Frontline apatinib plus gefitinib improves survival in EGFR-mutant NSCLC

A combined regimen of apatinib plus gefitinib as first-line treatment improves progression-free survival (PFS) vs placebo plus gefitinib in patients with advanced EGFR-mutant (EGFRm) non-squamous non-small-cell lung cancer (NSCLC), results of the phase III ACTIVE study have shown.

“[Results of this first phase III study suggest that] apatinib in combination with gefitinib can be expected to become a new first-line treatment option for EGFRm NSCLC,” pointed out Dr Li Zhang of Sun Yat-Sen University Cancer Centre, Guangzhou, China. “This dual oral regimen provides a convenient treatment option for patients who require long-term administration.”

The study included 313 patients with advanced, metastatic or recurrent non-squamous NSCLC and Eastern Cooperative Oncology Group (ECOG) Performance Status of 0–1 from 30 sites in China. The patients were randomized (1:1) to receive apatinib 500 mg QD plus gefitinib 250 mg QD, or placebo plus gefitinib. [Zhang L, et al, ESMO 2020, abstract LBA50]

Patient characteristics were well-balanced between the apatinib plus gefitinib and placebo plus gefitinib groups at baseline, with EGFR exon 19 deletion and exon 21 L858R present in 51.6 percent vs 53.2 percent and 47.1 percent vs 46.8 percent of the patients, respectively.

At a median follow-up of 15.8 months, apatinib plus gefitinib demonstrated a significant improvement in PFS by independent radiology review committee (IRRC) assessment vs placebo plus gefitinib in the intention-to-treat population (median PFS, 13.7 months vs 10.2 months; hazard ratio [HR], 0.71; 95 percent confidence interval [Cl], 0.54 to 0.95; p=0.0189).

The objective response rates (ORRs) were 77.1 percent vs 73.7 percent for apatinib plus gefitinib vs placebo plus gefitinib, with complete response (CR) achieved in 1 vs no patient. Significantly more patients treated with apatinib plus gefitinib vs placebo plus gefitinib achieved a depth of response (defined as the best percent change from baseline in sum of diameters of the target lesion) of ≥30 percent (89.2 percent vs 79.5 percent; p=0.0209).

Exploratory subgroup analysis by baseline mutation status (n=145) showed improved PFS with apatinib plus gefitinib vs placebo plus gefitinib in patients with TP53 mutation (HR, 0.56; 95 percent CI, 0.31 to 1.01), particularly in patients with TP53 exon 8 mutation (HR, 0.24; 95 percent CI, 0.06 to 0.91).

“Nonetheless, due to a very limited sample size of patients with TP53 exon 8 mutation [n=18; n=7 for apatinib plus gefitinib], the PFS benefit of apatinib plus gefitinib in those patients needs further confirmation by a large-scale clinical study,” said Zhang. 

Likewise, PFS improvement of apatinib plus gefitinib vs placebo plus gefitinib was observed in patients with EGFR exon 19 deletion and exon 21 L858R (exon 19 deletion: HR, 0.67; 95 percent Cl, 0.45 to 0.99) (exon 21 L858R: HR, 0.72; 95 percent CI, 0.48 to 1.09).

Among 91 patients with progressive disease, 37.8 percent vs 37.0 percent of patients in the apatinib plus gefitinib group vs placebo plus gefitinib group tested positive for T790M.

The safety profile of apatinib plus gefitinib was consistent with that of individual treatment components, with no additional safety signal identified. Rates of all-grade treatment-related adverse events (TRAEs) and grade ≥3 TRAEs were 98.7 percent vs 98.1 percent and 84.1 percent vs 37.7 percent for apatinib plus gefitinib vs placebo plus gefitinib, respectively.

Hypertension (46.5 percent for apatinib plus gefitinib vs 2.6 percent for placebo plus gefitinib), proteinuria (17.8 percent vs 0.6 percent) and alanine aminotransferase increase (7.6 percent vs 3.2 percent) were the most common grade ≥3 TRAEs.