Non-small cell lung cancer (NSCLC) patients with central nervous system (CNS) metastases represent a significant challenge in clinical practice. It is well known that up to 50 percent of patients with advanced NSCLC eventually develop CNS metastases, which significantly contribute to the overall mortality in this patient population.
Recent findings from the LASER301 study shed light on a potential breakthrough in managing CNS metastases in EGFR-mutated advanced NSCLC. Lazertinib, a third-generation tyrosine kinase inhibitor (TKI) with a specific focus on mutant epidermal growth factor receptor (EGFR), demonstrated notable improvements in intracranial outcomes when compared to the first-generation TKI gefitinib. The research was presented at the ESMO 2023 Congress, held in Madrid, Spain (Abstract 1324MO).
This Phase III LASER301 study (NCT04248829) compared the efficacy of lazertinib against the gefitinib in patients from the LASER301 study with CNS metastases. The study focused on treatment-naive patients with EGFR-mutated advanced or metastatic NSCLC.
These patients were randomly assigned to receive lazertinib (240 mg/day) or gefitinib (250 mg/day) in a 1:1 ratio. Patients with symptomatic or unstable CNS metastases were excluded from the study. In cases where treatment was required for patients with asymptomatic or stable CNS metastases, it was administered at least 2 weeks before randomization. Magnetic resonance imaging was performed at screening, every 6 weeks for the first 18 months and subsequently every 12 weeks using the same imaging modality for each follow-up. The study's endpoints, assessed through blinded independent central review and RECIST v1.1, included intracranial progression-free survival (iPFS), intracranial objective response rate (iORR), intracranial duration of response (iDoR), and depth of intracranial response.
Out of the 393 patients who participated in the LASER301 study, 23 percent (n=45) received lazertinib, while 21 percent (n=41) received gefitinib and had measurable and/or non-measurable baseline CNS metastases. The baseline characteristics of the two groups were comparable with the majority of patients in both groups having 1-3 CNS lesions (91% in the lazertinib group, 83% in the gefitinib group). The median baseline target lesion size was 20.0 mm in the lazertinib group and 16.0 mm in the gefitinib group. The key findings include the following:
* Median iPFS was 28.2 months (95% CI: 14.8, 28.2) in the lazertinib group, compared to 8.4 months (95% CI: 6.7, not reached) in the gefitinib group. The hazard ratio was 0.42 (95% CI: 0.20, 0.89), with a p-value of 0.02.
* iORR was higher in the lazertinib group, with 94 percent of patients showing a positive response, compared to 73 percent in the gefitinib group.
* Median iDoR was not reached in the lazertinib group (with a range of 8.3 months to not reached) and was 6.3 months (with a range of 2.8 months to not reached) in the gefitinib group.
* The median best change from baseline in CNS target lesion size was -57 percent in the lazertinib group and -47 percent in the gefitinib group. Importantly, no new safety signals were identified from the LASER301 study.
To learn more about the study, Oncology Times connected with study author Byoung Chul Cho, MD, PhD, Professor in the Division of Medical Oncology and Chief of the Lung Cancer Center at Yonsei Cancer Center in Seoul, Republic of Korea.
Oncology Times: Can you provide insights into the patient characteristics that may influence the choice between lazertinib and gefitinib, especially in the context of CNS metastases?
Chul Cho: "Nearly 30 percent of patients with NSCLC develop CNS metastases, which are a major source of mortality in NSCLC. Lazertinib is a third-generation, CNS-penetrant TKI that targets mutant EGFR in NSCLC. In the Phase III LASER301 study, lazertinib demonstrated significantly improved progression-free survival versus the first-generation TKI gefitinib. Currently available first- and second-generation TKIs show suboptimal efficacy against brain metastases, likely due to their limited blood-brain barrier (BBB) penetration. While the ability for first- and second-generation EGFR TKIs to penetrate the BBB is generally low, lazertinib has also demonstrated potent and more effective BBB penetration in comparison to the third-generation TKI osimertinib in preclinical studies."
Oncology Times: What are the potential implications of lazertinib's improved CNS outcomes for NSCLC patients, and how might this impact treatment strategies and patient care in the future?
Chul Cho: "Among patients with EGFR-mutated advanced NSCLC and baseline CNS metastases in LASER301, lazertinib significantly improved intracranial progression-free survival compared to gefitinib with more durable responses. Lower incidence of CNS progression, non-CNS progression, and death were also observed in the lazertinib group. The safety and tolerability profile of lazertinib in patients with CNS metastases was comparable to the overall population in the study. Overall, results of this subanalysis are consistent with preclinical studies and demonstrate the potential of lazertinib to improve CNS outcomes in NSCLC.
Dibash Kumar Das is a contributing writer.