Dasatinib, paclitaxel, and carboplatin in women with advanced-stage or recurrent endometrial cancer: A pilot clinical and translational study.

Purpose: To evaluate the effect of dasatinib therapy on EphA2 signaling in cancers of women with measurable (biopsy amenable) advanced-stage, chemo-naïve primary or recurrent endometrial cancer. Preliminary efficacy was also assessed.
Patients and Methods: We performed a pilot study of single-agent dasatinib lead-in, followed by triplet dasatinib, paclitaxel, and carboplatin. We measured the downstream effectors of EphA2 signaling in pre- and post-dasatinib treatment biopsy tissue samples; we also determined the severity of adverse events and patients' progression-free survival and overall survival durations.
Results: Eighteen patients were recruited and given dasatinib (150 mg orally daily for 14 days), followed by paclitaxel, carboplatin and dasatinib (daily) for six cycles (21-day cycles). Seventeen patients were evaluable for toxicity and 11 patients for response. A reverse phase protein array and proximity ligation assay revealed that CRAF/BRAF dimerization, caveolin-1 level, and Notch pathway signaling were predictive of response and resistance to dasatinib. Overall, the objective response rate was 45% (95% CI: 17%-77%), with median progression-free survival duration of 10.5 months and median overall survival duration of 30.4 months. The most common grade 3 or 4 adverse events were neutropenia (76%), thrombocytopenia (53%), anemia (53%), and fatigue (12%).
Conclusions: Caveolin-1 expression, in combination with CRAF/BRAF heterodimerization, is associated with resistance to EphA2 targeting by dasatinib. The triplet combination showed interesting clinical activity in endometrial cancer with acceptable toxicity. Pretreatment with dasatinib may accentuate combination therapy toxicity.
Competing Interests: Declaration of Competing Interest RLC has received grants from AstraZeneca, Roche/Genentech, Merck, Clovis Oncology, Esperance Pharmaceuticals, and AbbVie and serves as an advisor to AstraZeneca, Roche/Genentech, Janssen, OncoMed, Merck, Clovis Oncology, Esperance Pharmaceuticals, Tesaro, GamaMabs Pharma, Pfizer, Genmab, Agenus, Incyte, and AbbVie. AKS is a consultant for Merck and Kiyatec, has received research funding from M-Trap, and owns shares in BioPath. WH has received research funding from Geistlich Pharma AG. YY is a consultant for Amgen, Boehringer Ingelheim, Servier, Vertex, Starpax, and Midas. PTS has received research funding from Novartis and InCyte. SNW is a consultant for AstraZeneca, Clovis Oncology, GSK/Tesaro, Roche/Genentech, Novartis, Merck, Pfizer, Eisai and Circulogene and has received research funding from ArQule, AstraZeneca, Clovis Oncology, GSK/Tesaro, Roche/Genentech, Bayer, Cotinga Pharmaceuticals, Inc., and Novartis. LAM has received research funding from AstraZeneca.
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