Preclinical evaluation and Phase 1b study of prexasertib, a CHK1 inhibitor, and samotolisib (LY3023414), a dual PI3K/mTOR inhibitor.

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.