Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: A gynecologic oncology group study

Abstract

Background Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy. Methods We performed a randomized phase II trial of intravenous temsirolimus 25 mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20 mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma. Results There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT)and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded. Conclusions Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy. These findings will have implications for future trial design.

Chemotherapy for Endometrial Cancer in Adjuvant and Advanced Disease Settings

“…A trial testing the combination of temsirolimus with megestrol acetate and tamoxifen closed early because of an excess number of venous thromboses, with a 12.5% rate of deep vein thrombosis, pulmonary embolism, or stroke, compared with the 5% reported rate of venous thrombosis with megestrol acetate alone [84]. However, a subsequent study of the combination of everolimus and letrozole was more promising, with an overall response rate of 32%.…”

Emerging strategies for targeting PI3K in gynecologic cancer

“…In the clinic, response rates with monotherapy are modest, ranging from 4-25%, with the higher response rates often, but not consistently, occurring in patients who had not been heavily pretreated with chemotherapy [73][74][75][76][77][78]. A recent open label, multi-center, phase II trial comparing treatment with ridaforolimus to a progestin or investigator choice chemotherapy found higher stable disease rates in the ridaforolimus group (35% vs. 17%) and longer PFS (3.6 months vs. 1.9 months) with an overall safety profile consistent with prior studies [79].…”

Norethindrone substituted for megestrol in the treatment of metastatic endometrial carcinoma: Three cases.

“…No agent proved to be superior over the others. Subsequent phase 2 studies for this population attempted to improve on megestrol by adding tamoxifen (Fiorica et al, 2004) and subsequently tamoxifen and temsirolimus (Fleming et al, 2014). Reported outcomes for combinations were similar to those obtained with megestrol alone.…”