Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer

Area of Science:

• Oncology
• Clinical Pharmacology

Background:

• The I-SPY2 trial investigates novel neoadjuvant breast cancer therapies.
• Ganitumab targets the type I insulin-like growth factor receptor (IGF-1R).

Purpose of the Study:

• To evaluate ganitumab in combination with metformin and paclitaxel (PGM) versus standard-of-care for neoadjuvant breast cancer treatment.
• To identify predictive biomarkers for ganitumab response.

Main Methods:

• An adaptively randomized phase 2 clinical trial design.
• Comparison of PGM regimen against standard chemotherapy (paclitaxel, doxorubicin, cyclophosphamide).
• Evaluation of biomarkers including IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, and baseline HbA1c.

Main Results:

• Numerically higher pathologic complete response (pCR) rates in the PGM arm for hormone receptor-negative, HER2-negative breast cancer (32% vs. 21%), but did not meet the threshold for advancement.
• Increased incidence of hyperglycemia and elevated hemoglobin A1c (HbA1c) in the PGM arm, despite metformin use.
• No specific predictive biomarkers for PGM response were identified, though some signatures correlated with pCR in both treatment arms.

Conclusions:

• Further development of anti-IGF-1R therapies requires improved management of drug-induced hyperglycemia.
• Development of more accurate predictive biomarkers is crucial for guiding anti-IGF-1R therapy selection in breast cancer.