Lorbrena Demonstrates Superior Efficacy Over Xalkori in Phase 3 CROWN Trial for First-Line ALK-Positive NSCLC

November 22, 2020 News /BioValleyBIOON/ --PfizerPfizer recently announced positive results from the head-to-head Phase III CROWN study evaluating Lorbrena (lorlatinib) and Xalkori (crizotinib) as first-line treatments for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). The data showed that, compared with Xalkori,Lorbrena treatment significantly reduced the risk of disease progression or death by 72% (HR=0.28, p<0.001) and significantly improved intracranial response rates (objective response rate [ORR]: 82% vs. 23%; complete response rate [CR]: 71% vs. 8%).

BiomarkerDriver-targeted therapies have improved the prognosis of patients with ALK-positive non-small cell lung cancer (NSCLC), but innovative treatments are still needed to delay disease progression. The results of the CROWN study indicate that Lorbrena has the potential to become a first-line treatment option that transforms clinical practice for ALK-positive NSCLC. Relevant data have been published in the prestigious international medical journal, The New England Journal of Medicine (NEJM). For details, see:First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer。

Lung cancer is the leading cause of cancer-related deaths worldwide. NSCLC accounts for approximately 80-85% of lung cancers. ALK-positiveTumorIt accounts for approximately 3-5% of NSCLC cases. Prior to the availability of targeted therapies and immunotherapies, the 5-year survival rate for patients with advanced NSCLC was only 5%.

Xalkori, the world’s first ALK-targeted therapy launched by Pfizer, is a first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI). Since its market approval in 2011, it has significantly transformed the clinical management of patients with advanced ALK-positive non-small cell lung cancer (NSCLC).

Lorbrena is a third-generation ALK-TKI that was approved in the United States in November 2018FDAApproved for the treatment of patients with ALK-positive metastatic NSCLC, specifically: (1) patients whose disease has progressed after treatment with the first-generation ALK inhibitor Xalkori and at least one other ALK inhibitor for metastatic disease; (2) patients who have received the second-generation ALK inhibitor alectinib (brand name: Alecensa,Novartispharmaceutical) or ceritinib (brand name: Zykadia,Roche Pharmaceuticals) patients with disease progression after first-line treatment for metastatic disease.

Based on the tumor response rate and duration of response, Lorbrena received accelerated approval from the FDA for the aforementioned indications. The CROWN study is a confirmatory Phase III trial designed to convert the accelerated approval into full approval. Based on the positive results from the CROWN study, these data will be submitted in the United StatesFDAReal-timeTumorReviewed under the Real-Time Oncology Review (RTOR) pilot program, with findings shared with other regulatory agencies to support full approval and the application for approval of Lorbrena for the first-line treatment indication: for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who have not previously received treatment.

Chris Boshoff, M.D., Chief Development Officer of Oncology in Pfizer’s Global Product Development organization, stated, “Approximately 10 years ago, we pioneered the first therapy targeting ALK-positive NSCLC.”BiomarkersDriver drug—Xalkori, which has transformed the treatment landscape for this disease. Over the past decade, we have been committed to changing the treatment paradigm for non-small cell lung cancer (NSCLC) through the research and development of innovative medicines, such as the third-generation ALK inhibitor Lorbrena, specifically designed to inhibit the most commonTumormutations, thereby overcoming resistance to existing drugs and addressing brain metastases. The significantly improved progression-free survival (PFS) and intracranial response rates observed in the CROWN study highlight Lorbrena’s potential to markedly improve prognosis in previously untreated (treatment-naïve) patients with ALK-positive non-small cell lung cancer (NSCLC). We will work with regulatory authorities to bring this third-generation ALK inhibitor to the first-line treatment setting.”

CROWN is a global, randomized, open-label, parallel-group, two-arm, phase 3 trial that enrolled a total of 296 patients with previously untreated (treatment-naïve) ALK-positive advanced non-small cell lung cancer (NSCLC). In the study, these patients were randomized in a 1:1 ratio to receive either Lorbrena monotherapy (n=149) or Xalkori monotherapy (n=147). The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR). Secondary endpoints included PFS assessed by the study investigators, overall survival (OS), objective response rate (ORR), intracranial ORR, and safety.

The results showed that at the prespecified interim analysis, the study met its primary endpoint: based on BICR assessment, Lorbrena treatment demonstrated a statistically significant and clinically meaningful improvement in PFS compared with Xalkori (crizotinib) (HR=0.28; 95% CI: 0.19–0.41; p<0.001), equivalent to a 72% reduction in the risk of disease progression or death.

Regarding secondary endpoints, overall survival (OS) data were immature at the interim analysis. For objective response rate (ORR), the Lorbrena group achieved 76% (95% CI: 68–83), compared with 58% (95% CI: 49–66) in the Xalkori group. Furthermore, Lorbrena demonstrated enhanced intracranial activity compared with Xalkori: at 12 months, 96% (95% CI: 91–98) of patients in the Lorbrena group were free from central nervous system (CNS) progression, versus 60% (95% CI: 0.49–0.69) in the Xalkori group. Among patients with brain metastases (n=30), the intracranial ORR was 82% (95% CI: 0.57–0.96; n=14) in the Lorbrena group and 23% (95% CI: 0.05–0.54; n=3) in the Xalkori group, with intracranial complete response rates (CRR) of 71% and 8%, respectively.

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

Original Source: Results from Phase 3 CROWN Trial of Pfizer’s LORBRENA® (lorlatinib) in Previously Untreated ALK-Positive Lung Cancer Published in The New England Journal of Medicine