한빛사논문
- 조회579
David S. Hong1,*, Kathleen N. Moore2, Johanna C. Bendell3, Daniel D. Karp1, Judy S. Wang4, Susanna Ulahannan2, Suzanne Jones5, Wenjuan Wu6, Gregory P. Donoho6, Yan Ding6, Andrew Capen6, Xuejing Wang6, Aimee Bence Lin6, Manish R. Patel4
1The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Sarah Cannon Research Institute, Nashville, TN, USA
3Sarah Cannon Research Institute, Nashville, TN, USA; Tennessee Oncology, Nashville, TN, USA
4Sarah Cannon Research Institute, Nashville, TN, USA; Florida Cancer Specialists and Research Institute, Sarasota, FL, USA
5Sarah Cannon Research Institute, Nashville, TN, USA
6Eli Lilly and Company, Indianapolis, IN, USA
*Corresponding Author
Abstract
Purpose:Prexasertib, a checkpoint kinase-I inhibitor (CHK1), exhibited modest monotherapy antitumor activity in previous studies. Preclinical data were generated to support the clinical combination of prexasertib+samotolisib, a phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor.
Experimental Design: Prexasertib+samotolisib was first evaluated in triple-negative breast cancer (TNBC) cells, MDA-MB-231 orthotopic xenograft tumors, and TNBC patient-derived-xenograft (PDX) mouse models. In the Phase 1b trial, following dose-escalation, the initial expansion arm (E1-solid tumors) explored prexasertib 105-mg/m2 intravenously every 14 days +samotolisib 200-mg orally twice-daily (BID). Subsequent expansion arms evaluated samotolisib 150-mg-BID in patients carrying PIK3CA mutations (E2-solid tumors) or with TNBC (E3). Safety and antitumor activity were assessed.
Results:Prexasertib+samotolisib inhibited proliferation in TNBC lines and primary tumor growth in the MDA-MB-231 model. Prexasertib+samotolisib exhibited synergistic or additive effects in 30/38 PDX single-mouse ("n=1") models, providing rationale for clinical evaluation. In the Phase 1b study, fifty-three patients were enrolled (Escalation:n=13; E1:n=9; E2:n=15; E3:n=16). No dose-limiting toxicities (DLTs) were observed during escalation; however, DLT-equivalent toxicities were observed in E1 leading to samotolisib dose reduction (150-mg-BID) in E2/E3. Common treatment-related adverse events were leukopenia/neutropenia (94.3%), thrombocytopenia (62.3%), and nausea (52.8%). During escalation, 2 patients achieved partial response for an overall response rate (ORR) of 15.4%, and ORRs were 13.3% for E2 (PIK3CA) and 25.0% for E3 (TNBC).
Conclusions:Prexasertib+samotolisib showed antitumor activity in preclinical models and preliminary efficacy in heavily-pretreated patients. The clinical combination was associated with toxicity, suggesting supportive measures may be required. However, these data may inform future trials using other CHK1 and PI3K pathway inhibitors.
논문정보
- Research article
- 2021년 01월 (BRIC 등록일 2021-02-02)
- 국외 연구진
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