mTOR Inhibitor Ridaforolimus Shows Activity in Advanced Endometrial Cancer
The oral mTOR inhibitor ridaforolimus was modestly active and reasonably tolerated in women with recurrent or metastatic endometrial cancer, according to the results of a phase II study reported in Gynecologic Oncology. Tsoref et al suggested that it may prove to be an effective therapeutic strategy and that the potential synergy among mTOR inhibition, angiogenesis, and hormonal pathways warrants ongoing evaluation.
Endometrial cancer is the most common gynecologic malignancy diagnosed in the developed world. Treatment options in the setting of recurrent disease are limited, however, and center primarily on chemotherapy and hormonal therapies. Responses to such treatments are unpredictable and short-lived, and the search for effective targeted alternatives has continued.
Researchers have turned their attention toward the PI3K/AKT (phosphatidylinositol-3 kinase/serine-threonine kinase) pathway, considered to be a central route to the development of cancer cells. Mutations within this pathway have been reported in many endometrial carcinomas, and thus mTOR—the downstream effector protein within this pathway—has become a logical therapeutic target. As a result, several mTOR inhibitors or rapalogs have emerged over recent years, showing consistent single-agent antitumor activity in women with recurrent endometrial cancer.
Study Details
Tsoref and colleagues conducted an open-label, multicenter phase II study to evaluate the efficacy and safety of oral ridaforolimus (an analog of sirolimus and a small molecule inhibitor of mTOR) in 34 women with locally advanced, recurrent, and/or metastatic endometrial carcinoma. Although prior hormonal therapy was permitted, previous chemotherapy was allowed only if administered in the adjuvant setting. In addition, patients who had already received treatment with an mTOR inhibitor were not eligible for inclusion in the study.
Ridaforolimus (40 mg daily) was self-administered by patients for 5 consecutive days, followed by a break of 2 days. A full cycle of treatment was defined as 28 days. An average of three cycles of treatment were given, with a range of 1?24 cycles.
Patient demographics showed a median age of patients of 63 years (range, 43 to 89 years). In regard to histology, 22 patients had endometrioid disease, 5 had serous disease, 4 had adenocarcinoma, and 3 had mixed disease.
Response Rates Unaffected by Prior Exposure to Chemotherapy
Of the 31 patients evaluable for response, 3 (8.8%) had partial responses, with a duration of response ranging from 7.9 to 26.5 months. Of note, all of these partial responders had endometrioid disease, and 2 of them had not received previous therapy. In addition, 18 women (52.9%) had disease stabilization lasting an average of 6.6 months. Nearly 30% of patients experienced disease progression while on treatment.
The investigators noted that response rates did not appear to be affected by prior exposure to chemotherapy. Furthermore, there seemed to be no correlation between response and mutational status, and no predictive molecular markers were identified.
Fatigue, mucositis, anorexia, diarrhea, nausea, taste alteration, and rash were the most common adverse effects reported. Most toxicities were mild, but 13 patients had at least one drug-related grade 3 or higher side effect. Adverse events resulted in dose modifications or omissions in 28 and 29 of the 34 patients, respectively. Five hematologic events (two cases each of sepsis and mucositis) resulted in patients’ removal from the study.
Closing Thoughts
“Given the high level of mTOR inhibition observed with lower doses of ridaforolimus and the relatively high percentage of missed doses secondary to adverse events, consideration to modified dosing schedules may be appropriate,” concluded the investigators. Furthermore, they added, the future role of mTOR inhibitors in endometrial cancer should be evaluated in direct comparison with hormonal therapies, which should offer a clear perspective of the therapeutic index of these targeted agents.
Amit M. Oza, MD, of the Princess Margaret Hospital, University Health Network, University of Toronto, Ontario, Canada, is the corresponding author of the article in Gynecologic Oncology.
This study was supported by funding from the Canadian Cancer Society Research Institute, the Ontario Institute for Cancer Research, and Merck & Co., Inc. The authors disclosed no potential conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
