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Everolimus plus letrozole effective in recurrent endometrial carcinoma
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The combination of everolimus and letrozole yielded high rates of objective response and clinical benefit in patients with recurrent endometrial carcinoma, according to results of a phase 2 study.
In prior studies, hormonal therapy and single-agent treatment with mTOR inhibitors such as everolimus (Afinitor, Novartis) have demonstrated effectiveness in women with metastatic or recurrent endometrial carcinoma.
Robert L. Coleman
Robert L. Coleman, MD, professor, vice chair of clinical research and Ann Rife Cox chair in gynecology at The University of Texas MD Anderson Cancer Center, and colleagues hypothesized that combining an inhibitor with hormonal therapy could be synergistic and improve response.
“Given the limited therapeutic option for patients with recurrent endometrial cancer, and our increasing understanding of the molecular characteristics of this disease, we have been increasingly interested in the development of more focused and targeted approaches to care,” Coleman told HemOnc Today. “In this manner, and in response to the frequent alterations seen in the PI3K/Akt/mTOR pathway, we have been systematically investigating agents that directly and indirectly interact with pathway signaling.”
Coleman and colleagues designed and conducted a phase 2, open-label trial at MD Anderson Cancer Center and Morristown Medical Center in New Jersey.
The primary endpoint was to determine the efficacy of the everolimus/letrozole combination in patients with recurrent or progressive endometrial carcinoma. Additionally, the investigators evaluated toxicity, duration of disease control, time to disease progression and survival.
The study included 38 patients (median age, 62 years; range, 24-82) with progressive or recurrent endometrial carcinoma who had received no more than two prior chemotherapeutic regimens. All patients had a Zubrod performance score of 0 to 2 and had no history of an invasive malignancy other than endometrial carcinoma within 5 years of study entry.
All patients initially received 10 mg everolimus and 2.5 mg letrozole daily. Both drugs were administered orally, and treatment continued on an outpatient basis until disease progression, dose-limiting toxicities or confirmed complete response.
Thirty-five patients were evaluable for response; of these patients, 94% received prior chemotherapy and 43% received prior radiotherapy.
Twenty-six patients had died by the time of analysis. Median follow-up for all patients was 14 months (range, 1.4-46.8), and median follow-up for the nine patients still alive at last contact was 40.8 months (range, 28.7-46.8).
Eleven patients (32%; 95% CI, 17-49) demonstrated a confirmed objective response. They included nine who demonstrated a complete response and two who demonstrated a partial response.
The responders underwent a median 15 treatment cycles (range, 8-29).
Seven patients (20%) were taken off of therapy by their clinician after a lengthy complete response.
Median PFS was 3 months (95% CI, 1.9-15.7) and median OS was 14 months (95% CI, 9.5-24.4). Researchers reported 6-month OS of 71.4% (95% CI, 57.9-88.1) and 12-month OS of 54.3% (95% CI, 40.1-73.6).
Thirty-one patients experienced progressive disease; five of these patients were alive at last contact. Researchers reported a 6-month PFS rate of 42% (95% CI, 29.2-62.8) and a 12-month PFS rate of 37.1% (95% CI, 24.1-57.2).
All 38 patients enrolled on the study were evaluable for the safety analysis. Twelve (31.5%) required a dose reduction of everolimus to 5 mg daily due to adverse events, which included stomatitis, hyperglycemia, thrombocytopenia, elevated liver function tests, infection and nausea.
Most adverse events were either grade 1 or grade 2, and they were easily managed, according to researchers.
“The two drugs had a favorable toxicity profile,” Coleman said. “Each would help the other work better and make the tumors more responsive. The nice thing about this treatment was that it wasn’t a combination of conventional chemotherapies that would poison all cells. We wanted a targeted therapy, and we believed that the combination would improve the outcome of either drug alone.”
Researchers plan to conduct a randomized trial to compare this regimen with an alternating sequence of megestrol acetate and tamoxifen, shown in the Gynecologic Oncology Group 153 trial to induce durable responses in patients with advanced endometrial cancers. – by Anthony SanFilippo
For more information:
Robert L. Coleman, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Drive, Unit Number 1362, Houston, TX 77030; email: rcoleman@mdanderson.org
Disclosure: The study was supported in part by a grant from Novartis. The researchers report consultant/advisory roles with, research funding from and other relationships with Amgen, Astellas, AstraZeneca/MedImmune, Genentech/Roche, Johnson & Johnson, Merck, Novartis, Sanofi and other pharmaceutical companies.
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