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Lorviqua based on Lorlatinib as a first-line treatment for ALK-positive advanced lung cancer. European Commission approved

The European Commission ( EC ) granted marketing authorization for Lorviqua ( Lorlatinib, available in the U.S. under the brand name Lorbrena ) as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase ( ALK ) - positive advanced non-small cell lung cancer ( NSCLC ) previously not treated with an ALK inhibitor.

The approval for the first-line use of Lorviqua was based on the results of the pivotal phase 3 CROWN trial, in which Lorviqua reduced the risk of disease progression or death by 72% compared to Crizotinib ( Xalkori ).
As a secondary endpoint, the confirmed objective response rate ( ORR ) was 76% ( 95% CI, 68 to 83 ) with Lorlatinib and 58% ( 95% CI, 49 to 66 ) with Crizotinib.
In patients with measurable brain metastases, 82% of patients in the arm experienced an intracranial response ( 71% had an intracranial complete response ), compared to 23% of Crizotinib patients.
The CROWN is a randomized, open-label, parallel 2-arm trial in which 296 people with previously untreated advanced ALK-positive non-small cell lung cancer were randomized 1:1 to receive Lorlatinib monotherapy ( n=149 ) or Crizotinib monotherapy ( n=147 ).

The EC approval of Lorviqua follows a positive opinion from the Committee for Medicinal Products for Human Use ( CHMP ) in December 2021.

Lorlatinib is approved in the U.S. by FDA under the brand name Lorbrena for the treatment of adults with metastatic non-small cell lung cancer whose tumors are ALK-positive as detected by an FDA-approved test.

In 2019, the EC granted conditional marketing authorization for Lorviqua as a monotherapy for the treatment of adult patients with ALK-positive advanced non-small cell lung cancer whose disease has progressed after Alectinib or Ceritinib as the first ALK tyrosine kinase inhibitor ( TKI ) therapy, or Crizotinib and at least one other ALK tyrosine kinase inhibitor.

In the CROWN trial, 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 was progression-free survival ( PFS ) based on blinded independent central review ( BICR ). Secondary endpoints included overall survival ( OS ) and tumor assessment related data by BICR, including objective response rate, and duration of response ( DoR ).
In patients with measurable central nervous system ( CNS ) metastases at baseline, additional outcome measures were intracranial ( IC ) objective response rate and intracranial duration of response by BICR. The trial is continuing in order to further evaluate the secondary endpoint of overall survival, which was not mature at the time of analysis.

Overall, the safety profile of Lorlatinib was similar to that reported in previous studies. The most frequent adverse events in greater than or equal to 20% of 149 patients treated with Lorlatinib were edema, weight gain, peripheral neuropathy, cognitive effects, diarrhea, dyspnea and hypertriglyceridemia.
Serious adverse events occurred in 34% of people treated with Lorlatinib; the most frequently reported serious adverse effects were pneumonia, dyspnea, respiratory failure, cognitive effects and pyrexia.
Fatal adverse effects occurred in 3.4% of people treated with Lorlatinib. Permanent discontinuation of Lorlatinib due to adverse effcets occurred in 6.7% of people.

The results from the CROWN study were published in The New England Journal of Medicine ( NEJM ).

Lung cancer is the number one cause of cancer-related death around the world. non-small cell lung cancer accounts for approximately 80-85% of lung cancers, with ALK-positive tumors occurring in about 3-5% of NSCLC cases. Up to 40% of people with ALK-positive metastatic non-small cell lung cancer present with brain metastases at initial diagnosis. ( Xagena )

Source: Pfizer, 2022