Randomized Phase 0/I Trial of the Mitochondrial Inhibitor ME-344 or Placebo Added to Bevacizumab in Early HER2-Negative Breast Cancer

  • Clin Cancer Res. 2020 Jan 1;26(1):35-45. doi: 10.1158/1078-0432.CCR-19-2023.
Miguel Quintela-Fandino  1  2  3 ,  Serafín Morales  4 ,  Alfonso Cortés-Salgado  5 ,  Luis Manso  6 ,  Juan V Apala  7  2 ,  Manuel Muñoz  7 ,  Ariadna Gasol Cudos  4 ,  Joel Salla Fortuny  4 ,  María Gion  5 ,  Antonio Lopez-Alonso  7 ,  Javier Cortés  8  9 ,  Juan Guerra  2 ,  Diego Malón  2 ,  Eduardo Caleiras  10 ,  Francisca Mulero  11 ,  Silvana Mouron  7
Affiliations
  • 1. Breast Cancer Clinical Research Unit - Clinical Research Program, CNIO - Spanish National Cancer Research Center, Madrid, Spain. [email protected].
  • 2. Medical Oncology, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain.
  • 3. Medical Oncology, Hospital Universitario Quiron, Pozuelo de Alarcon, Spain.
  • 4. Medical Oncology, Hospital Universitari Arnau Vilanova, Lleida, Spain.
  • 5. Medical Oncology, Hospital Universitario Ramon y Cajal, Madrid, Spain.
  • 6. Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • 7. Breast Cancer Clinical Research Unit - Clinical Research Program, CNIO - Spanish National Cancer Research Center, Madrid, Spain.
  • 8. ION Institute of Oncology, Quironsalud Group - Madrid and Barceona, Spain.
  • 9. Vall d'Hebron Institute of Oncology, Barcelona, Spain.
  • 10. Histopathology Unit, CNIO - Spanish National Cancer Research Center, Madrid, Spain.
  • 11. Molecular Imaging Unit, CNIO - Spanish National Cancer Research Center, Madrid, Spain.
PMID: 31597662 DOI: 10.1158/1078-0432.CCR-19-2023
Abstract

Purpose: We previously demonstrated that mitochondrial inhibitors' efficacy was restricted to a metabolic context in which mitochondrial respiration was the predominant energy source, a situation achievable by inducing vascular normalization/hypoxia correction with antiangiogenics. Vascular normalization can be tracked with 2[18F]fluoro-2-deoxy-d-glucose (FDG)-PET. We tested the efficacy of the mitochondrial inhibitor ME-344 or placebo added to bevacizumab in early breast Cancer.

Patients and methods: Treatment-naïve HER2-negative patients with T > 1 cm (any N) underwent a breast-centered 18F-fluorodeoxyglucose (FDG)-PET (day 1) and received a single dose of bevacizumab (15 mg/kg), followed by a second FDG-PET (day 8). Patients were then randomized (1:1) to Arm A (ME-344 10 mg/kg intravenous on days 8, 15, and 21) or Arm B (placebo). Tumors were biopsied on days 0 and 29. Succinate Dehydrogenase enzyme histochemistry (SDH-EHC), confocal microscopy of vessel architecture, and HIF1α staining were performed in pre- and posttreatment biopsies to assess the pharmacodynamics, vessel normalization, and tissue re-oxygenation by bevacizumab, respectively.

Results: ME-344 displayed significant biological activity versus placebo: compared with a 186% increase in Arm B, Ki67 decreased by 23.4% from days 0 to 28 in Arm A (P < 0.001) (N = 42 patients). FDG-PET predicted vascular normalization in about one-third of the patients in each arm, which was confirmed using confocal microscopy and HIF1α staining. In the subgroup with vascular normalization, ME-344 induced a Ki67 decrease of 33.4% (placebo: 11.8 increase). SDH-EHC suggested on-target effects of ME-344.

Conclusions: ME-344 has significant biological antitumor activity in HER2-negative breast Cancer, particularly after induction of vascular normalization and tissue reoxygenation with bevacizumab.

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