Addition of Everolimus to Endocrine Therapy Did Not Improve Survival, Increased Toxicity Among Patients With High-Risk HR-Positive Early-Stage Breast Cancer

According to results from the phase 3 SWOG S127 study, the addition of everolimus, a mTOR inhibitor, to endocrine therapy did not improve survival outcomes among patients with high-risk, hormone receptor (HR)-positive, early-stage breast cancer. 

“Despite modern chemotherapy combinations and extended adjuvant [endocrine therapy], many patients have a substantial risk of recurrence,” stated Mariana Chavez-MacGregor, MD, MD Anderson Cancer Center, Houston, Texas, and coauthors. Prior study results “suggest that everolimus can increase the efficacy of [endocrine therapy]” in these patients. 

In this placebo-controlled trial, researchers randomized 1792 pre- and post-menopausal patients with histologically confirmed estrogen receptor (ER)- and/or progesterone receptor (PR)-positive and human epidermal growth factor receptor 2 (HER2)-negative invasive breast cancer to receive physician’s choice endocrine therapy plus either 10 mg of everolimus (n = 896) or placebo (n = 896) once daily for 52 weeks. Patients were required to have completed at least 4 cycles of taxane 1 cyclophosphamide or taxane 1 anthracycline chemotherapy within 42 weeks of trial enrollment. Patients with prior exposure to mTOR inhibitors were excluded. The primary end point was invasive disease-free survival (iDFS). Secondary end points included overall survival (OS) and safety. 

At a median follow-up of 55 months, study treatment was completed by 48% of patients in the everolimus arm and 73% in the placebo arm. Median treatment duration was 341 days and 377 days, respectively. Patients experienced 193 iDFS events in the everolimus arm and 211 iDFS events in the placebo arm (hazard ratio [HR] 0.94; 95% confidence interval [CI] 0.77 to 1.14; P = .52). The 5-year iDFS rate was 74.9% in the everolimus arm and 74.4% in the placebo arm. The 5-year OS rate was 88.1% in the everolimus arm and 85.8% in the placebo arm (HR 0.97; 95% confidence interval, 0.75 to 1.26; P = .84). Grade ≥3 adverse events occurred in 35% of patients in the everolimus arm and 7% of patients in the placebo arm. The most common events included stomatitis, lymphopenia, hypertriglyceridemia, hyperglycemia, fatigue, and neutropenia.

“Everolimus use resulted in high rates of AEs and lower treatment completion rates,” concluded Dr Chavez-MacGregor et al. “There continues to be a need to identify effective agents with a tolerable toxicity profile that can improve outcomes in patients with high-risk [HR]–positive [breast cancer].” 

“The experience of toxicity and willingness to accept toxicity differs in the metastatic and adjuvant settings,” added Journal of Clinical Oncology Senior Deputy Editor Kathy Miller, MD, Indiana University, Bloomington, Indiana. “We need to pay greater and earlier attention to the feasibility of incorporating new agents into the adjuvant setting.” 

Source: 

Chavez-MacGregor M, Miao J, Pusztai L, et al. Phase III randomized, placebo-controlled trial of endocrine therapy ± 1 year of everolimus in patients with high-risk, hormone receptor–positive, early-stage breast cancer. J Clin Oncol. Published online: June 4, 2024. doi:10.1200/JCO.23.02344