Everolimus as second- or third-line treatment of advanced endometrial cancer: ENDORAD, a phase II trial of GINECO

Abstract

Background:Patients with recurrent/metastatic endometrial cancer that progresses after chemotherapy have limited treatment options and poor outcomes. Preclinical data suggest the oral mammalian target of rapamycin inhibitor everolimus may provide clinical benefit in these patients.Methods:In this multicenter, open-label, phase 2 study, patients with advanced or metastatic endometrial cancer refractory to one or two previous chemotherapy regimens received everolimus 10 mg per day until progression or unacceptable toxicity. Primary end point was the non-progressive disease rate at 3 months. Secondary end points included duration of response, progression-free, and overall survival (OS), and safety.Results:Forty-four patients were enrolled (median age, 65 years); 66% received one previous chemotherapy regimen. The 3-month non-progressive disease rate was 36% (95% confidence interval 22–52%), including two patients (5%) with partial response (PR). At 6 months, two additional patients experienced PR. Median duration of response was 3.1 months. Median progression-free and OS were 2.8 months and 8.1 months, respectively. The most common adverse events were anaemia (100%), fatigue (93%), hypercholesterolaemia (81%), and lymphopenia (81%).Conclusion:Everolimus demonstrated efficacy and acceptable tolerability in patients with chemotherapy-refractory advanced or metastatic endometrial cancer. These results support the further development of phosphatidylinositol 3-kinase-targeted therapies in endometrial cancer.

Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma

“…This may be due to the high prevalence of insulin resistance in patients with endometrial cancer [34] as 14 patients (21%) in this trial had history of diabetes and/or hyperglycemia. The ORR observed with pilaralisib (6%) was consistent with Phase II trials with rapalogs in similar patient populations (ORR 0-11%) [16][17][18][19]35]. As single agents, temsirolimus, ridaforolimus, and everolimus have shown limited response rates between 0% and 14% depending upon the number of lines of prior chemotherapy, with more heavily pretreated patients having lower response rates [16][17][18][19].…”

“…PIK3CA mutations and PTEN deficiency have been demonstrated to correlate with poor prognosis in patients with endometrial carcinoma. In Phase II studies, rapamycin analog mTOR inhibitors everolimus, ridaforolimus and temsirolimus have shown evidence of clinical activity in advanced endometrial carcinoma [16][17][18][19]. New generation kinase inhibitors targeting the PI3K pathway are under evaluation in endometrial cancer, including pan-class I PI3K inhibitors such as BKM120, dual PI3K/mTOR inhibitors, such as GDC-0980, and the AKT inhibitor MK-2206 [6,[20][21][22].…”

New Strategies in Endometrial Cancer: Targeting the PI3K/mTOR Pathway—The Devil Is in the Details

“…Objective response rates range from 0%-30% depending upon the clinical population; clinical response rates are higher in populations that have not received prior chemotherapy and response occurs across histologic subtypes including endometroid, high-grade papillary serous, and clear cell cancers. Importantly, there is a subset, albeit small, of patients with complete and/or durable responses (32)(33)(34)(35)(36)(37).…”

Next-Generation Sequencing in Gynaecological Tumours: The Prognostic and Predictive Value of the Most Common Mutations Found in Ovarian, Endometrial, and Cervical Tumours: Literature Review and the University Medical Centre Utrecht Next-Generation Sequencing Data

“…AKT activation can result in activation of the mTOR signalling pathway providing a rationale for treatment with mTOR inhibitors [44]. In early clinical studies benefit is shown from mTOR inhibition, but there are no results from late-phase trials yet [45, 46]. Some endometrium tumours are highly mutated caused by a mutation in POLE [40].…”