Phase I Study of Apatinib in Combination with Gefitinib As First-Line Treatment in Patients with EGFR-Mutant Advanced Non-Squamous Non-Small Cell Lung Cancer

Abstract

Background: Dual blockade of the EGFR and VEGFR pathways in EGFR-mutant NSCLC have shown enhanced anti-tumor efficacy versus a (v)EGFR inhibitor alone. This phase I study evaluated the safety, pharmacokinetic (PK) profile and antitumor activity of apatinib, an orally effective VEGFR-2 tyrosine kinase inhibitor (TKI), plus gefitinib as a first-line treatment for EGFR-mutant advanced NSCLC. Methods: Advanced non-squamous NSCLC patients with the EGFR 19 deletion or the 21 L858R mutation who met this study's eligibility criteria were included. There were two cohorts. Cohort A: apatinib 500mg + gefitinib 250mg. Cohort B: apatinib 250mg + gefitinib 250mg. The primary endpoint was safety profile. Other endpoints included PK analysis, objective response rate (ORR) and progression free survival (PFS). Exploratory analysis was conducted using next generation sequencing of plasma circulating-tumor DNA with samples collected at baseline, best of response and after progression disease. Findings: Between July 2016 and April 2017, 13 patients with NSCLC were enrolled in this study. Six patients were enrolled in Cohort A and seven in Cohort B. Most adverse events (AEs) were grade 1-2 and the treatment-related AEs (TRAEs) were similar in both cohorts: rash (100% v 71.4%), diarrhea (66.7% v 71.4%), hypertension (66.7% v 71.4%), proteinuria (66.7% v 42.9%), and hand-foot skin reaction (33.3% v 28.6%). The area under the plasma concentration-time curve (AUC) for the steady state of apatinib was 2864.73 ± 2605.54 ng/ml*h in Cohort A and 2445.09 ± 1550.89 ng/ml*h Cohort B. Median follow-up was 29.7 months. The ORR was 80.0% and the median PFS was 19.2 months in Cohort and it 83.3% and 13.4 months in Cohort B. Patients without a concomitant mutation at baseline had a longer PFS compared with those with a detected concomitant mutation (20.99 months v 13.21 months, P=0.0624). The EGFR-T790M mutation remained the dominant resistance mechanism. Interpretation: Apatinib (500mg) plus gefitinib (250mg) had a tolerable safety profile and promising antitumor activity for EGFR-mutant NSCLC patients in the first-line setting. Phase III trials of apatinib (500mg) plus gefitinib (250mg) are warranted. Funding: This work was supported by National Key R&D Program of China (Grant number: 2016YFC0905500, 2016YFC0905503), The Science and Technology Planning Project of Guangdong Province of China (Grant number: 2017B020227001)，Natural Science Foundation of Guangdong Province of China (Grant number: 2018A0303130243) and The 5010 Clinical Research Foundation of Sun Yat-sen University (Grant number: 2016001). Li Zhang has received research support from the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDA12020101 to J.D.). Yan Huang has received research support from Science and Technology Program of Guangzhou (201704020072). Yunpeng Yang was supported by Outstanding Young Talents Program of Sun Yat-sen University Cancer Center (16zxyc03) and Central Basic Scientific Research Fund for Colleges-Young Teacher Training Program of Sun Yat-sen University (17ykpy85). Declaration of Interest: All authors declare no competing interests. Ethical Approval: This trial has been approved by the institutional review boards (ID: 2016-FXY-023) and the independent ethics committees of Sun Yat-sen University Cancer Center (Ethic approval ID: 5010-2016-03). And other participating centers have also obtained the approval from their institutional review boards/independent ethics committees before enrollment. All patients will be required to sign the informed consent form before enrollment.