Lorlatinib Improves Long-Term Efficacy in Advanced ALK+ NSCLC

Lorlatinib (Lorbrena) improved long-term efficacy outcomes vs crizotinib (Xalkori) among patients with advanced ALK-positive non–small cell lung cancer, according to 7-year follow-up data from the phase 3 CROWN trial (NCT03036488) presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

At a median follow-up of 83.0 months (95% CI, 81.2-86.3) for lorlatinib (n = 149) and 77.2 months (95% CI, 36.8-not evaluable) for crizotinib (n = 147), the median PFS was still not reached (NR; 95% CI, 68.5 months-NR) vs 9.1 months (95% CI, 7.4-10.9), respectively (HR, 0.19; 95% CI, 0.13-0.26), in patients with advanced ALK-positive NSCLC. The 7-year PFS rates in the respective arms were 55% and 3%. In total, 7 new PFS events were reported between 5 and 7 years in the lorlatinib arm; 4 were progression events, and 3 were deaths (all of which were deemed not related to treatment).

No new intracranial (IC) progression events occurred after the first 30 months on lorlatinib. The median times to IC progression was NR (95% CI, NR-NR) and 16.4 months (95% CI, 12.7-21.9), respectively (HR, 0.06; 95% CI, 0.03-0.12). The 7-year IC PFS rates were 92% vs 16%, respectively.

Long-term efficacy outcomes with lorlatinib were similar between patients who did and did not undergo dose reductions within 26 weeks. Among patients with dose reductions, the median PFS (n = 23) was NR (95% CI, 79.8 months-NR), and the median time to IC progression was NR (95% CI, NR-NR). Among patients without dose reductions, the median PFS (n = 98) was NR (95% CI, 81.9%-NR), and the median time to IC progression (n = 99) was NR (95% CI, NR-NR). Notably, the PFS and time to intracranial progression outcomes were also consistent across lorlatinib dose levels (100 mg, 75 mg, or 50 mg).

The PFS benefit with lorlatinib was consistent across all prespecified subgroups, including patients with brain metastases (HR, 0.08; 95% CI, 0.04-0.19) or without brain metastases (HR, 0.23; 95% CI, 0.16-0.34), as well as in Asian (HR, 0.24; 95% CI, 0.15-0.39) and non-Asian (HR, 0.18; 95% CI, 0.11-0.28) populations.

The presentation follows a 5-year post hoc analysis published in the Journal of Clinical Oncology that showed median progression-free survival (PFS) had not been reached with lorlatinib vs a median of 9.1 months (95% CI, 7.4-10.9) with crizotinib, corresponding to an HR of 0.19 (95% CI, 0.13-0.27) in patients with advanced ALK-positive NSCLC.²

How was the CROWN trial designed?

CROWN is an ongoing, international, open-label, randomized, phase 3 trial conducted across 104 centers in 23 countries that evaluates lorlatinib vs crizotinib in patients with previously untreated, advanced, ALK-positive NSCLC.

A total of 296 patients were randomly assigned 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147) in 28-day cycles. Eligible patients had stage IIIB/IV ALK-positive NSCLC without prior systemic treatment for metastatic disease, an ECOG performance status of 2 or lower, and at least 1 extracranial measurable target lesion. Patients with asymptomatic, treated, or untreated central nervous system metastases were eligible, and no crossover between arms was permitted. Patients were stratified by the presence of brain metastases (yes vs no) and ethnicity (Asian vs non-Asian).

The primary end point was PFS by blinded independent central review (BICR) per RECIST 1.1 criteria; the key secondary end point was overall survival (OS), to be assessed at a protocol-specified second interim analysis after at least 139 deaths.

What CROWN findings have previously been reported?

At the initial interim analysis, lorlatinib produced a 72% reduction in the risk of progression or death vs crizotinib per BICR assessment (HR, 0.28; 95% CI, 0.19-0.41; P <.0001), with median PFS not reached in the lorlatinib arm.³

These data supported the March 2021 FDA approval of lorlatinib for adult patients with metastatic NSCLC whose tumors are ALK-positive as detected by an FDA-approved test, expanding the agent's indication and converting its November 2018 accelerated approval to a full approval.⁴ At the 3-year post hoc analysis, median PFS by BICR remained not reached in the lorlatinib arm with continued superior benefit over crizotinib.²

The 5-year post hoc analysis,⁵ presented at the 2024 ASCO Annual Meeting and simultaneously published in the Journal of Clinical Oncology, demonstrated that median PFS had still not been reached with lorlatinib at a median follow-up of 60.2 months (95% CI, 57.4-61.6), vs 9.1 months (95% CI, 7.4-10.9) with crizotinib (HR, 0.19; 95% CI, 0.13-0.27). The 5-year PFS rates were 60% (95% CI, 51-68) vs 8% (95% CI, 3-14), respectively. Among patients with baseline brain metastases (n = 35 lorlatinib; n = 38 crizotinib), lorlatinib led to a median PFS of not reached (95% CI, 32.9-NR) vs 6.0 months (95% CI, 3.7-7.6) with crizotinib (HR, 0.08; 95% CI, 0.04-0.19); 5-year PFS was 53% with lorlatinib, and no patients in the crizotinib arm remained progression free at 2 years. At 5 years, 50% of patients in the lorlatinib arm were still receiving treatment, compared with 5% in the crizotinib arm.

References

1. Mok TS, 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. J Clin Oncol. 2026;44(suppl 16):8502. doi:10.1200/JCO.2026.44.16_suppl.8502
2. Solomon BJ, Liu G, Felip E, et al. Lorlatinib versus crizotinib in patients with advanced ALK-positive non-small cell lung cancer: 5-year outcomes from the phase III CROWN study. J Clin Oncol. 2024;42(29):3400-3409. doi:10.1200/JCO.24.00581
3. Shaw AT, Bauer TM, de Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(9):2018-2029. doi:10.1056/NEJMoa2027187
4. FDA approves lorlatinib for metastatic ALK-positive NSCLC. News release. FDA. March 3, 2021. Accessed May 21, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lorlatinib-metastatic-alk-positive-nsclc
5. Solomon BJ, Liu G, Felip E, et al. Lorlatinib versus crizotinib in patients with advanced ALK-positive non–small cell lung cancer: 5-year outcomes from the phase III CROWN study. J Clin Oncol. 2024;42(29):3400-3409. doi:10.1200/JCO.24.00581