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

  • Author(s): Falchook, Gerald S
  • Naing, Aung
  • Hong, David S
  • Zinner, Ralph
  • Fu, Siqing
  • Piha-Paul, Sarina A
  • Tsimberidou, Apostolia M
  • Morgan-Linnell, Sonia K
  • Jiang, Yunfang
  • Bastida, Christel
  • Wheler, Jennifer J
  • Kurzrock, Razelle
  • et al.
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.

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