Amit M Oza1, Sandro Pignata2, Andres Poveda2, Mary McCormack2, Andrew Clamp2, Benjamin Schwartz2, Jonathan Cheng2, Xiaoyun Li2, Kristy Campbell2, Pierre Dodion2, Frank G Haluska2. 1. Amit M. Oza, Princess Margaret Cancer Centre, Toronto, ON, Canada; Sandro Pignata, Istituto Nazionale Tumori "Fondazione G Pascale"-Istituto Di Ricovero e Cura a Carattere Scientifico, Naples, Italy; Andres Poveda, Instituto Valenciano de Oncologia, Valencia, Spain; Mary McCormack, University College Hospital, London; Andrew Clamp, Institute of Cancer Sciences-University of Manchester and the Christie National Health Service Foundation Trust, Manchester, United Kingdom; Benjamin Schwartz, Island Gynecologic Oncology, Brightwaters, NY; Jonathan Cheng, Xiaoyun Li, and Kristy Campbell, Merck, Kenilworth, NJ; and Pierre Dodion and Frank G. Haluska, ARIAD Pharmaceuticals, Cambridge, MA. amit.oza@uhn.ca. 2. Amit M. Oza, Princess Margaret Cancer Centre, Toronto, ON, Canada; Sandro Pignata, Istituto Nazionale Tumori "Fondazione G Pascale"-Istituto Di Ricovero e Cura a Carattere Scientifico, Naples, Italy; Andres Poveda, Instituto Valenciano de Oncologia, Valencia, Spain; Mary McCormack, University College Hospital, London; Andrew Clamp, Institute of Cancer Sciences-University of Manchester and the Christie National Health Service Foundation Trust, Manchester, United Kingdom; Benjamin Schwartz, Island Gynecologic Oncology, Brightwaters, NY; Jonathan Cheng, Xiaoyun Li, and Kristy Campbell, Merck, Kenilworth, NJ; and Pierre Dodion and Frank G. Haluska, ARIAD Pharmaceuticals, Cambridge, MA.
Abstract
PURPOSE: The prognosis for women with recurrent and metastatic endometrial cancer is poor, and improved therapies are needed. The mammalian target of rapamycin (mTOR) pathway is an important target, and mTOR inhibitors show clinical activity in endometrial cancer. PATIENTS AND METHODS: An open-label, multicenter, randomized, phase II trial of oral ridaforolimus compared with progestin or investigator choice chemotherapy (comparator) was undertaken in women with metastatic or recurrent endometrial cancer who had progressive disease following one or two lines of chemotherapy and no hormonal therapy. The primary end point was progression-free survival (PFS) assessed by independent radiologic review. RESULTS:One hundred thirty patients were enrolled (64 received ridaforolimus and 66 received the comparator), and median age was 66 years. Treatment discontinuation as a result of adverse events was 33% with ridaforolimus versus 6% with the comparator, with common (> 10%) grade 3 toxicities being hyperglycemia, anemia, and diarrhea. Thirty-eight percent (ridaforolimus) versus 71% (comparator) of patients discontinued treatment as a result of disease progression. Median PFS at the protocol prespecified interim analysis with 58 PFS events (primary end point) was 3.6 months (95% CI, 2.7 to 7.3 months) for ridaforolimus and 1.9 months (95% CI, 1.9 to 2.3 months) for the comparator (hazard ratio, 0.53; 95% CI, 0.31 to 0.90; P = .008). PFS rate for ridaforolimus versus comparator was 48% versus 18% at 16 weeks and 38% versus 15% at 24 weeks. Objective response rate for ridaforolimus versus comparator was 0% versus 4% (P = .925), and stable disease was achieved in 35% versus 17% of patients (P = .021). CONCLUSION:Oral ridaforolimus shows encouraging activity in advanced endometrial cancer but is associated with significant toxicity. Inhibition of the PI3K/Akt/mTOR pathway may be a viable therapeutic target.
RCT Entities:
PURPOSE: The prognosis for women with recurrent and metastatic endometrial cancer is poor, and improved therapies are needed. The mammalian target of rapamycin (mTOR) pathway is an important target, and mTOR inhibitors show clinical activity in endometrial cancer. PATIENTS AND METHODS: An open-label, multicenter, randomized, phase II trial of oral ridaforolimus compared with progestin or investigator choice chemotherapy (comparator) was undertaken in women with metastatic or recurrent endometrial cancer who had progressive disease following one or two lines of chemotherapy and no hormonal therapy. The primary end point was progression-free survival (PFS) assessed by independent radiologic review. RESULTS: One hundred thirty patients were enrolled (64 received ridaforolimus and 66 received the comparator), and median age was 66 years. Treatment discontinuation as a result of adverse events was 33% with ridaforolimus versus 6% with the comparator, with common (> 10%) grade 3 toxicities being hyperglycemia, anemia, and diarrhea. Thirty-eight percent (ridaforolimus) versus 71% (comparator) of patients discontinued treatment as a result of disease progression. Median PFS at the protocol prespecified interim analysis with 58 PFS events (primary end point) was 3.6 months (95% CI, 2.7 to 7.3 months) for ridaforolimus and 1.9 months (95% CI, 1.9 to 2.3 months) for the comparator (hazard ratio, 0.53; 95% CI, 0.31 to 0.90; P = .008). PFS rate for ridaforolimus versus comparator was 48% versus 18% at 16 weeks and 38% versus 15% at 24 weeks. Objective response rate for ridaforolimus versus comparator was 0% versus 4% (P = .925), and stable disease was achieved in 35% versus 17% of patients (P = .021). CONCLUSION: Oral ridaforolimus shows encouraging activity in advanced endometrial cancer but is associated with significant toxicity. Inhibition of the PI3K/Akt/mTOR pathway may be a viable therapeutic target.
Authors: Andrea P Myers; Virginia L Filiaci; Yuping Zhang; Michael Pearl; Kian Behbakht; Vicky Makker; Parviz Hanjani; Susan Zweizig; James J Burke; Gordon Downey; Kimberly K Leslie; Paul Van Hummelen; Michael J Birrer; Gini F Fleming Journal: Gynecol Oncol Date: 2016-04 Impact factor: 5.482
Authors: Andrea P Myers; Panagiotis A Konstantinopoulos; William T Barry; Weixiu Luo; Russell R Broaddus; Vicky Makker; Ronny Drapkin; Joyce Liu; Austin Doyle; Neil S Horowitz; Funda Meric-Bernstam; Michael Birrer; Carol Aghajanian; Robert L Coleman; Gordon B Mills; Lewis C Cantley; Ursula A Matulonis; Shannon N Westin Journal: Int J Cancer Date: 2019-12-13 Impact factor: 7.396
Authors: Shannon N Westin; Michael W Sill; Robert L Coleman; Steven Waggoner; Kathleen N Moore; Cara A Mathews; Lainie P Martin; Susan C Modesitt; Sanghoon Lee; Zhenlin Ju; Gordon B Mills; Russell J Schilder; Paula M Fracasso; Michael J Birrer; Carol Aghajanian Journal: Gynecol Oncol Date: 2019-10-15 Impact factor: 5.482