In an updated analysis from the CROWN study, after 5 years of follow-up, lorlatinib continued to show superior efficacy over crizotinib in patients with previously untreated, advanced, ALK-positive non-small cell lung cancer (NSCLC), with remarkable progression-free survival (PFS) benefit and intracranial efficacy. At a median follow-up of 60.2 months, median PFS was still not reached (NR) with lorlatinib.
Benefit in PFS, which exceeds 5 years, is the longest reported PFS in advanced NSCLC to date and the longest reported PFS outcome with any molecular targeted therapy across metastatic solid tumours. The findings were reported at ASCO 2024 Annual Meeting along with a simultaneous publication by Dr. Benjamin J. Solomon of the Peter MacCallum Cancer Centre in Melbourne, VIC, Australia and colleagues on 31 May 2024 in the JCO.
Lorlatinib is a brain-penetrant, third-generation ALK tyrosine kinase inhibitor (TKI) that has greater coverage of ALK resistance mutations than second-generation ALK inhibitors. In the phase III CROWN study, lorlatinib showed improved benefit over crizotinib in patients with previously untreated, advanced, ALK-positive NSCLC. At the interim analysis, median PFS by blinded independent central review (BICR) was NR (95% confidence interval [CI] NR to NR]) with lorlatinib and 9.3 months (95% CI 7.6 to 11.1) with crizotinib, with a hazard ratio (HR) of 0.28 (95% CI 0.19 to 0.41; p < 0.001).
In a subsequent post hoc analysis, after approximately 3 years of follow-up, lorlatinib continued to show superior PFS benefit over crizotinib irrespective of the presence or absence of baseline brain metastases. At a median 36.7 months of follow-up in the lorlatinib group, median PFS by BICR was still NR (95% CI NR to NR), and time to intracranial progression by BICR was also longer with lorlatinib than with crizotinib in the overall patient population.
The authors wrote in the background that EML4::ALK variant 3 and/or a TP53 mutation are poor prognostic markers and may influence development of specific secondary ALK resistance mutations. When lorlatinib was used in the first-line setting, preliminary data indicated that no emerging new ALK resistance mutations were detected in circulating tumour DNA (ctDNA) collected at the end of treatment.
How the median PFS was not reached after 3 years of follow-up, the CROWN investigators aimed to further quantify long-term systemic and intracranial outcomes at the clinically meaningful landmark follow-up of 5 years in this post hoc analysis. A total of 296 patients with ALK-positive NSCLC were randomly assigned 1:1, of whom 149 to receive lorlatinib 100 mg once daily and 147 to receive crizotinib 250 mg twice daily. This post hoc analysis presents updated investigator-assessed efficacy outcomes, safety, and biomarker analyses.
With a median follow-up for PFS of 60.2 and 55.1 months, median PFS was NR (95% CI 64.3 to NR) with lorlatinib and 9.1 months (95% CI 7.4 to 10.9) with crizotinib (HR 0.19, 95% CI 0.13 to 0.27); 5-year PFS was 60% (95% CI 51 to 68) and 8% (95% CI 3 to 14), respectively. Median time to intracranial progression was NR (95% CI NR to NR) with lorlatinib and 16.4 months (95% CI 12.7 to 21.9) with crizotinib (HR 0.06, 95% CI 0.03 to 0.12).
In patients with baseline brain metastases after 5 years of follow-up, lorlatinib resulted in high intracranial response, the majority of which were complete and durable responses; only five of 35 patients overall experienced intracranial progression, all within 30 months. Consistent with these results, only four patients developed intracranial lesions of the 114 without baseline brain metastases in lorlatinib group, notwithstanding discrepancies between investigator and independent radiologic review. These results indicate that lorlatinib was effective in controlling preexisting brain metastases and in protecting against the development of new brain metastases.
At the time of this analysis, the required number of overall survival (OS) events for a protocol-specified second interim analysis was not met. OS follow-up is currently ongoing in the CROWN study, and the results will be reported in the future.
The safety profile of lorlatinib remains similar to that reported in previous analyses of the CROWN study, with no new safety signals detected after additional treatment exposure and longer follow-up. Lorlatinib was associated with a higher incidence of grade 3/4 adverse events (77% versus 57% with crizotinib), mostly due to an increase in blood lipid values.
Management of hyperlipidaemia should include monitoring for cholesterol and triglyceride levels while on lorlatinib treatment. The guide recommends treatment with statins (e.g. rosuvastatin or pravastatin) at the first sign of hyperlipidaemia. For hyperlipidaemia that persists despite treatment, increasing the dosage or inclusion of an additional lipid-lowering therapy is recommended.
The authors commented that with long-term follow-up, the median PFS with lorlatinib was 60.0 months in EML4::ALK variant 3a/b subgroup and 51.6 months in TP53 mutation–positive subgroup. The results from this study emphasise that lorlatinib treatment can benefit patients with poor prognostic biomarkers or difficult-to-treat alterations such as EML4::ALK variant 3 or TP53 co-mutation relatively more than other second-generation ALK TKIs.
ctDNA samples at the end of lorlatinib treatment indicated that lorlatinib was effectively able to suppress the emergence of new ALK kinase domain mutations; instead, aberrations in bypass signalling pathways were the main resistance mechanism in patients who developed lorlatinib resistance. By delaying the emergence of on-target resistance, lorlatinib is able to improve the durability of treatment outcomes.
The long-term efficacy of lorlatinib in the CROWN study surpassed that of other currently approved ALK TKIs. Acknowledging the absence of head-to-head trials comparing second-generation ALK TKIs with lorlatinib and the limitations of cross-trial comparisons, findings from this study represent the longest reported PFS in patients with ALK-positive NSCLC. Most (76%) PFS events occurred in the first 2 years with lorlatinib in the CROWN study, with only six additional PFS events occurring between 3 and 5 years.
The authors concluded that systemic efficacy results coupled with prolonged intracranial efficacy and the absence of new safety signals represent unprecedented outcomes for patients with advanced ALK-positive NSCLC and set a new benchmark for targeted therapies in oncology.
The study was supported by Pfizer.
Reference
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. JCO; Published online 31 May 2024. DOI: https://doi.org/10.1200/JCO.24.00581