FDA Expands Lorlatinib Approval To Frontline Treatment of ALK-Positive Metastatic NSCLC


The agency approved the supplemental new drug application to include the first-line treatment of adult patients with metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer.

The FDA approved the supplemental new drug application (NDA) for lorlatinib (Lorbrena) to include the first-line treatment of adult patients with metastatic anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, according to Pfizer – the agent’s manufacturer.

“For more than a decade, Pfizer has been a pioneer in delivering biomarker-driven therapies and addressing the diverse and evolving needs of people with non-small cell lung cancer,” Andy Schmeltz, global president of Pfizer Oncology, said in a company issued release. “Lorbrena has been a transformative medicine for people with ALK-positive advanced NSCLC, and this FDA approval in the first-line setting means that we can now extend hope to even more people.”

The expanded approval was based on data from the pivotal, randomized, open-label, parallel 2-arm phase 3 CROWN trial, designed to evaluate lorlatinib (n = 149) compared with crizotinib (Xalkori; n = 147) in previously untreated patients.

The primary end point was progression-free survival (PFS) based on blinded independent central review (BICR). Secondary end points included overall survival (OS) and tumor assessment related data by BICR, including overall response rate (ORR) and duration of response (DOR).

Treatment with lorlatinib demonstrated a 72% reduction in the risk for progression or death (HR 0.28; 95% CI, 0.19-0.41; P < .0001).

“The CROWN data have shown Lorbrena can significantly improve outcomes in the first-line treatment of ALK-positive non-small cell lung cancer, including those that present with brain metastases,” Benjamin Solomon, MD, form the Department of Medical Oncology at thee Peter MacCallum Cancer Centre, said in the release. “This approval is meaningful for my patients because we now have a highly effective treatment option that can delay the progression of a typically aggressive disease.”

Moreover, central nervous system (CNS) involvement was assessed in all patients. A prespecified exploratory analysis show that, among these patients, the intracranial objective response rate (IC-ORR), as assessed by BICR, was 82% (95% CI, 57-96) with lorlatinib, compared with 23% (95% CI, 5-54) with crizotinib. The intracranial duration of response (IC-DOR) was 12 months or longer in 79% of patients treated with lorlatinib (n = 11), compared with 0% of those who received crizotinib.

The most common adverse events (AEs) associated with lorlatinib included edema (56%), weight gain (38%), peripheral neuropathy (35%), cognitive effects (21%), diarrhea (21%), dyspnea (20%), and hypertriglyceridemia (22%). Serious AEs occurred in 34% of patients treated with lorlatinib, with the most frequently including pneumonia (4.7%), dyspnea (2.7%), respiratory failure (2.7%), cognitive effects (2.0%), and pyrexia (2.0%). Fatal AEs occurred in 3.4% of the lorlatinib arm, and included pneumonia (0.7%), respiratory failure (0.7%), cardiac failure acute (0.7%), pulmonary embolism (0.7%), and sudden death (0.7%). Permanent discontinuation of treatment due to AEs occurred in 6.7% of patients in the lorlatinib arm. AEs leading to dose interruptions and dose reductions occurred in 49% and 21% of people treated with lorlatinib, respectively.

With this approval, the FDA converted the 2018 accelerated approval of lorlatinib to full approval. The drug was approved under the agency’s Real-Time Oncology Review pilot program. The sNDA was also reviewed by the FDA under Project ORBIS


Pfizer Investor News. U.S. FDA Expands Approval of Pfizer’s Lorbrena as First-Line Treatment for ALK-Positive Metastatic Lung Cancer. Published March 3, 2021. https://investors.pfizer.com/investor-news/press-release-details/2021/U.S.-FDA-Expands-Approval-of-Pfizers-LORBRENA-as-First-Line-Treatment-for-ALK-Positive-Metastatic-Lung-Cancer/default.aspx. Accessed March 3, 2021.

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