The FDA ( U.S. Food and Drug Administration ) has approved supplemental New Drug Application ( sNDA ) for Lorbrena ( Lorlatinib ), a tyrosine kinase inhibitor ( TKI ), 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 FDA-approved test.
The FDA action has also converted the 2018 accelerated approval to full approval.
Lorlatinib 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 has shown a 72% reduction in risk of progression or death versus Crizotinib ( Xalkori ) in a previously untreated patient population ( hazard ratio, HR=0.28: 95% CI, 0.19 to 0.41; p less than 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 Lorlatinib arm and 13 in the Crizotinib arm with measurable brain metastases based on baseline brain imaging.
A prespecified exploratory analysis has shown that among these patients, the intracranial objective response rate ( IC-ORR ), as assessed by BICR, was 82% ( 95% CI, 57 to 96 ) in the Lorlatinib arm and 23% ( 95% CI, 5 to 54 ) in the Crizotinib arm.
The intracranial duration of response ( IC-DOR ) was 12 months or longer in 79% ( n=11 ) and 0% of patients in the Lorlatinib and Crizotinib arms, respectively.
The most common adverse events of any grade and grade 3-4 worsening laboratory abnormalities occurring in 20% or more of people treated with Lorlatinib were edema ( 56% ), weight gain ( 38% ), peripheral neuropathy ( 35% ), cognitive effects ( 21% ), diarrhea ( 21% ), dyspnea ( 20% ), and hypertriglyceridemia ( 22% ).
Serious adverse effects occurred in 34% of people treated with Lorlatinib; the most frequently reported serious adverse effects were pneumonia ( 4.7% ), dyspnea ( 2.7% ), respiratory failure ( 2.7% ), cognitive effects ( 2.0% ), and pyrexia ( 2.0% ).
Fatal adverse effects occurred in 3.4% of people treated with Lorlatinib 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 Lorlatinib due to adverse effects occurred in 6.7% of people. Adverse effects leading to dose interruptions and dose reductions occurred in 49% and 21% of people treated with Lorlatinib, respectively. ( Xagena )
Source: Pfizer, 2021