Apatinib Plus Gefitinib as First-Line Treatment in Advanced EGFR-Mutant NSCLC: The Phase III ACTIVE Study (CTONG1706)
Hongyun Zhao1, Wenxiu Yao2, Xuhong Min3
1Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.
Introduction:
Blocking vascular endothelial growth factor pathway can enhance the efficacy of EGFR tyrosine kinase inhibitors in EGFR-mutant NSCLC. ACTIVE is the first phase 3 study conducted in the People's Republic of China evaluating apatinib, a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, plus gefitinib as first-line therapy in EGFR-mutant NSCLC.
Methods:
Treatment-naive patients with stage IIIB or IV nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and EGFR exon 19 deletion or exon 21 L858R mutation were randomized 1:1 to receive oral gefitinib (250 mg/d), plus apatinib (500 mg/d; apatinib [A] + gefitinib [G] group), or placebo (placebo [P] + gefitinib [G] group). Stratification factors were mutation type, sex, and performance status. The primary end point was progression-free survival (PFS) by blinded independent radiology review committee (IRRC). Secondary end points were investigator-assessed PFS, overall survival, quality of life (QoL), safety, etc. Next-generation sequencing was used to explore efficacy predictors and acquired resistance.
Results:
A total of 313 patients were assigned to the A + G (n = 157) or P + G group (n = 156). Median IRRC PFS in the A + G group was 13.7 months versus 10.2 months in the P + G group (hazard ratio 0.71, p = 0.0189). Investigator- and IRRC-assessed PFS were similar. Overall survival was immature. The most common treatment-emergent adverse events greater than or equal to grade 3 were hypertension (46.5%) and proteinuria (17.8%) in the A + G group and increased alanine aminotransferase (10.4%) and aspartate aminotransferase (3.2%) in the P + G group. QoL in the two groups had no statistical differences. Post hoc analysis revealed PFS benefits tended to favor the A + G group in patients with TP53 exon 8 mutation.
Conclusions:
Apatinib + gefitinib as first-line therapy had superior PFS in advanced EGFR-mutant NSCLC versus placebo + gefitinib. Combination therapy brought more adverse events but did not interfere QoL.
Trial Registration:
NCT02824458.
Insights
First-line apatinib plus gefitinib significantly improved progression-free survival in advanced EGFR-mutant non-small cell lung cancer. This combination therapy demonstrated superior efficacy without negatively impacting quality of life.
Area of Science:
- Oncology
- Medical Research
- Clinical Trials
Background:
- Vascular Endothelial Growth Factor (VEGF) pathway blockade can enhance EGFR tyrosine kinase inhibitor (TKI) efficacy in EGFR-mutant non-small cell lung cancer (NSCLC).
- The ACTIVE study is the first Phase 3 trial in China evaluating apatinib, a VEGF receptor 2 TKI, combined with gefitinib for first-line treatment of EGFR-mutant NSCLC.
Purpose of the Study:
- To evaluate the efficacy and safety of first-line apatinib plus gefitinib compared to gefitinib plus placebo in patients with EGFR-mutant NSCLC.
- To assess progression-free survival (PFS), overall survival, quality of life (QoL), and safety outcomes.
Main Methods:
- A randomized, double-blind, placebo-controlled Phase 3 trial (NCT02824458) involving 313 treatment-naive patients with stage IIIB/IV non-squamous NSCLC and EGFR mutations (exon 19 or 21).
- Patients received either gefitinib plus apatinib (A+G group) or gefitinib plus placebo (P+G group).
- Primary endpoint was PFS assessed by an independent radiology review committee (IRRC).
Main Results:
- Median IRRC PFS was 13.7 months in the A+G group versus 10.2 months in the P+G group (Hazard Ratio: 0.71, p=0.0189).
- Common Grade 3+ adverse events in the A+G group included hypertension (46.5%) and proteinuria (17.8%).
- Quality of life showed no significant difference between the groups.
Conclusions:
- First-line apatinib plus gefitinib demonstrated superior PFS in advanced EGFR-mutant NSCLC compared to gefitinib plus placebo.
- The combination therapy led to increased adverse events but did not compromise patient quality of life.
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