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Ridaforolimus improves PFS, yet increases toxicity in advanced endometrial cancer
Oral ridaforolimus appeared active in patients with advanced endometrial cancer, according to the results of a phase 2 study.
However, ridaforolimus (AP23573, Ariad Pharmaceuticals) also increased the rate for toxicity compared with progestin or investigator choice chemotherapy, results showed.
Endometrial carcinomas are the most common gynecologic malignancy, and women with recurrent or metastatic endometrial cancer face unfavorable prognoses. Inhibitors of the mTOR pathway — such as ridaforolimus — have shown promising clinical activity in this setting and other solid tumors, according to study background.
Amit M. Oza, MD, FRCP, professor of medicine at the University of Toronto and senior staff physician at Princess Margaret Hospital, and colleagues conducted an open label, randomized phase 2 study to examine the safety and efficacy of oral ridaforolimus compared with progestin or investigator choice chemotherapy.
The analysis included data from 130 women (median age, 66 years; range, 37-81) with metastatic or recurrent endometrial cancer. All women experienced progressive disease after one to two prior lines of chemotherapy and underwent no hormonal therapy.
The researchers randomly assigned patients to the experimental (n = 64) or comparator arm (n = 66). Patients in the experimental arm received 40 mg of ridaforolimus daily for 5 consecutive days per week and patients in the comparator arm received daily progestin (200 mg oral medroxyprogesterone or 160 mg oral megestrol) or investigator-chosen chemotherapy.
Researchers expected all patients would receive two or more treatment cycles, with each cycle lasting 4 weeks.
PFS observed by independent radiologic review (IRR) served as the primary endpoint. Secondary endpoints included OS, PFS at 16 and 24 weeks, best response rate and ridaforolimus safety and tolerability.
Patients treated with oral ridaforolimus achieved a median PFS of 3.6 months, compared with 1.9 months in the comparator arm (HR = 0.53; 95% CI, 0.31-0.9). More patients assigned ridaforolimus achieved PFS at 16 weeks (48% vs. 18%) and 24 weeks (38% vs. 15%).
Two patients in the comparator arm and no patients in the ridaforolimus arm had an objective response, according to the IRR analysis. However, more patients in the ridaforolimus arm achieved stable disease (35% vs. 17%; P = .021).
Ninety-three deaths occurred in the intent-to-treat population, with similar median OS rates observed in both arms (10 months vs. 9.6 months). When researchers excluded patients treated with chemotherapy, the median OS in the comparator arm fell to 9 months.
Seventy-one percent of patients in the comparator arm discontinued treatment due to disease progression, compared with 38% of patients in the ridaforolimus arm.
Significantly more patients in the ridaforolimus arm discontinued therapy due to adverse events (33% vs. 6%).
Commonly reported grade 3 treatment-emergent adverse events among patients treated with ridaforolimus included diarrhea (48%), mucosal inflammation (41%), anorexia (37%), nausea (29%) and hypoglycemia (29%). The most common adverse events in the comparator arm included nausea (22%), fatigue (19%) and vomiting (17%).
More patients in the ridaforolimus arm experienced a serious adverse event (57% vs. 34%).
Serious adverse events associated with ridaforolimus included diarrhea (8%), vomiting (6%), hypoglycemia (6%) and pleural effusion (6%).
Although the researchers observed no treatment-related deaths, 12 non–treatment-related deaths occurred during the trial, most of which were due to neoplasm malignancy.
“A doubling of median PFS in the face of discontinuation rates for adverse events at 33% suggests that a better-tolerated dose and schedule have the prospect of making a substantial impact in patients with endometrial cancer," Oza and colleagues concluded. “Further research should build on this finding and use ridaforolimus alone or in combination with other approaches to improve outcome for these patients.” – by Cameron Kelsall
Disclosure: Oza reports research funding and travel expenses from AstraZeneca, ImmunoGen, Immunovaccine and Roche and consulting roles with Amgen, Clovis Oncology and Verastem. Please see the full study for a list of all other researchers’ relevant financial disclosures.