ACTIVE is the first phase 3 trial of an oral vascular epidermal growth factor receptor–2 (VEGFR2) tyrosine kinase inhibitor (TKI) added to an EGFR-TKI as first-line therapy in this population, according to, of Sun Yat-sen University Cancer Center in Guangzhou, China.
Dr. Zhangfrom ACTIVE at the European Society for Medical Oncology Virtual Congress 2020.
“This dual oral regimen will provide more convenient treatment for patients who require long-term administration,” Dr. Zhang said. He added that apatinib plus gefitinib “is expected to become a new first-line treatment option for EGFR-mutant NSCLC.”
A discussant for the ACTIVE study was less optimistic, however, noting that the regimen proved tough to tolerate for some patients, and the PFS benefit may not translate to overall survival.
Study rationale and details
Sensitizing EGFR mutations occur in about 10% of White patients and up to 50% of Asian patients, Dr. Zhang noted. Unfortunately, most patients progress after first-line treatment with EGFR-TKIs because of acquired resistance.
Blocking VEGF receptor pathways has been shown to enhance EGFR-TKIs in EGFR-mutated NSCLC, and pilot study results have shown apatinib – an oral VEGFR2–TKI – to be safe and well-tolerated with promising efficacy in combination with gefitinib, Dr. Zhang added.
To expand upon those results, he and his colleagues tested apatinib with gefitinib in the phase 3, double-blind, placebo-controlled ACTIVE trial (CTONG1706).
The trial included 313 patients (median age, 58.5 years) with locally advanced, metastatic, or recurrent nonsquamous NSCLC. All were chemotherapy-naive and EGFR mutation-positive (exon 19 deletion or exon 21 L858R).
Patients were randomized 1:1 to first-line apatinib at 500 mg daily plus gefitinib at 250 mg daily (n = 157) or placebo plus gefitinib at 250 mg daily (n = 156) until progressive disease or unacceptable toxicity.
Efficacy and safety
The primary endpoint was PFS by independent review. The median follow-up was 15.8 months.
The median PFS was 13.7 months in the apatinib group and 10.2 months in the placebo group (hazard ratio, 0.71; P = .0189).
Objective response rates were similar for both groups – 77.1% with apatinib and 73.7% with placebo. However, depth of response ≥30% and depth of response ≥50% both favored the apatinib arm – 89.2% versus 79.5% for ≥ 30% (P = .0209) and 64.3% versus 52.6% for ≥50% (P = .0238).
In addition, the median duration of response was longer for the apatinib group – 12.9 months versus 9.3 months (HR, 0.64; P = .005).
Exploratory biomarker analyses showed the benefit of apatinib was more common in patients with TP53 exon 8 mutations.
The rate of grade 3 or higher treatment-emergent adverse events was 84.1% in the apatinib arm and 37.7% in the placebo arm. Diarrhea (73.2%) and hypertension (68.2%) were the most common treatment-emergent adverse events in the apatinib group.
Dose interruptions were more common in the apatinib group (59.5% vs. 22.7%) as were dose reductions (48.4% vs. 4.5%). However, treatment discontinuations attributable to treatment-emergent adverse events were few in both arms (5.1% in the apatinib arm and 3.2% in the placebo arm).