Blocking vascular endothelial growth factor receptor (VEGFR) pathway can enhance the efficacy of EGFR-TKI in EGFRm NSCLC. ACTIVE is the first phase III study evaluating apatinib, an oral small molecule VEGFR2-TKI, or placebo plus gefitinib as first-line therapy in patients (pts) with EGFRm NSCLC.
Treatment-naïve pts with classic EGFR mutation (ex19del or L858R) were randomized (1:1) to receive once-daily oral apatinib 500 mg plus gefitinib 250 mg (AG arm) or placebo plus gefitinib 250 mg (G arm). Stratification factors: EGFR mutation type (ex19del, L858R), sex, and performance status (0, 1). The primary endpoint was PFS (RECIST 1.1) assessed by blinded independent radiology review committee (IRRC). Secondary endpoints: PFS by investigator (INV), OS, ORR, DCR, DOR, TTPD, QoL and safety. Next-generation sequencing (NGS) was used to analyze baseline and post-progression samples for exploring efficacy predictors and acquired resistance.
313 pts were enrolled (AG arm, n=157; G arm, n=156). Median follow-up was 15.8 months (IQR 12.6, 20.4). Median PFS by IRCC was 13.7 versus 10.2 months in AG and G arms (HR = 0.71, 95% CI 0.54-0.95; p = 0.0189). Prolonged PFS by INV (HR = 0.71, 95% CI 0.53-0.95) was observed. OS data are immature at cutoff (29.4% events). ORR was 77.1% and 73.7% in AG and G arms (p = 0.5572). Pts with ex19del had better HR than L858R (HR = 0.67, 0.45-0.99; 0.72, 0.48-1.09). NGS results of baseline samples showed a marginally significant improved PFS in TP53-mutant disease. Pts with TP53 exon 8 mutation significantly benefited from dual blockade (HR = 0.24, 0.06-0.91). Grade 3-4 adverse events (AEs) of the two arms were similar, except increased risk of hypertension and proteinuria (46.5%; 17.8%) in AG arm. No AEs beyond expectation were reported. Other endpoints and NGS results for resistance will be presented onsite.
Apatinib plus gefitinib as first-line therapy demonstrated superior PFS. TP53 exon 8 mutation status could serve as an efficacy predictor. Safety profiles were consistent with that of the individual drugs and acceptable.
Clinical trial identification
Legal entity responsible for the study
Sun Yat-sen University Cancer Center.
The 5010 Clinical Research Foundation of Sun Yat-sen University; Jiangsu Hengrui Medicine Co., Ltd.
All authors have declared no conflicts of interest.