Dual blockade of EGFR and VEGFR pathways: Results from a pilot study evaluating apatinib plus gefitinib as a first-line treatment for advanced EGFR-mutant non-small cell lung cancer

Abstract

Background: Dual blockade of both EGFR and VEGFR pathways in EGFR-mutant NSCLC have shown enhanced antitumor efficacy versus EGFR-TKIs alone. Apatinib is an orally effective VEGFR-2 tyrosine kinase inhibitor (TKI). This pilot study aims to evaluate the tolerability, pharmacokinetic profile, and antitumor activity of apatinib plus gefitinib as a therapy for EGFR-mutant advanced NSCLC.

Methods: Advanced non-squamous NSCLC participants harbored with the EGFR 19 deletion or the 21 L858R point mutation were included. There were two cohorts: Cohort A: apatinib 500 mg + gefitinib 250 mg. Cohort B: apatinib 250 mg + gefitinib 250 mg. The primary endpoint was safety profile. Other endpoints consisted of PK analysis, objective response rate (ORR), and progression-free survival (PFS). Exploratory analysis was conducted using next-generation sequencing of plasma circulating-tumor DNA.

Results: Between July 2016 and April 2017, 13 of NSCLC patients were recruited. Six patients were pooled in Cohort A, while seven patients were in Cohort B. Adverse events (AEs) were tolerable (mostly grade 1-2) and the treatment-related AEs were similar in both cohorts: rash (100% vs 71.4%), diarrhea (66.7% vs 71.4%), hypertension (66.7% vs 71.4%), proteinuria (66.7% vs 42.9%), and hand-foot skin reaction (33.3% vs 28.6%). The area under plasma concentration-time curve for the steady state of apatinib was 2864.73 ± 2605.54 ng mL-1 h-1 in Cohort A and 2445.09 ± 1550.89 ng mL-1 h-1 in Cohort B. Of the 11 patients evaluable for efficacy, Cohort A achieved an ORR of 80.0% and reached a median PFS of 19.2 months, while it was 83.3% and 13.4 months in Cohort B. Patients without a concomitant mutation at baseline had a prolonged PFS tendency (20.99 months v 13.21 months, P = .0624). The EGFR-T790M mutation remained the dominant resistance mechanism.

Conclusion: Apatinib (500 mg) plus gefitinib (250 mg) showed a tolerable safety profile and encouraging antitumor activity for advanced EGFR-mutant NSCLC in the first-line setting. Phase III trials of apatinib (500 mg) plus gefitinib (250 mg) are warranted.

Trial registration: Clinicaltrials.gov, NCT02824458, date of registration June 23, 2016.

Keywords: Apatinib; EGFR-TKIs; Gefitinib; NSCLC; antiangiogenic therapy.

Conflict of interest statement

The authors declare no conflict of interest.

© 2020 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

Figures

FIGURE 1

Trial profile

FIGURE 2

The concentration time curve of apatinib and gefitinib. A‐D, Mean Apatinib plasma concentration–time profile on Day 1 (single dose) and Day 15 (continuous dose). Patients were administered with 500 mg or 250 mg Apatinib plus 250 mg Gefitinib once a day; PK evaluation was performed on Cycle 1, Day 1 and Day 15. E and F, Mean Gefitinib plasma concentration–time profile on Day 1 (single dose) and Day 15 (continuous dose). Patients were administered with 250 mg Gefitinib 250 mg and 500 mg or 250 mg Apatinib once a day; PK evaluation was performed on Cycle 1, Day 1, and Day 15. *Two patients did not have PK data on Cycle 1, Day 15 (one patient had SAE and one was no longer willing to participate and was lost to follow‐up after C1D14)

FIGURE 3

Objective response rate (n = 11). A, Waterfall plot: A maximum tumor change from baseline by best overall response (intention‐to‐treat population). Best change of target‐lesion compared to baseline at best overall response of Apatinib combined with Gefitinib treatment. Waterfall plots for best change of target‐lesion for all patients. The colored bars represent the different doses of Apatinib. The dashed lines are at 20% and −30% represents the boundary for determination of PD and PR, respectively. Asterisks represent PD. B, Swimmer plot: Time to treatment failure from enrollment to PD during treatment with apatinib and gefitinib. Each bar represents one patient's duration exposure of apatinib plus gefitinib, and each color presents the best response of one patient. ∆ represent PD

FIGURE 4

Plasma circulating‐tumor DNA (ct‐DNA) sequencing description summary and clinical outcome exploratory analysis results of 11 patients. A, Mutation plots of sequencing profile at baseline, best of response, and after PD samples, were sorted by the apatinib dosage (500 or 250 mg). Each column represents a distinct patient. BOR, smoking status, and sex groups are shown at the top. B, Kaplan‐Meier curves of progression‐free survival (PFS) in patients whose ct‐DNA had concomitant mutations compared with those without concomitant mutations at baseline. (C) Kaplan‐Meier curves of progression‐free survival (PFS) in 8 patients who received Osimertinib after PD in the second‐line. D, Pie chart depicting the T790M resistant distribution. E, Scatter plot of EGFR‐T790M VAFs (%). The red dashed line represents the median (0 at baseline, 0.6375 at PR/SD, and 4.145 at PD). F, Percentage changes in SLD of target lesions correlated with T790M VAFs. Abbreviations: del, deletion; EGFR, epidermal growth factor receptor; HR, hazard ratio; NR, not reached; PD, progressive disease; PR, partial response; SD, stable disease; PD, progression disease and VAF, variant allele frequency; SLD, sum of the longest diameters