Abstract P1-16-03: Phase II randomized clinical trial (RCT) of metformin (MET) vs placebo (PLAC) in combination with chemotherapy (CXT) in refractory locally advanced (LABC) or metastatic breast cancer (MBC)
Authors: Goodwin PJ , Ennis M , Cescon DW , Elser C , Haq R , Hamm CM , Lohmann AE , Pimentel I , Chang MC , Dowling RJ , Stambolic V 
Published: May 2019

Abstract
Background: MET treatment of diabetes is associated with improved BC outcomes. Hirsch et al (Cancer Res 2009;69:7505-7511) suggested MET may act synergistically with CXT in BC rodent models. We conducted a double-blind Phase II RCT of CXT plus MET vs placebo in LABC/MBC.
Methods: Non-diabetic BC patients (pts) about to commence 1st-4th line CXT (prespecified anthracycline, taxane, vinorelbine, platinum or capecitabine; HER2 Rx permitted) for MBC or refractory LABC (any ER, PgR, HER2) were eligible if (i) age 18-75, (ii) ECOG 0-2, (iii) adequate hepatic, renal, bone marrow, cardiac function and (iv) measurable or evaluable disease. Those with CNS metastases, recent MET use or radiotherapy to target lesions, intake of ≥ 3 alcoholic drinks/day, history of lactic acidosis or current/planned pregnancy or lactation were ineligible. Randomization was to MET 850 mg po bid (or identical PLAC bid) with a 2 day ramp up of one tablet/day; dose was reduced/drug discontinued in a pre-specified manner for grade 2-4 toxicity. Disease status and toxicity/HRQOL were assessed at baseline and q9 weeks until progression. Primary outcome was progression-free survival (PFS); secondary outcomes included survival (OS), response and toxicity. With 40 subjects and type one error 0.2 (1-sided), a PFS HR of 0.58 could be detected with 80% power. PFS was analyzed using Cox proportional hazards regression.
Results: 40 pts were randomized (22 MET, 18 PLAC). Mean age 55.4 vs 56.9 years; ER/PgR+ in 86.4 vs 83.3%; time from 1st metastases to randomization 297 vs 405 days, in MET vs PLAC respectively. MET pts were more likely to have visceral metastases (95.5% vs 72.2% PLAC) and less likely to be HER2+ (9.1% vs 23.5% PLAC). CXT was 1st line in 68.2% MET and 66.7% PLAC pts. Toxicity - # events: Gr 4: 0 MET vs 1 PLAC, Gr 3: 14 MET vs 14 PLAC; Gr 1 or 2: 193 MET (mainly GI) vs 53 PLAC. Best response: PR 18.2% MET vs 22.2% PLAC, SD 31.8% MET vs 11.1% PLAC, PD 45.4% MET vs 50.0% PLAC, P = 0.41. Mean PFS 164 days MET vs 192 days PLAC; HR (MET vs PLAC) 1.14 (95% CI 0.59-2.2), 1-sided p=0.65. Mean OS 645 MET vs 831 PLAC days; HR (MET vs PLAC) 1.6, 95% CI 0.72-3.54, 1-sided p=0.88.
Conclusion: In these BC pts receiving 1st-4th line CXT, MET (vs PLAC) did not improve response rates, PFS or OS. Gr 1 and 2 toxicity was higher with MET than PLAC. These results do not support use of MET with CXT in refractory LABC/MET BC. MA32, an adjuvant trial of MET vs PLAC in early BC will provide information on MET in the adjuvant setting.
Funded by the Breast Cancer Research Foundation (New York) and Hold'em for Life Charity (Toronto)
Citation Format: Goodwin PJ, Ennis M, Cescon DW, Elser C, Haq R, Hamm CM, Lohmann AE, Pimentel I, Chang MC, Dowling RJ, Stambolic V. Phase II randomized clinical trial (RCT) of metformin (MET) vs placebo (PLAC) in combination with chemotherapy (CXT) in refractory locally advanced (LABC) or metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-16-03.