Initial Phase I Safety Study of Gedatolisib plus Cofetuzumab Pelidotin for Patients with Metastatic Triple-Negative Breast Cancer

Abstract

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.

Metabolic Interventions in Tumor Immunity: Focus on Dual Pathway Inhibitors

“…Moreover, gedatolisib can enhance radio and chemosensitivity by inhibiting the PI3K/AKT/mTOR pathways to decrease DNA damage repair mechanisms [ 106 ]. Recently, an investigation reported that combining PKI-587 with Cofetuzumab Pelidotin, a protein tyrosine kinase 7 (PTK7)-targeted, auristatin-based antibody-drug conjugate in patients with metastatic triple-negative breast cancer (TNBC) was associated with promising clinical activity, two months median PFS, and moderate toxicity (anorexia nausea, mucositis, and fatigue) [ 107 ]. PKI-587 can increase radiosensitization.…”

The mechanisms of class 1A PI3K and Wnt/β-catenin coupled signaling in breast cancer

“…Cofetuzumab pelidotin (PTK7 inhibitor) enhanced anti-tumor effects of gedatolisib in phase I trials of individuals with ER − breast cancer [ 113 ].…”

“…Similar effects have been observed in other cancers such as pancreatic cancer, where combined ETC-159 (PORCN inhibitor) and pictilisib treatment synergistically reduced pancreatic cancer cell proliferation and xenograft tumor growth [ 112 ]. Recently, phase I clinical trials were conducted in individuals with metastatic ER − breast cancer using the dual PI3Kα/γ and mTOR inhibitor, gedatolisib, in combination with cofetuzumab pelidotin, an antibody–drug conjugate with an auristatin payload targeting the Wnt co-receptor, protein tyrosine kinase 7 (PTK7) [ 113 ]. This PI3K/Wnt combination therapy had manageable toxicity, and some individuals exhibited a partial clinical response with disease stabilization [ 113 ].…”

“…Recently, phase I clinical trials were conducted in individuals with metastatic ER − breast cancer using the dual PI3Kα/γ and mTOR inhibitor, gedatolisib, in combination with cofetuzumab pelidotin, an antibody–drug conjugate with an auristatin payload targeting the Wnt co-receptor, protein tyrosine kinase 7 (PTK7) [ 113 ]. This PI3K/Wnt combination therapy had manageable toxicity, and some individuals exhibited a partial clinical response with disease stabilization [ 113 ]. However, further trials are required to assess whether PI3K/Wnt combination therapies can improve ER − breast cancer outcomes.…”

Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy

“…PIK3CA mutations caused by activation of the WNT/β-catenin signaling pathway may decrease colorectal cancer cell sensitivity to the dual PI3K/mTOR inhibitor PKI-587 [ 176 ]. PKI-587 plus cofetuzumab pelidotin in metastatic triple-negative breast cancer (TNBC) showed moderate toxicity and promising clinical activity [ 177 ]. PKI-587 combined with carboplatin and paclitaxel in clear cell ovarian cancer exhibited similar trends [ 178 ].…”