The recommendation, which is based on data from the phase 3 CROWN trial (NCT03052608), will allow patients in England and Wales access to the ALK-directed TKI within 90 days.
“NICE’s approval of lorlatinib as a first treatment for ALK-positive lung cancer is a big step forward for patients in England. Not only does it give those who have been newly diagnosed an additional targeted treatment option, but pivotal research shows it can help prevent the disease from progressing, for longer—and it can help prevent it from spreading to the brain,” Dr Shobhit Baijal, consultant medical oncologist at University Hospitals Birmingham, said in a news release.1
What Do I Need to Know About Lorlatinib and ALK+ NSCLC?
Patients with ALK-positive NSCLC often present with stage III or IV disease at diagnosis and approximately 25% of patients with ALK-driven disease have brain metastases at baseline, underscoring the need for effective treatments that provide central nervous system (CNS) control.2
Lorlatinib is a brain-penetrant, third-generation ALK TKI that is active against more ALK resistance mutations that second-generation inhibitors.
Who Was Enrolled in the CROWN Trial and What Was Tested?
Lorlatinib was compared with crizotinib (Xalkori) in the CROWN trial, which enrolled patients with stage IIIB/IV ALK-positive NSCLC who had not received prior systemic therapy for metastatic disease. To be eligible, patients needed to have an ECOG performance status between 0 and 2, asymptomatic treated or untreated CNS metastases, and at least 1 extracranial measurable target lesion per RECIST 1.1 with no prior radiation.
A total of 296 patients were randomly assigned 1:1 to 100 mg of oral lorlatinib (n = 149) or 250 mg of crizotinib twice daily (n = 247). Notably, crossover was not permitted.
The primary end point was progression-free survival (PFS) by blinded independent central review (BICR). Secondary end points included overall survival, investigator-assessed PFS, and objective response rate (ORR) by BICR and investigator; intracranial (IC)-ORR, duration of response (DOR), IC-DOR, intracranial time to progression, and time to response (TTR) and IC-TTR were also evaluated according to BICR. Safety, quality of life, and biomarker analysis was also assessed.
What Did the 5-Year Data Show?
The median duration of follow-up for PFS was 60.2 months (95% CI, 57.4-61.6) in the lorlatinib arm and 55.1 months (95% CI, 36.8-62.5) in the crizotinib arm.
Data from the trial, which were presented at the 2024 ASCO Annual Meeting, showed that the median PFS was not reached (NR) with lorlatinib (95% CI, 64.3 months-NR) 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%) and 8% (95% CI, 3%-14%) with lorlatinib and crizotinib, respectively.
Lorlatinib also proved effective regardless of patients’ brain metastases status. In patients with baseline brain metastases, the median PFS was NR (95% CI, 32.9-NR) with lorlatinib (n = 35) vs 6.0 months (95% CI, 3.7-7.6) with crizotinib (n = 38; HR, 0.08; 95% CI, 0.04-0.19). The 60-month PFS rates were 53% (95% CI, 35%-68%) and not evaluable [NE], respectively. In patients without baseline brain metastases, the median PFS was NR (95% CI, 64.3 months-NR) and 10.8 months (95% CI, 9.0-12.8) with lorlatinib (n = 114) and crizotinib (n = 109), respectively (HR, 0.24; 95% CI, 0.16-0.36). The 60-month PFS rates were 63% (95% CI, 52%-71%) and 10% (95% CI, 5%-18%), respectively.
The time to IC progression was also extended with lorlatinib regardless of brain metastases status. In patients with baseline brain metastases, the median time to IC progression was NR (95% CI, NR-NR) with lorlatinib vs 7.2 months (95% CI, 3.7-11.0) with crizotinib (HR, 0.03; 95% CI, 0.01-0.13). The 60-month rates of being free of intracranial progression were 83% (95% CI, 64%-93%) and NE, respectively. In patients without baseline brain metastases, the median time to IC progression was NR (95% CI, NR-NR) and 23.9 months (95% CI, 16.4-30.8) with lorlatinib and crizotinib, respectively (HR, 0.05; 95% CI, 0.02-0.13). The 60-month rates of being free of intracranial progression were 96% (95% CI, 89%-98%) and 27% (95% CI, 14%-43%), respectively.
Additional data demonstrated that the confirmed ORR was 81% (95% CI, 73%-87%) with lorlatinib vs 63% (95% CI, 54%-70%) with crizotinib (odds ratio [OR], 2.43; 95% CI, 1.43-4.43). The median DOR was NR (95% CI, NR-NR) with lorlatinib vs 9.2 months (95% CI, 7.5-11.1) with crizotinib. Among patients with measurable brain metastases at baseline in the lorlatinib (n = 12) and crizotinib arms (n = 6), the confirmed IC-ORR was 92% (95% CI, 62%-100%) and 33% (95% CI, 4-78%), respectively (OR, 15.00; 95% CI, 0.99-786.47). The median IC-DOR was NR (95% CI, NR-NR) and 10.2 months (95% CI, 7.5-NR), respectively.
With respect to safety, the most common adverse effects that occurred in the lorlatinib arm included hypercholesterolemia (any grade, 72%; grade 3, 20%; grade 4, 1%), hypertriglyceridemia (any grade, 66%; grade 3, 17%; grade 4, 8%), and edema (any grade, 57%; grade 3, 4%; grade 4, 0%), vs diarrhea (any grade, 53%; grade 3, 1%; grade 4, 0%), nausea (any grade, 53%; grade 3, 2%; grade 4, 0%), and edema (any grade, 43%; grade 3, 1%; grade 4, 0%) in the crizotinib arm.
What Are the Implications of the Recommendation From NICE?
“This is welcome progress and brings hope to those newly diagnosed with ALK-positive lung cancer. Early access to the most effective treatment is vital, and today’s decision reflects our call for equitable testing and optimal care without delay. It now means that more people with ALK-positive lung cancer across the UK can live better, for longer,” Debra Montague, chair of ALK Positive UK, stated in the news release.1
References
- Charity welcomes NICE approval of first-line treatment for ALK-positive lung cancer. News release. ALK Positive UK. October 7, 2025. Accessed October 7, 2025.
- 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
- Lorlatinib for ALK-positive advanced non-small-cell lung cancer that has not been treated with an ALK inhibitor [ID6434]. National Institute for Health and Care Excellence. October 7, 2025. Accessed October 7, 2025. https://www.nice.org.uk/guidance/indevelopment/gid-ta11570
