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Adding everolimus to carboplatin was associated with significantly increased progression-free survival (PFS) among patients with advanced triple-negative breast cancer (TNBC), according to a recent phase 2 study.

The everolimus combination also had a manageable safety profile, according to lead author Rima Patel, MD, of Icahn School of Medicine at Mount Sinai, New York City, and colleagues.

“In the metastatic setting, patients who are ineligible for immunotherapy are treated with sequential cytotoxic chemotherapy agents as well as antibody-drug conjugates if indicated,” the investigators wrote in Breast Cancer Research and Treatment on August 16. “Unfortunately, response rates to single-agent chemotherapy are low.”

They noted that early-phase clinical studies combining everolimus and carboplatin have demonstrated manageable safety and signals of efficacy, leading to the present study. The new study was classified as phase 2 rather than 3 because of its small sample size and hypothesis-generating intent. Although randomized with a control arm, it wasn’t powered to provide definitive practice-changing evidence like a phase 3 trial.

Methods and Results

The new trial enrolled patients with metastatic TNBC across three sites, allowing up to three prior lines of systemic therapy. Patients were randomized 2:1 to receive either carboplatin plus everolimus or carboplatin alone, with stratification by estrogen receptor status and study site.

Carboplatin was administered every 3 weeks at a dose calculated by the Calvert formula to achieve a target drug exposure of 4 mg/min/mL, and everolimus was given orally at 5 mg once daily. Imaging was performed every 9 weeks, and treatment continued until progression, unacceptable toxicity, withdrawal, or death.

The primary endpoint was PFS, with secondary endpoints including overall survival, overall and clinical benefit response rates, duration of response, and safety. Additional exploratory analyses sought biomarkers of response, focusing on PI3K-AKT-mTOR pathway alterations.

A total of 59 patients were randomized between 2015 and 2022, with 38 assigned to carboplatin plus everolimus and 21 to carboplatin alone. Median age was 62 years, and two thirds had received at least one prior line of therapy.

The combination significantly prolonged median PFS compared with carboplatin alone (4.7 vs 4.2 months; hazard ratio, 0.48; P = .036), representing a 52% reduction in risk for progression or death. Sensitivity analyses supported this finding.

Overall survival was numerically longer with the combination than with carboplatin alone (17.6 vs 14.6 months) but not statistically significant. Objective responses were more frequent with carboplatin and everolimus (24% vs 10%), as was clinical benefit (63% vs 52%), although these differences did not reach statistical significance, either.

Of note, one patient receiving the combination remained progression free for more than 4 years. Exploratory biomarker analyses did not show clear differences in PFS by PI3K-AKT-mTOR pathway mutation status.

Higher Toxicities Seen in Combination Arm

Adverse events were consistent with the known profiles of both drugs.

Hematologic toxicities were notably higher in the combination arm, including thrombocytopenia (84% vs 33%), anemia (76% vs 43%), leukopenia (66% vs 38%), and neutropenia (63% vs 33%). Most of these were grade 1-2, though grade 3 or higher cytopenias were more frequent with the combination.

Nonhematologic events were also more common with combination therapy, including nausea (61% vs 48%), fatigue (50% vs 38%), hyperglycemia (40% vs 29%), hypoalbuminemia (37% vs 19%), edema (37% vs 5%), and hypocalcemia (34% vs 5%).

Serious treatment-related adverse events occurred in 13% of patients in the combination arm vs 10% of patients in the carboplatin arm, while discontinuations due to toxicity occurred in 18% vs 5%. Two treatment-related deaths occurred in the experimental arm (pneumonitis and leukemia). While two deaths also occurred in the carboplatin arm, neither was deemed treatment-related.

Findings Won’t Change Clinical Practice

“While I don’t think the data are strong enough to change clinical practice, I do think there is an interesting signal seen in this study and that further study may be warranted,” principal investigator Amy Tiersten, MD, of Mount Sinai, told Medscape Medical News.

Oncologists not involved in the study agreed that the results were not practice changing.

The findings were “not very clinically meaningful,” Lisa A. Carey, MD, an oncologist at The University of North Carolina at Chapel Hill, told Medscape Medical News.

The sample size was small, and the PFS improvement was modest, “but at least [the regimen has] a nonchemotherapy element,” she said.

This trial was supported by US National Institutes of Health, and Novartis provided everolimus. Carey reported no relevant conflicts of interest.