Purpose: The PI3K pathway is dysregulated in the majority of triple-negative breast cancer(TNBCs), yet single agent inhibition of PI3K has been ineffective in TNBC. PI3K inhibition leads to an immediate compensatory up-regulation of the Wnt pathway. Dual targeting of both pathways is highly synergistic against TNBC models in vitro and in vivo. We initiated a Phase I clinical trial combining gedatolisib, a pan-class I isoform PI3K/mTOR inhibitor, and cofetuzumab pelidotin, an antibody-drug conjugate against the cell-surface PTK7 protein (Wnt pathway co-receptor) with an auristatin payload. Experimental Design: Participants(pts) had metastatic TNBC or ER low (ER and PgR<5%, HER2-negative) breast cancer, and had received at least one prior chemotherapy for advanced disease. The primary objective was safety. Secondary endpoints included objective response(ORR), clinical benefit at 18 weeks(CB18), progression-free survival(PFS), and correlative analyses. Results: 18 pts were enrolled in 3 dose cohorts: gedatolisib 110 mg weekly + cofetuzumab pelidotin 1.4mg/kg every 3 weeks (n=4), 180mg + 1.4mg/kg (n=3), and 180mg + 2.8mg/kg (n=11). Nausea, anorexia, fatigue, and mucositis were common but rarely reached {greater than or equal to} Grade 3 severity. Myelosuppression was uncommon. ORR was 16.7% (3/18). An additional 3 pts had stable disease, of these 2 had stable disease for >18 weeks; CB18 was 27.8%. Median PFS was 2.0 months (95%CI for PFS:1.2-6.2). Pts with clinical benefit were enriched with genomic alterations in the PI3K and PTK7 pathways. Conclusions: The combination of gedatolisib + cofetuzumab pelidotin was well tolerated and demonstrated promising clinical activity. Further investigation of this drug combination in metastatic TNBC is warranted.

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