Abrogation Of Resistance Against Bevacizumab (Bev) By Mitochondrial Inhibition: A Phase 0 Randomized Trial Of Bev Plus Me344 Or Placebo In Early Her2-Negative Breast Cancer (Hernebc).

2552 Background: Our preclinical data show that one mechanism of acquired resistance to anti-angiogenic therapy involves hypoxia correction, measured by decreased SUV ( ↓ SUV) on FDG-PET followed by mitochondrial up-regulation. ME344 is a potent inhibitor of mitochondrial respiration. The aims of this study were to assess 1) the fraction of HERNEBC patients that show ↓SUV in response to single dose Bev and 2) if adding ME344 to Bev inhibits cell proliferation as determined by Ki67% decrease, a surrogate marker of efficacy in neoadjuvant breast cancer. Methods: Treatment-naïve HERNEBC patients (T > 1 cm, any N, M0) received 15 mg/kg Bev on d0 and were then randomized 1:1 to ME344 10 mg/kg IV d8, 15 and 21 (arm A) or placebo (arm B) followed by physician’s choice of definitive therapy. FDG-PET was performed on d0 and d7 and tumor biopsy on day 0 and 28. The primary endpoint was Ki67% relative reduction from d0 to 28. A 40 patient sample size was powered to detect a 30% relative difference in Ki67% between arm A and B (alpha 0.05, beta 0.2). Threshold for hypoxia correction by PET was 10% ↓ SUV. A predefined interim analysis was planned when 20 patients had completed treatment. Results: 19 patients were randomized (arm A/B: 7/7 LumA, 2/2 LumB, 1/0 TNBC). Baseline characteristics: Ki67 by IHC: mean 10.3% (1%-48%), age: mean 56 (44-75), T (8 T1, 10 T2, 1 T3), N (14 N0, 5 N1) and G (4 G1, 12 G2, 3 G3) were balanced between arms. 31% of patients experienced ↓SUV > 10%. Mean absolute (relative) Ki67 decreases were 5.13 (29%) and 1.2 (9%) in arms A and B (P = 0.06). Patients with ↓ SUV > 10% experienced an absolute average Ki67 decrease of 16.6 vs. 2.3 in arms A and B (P = 0.19). Two G3 adverse events (high blood pressure) were reported (1 per arm) and deemed related to Bev. Conclusions: ME344 results in significant Ki67 reduction compared to placebo in HERNEBC patients exposed to single-dose Bev. This effect may be greater in those patients with Bev induced hypoxia correction. These clinical results are consistent with preclinical data suggesting that ME-344 can reverse resistance to anti-angiogenic therapy and warrant further studies to assess clinical efficacy of the combination. Clinical trial information: NCT02806817.