Dual EGFR blockade with cetuximab and erlotinib combined with anti-VEGF antibody bevacizumab in advanced solid tumors: a phase 1 dose escalation triplet combination trial

Vivek Subbiah, Ecaterina Ileana Dumbrava, Yunfang Jiang, Kyaw Z Thein, Aung Naing, David S Hong, Siqing Fu, Sarina A Piha-Paul, Apostolia M Tsimberidou, Filip Janku, Funda Meric-Bernstam, Razelle Kurzrock, Gerald Falchook, Vivek Subbiah, Ecaterina Ileana Dumbrava, Yunfang Jiang, Kyaw Z Thein, Aung Naing, David S Hong, Siqing Fu, Sarina A Piha-Paul, Apostolia M Tsimberidou, Filip Janku, Funda Meric-Bernstam, Razelle Kurzrock, Gerald Falchook

Abstract

Background: Angiogenesis and activation of the epidermal growth factor (EGFR) pathway play an essential role in tumor proliferation and metastasis. Targeting angiogenesis or EGFR alone does not yield adequate tumor control in most solid tumors. Overcoming intrinsic and/or acquired resistance may need a doublet or triplet therapy strategy. Herein, we report the safety and feasibility of dual EGFR blockade with EGFR monoclonal antibody and EGFR tyrosine kinase inhibitor combined with anti-VEGF antibody in advanced solid tumors.

Methods: We conducted a phase I study combining erlotinib, cetuximab, and bevacizumab. Patients with advanced or metastatic solid tumors (excluding colorectal and non-small cell lung cancers) were analyzed for safety, toxicity profile, and response. Anti-tumor activity was evaluated per response evaluation criteria in solid tumors (RECIST 1.0).

Results: Thirty-six patients received treatment on a range of dose-levels. The most frequent tumor types enrolled were cervical (n = 10), head and neck squamous cell (n = 10), and follicular thyroid (n = 4) cancers. The most common treatment-related grade ≥ 2 adverse events were rash (56%), hypomagnesemia (17%), pruritus (11%), diarrhea (8%), and tumor-related bleeding (8%). Seventeen of 19 patients (89%) treated at the maximum tolerated dose did not present treatment-related dose-limiting toxicity. Fifteen (63%) of the 24 evaluable patients achieved a disease control (stable disease ≥ 4 months (n = 14) and partial response (n = 1). The median number of prior lines of therapies was 3 (range 1-10).

Conclusions: The triplet combination of erlotinib, cetuximab, and bevacizumab was well tolerated, conferring clinical benefit in heavily pretreated patients. Future studies are warranted with second or third-generation EGFR tyrosine kinase triplet combinations in the EGFR pathway aberrant patients.Trial Registration: ClinicalTrials.gov Identifier: NCT00543504. Sponsor(s): National Cancer Institute (NCI), MD Anderson Cancer Center.

Keywords: Advanced solid tumors; Cetuximab, erlotinib and bevacizumab; Dual EGFR blockade; Phase 1 dose escalation.

Conflict of interest statement

Competing interestsA full list of the authors’ competing interests can be found in Additional file 1.

© The Author(s) 2020.

Figures

Fig. 1
Fig. 1
Best response and time under treatment (3D waterfall plot)

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