Results of the phase III CROWN trial, discussed during a presidential session at ESMO 2020, demonstrate that the third degeneration ALK inhibitor lorlatinib significantly delays the disease progression in previously untreated, ALK-positive advanced non-small cell lung cancer (NSCLC) patients compared to crizotinib. In addition, lorlatinib demonstrated impressive intracranial activity, with an intracranial response rate of 82% in patients with measurable brain metastases at baseline. As such, CROWN provides convincing evidence to support the use of lorlatinib as a first-line treatment for patients with ALK-positive advanced NSCLC.
INTRODUCTION
NSCLC is a heterogeneous disease with approximately 3-5% of patients exhibiting genetic rearrangements involving the ALK gene. The presence of these oncogenic driver mutations makes patients sensitive to treatment with an ALK tyrosine kinase inhibitor (TKI). Despite the high response rates that can be obtained with first and second generation ALK TKIs, resistance will ultimately develop in the majority of patients, resulting in disease progression often under the form of central nervous system (CNS) metastases. Lorlatinib is a highly potent brain penetrant, third generation ALK TKI with established overall and intracranial anti-tumour activity in advanced ALK-positive NSCLC who have previously been treated with an ALK TKI. In the phase III CROWN study, the efficacy and safety of lorlatinib was compared to that of crizotinib in the first-line treatment of patients with advanced ALK-positive NSCLC.
The CROWN trial randomised a total of 296 patients to continuously receive lorlatinib 100mg four times daily, or crizotinib 250mg twice daily. In order to be eligible for the study patients had to have stage IIIB/IV ALK-positive NSCLC, no prior systemic treatment for metastatic disease, an ECOG performance status of 0-2, asymptomatic treated or untreated CNS metastases and ≥1 extracranial measurable target lesion according to RECIST v1.1 criteria with no prior radiation required. The primary endpoint of the study was progression-free survival (PFS), assessed by blind independent central review (BICR) with investigator-assessed PFS, overall response rate (ORR), intracranial (IC)-ORR, duration of response (DoR), IC-DoR, IC-complete response rate, IC-time to progression, overall survival (OS), safety and patient reported outcomes (PROs) as secondary study objectives.
RESULTS
Baseline patient and disease characteristics were well balanced between the two treatment arms, with about a quarter of patients having brain metastases at baseline. The PFS by BICR was significantly improved in patients treated with lorlatinib, with a median PFS that was not reached for lorlatinib as compared to 9.3 months for crizotinib (HR [95%CI]: 0.28 [0.19-0.41], p<0.001). At 12 months, this translated into a PFS rate of 78% and 39%, for lorlatinib and crizotinib, respectively. The improvement in PFS with lorlatinib compared to crizotinib was observed across all investigated subgroups, irrespective of age, ECOG performance status, smoking status, and the presence of brain metastases. With respect to the latter, the CROWN trial revealed that patients with brain metastases at baseline seemed to derive a particularly high PFS benefit with a hazard ratio of 0.2 (HR [95%CI]: 0.20 [0.10-0.43]). In addition to significantly delaying disease progression, lorlatinib was also associated with a significantly higher ORR (76%), compared to crizotinib (58%). The median DoR was not reached in the lorlatinib arm and was reported to be 11.0 months in the crizotinib arm.
Specifically looking into the intracranial activity of lorlatinib reveals an IC-ORR of 82% with lorlatinib in patients with measurable brain metastases at baseline. This is significantly higher than the 23% IC-ORR reported for crizotinib (OR [95%CI]: 16.83 [1.95-163.23]). With lorlatinib, a striking 71% of patients experienced a complete intracranial response as compared to 8% with crizotinib. The IC-time to progression was significantly longer with lorlatinib, compared to crizotinib (HR [95%CI]: 0.07 [0.03-0.17], p<0.001). Although overall survival data remain immature, the preliminary hazard ratio was in favour of lorlatinib (HR [95%CI]: 0.72 [0.41-1.15]).
Grade 3/4 adverse events (AEs) occurred in 72% of lorlatinib patients as compared to 56% of crizotinib patients. With lorlatinib, the most common AEs were asymptomatic increases in cholesterol and triglycerides. Fatal AEs occurred in 5% of both study arms. AEs leading to permanent discontinuation occurred at a rate of 7% in the lorlatinib arm, and 9% in the crizotinib arm. AEs leading to temporary dose interruption occurred in 49% of lorlatinib patients and 47% of crizotinib patients. Significantly greater improvement in global quality of life (QoL) was observed in patients who received lorlatinib compared to those given crizotinib.
CONCLUSION
Lorlatinib significantly prolongs the PFS compared to crizotinib as first-line therapy for treatment naïve ALK-positive NSCLC. Lorlatinib also significantly improved the overall and IC response rates and improved global QoL compared to crizotinib in this trial. Interestingly, the lorlatinib IC response rate was 82% in patients with measurable brain metastases, with 71% of patients obtaining an IC-CR. This benefit was sustained, as exhibited by a significantly longer time to IC progression. The safety profile of lorlatinib was similar to that reported in previous studies. As such, these results support the use of lorlatinib as an effective first-line therapy for patients with advanced ALK-positive NSCLC.
Reference
Solomon et al., Lorlatinib vs Crizotinib in the First-line Treatment of Patients (pts) with Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC): Results of the Phase 3 CROWN Study. Presented at ESMO 2020; Abstract LBA2.
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