Dual EGFR inhibition in combination with anti-VEGF treatment: A phase I clinical trial in non-small cell lung cancer

Gerald S Falchook,Ralph Zinner,Razelle Kurzrock,Yunfang Jiang,Sarina A Piha-Paul,Aung Naing,Christel Bastida,Sonia K Morgan-Linnell,Apostolia M Tsimberidou,Jennifer J Wheler,Siqing Fu,David S Hong

doi:10.18632/oncotarget.763

Abstract

Preclinical data indicate EGFR signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic in animal models. We conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with non-small cell lung cancer (NSCLC) was analyzed for safety and response. Thirty-four patients with NSCLC (median four prior therapies) received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (n=14, 41%), hypomagnesemia (n=9, 27%), and fatigue (n=5, 15%). Seven patients (21%) achieved stable disease (SD) ≥6 months, two achieved a partial response (PR) (6%), and two achieved an unconfirmed partial response (uPR) (6%) (total=32%). We observed SD≥6 months/PR/uPR in patients who had received prior erlotinib and/or bevacizumab, those with brain metastases, smokers, and patients treated at lower dose levels. Five of 16 patients (31%) with wild-type EGFR experienced SD≥6 months or uPR. Correlation between grade of rash and rate of SD≥6 months/PR was observed (p less than 0.01). The combination of erlotinib, cetuximab, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with NSCLC.

Highlights

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that plays an important role in tumorigenesis [1], and signals via downstream effectors [2]
Three of 19 patients tested (16%) had EGFR mutations; 19 patients tested for KRAS mutations were all wild-type
The rationale for this combination was: (1) preclinical and clinical studies that suggested increased activity when erlotinib was combined with bevacizumab [30, 31]; (2) preclinical studies indicating that EGFR signals through both kinase-dependent and -independent pathways [17]; and (3) studies demonstrating that combining an EGFR kinase inhibitor with EGFR antibodies was synergistic in animal models [18, 19]

Summary

Introduction

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that plays an important role in tumorigenesis [1], and signals via downstream effectors [2]. An EGFR inhibitor, is approved by the Federal Drug Administration (FDA) to treat locally advanced or metastatic NSCLC [9]. Most responses to erlotinib occur in patients with EGFR mutations [3, 10,11,12], and both resistant (e.g., L861Q) and sensitive (e.g., exon G719S, exon deletion or exon 21 L858R point mutation) mutations have been identified [12,13,14,15]. A monoclonal antibody to EGFR, has demonstrated efficacy in NSCLC when combined with chemotherapy [16], but is not currently FDA-approved for NSCLC. Preclinical data indicate EGFR signals through both kinasedependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic in animal models

Methods

Results

Conclusion