Clinical study of osimertinib (Tagrisso) combined with metformin in the treatment of lung adenocarcinoma

Research on the combination of osimertinib and metformin mainly comes from mechanism studies in vitro and animal models and several retrospective/small clinical observations. A number of basic studies have shown that metformin can enhance the sensitivity of EGFR inhibitors to tumor cells by activating AMPK, inhibiting autophagy or changing cancer cell metabolism. It can significantly reduce the survival of osimertinib-resistant cells in vitro and delay the development of drug resistance, which provides a biological basis for clinical combination use.

At the clinical level, there have been retrospective cohort and small sample studies suggesting that when diabetic patients who also use metformin receive EGFR-TKI treatment, the objective response rate, progression-free survival (PFS) or overall survival (OS) may be better than that of those who do not use metformin. However, these studies are mostly non-randomized, have confounding factors (such as diabetes itself and metabolic status) and mainly focus on first- and second-generation EGFR-TKIs. High-quality randomized controlled evidence for osimertinib is still lacking.

Mechanism and safety considerations illustrate the need for cautious advancement: Metformin may enhance the effect of TKIs by affecting cellular energy metabolism, inhibiting autophagy, or synergistically inducing cancer cell apoptosis, but some studies have pointed out that antagonistic effects or additive toxicity may occur at different doses or timings; in addition, when used together, attention must be paid to the patient's renal function, the rare risk of lactic acidosis, and the impact of drug interactions on overall tolerance. Before clinical implementation, it should be subject to doctor's evaluation and carried out under strict monitoring.
In summary, current evidence supports the potential of metformin to enhance the anti-tumor activity of EGFR-TKIs (including osimertinib), but there is still a lack of large-sample, randomized, prospective trials to directly prove that osimertinib + metformin can improve key clinical endpoints. For clinical decision-making, priority is given to evaluation and application under the clinical trial framework or under the joint management of the Department of Oncology/Endocrinology, strict recording of efficacy and adverse reactions, and participation in relevant clinical research to obtain more convincing evidence as soon as possible.
Reference: https://www.fda.gov/