorlatinib were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. Serious adverse reactions occurred in 32% of patients; these included pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). Fatal adverse reactions occurred in 2.7% of patients; these 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%).
Permanent discontinuation of lorlatinib for adverse reactions occurred in 8% of patients; nearly half (48%) of patients required dose interruptions, and 24% required at least one dose reduction, according to the company.
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