89P - Impact of metformin on glucocorticoid-induced changes in systemic metabolism in patients with brain metastases from solid malignancies

Background

Glucocorticoids (GC) are commonly used in patients (pts) with brain metastases to palliate symptoms and to prevent radiotherapy-induced side effects. GCs can cause metabolic adverse events (AEs), such as hyperglycemia or diabetes, which could negatively impact on clinical outcomes. Here, we evaluated if the antidiabetic compound metformin (MET) prevents GC-induced hyperglycemia and diabetes in pts with brain metastases from melanoma, breast or lung cancer.

Methods

We conducted a monocentric, prospective, phase II clinical trial (OPTIMAL: NCT02705157) that randomized pts with a de novo diagnosis of brain metastases to receive dexamethasone (DEX) at a minimum daily dosage of 8 mg, or DEX plus oral MET, up to a maximum daily dosage of 2550 mg. The primary study objective was to investigate if MET reduces the incidence of diabetes at 14 days after DEX initiation. Secondary study endpoints were changes in other systemic metabolic parameters, as well as in peripheral blood cell counts. Here we present an interim analysis of the study, which included 33 pts.

Results

Of 33 pts randomized between October 2019 and July 2021, 15 pts received DEX, while 18 pts received DEX plus MET. None of pts enrolled in the study developed treatment-induced diabetes at 14 days; in addition, DEX, with or without MET, did not result in increased fasting plasma glucose concentration. Based on these findings, the OPTIMAL trial was precociously interrupted. Of note, MET use resulted in statistically significant reduction of post-prandial glycemia, as measured as capillary blood glucose levels, and in an attenuation of DEX-induced increased in fasting plasma HDL cholesterol. Plasma triglyceride, total cholesterol and LDL cholesterol levels are not affected by GCs, either alone or in combination with MET. Finally, MET did not reverse DEX-induced increase in blood leukocyte, neutrophil and monocyte counts.

Conclusions

High-dose GCs, +/- MET, do not precociously affect fasting blood glucose concentration in pts with brain metastases from solid malignancies. MET could potentially reverse some GC-induced metabolic changes. However, the impact of these metabolic modifications on systemic immunity and on clinical outcomes remains unclear.

Clinical trial identification

NCT02705157.

Editorial acknowledgement

Legal entity responsible for the study

F.G.M. De Braud.

Funding

Has not received any funding.

Disclosure

F.G.M. De Braud: Financial Interests, Personal, Invited Speaker: BMS, Healthcare Research & Pharmacoepidemiology, Merck Group, MSD, Pfizer, Servier, Sanofi, Roche, Amgen, Incyte, Dephaforum, Seagen, Novartis, F.Hoffmann-LaRoche Ltd, BMS, Ignyta Operating INC, Merck Sharp & Dohme, Kymab, Pfizer, Tesaro, MSD, MedImmune, Exelixis Inc, LOXO Oncology Incorporated, Daiichi Sankio, Basilea Pharmaceutica International, Janssen-Cilag International, Merck KGAA; Financial Interests, Personal, Other, Consultant Advisory Board: Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, MSD, Novartis, Incyte, BMS, Menarini, AstraZeneca, Pierre Fabre. G. Lo Russo: Financial Interests, Personal, Advisory Board: MSD, Novartis, AstraZeneca, BMS, Pfizer, Roche, Sanofi; Financial Interests, Personal, Invited Speaker: Italfarmaco, Sanofi; Financial Interests, Institutional, Invited Speaker: BMS, MSD, GSK, Celgene, Novartis, Roche, AstraZeneca, Amgen. L. Rivoltini: Financial Interests, Personal, Invited Speaker, teaching in educational events: BMS; Non-Financial Interests, Personal, Advisory Role: DKTK. All other authors have declared no conflicts of interest.