Pfizer Announces Three-Year Follow-Up Results from Phase 3 CROWN Trial of LORBRENA® (Lorlatinib) Demonstrating Significant Long-Term Benefit in First-Line ALK-Positive Advanced NSCLC

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Recently, Pfizer announced the latest results of the Phase 3 CROWN trial at the 2022 American Association for Cancer Research (AACR) Annual Meeting. The trial was conducted in patients with previously untreated anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC), evaluating the efficacy of the third-generation ALK-targeted drug Lorbrena (lorlatinib; European brand name Lorviqua) compared to the first-generation ALK-targeted drug Xalkori (crizotinib) as a first-line treatment.

Preliminary results published in the New England Journal of Medicine in 2020 showed that the CROWN trial met its primary endpoint: compared with Xalkori, Lorbrena treatment significantly improved progression-free survival (PFS) assessed by independent central review (BICR), reducing the risk of disease progression or death by 72% (HR=0.28; 95% CI: 0.19-0.41; stratified one-sided p<0.001).

The latest analysis results reported at this year's AACR annual meeting showed that after a median follow-up of 3 years, Lorbrena continued to demonstrate significant improvement over Xalkori in the primary endpoint—PFS assessed by BICR (HR=0.27; 95% CI: 0.18-0.39), equivalent to a 73% reduction in the risk of disease progression or death.

In this analysis, 64% of patients in the Lorbrena treatment group had no disease progression after 3 years (95% CI: 55-71, n=149), compared to only 19% in the Xalkori treatment group (95% CI: 12-27, n=147) during the same period. For secondary endpoints, the objective response rate (ORR) was 77% (95% CI: 70-84) for the Lorbrena group and 59% (95% CI: 50-67) for the Xalkori group.

In addition, Lorbrena treatment reduced the intracranial progression rate by 92% (HR=0.08; 95% CI: 0.04–0.17). Among patients with measurable brain metastases at baseline, the intracranial objective response rate (IC-ORR) was 83% (95% CI: 59-96, n=15) in the Lorbrena treatment group and 23% (95% CI: 5-54, n=3) in the Xalkori treatment group, with intracranial complete response rates (IC-CR) of 72% and 8%, respectively. Among patients without brain metastases at baseline, Lorbrena demonstrated a 98% reduction in the intracranial progression rate (HR=0.02; 95% CI: 0.002-0.136).

Lung cancer is the leading cause of cancer-related deaths globally, with NSCLC accounting for approximately 80-85% of lung cancer cases. ALK-positive tumors make up about 3-5% of NSCLC cases. Approximately 25-40% of patients with ALK-positive NSCLC will develop brain metastases within two years of initial diagnosis. Lorbrena, a tyrosine kinase inhibitor capable of crossing the blood-brain barrier, has been approved for first-line treatment of ALK-positive NSCLC.

In terms of safety, the safety profile observed in the 3-year follow-up analysis was consistent with the established safety profiles of Lorbrena and Xalkori. In the primary analysis of the 2020 CROWN trial, the most common adverse events (incidence rate ≥20%) among the 149 patients treated with Lorbrena were edema, weight gain, peripheral neuropathy, cognitive effects, diarrhea, dyspnea, and hypertriglyceridemia. Serious adverse events occurred in 34% of patients treated with Lorbrena, with the most frequently reported serious adverse events being pneumonia, dyspnea, respiratory failure, cognitive effects, and fever. Among patients receiving Lorbrena, 3.4% experienced fatal adverse events, and 6.7% discontinued treatment permanently due to adverse events.

Reference Source: Three Year Follow-Up Data from Phase 3 CROWN Trial of Pfizer’s LORBRENA® (lorlatinib) Confirm Prolonged Progression-Free Survival in First-Line ALK-Positive Advanced Lung Cancer