Lazertinib Versus Gefitinib as First-line Treatment in EGFR-mutated Advanced NSCLC
1. Progression-free survival was longer in the lazertinib group vs the gefitinib group (20.6 months vs 9.7 months, with HR 0.45), however, OS data were immature.
2. Treatment-related adverse events were similar across both groups, however, lazertinib had higher rates of parasthesia and pruritus but lower levels of ALT elevations and diarrhea.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Non-small cell lung cancer (NSCLC) with EGFR mutations are sensitive to tyrosine kinase inhibitors (TKIs). First/second generation TKI such as gefitinib is inferior to third-generation TKI such as osimertinib, which is currently the only approved first-line third-generation TKI for advanced EGFR-mutated NSCLC, thus providing a need for additional treatment options. Lazertinib is a mutant-selective TKI with potential advantages over osimertinib, such as better activity against certain mutations, fewer side effects, and improved blood-brain barrier penetration. This study investigated the efficacy and safety of lazertinib vs gefitinib as a first-line treatment for advanced EGFR-mutated NSCLC. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), disease control rate (DCR), and safety. This study found that median PFS was 20.6 months in the lazertinib group vs 9.7 months in the gefitinib with HR 0.45, and this PFS benefit was shown across all predefined subgroups (EGFR mutations, brain metastasis, and race). Importantly, there was no significant difference in PFS between patients taking a higher vs lower dose lazertinib group with HR 1.006. ORR and DCR were similar between treatment groups. Median DoR was 19.4 months in the lazertinib group vs 8.3 months in the gefitinib group. Median OS was not reached in either group, but at 24 months the OS rate was 66.4% vs 58.4%, however not statistically significant. With regards to safety, 41-43% of patients in both groups experienced grade 3 and above events. The most common adverse events in the lazertinib and gefitinib groups respectively were paresthesia (39% vs 7%), rash (36% vs 37%), pruritus (27% vs 18%), elevated ALT (15% vs 30%), and diarrhea (26% vs 39%). The strengths of this study included its subgroup analysis and the limitations of this study included immature OS data, as well as a lack of comparison to other TKIs. Overall, this study showed that lazertinib is a potential first-line treatment option for EGFR-mutated advanced NSCLC.
Click to read the study in JCO
Relevant Reading: A Phase 1/2 Study of Lazertinib 240 mg in Patients With Advanced EGFR T790M-Positive NSCLC After Previous EGFR Tyrosine Kinase Inhibitors
In-Depth [randomized controlled trial]: This multinational, double-blind, phase 3 study randomized treatment-naïve adults with confirmed EGFR-mutated (with TKI sensitivity) advanced NSCLC into a lazertinib group (196 patients) vs gefitinib group (197). The median duration of follow-up was 20.5 months in the lazertinib group vs 20.6 months in the gefitinib group. Median PFS was 20.6 months vs 9.7 months respectively, with HR 0.45 (95%CI, 0.34 to 0.58, p<0.001). This PFS benefit was shown across all predefined subgroups (EGFR mutations, brain metastasis, and race) with HR ranging from 0.38 to 0.46. ORR was similar between treatment groups (76.0% vs 76.1%, OR 0.99, p=0.973). DCR was similar between treatment groups (93.9% vs 93.9%, OR 1.00, p=0.922). Median DoR was 19.4 months (95%CI, 16.6 to 24.9) in the lazertinib group vs 8.3 months (95%CI, 6.9 to 10.9) in the gefitinib group. Median OS was not reached in either group, but at 24 months the OS rate was 66.4% (95%CI, 56.5 to 74.6) vs 58.4% (95%CI, 48.6 to 67.0). With regards to safety, overall treatment-related adverse events were similar in both groups, with around 41-43% of patients in both groups experiencing grade 3 and above events. The most common adverse events in the lazertinib and gefitinib groups respectively were paresthesia (39% vs 7%), rash (36% vs 37%), pruritus (27% vs 18%), elevated ALT (15% vs 30%), and diarrhea (26% vs 39%). Treatment-related adverse events resulted in discontinuations occurring in 6% vs 8% respectively. Specifically for lazertinib, patients were able to reduce the dose if required due to toxicity (from 240mg/day to 160mg/day), and there was no significant difference in PFS between patients in the 160mg and 240mg dose, with HR 1.006 (95%CI, 0.613 to 1.650). Overall, this study showed that lazertinib is a potential first-line treatment option for EGFR-mutated advanced NSCLC.
Image: PD
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