FDA Expands Lorlatinib Approval for Frontline ALK+ NSCLC


The FDA expanded the indication for lorlatinib to include the front-line treatment of patients with ALK-positive non–small cell lung cancer.

The FDA has approved a supplemental new drug application for lorlatinib (Lorbrena) to expand the indication to include the frontline treatment of patients with ALK-positive non–small cell lung cancer (NSCLC) as detected by an FDA-approved test.

The regulatory based on the data from the pivotal phase 3 CROWN trial (NCT03052608), where lorlatinib resulted in a 72% reduction in risk of progression or death compared with crizotinib (Xalkori) in treatment-naïve patients (HR 0.28; 95% CI, 0.19-0.41; P <.0001) per blinded independent central review (BICR) assessment.

“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, stated in a press release. “[Lorlatinib] 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.”

Central nervous system (CNS) involvement was evaluated in all study participants. Seventeen patients in the investigative arm and 13 in the control arm had measurable brain metastases per baseline brain imaging.

Results from a prespecified exploratory analysis demonstrated that among these patients, the intracranial objective response rate per BICR assessment was 82% (95% CI, 57-96) in the lorlatinib arm vs 23% (95% CI, 5-54) in the crizotinib arm. Moreover, the intracranial duration of response was 12 months or longer in 79% of those who received lorlatinib (n = 11) vs 0% in those given crizotinib.

Regarding safety, the most frequent toxicities reported with lorlatinib included edema (56%), weight gain (38%), peripheral neuropathy (35%), cognitive effects (21%), diarrhea (21%), dyspnea (20%), and hypertriglyceridemia (22%).

Serious adverse effects (SAEs) were reported in 34% of patients on the investigative arm and the most commonly observed SAEs included pneumonia (4.7%), dyspnea (2.7%), respiratory failure (2.7%), cognitive effects (2.0%), and pyrexia (2.0%).

Approximately 3% of patients who received lorlatinib experienced toxicities that were fatal; these included pneumonia (0.7%), respiratory failure (0.7%), cardiac failure acute (0.7%), pulmonary embolism (0.7%), and sudden death (0.7%).

Moreover, 6.7% of patients who received lorlatinib permanently discontinued treatment due to toxicities. AEs that resulted in dose interruptions and reductions were reported in 49% and 21%, respectively, of patients on the investigative arm.

Previously, in 2018, the FDA approved lorlatinib for use in patients with ALK-positive metastatic NSCLC who had progressed on crizotinib and at least 1 other ALK inhibitor for metastatic disease, or who had disease that progressed on alectinib (Alecensa) or ceritinib as the first ALK inhibitor therapy for metastatic disease.


US FDA expands approval of Pfizer's Lorbrena as first-line treatment for ALK-positive metastatic lung cancer. News release. March 3, 2021. Accessed March 3, 2021. http://bit.ly/30e9cWU

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