ALK-positive lung cancer: Pfizer’s third-generation ALK inhibitor Lorbrena

ALK-positive lung cancer: Pfizer’s third-generation ALK inhibitor Lorbrena.  Change the first-line clinical practice of ALK-positive lung cancer! Pfizer’s third-generation ALK inhibitor Lorbrena has been approved by the US FDA to expand its indications!

Pfizer recently announced that the US Food and Drug Administration (FDA) has approved a supplementary new drug application (sNDA) for the targeted anticancer drug Lorbrena (lorlatinib), expanding its indications: for first-line use Treatment of adult patients with anaplastic lymphoma kinase (ALK) positive metastatic non-small cell lung cancer (NSCLC). The sNDA was approved under the FDA’s real-time oncology review (RTOR) pilot program, and this approval also transformed the accelerated approval in 2018 into a full approval.

Lorbrena is a third-generation ALK inhibitor, specifically developed to inhibit the most common tumor mutations that drive resistance to current drugs, and to solve the problem of brain metastasis at the most common site of ALK-positive NSCLC disease progression. Among ALK-positive lung cancer patients, up to 40% have brain metastases at the time of initial diagnosis.

This expanded indication approval is based on data from the key Phase 3 CROWN study. This is a head-to-head study that evaluated the efficacy and safety of two ALK-targeted anticancer drugs, Lorbrena and Xalkori (crizotinib, crizotinib) in the first-line treatment of advanced ALK+NSCLC. Data show that compared with Xalkori, Lorbrena treatment significantly reduces the risk of disease progression or death by 72% (HR=0.28, p<0.001), and the intracranial response rate is significantly improved (objective response rate ORR: 82% vs 23% ;Complete response rate (CR: 71% vs 8%), the duration of intracranial response (IC-DOR) ≥ 12 months, the proportion of patients was significantly higher (79% vs 0%).

Biomarker-driven drugs have improved the prognosis of ALK-positive NSCLC patients, but innovative therapies are still needed to delay the progression of the disease. The results of the CROWN study show that Lorbrena has the potential to become a first-line treatment option to change the clinical practice of ALK-positive NSCLC. Relevant data has been published in the top international medical journal “New England Journal of Medicine” (NEJM). See: First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer.

Lung cancer is the number one cause of cancer-related deaths worldwide. NSCLC accounts for approximately 80-85% of lung cancers. ALK-positive tumors account for about 3-5% of NSCLC cases. Before targeted therapies and immunotherapy were launched, the 5-year survival rate for patients with advanced NSCLC was only 5%.

Xalkori is the world’s first ALK targeted drug launched by Pfizer. This drug is the first generation of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI). Since its launch in 2011, it has greatly changed the advanced stage. Clinical treatment of ALK+NSCLC patients.

Lorbrena is the third-generation ALK-TKI, which was approved by the US FDA in November 2018 for the treatment of ALK-positive metastatic NSCLC patients, specifically: (1) receiving the first-generation ALK inhibitor Xalkori and at least one other ALK inhibitor (2) The second-generation ALK inhibitor alectinib (brand name: Alecensa, Novartis) or certinib (brand name: Zykadia, Roche) is the first-line treatment of metastatic disease. Of patients.

Based on the tumor remission rate and duration of remission, Lorbrena obtained accelerated approval from the FDA for the above indications. The CROWN study is a confirmatory phase III study designed to convert accelerated approval to full approval. Based on the positive results of the CROWN study, these data will be reviewed under the US FDA Real-Time Oncology Review (RTOR) pilot project and will be shared with other regulatory agencies to support full approval and apply for approval for Lorbrena’s first-line treatment. Indications: Yu treats patients with ALK-positive metastatic NSCLC who have not previously received treatment.

Andy Schmeltz, Global President of Pfizer Oncology, said: “For more than ten years, Pfizer has been a pioneer in providing biomarker-driven therapies and meeting the diverse and evolving needs of patients with non-small cell lung cancer. Lorbrena has become one of the most advanced ALK-positive NSCLC patients A revolutionary drug, approved by the FDA in the first-line treatment, means that we can now extend our hopes to more patients.”

CROWN is a global, randomized, open-label, parallel, dual-arm, phase 3 trial that enrolled 296 patients with ALK-positive advanced NSCLC who had not previously received treatment (naïve). In the study, these patients were randomly assigned at a 1:1 ratio and received Lorbrena monotherapy (n=149) or Xalkori monotherapy (n=147). The primary endpoint is progression-free survival (PFS) based on blinded independent central review (BICR) assessment. Secondary endpoints include PFS, overall survival (OS), objective response rate (ORR), intracranial ORR, and safety based on the assessment of the research investigator.

The results showed that in the pre-specified interim analysis, the study reached the primary endpoint: according to the BICR assessment results, compared with Xalkori (crizotinib), Lorbrena treatment had a statistically significant and clinically significant improvement in PFS ( HR=0.28; 95%CI: 0.19-0.41; p<0.001), which is equivalent to reducing the risk of disease progression or death by 72%.

In terms of secondary endpoints, OS data was not yet mature at the time of the interim analysis. In terms of ORR, the Lorbrena group was 76% (95% CI: 68-83) and the Xalkori group was 58% (95% CI: 49-66). In addition, compared with Xalkori, Lorbrena showed enhanced intracranial activity: at 12 months, 96% (95% CI: 91-98) of patients in the Lorbrena group had no central nervous system (CNS) progression, compared with 60 in the Xalkori group % (95%CI: 0.49-0.69). In patients with brain metastases (n=30), the intracranial ORR in the Lorbrena group was 82% (95%CI: 0.57-0.96; n=14), and the Xalkori group was 23% (95%CI: 0.05-0.54, n =3) The complete intracranial response rate (CRR) was 71% and 8%, respectively.

In this study, adverse events (AEs) that occurred in more than 20% of patients in the Lorbrena group included hypercholesterolemia (70%), hypertriglyceridemia (64%), edema (55%), and weight gain ( 38%), peripheral neuropathy (34%), cognitive function (21%) and diarrhea (21%). 72% of the Lorbrena group and 56% of the Xalkori group had grade 3 or 4 adverse events. The most common grade 3 or 4 adverse events in the Lorbrena group were hypertriglyceridemia (20%), weight gain (17%), hypercholesterolemia (16%), and hypertension (10%). Adverse events leading to permanent discontinuation occurred in 7% of patients in the Lorbrena group and 9% of patients in the Xalkori group.

(source:internet, reference only)

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