Abstract 1675: Enhanced antitumor effect of dual EGFR and VEGFR2 inhibition in EGFR-mutated non-small cell lung cancer (NSCLC) patient-derived tumor xenograft (PDX) models
Authors: Chintharlapalli Sudhakar , Fischl Anthony , Yu Chun Ping , Iversen Philip 
Published: September 2020

Background: NSCLC accounts for nearly 85% of all lung cancers. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for EGFR mutated NSCLCs, but these drugs often stop working after EGFR acquires additional mutations. Preclinical and clinical data suggest a stronger antitumor effect with dual blockade of the EGFR and vascular endothelial growth factor (VEGF) pathways in EGFR-mutated NSCLC. RELAY, a randomized, double-blind, phase 3 trial, demonstrated superior progression-free survival (PFS) with ramucirumab (RAM) + erlotinib compared with placebo + erlotinib in patients with untreated EGFR-mutated advanced NSCLC. Additionally, RAM was tested in a Phase 1 study with the third-generation irreversible EGFR TKI osimertinib (OSI); AstraZeneca) in NSCLC patients with advanced T790M-positive EGFR mutant tumors after progression on first-line EGFR TKI therapy. OSI can be used with L858R, exon 19 del and T790M EGFR mutant tumors. We investigated the combined use of OSI+RAM in EGFR mutated NSCLC PDX mouse models.

Materials and Methods: The antimurine VEGFR2 antibody DC101 (40 mg/kg, BIW) and the EGFR TKI OSI (10 mg/kg, QD) were used in this study. Twenty-seven PDX NSCLC mouse models carrying EGFR activating and/or T790M resistance mutations, commonly detected in patients with advanced NSCLC, were evaluated at 3 independent sites. Mice were divided into 4 treatment arms: vehicle (PBS), DC101, OSI and combination (DC101+OSI). Each study arm included two transplanted mice per model. Sensitivity to DC101 and OSI monotherapies, enhancement of anti-tumor activity with the combination therapy and durability of the response were evaluated. Desirability score, a weighted composite score of six features of tumor growth curves including best median % response, number of days in best response category, time to doubling, re-growth rate (last 5 observations) relative to vehicle growth rate, last observed tumor volume and last observed day, was calculated for each treatment arm. Analysis of variance was used to compare summary scores per animal across treatments.

Results: OSI alone and OSI+DC101 combination therapy had stronger antitumor effects than DC101 monotherapy in significantly more models 11 vs 1 and 12 vs 0, respectively. A small but consistent shift in favor of OSI+DC101 vs OSI was observed across most of the models. Paired t-test analyses showed a moderate but significant benefit with combination OSI+DC101 vs OSI. Overall desirability score was statistically improved with OSI+DC101 compared to either single agent.

Conclusions: Dual inhibition of EGFR and VEGFR2 with OSI+DC101 had a stronger antitumor effect than those of the respective monotherapies in EGFR mutated NSCLCs in vivo. Future studies will investigate the molecular mechanisms underlying the enhanced antitumor effect of OSI+DC101 combination therapy.

Citation Format: Sudhakar Chintharlapalli, Anthony Fischl, Chun Ping Yu, Philip Iversen. Enhanced antitumor effect of dual EGFR and VEGFR2 inhibition in EGFR-mutated non-small cell lung cancer (NSCLC) patient-derived tumor xenograft (PDX) models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1675.