Lazertinib improves PFS vs gefitinib in 1L treatment of EGFR-mutated NSCLC

The third-generation EGFR tyrosine kinase inhibitor (TKI) lazertinib significantly improves progression-free survival (PFS) vs gefitinib in first-line (1L) treatment of patients with EGFR -mutated, locally advanced or metastatic non-small-cell lung cancer (NSCLC) harbouring an exon 19 deletion or exon 21 L858R mutation, results of the phase III LASER301 trial have shown.

Lazertinib is a potent, central nervous system (CNS)–active, mutant-selective agent that targets EGFR^T790M and sensitizing mutations. [Clin Cancer Res 2019;25:2575-2587]

The double-blind LASER301 trial involved 393 eligible treatment-naïve patients, including those with asymptomatic and stable brain metastasis who had completed radiation therapy or surgery and had not received steroids for >2 weeks prior to randomization. Recruited from 13 countries across Asia Pacific and Europe, the patients were randomized (1:1) to receive lazertinib 240 mg orally QD (n=196; median age, 67 years; female, 67 percent; never smokers, 69 percent) or gefitinib 250 mg orally QD (n=197; median age, 64 years; female, 60 percent; never smokers, 76 percent) until disease progression or request for treatment discontinuation. [J Clin Oncol 2023;doi:10.1200/JCO.23.00515]

PFS, the trial’s primary endpoint, showed significant improvement with lazertinib vs gefitinib (median, 20.6 months vs 9.7 months; hazard ratio [HR], 0.45; 95 percent confidence interval [CI], 0.34–0.58; p<0.001) after a median follow-up of 20.5 months vs 20.6 months in the respective arms.

“A consistent PFS benefit of lazertinib over gefitinib was shown across all predefined subgroups,” the investigators reported.

In Asian patients, who constituted 66 percent of the trial’s population, median PFS was 20.6 months with lazertinib vs 9.7 months with gefitinib (HR, 0.46; 95 percent CI, 0.34–0.63). “In non-Asian patients, median PFS was not reached with lazertinib [HR, 0.38; 95 percent CI, 0.23–0.64],” the investigated noted.

In patients with exon 19 deletion and those with exon 21 L858R mutation, median PFS was 20.7 months vs 10.9 months (HR, 0.46; 95 percent CI, 0.33–0.65) and 17.8 months vs 9.6 months (HR, 0.41; 95 percent CI, 0.27–0.62) with lazertinib vs gefitinib, respectively.

Among patients with and without brain metastasis at baseline, median PFS was 16.4 months vs 9.5 months (HR, 0.42; 95 percent CI, 0.26–0.68) and 20.8 months vs 10.9 months (HR, 0.44; 95 percent CI, 0.32–0.60), respectively.

While overall response rate was similar between the lazertinib and gefitinib arms (76 percent vs 76.1 percent), median duration of response was longer with lazertinib (19.4 months) vs gefitinib (8.3 months).

Overall survival (OS) data were immature (29 percent maturity) at the time of interim analysis, with median OS not reached in either arm. At 18 months and 24 months, OS rates for lazertinib vs gefitinib were 80.3 percent vs 72.4 percent (HR, 0.74; 95 percent CI, 0.51–1.08; p=0.116) and 66.4 percent vs 58.4 percent, respectively.

“Notably, 36 percent of gefitinib recipients received lazertinib or osimertinib after [assigned] treatment ended, either as crossover per protocol [24 percent] or outside the trial as second- or later-line therapy [12 percent],” the investigators pointed out.

“Observed safety of both treatments was consistent with their previously reported safety profiles,” they added.

Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 20 percent vs 21 percent of patients in the lazertinib vs gefitinib arm, while serious TEAEs were reported in 5 percent of patients in both arms. TEAEs resulted in treatment interruption in 34 percent vs 32 percent, dose reduction in 21 percent vs 11 percent, and withdrawal of treatment in 10 percent vs 9 percent of patients.

“Our results suggest that lazertinib is an important new treatment option with a potentially differentiated efficacy and safety profile,” the investigators concluded. “Ongoing research will evaluate lazertinib’s efficacy with other agents, such as amivantamab plus platinum-based chemotherapy, to determine its positioning in the treatment paradigm for EGFR-mutated NSCLC.”