Lorlatinib (LORBRENA), Pfizer’s third-generation ALK inhibitor (marketed as LORVIQUA in Europe), was specifically engineered to overcome resistance mutations associated with earlier-generation ALK inhibitors while achieving robust central nervous system penetration. The therapy is approved in more than 80 countries worldwide, including the US, EU, China, Japan, Canada, Australia, and South Korea, for the treatment of ALK-positive metastatic NSCLC.

The Phase III CROWN trial has consistently demonstrated the long-term clinical benefit of lorlatinib in the frontline setting. At the initial interim analysis, lorlatinib reduced the risk of disease progression or death by 72% versus crizotinib, with median progression-free survival (PFS) not reached, supporting its full FDA approval in 2021. Long-term follow-up has continued to reinforce its durable efficacy. At the 5-year post hoc analysis, presented at the 2024 ASCO Annual Meeting and simultaneously published in the Journal of Clinical Oncology, median PFS remained unreached with lorlatinib after a median follow-up of 60 months. The subsequent 7-year update further confirmed lorlatinib’s sustained advantage, solidifying its position as the benchmark first-line therapy for ALK-positive advanced NSCLC.

Key Efficacy Highlights (Phase III CROWN 7-Year Update):

• Median PFS remained not reached with lorlatinib after 7 years of follow-up.

• 81% reduction in the risk of disease progression or death versus crizotinib (HR = 0.19).

• 55% of patients remained progression-free at 7 years compared with 3% in the crizotinib arm.

• Lorlatinib delivered the longest PFS reported to date in advanced/metastatic NSCLC.

• 94% reduction in the risk of intracranial progression (HR = 0.06).

• No new intracranial progression events were reported after 30 months.

• Median time to intracranial progression was not reached versus 16.4 months with crizotinib.

• 44% of patients remained on treatment at data cutoff versus 3% with crizotinib, highlighting durable long-term disease control. 

Key Safety Highlights

• Long-term safety remained consistent with previously reported lorlatinib data, with no new safety signals identified. 

• The most common Grade ≥3 adverse events were hypertriglyceridemia, weight increase, hypercholesterolemia, and hypertension

• Treatment discontinuation due to adverse events remained relatively low (7% with lorlatinib vs. 9% with crizotinib). 

• Findings support a manageable long-term safety profile despite prolonged treatment exposure.

KOL insights

“These seven-year outcomes from the CROWN study are remarkable not only for their durability of tumor response but for what they represent—a fundamental shift in what clinicians and patients might reasonably expect from treatment for advanced-stage NSCLC” –Expert Opinion

“Among patients randomized to the lorlatinib arm, patients without a PFS event at the end of 24 months had a 79% probability of survival without progression at year seven, and the “PFS benefit was consistent across all prespecified subgroups”–Expert Opinion

Conclusion:

NSCLC accounts for approximately 80% of all lung cancer cases, with ALK-positive tumors representing 3–5% of the NSCLC population. ALK gene rearrangements define a highly actionable subgroup of NSCLC that is strongly responsive to ALK tyrosine kinase inhibitors (TKIs), which have significantly transformed outcomes in this disease. Treatment began with the first-generation ALK inhibitor XALKORI (crizotinib), followed by second-generation agents including ALECENSA (alectinib), ZYKADIA (ceritinib), ALUNBRIG (brigatinib), and ENSACOVE (ensartinib), all of which offer improved selectivity, durability of response, and enhanced central nervous system (CNS) penetration compared with earlier therapy. The therapeutic landscape was further advanced by the third-generation ALK inhibitor LORBRENA (lorlatinib), designed specifically to overcome resistance mutations and provide superior intracranial disease control, and it was approved on April 30, 2022, further broadening treatment options in ALK-positive NSCLC.

In the first-line metastatic setting, next-generation ALK inhibitors such as ALECENSA, LORBRENA/LORVIQUA have become key standards of care due to their superior progression-free survival outcomes and strong intracranial efficacy, which is particularly important given the high frequency of brain metastases in ALK-positive patients. At ASCO 2026, updated results from the Phase III CROWN trial demonstrated that Pfizer’s lorlatinib continues to deliver deep, durable, and long-lasting clinical benefit in treatment-naïve patients with advanced ALK-positive NSCLC, further strengthening its position as a frontline benchmark therapy. Overall, long-term CROWN trial follow-up continues to reinforce lorlatinib as a leading standard of care in this setting, setting a high bar for efficacy and CNS control in ALK-driven lung cancer.