Is first-line lazertinib monotherapy a potential new SoC for EGFRm NSCLC?

Patients with EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) exhibited significantly improved progression-free survival (PFS) when treated with lazertinib compared with gefitinib in the first-line setting, results of the LASER301 trial showed.

There was a 55 percent lower risk of disease progression or death in the lazertinib than gefitinib group, said Professor Byoung Chul Cho from the Yonsei Cancer Center, Seoul, Korea, at ESMO Asia 2022.

“These data suggest that lazertinib is a new standard of care (SoC) for first-line treatment for patients with EGFRm advanced NSCLC,” said Cho.

Adults with locally advanced or metastatic NSCLC and WHO performance status 0–1 with exon 19 deletion (Ex19Del)/Exon 21 L858R substitution (L858R) and with no prior exposure to systemic therapy were included. They were randomized 1:1 to receive either oral lazertinib (240 mg QD; n=196; median age 67 years, 33 percent male) or gefitinib (250 mg QD; n=197; median age 64 years, 40 percent male). Approximately two-thirds of the population was Asian, three-quarters had a WHO status of 1, and a quarter had central nervous system (CNS) metastases at baseline. Sixty-two percent had Ex19Del and 38 percent L858R mutations.

At data cut-off (61 percent maturity), investigator-assessed PFS was significantly improved with lazertinib compared with gefitinib (median 20.6 vs 9.7 months; hazard ratio [HR], 0.45, 95 percent confidence interval [CI], 0.34–0.58; p<0.001). [ESMO Asia 2022, abstract LBA7]

The PFS outcome consistently favoured lazertinib in all predefined subgroups including age, sex, and smoking history. Specifically, the PFS benefit with lazertinib vs gefitinib was noted regardless of CNS metastases (present: median 16.4 vs 9.5 months; HR, 0.42, 95 percent CI, 0.26–0.68; absent: median 20.8 vs 10.9 months; HR, 0.44, 95 percent CI, 0.32–0.60), race* (Asian: median 20.6 vs 9.7 months; HR, 0.46, 95 percent CI, 0.34–0.63; non-Asian: median not reached [NR] vs 9.7 months; HR, 0.38, 95 percent CI, 0.23–0.64), and type of EGFR mutation (Ex19Del: median 20.7 vs 10.9 months; HR, 0.46, 95 percent CI, 0.33–0.65; L858R: median 17.8 vs 9.6 months; HR, 0.41, 95 percent CI, 0.27–0.62).

Objective response rate was 76 percent in both groups, with two and one patient in the lazertinib and gefitinib groups, respectively, achieving a complete response. Partial response was documented in 75 and 76 percent, respectively, and stable disease (for ≥6 weeks) in 18 percent of each group. Disease control rate was 94 percent in both groups. Patients in the lazertinib group had a longer duration of response than those in the gefitinib group (median 19.4 vs 8.3 months).

Overall survival was still immature at data cut-off but veered towards an improvement with lazertinib vs gefitinib (median NR in both groups; HR, 0.74; p=0.116).

Seventy-one patients in the gefitinib group (36 percent) received a third-generation EGFR TKI** after treatment end.

Grade ≥3 adverse events (AEs) occurred at a comparable rate between the lazertinib and gefitinib groups (41 percent vs 43 percent), as did grade ≥3 treatment-related AEs (20 percent vs 21 percent), serious AEs (26 percent each), and treatment-related serious AEs (5 percent each). AEs led to death in 6 percent vs 4 percent, with one incidence of a treatment-related AE (interstitial lung disease) leading to death in the lazertinib group. AEs led to temporary treatment interruption in 34 percent vs 32 percent, dose reduction in 21 percent vs 11 percent, and permanent treatment discontinuation in 10 percent vs 9 percent. The most common (≥10 percent) grade 3 AEs in lazertinib recipients were anaemia (4 percent), diarrhoea, and paraesthesia (3 percent each), and in gefitinib recipients, elevated alanine aminotransferase and aspartate aminotransferase levels (9 and 7 percent, respectively).

“The observed safety data of lazertinib and gefitinib were consistent with their previously reported safety profiles,” said Cho.

According to discussant Professor Ben Solomon from the Peter MacCallum Cancer Centre in Melbourne, Australia, the efficacy of lazertinib, as shown in the LASER301 trial, is similar to that of other third-generation EGFR TKIs, including osimertinib.

“It is hoped that additional options will improve global equity of access to first-line third-generation EGFR TKIs,” he said.

“[Additionally,] single-agent activity [in this trial] confirms that lazertinib is an appropriate partner for first-line combination studies in EGFRm NSCLC,” he concluded.