Gefitinib (an EGFR tyrosine kinase inhibitor) plus anlotinib (an multikinase inhibitor) for untreated, EGFR-mutated, advanced non-small cell lung cancer (FL-ALTER): a multicenter phase III trial

Abstract

Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1-14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48-0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.

Fig. 1

The study flowchart and patient disposition. Enhancement MRI was performed during screening to evaluate each patient for brain metastasis and MRI/CT scans were undertaken in patients with brain metastasis at baseline during follow up and in other patients at the discretion of the investigators

Fig. 2

Gefitinib plus anlotinib improves progression-free survival (PFS) of advanced NSCLC patients. a The Kaplan–Meier curves PFS of advanced NSCLC patients treated with gefitinib plus anlotinib or gefitinib plus placebo in the FAS. b Forest plots for PFS. The Kaplan–Meier curves of PFS of patients harboring EGFR Exon 19 Del c or EGFR Exon 21 L858R d treated with gefitinib plus anlotinib or gefitinib plus placebo. e The Kaplan–Meier curves of PFS of patients with e or without f brain metastasis treated with gefitinib plus anlotinib or gefitinib plus placebo

Fig. 3

The flowchart for next generation sequencing (NGS) analysis. P1, baseline, P2, first posttreatment efficacy evaluation and P3, progressive disease

Fig. 4

Dual inhibition of VEGF and EGFR signaling pathways reduces the tumor mutational load and the frequencies of key driver gene mutations. a Tumor mutational load in individual patients at baseline (P1), the first posttreatment efficacy evaluation (P2) and disease progression (P3) (left panel). Each column represents one patient in efficacy evaluable patients. Boxplots of tumor mutational load in patients in the gefitinib plus anlotinib group and the gefitinib plus placebo group are shown on the right. Temporal changes in the rates of mutated EGFR gene b, EGFR Exon 21 L858R c and Exon 19 Del d, mutated TP53 gene e and copy number variations (amplification) f in the two groups from baseline to disease progression

Fig. 5

Dual inhibition of VEGF and EGFR signaling pathways derives more benefits in patients with EGFR amplification or a high tumor mutational load. a Heatmaps show frequent somatic mutations (≥2%) in pretreatment NSCLC samples. Left, gefitinib plus placebo, right, gefitinib plus anlotinib. b The Kaplan–Meier PFS curves of advanced NSCLC patients with blood sample available at baseline c The Kaplan–Meier PFS curves of patients with high (left) and low tumor mutational load (right) treated with gefitinib plus anlotinib versus gefitinib plus placebo. d The Kaplan–Meier PFS curves of patients with (left) or without EGFR amplification (right) who were treated with gefitinib plus anlotinib versus those who were treated with gefitinib plus placebo

Fig. 6. Possible resistance mechanisms at the time of disease progression.

a The gefitinib plus placebo group; b The gefitinib plus anlotinib group