Randomized Phase II Trial of Ridaforolimus in Advanced Endometrial Carcinoma.

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.

• Authors: Amit M Oza, Sandro Pignata, Andres Poveda, Mary McCormack, Andrew Clamp, Benjamin Schwartz, Jonathan Cheng, Xiaoyun Li, Kristy Campbell, Pierre Dodion, Frank G Haluska
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 33 Issue 31 Pg. 3576-82 (Nov 01 2015) ISSN: 1527-7755 [Electronic] United States
• PMID: 26077241 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by American Society of Clinical Oncology.

Chemical References

• Antibiotics, Antineoplastic
• Progestins
• ridaforolimus
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Anemia (chemically induced)
• Antibiotics, Antineoplastic (administration & dosage, adverse effects)
• Diarrhea (chemically induced)
• Disease-Free Survival
• Endometrial Neoplasms (drug therapy)
• Female
• Humans
• Hyperglycemia (chemically induced)
• Kaplan-Meier Estimate
• Middle Aged
• Progestins (administration & dosage)
• Prognosis
• Proportional Hazards Models
• Sirolimus (administration & dosage, adverse effects, analogs & derivatives)
• TOR Serine-Threonine Kinases (metabolism)
• Treatment Outcome