Adding anlotinib to gefitinib improves PFS in treatment-naïve Chinese patients with EGFRmut NSCLC

Adding anlotinib to gefitinib significantly improves progression-free survival (PFS) in treatment-naïve Chinese patients with EGFR-mutated (EGFRmut) advanced non-small-cell lung cancer (NSCLC), according to the results of the FL-ALTER phase III study.

EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, are established standard first-line treatments for EGFRmut NSCLC. [Ann Oncol 2018;29:i3-i9] However, acquired resistance to EGFR TKIs inevitably develops, leading to disease progression in most cases. [Clin Cancer Res 2013;19:2240-2247]

Anlotinib is an oral multikinase inhibitor, which suppresses oncoangiogenesis and tumour growth via VEGF receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, and c-Kit blockade. [J Hematol Oncol 2018;11:120] As dual inhibition of VEGF and EGFR signalling pathways offers the prospect of overcoming EGFR TKI resistance, the researchers hypothesized that anlotinib in combination with an EGFR TKI would be more effective than EGFR TKI monotherapy for advanced NSCLC in the first-line setting.

FL-ALTER was a multicentre, randomized, double-blind, phase III trial conducted across 18 hospitals in China. A total of 315 patients (median age, 59 years; male, 43.9 percent) with treatment-naïve, EGFRmut advanced NSCLC were randomized 1:1 to receive gefitinib plus anlotinib (GA) or gefitinib plus placebo (GP) QD on days 1–14 of a 3-week cycle. Approximately half of the patients (51.9 percent) harboured EGFR ex19del mutation, while the rest had EGFR ex21L858R mutation. Brain metastases were present at baseline in 31.9 percent of patients. [Signal Transduct Target Ther 2024;9:215]

Patients were followed up for median duration of 18.5 months in the GA group and 18.2 months in the GP group. Median PFS was 14.8 vs 11.2 months in the respective groups (hazard ratio [HR], 0.64; 95 percent confidence interval [CI], 0.48–0.80; stratified log rank test p=0.003).

The significant PFS benefit associated with the addition of anlotinib to gefitinib was observed regardless of EGFR mutation type and brain metastases status. In patients with EGFR ex19del, median PFS was 15.2 vs 12.2 months in the GA vs GP group (HR, 0.60; 95 percent CI, 0.40–0.90). In patients with EGFR ex21L858R treated with GA vs GP, median PFS was 12.9 vs 8.6 months (HR, 0.63; 95 percent CI, 0.42–0.93). Among patients with brain metastasis, GA extended median PFS by 5.5 months vs GP (13.8 vs 8.3 months; HR, 0.47; 95 percent CI, 0.29–0.77; log rank test p=0.002). In patients without brain metastasis receiving GA vs GP, median PFS was 15.0 vs 12.0 months (HR, 0.72; 95 percent CI, 0.51–1.01; log rank test p=0.05).

Treatment was interrupted in 32.3 vs 21.9 percent of patients receiving GA vs GP. Treatment-emergent AEs (TEAEs) led to dose reductions in 31.0 vs 13.6 percent and treatment termination in 10.3 vs 4.5 percent of patients. Grade ≥3 TEAEs were reported in 49.7 and 31.0 percent of patients, respectively. The most frequent grade ≥3 TEAEs in the GA group were hypertension (29.7 percent) and elevated ALT (6.5 percent), which occurred in 5.2 and 12.3 percent of patients given GP, respectively.

The researchers noted that a major limitation of the study was that third-generation EGFR TKIs, such as osimertinib, which are being increasingly employed in the treatment of NSCLC, were not investigated in the current trial, as they were not yet available in China when FL-ALTER started. “It remains to be investigated whether anlotinib added to a third-generation EGFR TKI would confer similar or greater benefit to patients with EGFRmut advanced NSCLC,” they wrote.