Abstract PS10-26: An initial safety study of gedatolisib plus cofetuzumab pelidotin for metastatic triple-negative breast cancer
Authors: Radovich Milan , Solzak Jeffrey P. , Hancock Bradley A. , Badve Sunil , Storniolo Anna Maria V. , Ballinger Tarah J. , Schneider Bryan P. , Miller Kathy D. 
Published: February 2021

Abstract
Background: The PI3K pathway is dysregulated in the majority of triple-negative breast cancer (TNBCs), yet single agent inhibition of PI3K in TNBC has minimal clinical activity. We previously reported that 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 of 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. PTK7 is up-regulated after PI3K inhibition and auristatin is in itself synergistic with gedatolisib providing the potential for a dual mechanism of synergy.
Methods: Dose escalation proceeded using a traditional 3+3 schema with a small expansion cohort at the final dose level to better characterize safety. Participants had metastatic TNBC or ER low (ER and PgR &lt;5%, HER2 negative) breast cancer, and had received at least one prior line of chemotherapy. The primary objective was safety. Secondary endpoints included objective response (ORR), clinical benefit at 18 weeks (CB18), and progression-free survival (PFS). Exploratory analyses probed the association of tumor DNA, RNA, and IHC with clinical efficacy to identify putative biomarkers.
Results: Between January 2018 and January 2020, 18 patients were enrolled in 3 dose cohorts: gedatolisib (qw) & cofetuzumab pelidotin (q3w) 110mg+1.4mg/kg (n=4), 180mg+1.4mg/kg (n=3), and 180mg+2.8mg/kg dose levels (n=11). The median age was 53 years (32-77). Nausea (n=16), anorexia (n=13), fatigue (n=12), and mucositis (n=12) were common but rarely reached &gt;Grade 3 severity (nausea, n=1; fatigue, n=2). Myelosuppression was uncommon (Grade &gt;3 neutropenia, n=2). 16 participants were evaluable for response. 3 achieved a confirmed partial response (PR), and 3 had stable disease (SD). ORR=18.8%. All 3 PRs lasted &gt; 6 months. CB18=31.3%. Median PFS was 2.0 months (95% CI for PFS:1.2-6.2); median OS was 9.5 months (95% CI for OS:4.3-not reached). Correlative analyses of genomic, transcriptomic, and protein biomarkers with response are currently ongoing.
Conclusions: The combination of gedatolisib + cofetuzumab pelidotin for the treatment of metastatic TNBC was found to be well tolerated and demonstrated promising clinical activity. Further investigation of this drug combination in metastatic TNBC is warranted.
Trial Registration: NCT03243331
Citation Format: Milan Radovich, Jeffrey P. Solzak, Bradley A. Hancock, Sunil Badve, Anna Maria V. Storniolo, Tarah J. Ballinger, Bryan P. Schneider, Kathy D. Miller. An initial safety study of gedatolisib plus cofetuzumab pelidotin for metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-26.