7 Years and Still Going—Lorlatinib Continues to Rewrite the Rules in ALK+ NSCLC

Seven years of follow-up without a median progression-free survival (PFS) is virtually unheard of in advanced non–small cell lung cancer (NSCLC). Yet that is precisely where lorlatinib (Lorbrena; Pfizer Inc) stands in the phase 3 CROWN trial (NCT03052608)—and the latest data, presented at the 2026 American Society of Clinical Oncology Annual Meeting in Chicago, continue to build on an already compelling picture.

Examining Lorlatinib and the CROWN Trial

NSCLC accounts for over 80% of all lung cancer diagnoses and is associated with more aggressive disease and a poor prognosis. Decades of research have led to the identification and understanding of oncogenic drivers and to targeted therapies that improve response and survival while limiting off-target toxicities. Tyrosine kinase inhibitors (TKIs) represent an efficacious option that prolongs survival for patients with advanced NSCLC. Among driver mutations, ALK genomic alterations are found in 3% to 7% of patients with NSCLC.¹

Lorlatinib is a third-generation TKI approved for first- and second-line treatment of ALK-positive advanced NSCLC. Following 5-year outcomes from the CROWN trial, lorlatinib became the first therapy in advanced NSCLC to achieve a median PFS that had not been reached.¹

The CROWN trial is a phase 3, randomized, open-label study comparing lorlatinib monotherapy with crizotinib monotherapy as first-line treatment for patients with advanced ALK-positive NSCLC. The trial enrolled 296 treatment-naive patients with advanced ALK-positive NSCLC, randomly assigned 1:1 to lorlatinib 100 mg once daily (n = 149) or crizotinib (Xalkori; Pfizer) 250 mg twice daily (n = 147).²

The Data Favor Lorlatinib

As of the October 31, 2025, data cutoff, 44% of patients in the lorlatinib arm were still receiving treatment compared with 3% in the crizotinib arm. Median PFS remained not reached with lorlatinib vs 9.1 months with crizotinib (HR, 0.19; 95% CI, 0.13-0.26). The 7-year PFS rate was 55% with lorlatinib and 3% with crizotinib, underscoring the remarkable durability of disease control achieved with lorlatinib.²

Perhaps most striking is that patients who were progression-free at 24 months had a 79% probability of remaining progression-free at year 7. In other words, reaching the 2-year mark with lorlatinib is a meaningful early signal of long-term benefit.²

Lorlatinib Demonstrates Intracranial Benefits

Intracranial (IC) disease control is a critical concern in ALK-positive NSCLC, and lorlatinib’s brain penetration has long been one of its defining advantages. The 7-year data reinforce this: No new IC progression events occurred after the first 30 months on lorlatinib. The median time to IC progression was not reached with lorlatinib vs 16.4 months with crizotinib (HR, 0.06; 95% CI, 0.03-0.12)—a 94% reduction in the hazard of intracranial progression.²

Long-Term Safety Is Favorable and Expected

The safety profile at 7 years was consistent with that of prior reports. Grade 3 to 4 adverse events occurred in 77% of lorlatinib patients and in 57% of crizotinib patients, but treatment-related discontinuations remained low at 5% and 6%, respectively, with no new permanent discontinuations due to treatment-related adverse events after the first 26 months. Dose reductions were reported in 34% of lorlatinib patients, and notably, long-term efficacy was similar regardless of whether a dose reduction occurred.²

What 7 Years Actually Means

Overall survival follow-up remains ongoing, as the protocol-specified number of events has not yet been met. But with more than half of lorlatinib-treated patients still progression-free at 7 years and virtually no new safety or efficacy events emerging after the first 2 years, CROWN continues to set a benchmark that other therapies in advanced NSCLC have yet to approach.

REFERENCES

1. Ardizzoni A, Cortinovis D, Gori B, Nuzzo A, Pasello G, de Marinis F. Lorlatinib atypical safety profile in ALK-positive aNSCLC: tips for management from an Italian expert panel. Future Oncol. 2026;22(3):383-393. doi:10.1080/14796694.2025.2612605

2. Mok MS, Solomon BJ, Felip E, et al. Lorlatinib vs crizotinib as first-line treatment for advanced ALK+ non-small cell lung cancer: 7-year update from the phase 3 CROWN study. Presented at: 2026 ASCO Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract 8502.