Ganitumab + Metformin + Paclitaxel (PGM)

Ganitumab + metformin + paclitaxel (PGM) is a combination therapy that was evaluated in the I-SPY2 adaptive randomized phase 2 clinical trial for neoadjuvant treatment of breast cancer. This regimen combines: 1. **Ganitumab**: A monoclonal antibody designed to bind and inhibit the function of the type I insulin-like growth factor receptor (IGF-1R) 2. **Metformin**: An antidiabetic drug that was included to potentially reduce insulin resistance caused by ganitumab 3. **Paclitaxel**: A standard chemotherapy agent that targets tubulin during cell division The combination was tested against standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide (AC). While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this increase did not meet the trial's prespecified threshold for graduation[1][2]. The PGM combination was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the inclusion of metformin specifically to counteract these effects[1][2]. Researchers evaluated several potential biomarkers to predict response to ganitumab (including IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, and baseline HbA1c), but none were found to be specific predictors of response to the PGM combination[1][2].