Mefatinib Improves PFS vs Gefitinib in EGFR-Mutated NSCLC

Key Takeaways

• In Chinese adults with untreated advanced EGFR-mutated nonsquamous non-small cell lung cancer receiving first-line mefatinib or gefitinib, progression-free survival was longer with mefatinib in the overall trial population.
• The clearest efficacy difference emerged in EGFR L858R disease, while exon 19 deletion outcomes were similar between treatment groups.
• Objective response and disease control were similar with both agents, while duration-based efficacy measures favored mefatinib.
• Overall survival remained immature, and higher-grade treatment-related toxicity was more frequent with mefatinib despite generally comparable health-related quality of life.

In advanced epidermal growth factor receptor (EGFR)-mutated nonsquamous non-small cell lung cancer (NSCLC), tumors with the L858R substitution have often been harder to control durably than exon 19 deletion disease. Balancing disease control against tolerability remains central when selecting an EGFR tyrosine kinase inhibitor at treatment start.

Investigators conducted the phase III mefatinib-versus-gefitinib trial as a randomized, double-blind, double-dummy, parallel-group multicenter study at 45 sites in China. Eligible participants were adults aged 18 to 75 years with unresectable stage IIIb to IVb nonsquamous NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1, no prior systemic therapy for advanced disease, and a single EGFR L858R or exon 19 deletion mutation. Of 717 patients screened, 336 were randomized in a 2:1 ratio, with 223 assigned mefatinib 60 mg once daily and 113 assigned gefitinib 250 mg once daily. The primary endpoint was independent review committee (IRC)-assessed progression-free survival under Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, with imaging at baseline and every 6 weeks, and the June 30, 2023 data cutoff captured median follow-up of 15.9 months and 18.5 months, respectively.

In the randomized trial results in advanced EGFR-mutated nonsquamous NSCLC, median IRC-assessed progression-free survival was 13.7 months with mefatinib versus 9.7 months with gefitinib, hazard ratio 0.68 (95% CI 0.53-0.87; p=0.002). The clearest subgroup separation appeared in EGFR L858R disease, with progression-free survival of 13.7 versus 8.3 months, hazard ratio 0.55 (95% CI 0.38-0.78; p=0.001), whereas exon 19 deletion outcomes were similar between groups. Objective response rate and disease control rate did not differ significantly, but duration of response favored mefatinib at 12.5 versus 9.7 months, hazard ratio 0.68 (95% CI 0.52-0.91; p=0.008), and other duration-based endpoints moved in the same direction. Overall survival remained immature without a significant difference at this analysis, health-related quality of life was generally comparable overall despite worse diarrhea, mouth pain, and peripheral neuropathy symptom changes at 24 weeks with mefatinib, and grade 3 or higher treatment-related adverse events occurred in 45.7% versus 24.8%, respectively. No new safety signals were reported.

Notably, patients with brain metastases were excluded, overall survival follow-up was still maturing, and the protocol did not include systematic biomarker or resistance analyses.

Clinician Questions

Which patients with EGFR-mutated advanced nonsquamous NSCLC were represented in the mefatinib-versus-gefitinib trial?

The trial represented adults aged 18 to 75 years in China with unresectable stage IIIb to IVb nonsquamous NSCLC, ECOG performance status 0 to 1, no prior systemic therapy for advanced disease, and a single EGFR L858R or exon 19 deletion mutation. Patients with brain metastases were excluded, so the findings do not directly address that subgroup.

How was progression-free survival measured in the mefatinib first-line NSCLC trial?

Progression-free survival was the primary endpoint and was assessed by an independent review committee using RECIST 1.1. It was defined from randomization to disease progression or death from any cause, with radiologic assessments performed at baseline and every 6 weeks.

What secondary outcomes separated mefatinib from gefitinib beyond objective response in EGFR-mutated NSCLC?

Overall response rate and disease control rate were similar with mefatinib and gefitinib, but duration-based endpoints favored mefatinib, including duration of response, time to progression, and time to treatment failure. Overall survival remained immature and was not significantly different at the reported analysis.

What toxicity pattern distinguished mefatinib from gefitinib in this phase III EGFR-mutated NSCLC trial?

Higher-grade treatment-related toxicity was more common with mefatinib, especially gastrointestinal and dermatologic events such as diarrhea, rash, and stomatitis, whereas high-grade alanine aminotransferase and aspartate aminotransferase elevations were more frequent with gefitinib. The authors reported no new safety signals for mefatinib, and health-related quality of life was otherwise generally comparable apart from worse diarrhea, mouth pain, and peripheral neuropathy symptom changes at 24 weeks.