Pfizer’s Lorbrena gets US FDA approval to treat ALK-positive non-small cell lung cancer

The US Food and Drug Administration (FDA) approved Pfizer Inc’s supplemental New Drug Application (sNDA) for Lorbrena (lorlatinib), expanding the indication to include first-line treatment of people with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Lorbrena is now indicated for adults with metastatic NSCLC whose tumors are ALK-positive as detected by an US FDA-approved test. The US FDA action also converts the 2018 accelerated approval to full approval. The application was approved under the US FDA’s Real-Time Oncology Review (RTOR) pilot program.

“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,” said Andy Schmeltz, global president, Pfizer Oncology. “Lorbrena has been a transformative medicine for people with ALK-positive advanced NSCLC, and this US FDA approval in the first-line setting means that we can now extend hope to even more people.”

Lorbrena is a third-generation ALK inhibitor specifically designed to inhibit the most common tumor mutations that drive resistance to current medications and to address metastases in the brain, a frequent site for disease progression in ALK-positive NSCLC. Up to 40% of people with ALK-positive metastatic NSCLC present with brain metastases at initial diagnosis.

The expanded approval of Lorbrena is based on the results from the pivotal phase 3 CROWN trial, which showed a 72% reduction in risk of progression or death vs. Xalkori (crizotinib) in a previously untreated patient population (HR 0.28: 95% CI, 0.19 to 0.41; p<0.0001) as assessed by blinded independent central review (BICR). Central nervous system (CNS) involvement was assessed in all patients. There were 17 patients in the Lorbrena arm and 13 in the Xalkori arm with measurable brain metastases based on baseline brain imaging. A prespecified exploratory analysis showed that among these patients, the intracranial objective response rate (IC-ORR), as assessed by BICR, was 82% (95% CI, 57 to 96) in the Lorbrena arm and 23% (95% CI, 5 to 54) in the XALKORI arm. The intracranial duration of response (IC-DOR) was 12 months or longer in 79% (n=11) and 0% of patients in the Lorbrena and Xalkori arms, respectively.

“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,” said Benjamin Solomon, M.D., Department of Medical Oncology, Peter MacCallum Cancer Centre. “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.”

In 2018, the US FDA approved Lorbrena for the treatment of patients with ALK-positive metastatic 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. This indication was approved under accelerated approval based on tumor response rate and duration of response. Based on the CROWN data, the US FDA has also converted the accelerated approval to full approval.

This sNDA was also reviewed by the US FDA under Project ORBIS, an initiative introduced in 2019, which provides a framework for potential concurrent submissions and collaborative review with health authorities in Canada, Singapore, Switzerland, Australia, Brazil and the United Kingdom. Under Project ORBIS, collaboration among international regulators may allow people with cancer to receive earlier access to products in other countries. The European Medicines Agency is also reviewing a Type II variation application for Lorbrena in the first line indication.

CROWN trial is a phase 3, randomized, open-label, parallel 2-arm trial in which 296 people with previously untreated advanced ALK-positive NSCLC were randomized 1:1 to receive LORBRENA monotherapy (n=149) or XALKORI monotherapy (n=147). Patients were required to have an ECOG performance status of 0-2 and ALK-positive NSCLC as identified by the VENTANA ALK (D5F3) CDx assay. The primary endpoint of the CROWN trial is PFS based on BICR. Secondary endpoints include overall survival (OS) and tumor assessment related data by BICR, including ORR, and DOR. In patients with measurable CNS metastases at baseline, additional outcome measures were IC-ORR and IC-DOR by BICR.

Lung cancer is the number one cause of cancer-related death around the world. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 80-85% of lung cancers, with ALK-positive tumors occurring in about 3-5% of NSCLC cases. In 2020, an estimated 228,820 new cases of lung cancer were diagnosed in the US.

Lorbrena (lorlatinib) is a tyrosine kinase inhibitor (TKI) that has been shown to be highly active in preclinical lung cancer models harboring chromosomal rearrangements of ALK. Lorbrena was specifically developed to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood brain barrier.

Lorbrena is approved in the US for the treatment of adults with metastatic NSCLC whose tumors are ALK-positive as detected by an US FDA-approved test.



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