FDA approves Lorbrena for ALK-positive metastatic NSCLC

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The FDA granted accelerated approval to lorlatinib for the treatment of ALK-positive metastatic non-small cell lung cancer.

Lorlatinib (Lorbrena, Pfizer) — a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor — is indicated for patients whose disease progressed during treatment with crizotinib (Xalkori, Pfizer) and at least one other ALK inhibitor, or whose disease progressed on ceritinib (Zykadia, Novartis) or alectinib (Alecensa, Genentech) as first ALK inhibitor for metastatic disease.

“We believe that Lorbrena will benefit patients with ALK-positive metastatic non-small cell lung cancer [who] have progressed on prior therapy,” Andy Schmeltz, global president of Pfizer Oncology, said in a press release.

Many patients with ALK-positive metastatic NSCLC respond to initial TKI therapy; however, they often experience tumor progression.

Options for patients whose disease progress after treatment with second-generation ALK TKIs — such as alectinib, ceritinib or brigatinib (Alunbrig, Takeda) — are limited.

“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,” Alice T. Shaw, MD, PhD, professor of medicine at Harvard Medical School and director of Center for Thoracic Cancers at Massachusetts General Hospital Cancer Center, said in the release.

“Yet almost all patients still relapse due to drug resistance, with a large proportion of patients developing new or worsening brain metastases,” Shaw added. ““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.”

The FDA based the approval of lorlatinib on results of a nonrandomized, multicohort, multicenter phase 1/phase 2 study that included 215 patients with ALK-positive metastatic NSCLC previously treated with one or more ALK TKIs. More than half (57%) had undergone treatment with more than one ALK TKI.

Researchers reported a 48% (95% CI, 42-55) response rate. Sixty-nine percent of patients had a history of brain metastases, and results showed a 60% (95% CI, 49-70) intracranial response rate.

The most common adverse reactions were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects and diarrhea.

Approximately one-third (32%) of patients experienced serious adverse reactions, the most frequent of which were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%) and respiratory failure (1.4%).

Researchers reported fatal adverse reactions among 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%).

Eight percent of patients discontinued lorlatinib due to adverse reactions; 48% required dose interruptions and 24% required ad least one dose reduction.

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