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Inhibition of VEGFR and EGFR with Apatinib + Gefitinib as First-Line Therapy Increased Progression-Free Survival

2020 Year in Review - Non–Small-Cell Lung Cancer - Lung Cancer

Treatment with combination apatinib and gefitinib is associated with improved progression-free survival compared with treatment with gefitinib alone in patients with NSCLC and EGFR mutations.

Apatinib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. VEGFR inhibition can enhance EGFR inhibitors in patients with non–small-cell lung cancer (NSCLC) and EGFR mutations. ACTIVE is a phase 3 trial evaluating the dual inhibition of VEGFR and EGFR with apatinib + gefitinib versus gefitinib alone as a first-line therapy for NSCLC with EGFR mutations. Trial investigators presented their findings during the ESMO Virtual Congress 2020.

Patients with ex19del or L858R EGFR mutations were randomized 1:1 to receive a daily dose of oral apatinib 500 mg + gefitinib 250 mg (AG arm) or placebo + gefitinib 250 mg (G arm). Patients were grouped by sex, performance status (0-1), and EGFR mutation type (exon 19 deletion [ex19del], L858R). The primary and secondary end points, based on Response Evaluation Criteria in Solid Tumours guidelines, were progression-free survival (PFS) as assessed by a blinded independent radiology review committee (IRRC) or investigator, overall survival, overall response rate (ORR), disease control rate, duration of response, time to progressive disease, quality of life, and safety. Efficacy predictors and acquired resistance were monitored using next-generation sequencing to analyze baseline and postprogression samples.

A total of 313 patients were enrolled in the study, with 157 patients in the AG arm and 156 patients in the G arm. The AG arm had a PFS of 13.7 months versus 10.2 months in the G arm (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.54-0.95; P = .0189) as assessed by both IRRC and investigator. No significant change in ORR was observed between the AG arm and the G arm (77.1% vs 73.7%; P = .5572). The HR for ex19del patients was slightly better than that of L858R patients (ex19del: HR, 0.67; CI, 0.45-0.99; L858R: HR, 0.72; CI, 0.48-1.09).

Next-generation sequencing identified that patients with TP53 mutations showed a marginally significant improved PFS. For example, patients with a TP53 exon 8 mutation significantly benefited from the VEGFR-EGFR dual blockade (HR, 0.24; CI, 0.06-0.91).

No adverse events were beyond expectation. The only grade 3/4 adverse events were increased risks for hypertension (46.5%) and proteinuria (17.8%) in the AG arm.

The researchers concluded that apatinib + gefitinib improves PFS compared with gefitinib treatment alone. In addition, TP53 exon 8 mutation could be used as a predictor for the efficacy of the dual treatment of apatinib + gefitinib.

Reference
Zhang L, et al. ESMO 2020. Abstract LBA50.

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