Everolimus Plus Adjuvant Endocrine Therapy Fails to Improve iDFS, OS in HR+/HER2- Breast Cancer

The addition of 1 year of everolimus (Afinitor) to adjuvant endocrine therapy did not demonstrate a statistically significant improvement in invasive disease-free survival (iDFS) or overall survival (OS) in patients with high-risk, hormone receptor–positive, HER2-negative breast cancer, according to findings from the phase 3 SWOG S1207 trial (NCT01674140) presented at the 2022 San Antonio Breast Cancer Symposium.

With a median follow-up of 55.2 months among alive patients, neither the primary end point of iDFS (HR, 0.94; 95% CI, 0.77-1.14; P = .52) or secondary end point of OS were met (HR, 0.97; 95% CI, 0.75-1.26; P = .84). However, in an exploratory analysis, premenopausal patients were shown to derive a statistically significant improvement in iDFS (HR, 0.64; 95% CI, 0.44-0.94; P = .02) and OS (HR, 0.49; 95% CI, 0.28-0.86; P = .012). Postmenopausal patients did not experience a benefit in either iDFS (HR, 1.08; 95% CI, 0.86-1.36; P = .52) or OS (HR, 1.19; 95% CI, 0.89-1.60; P = .25).

“Among premenopausal patients, the addition of everolimus to endocrine therapy improved iDFS and OS, which is hypothesis generating. Future translational studies will evaluate potential predictors of everolimus benefit and drug toxicity,” lead study author Mariana Chavez-MacGregor, MD, of the Department of Health Services Research and Division of Cancer Prevention and Population Sciences at The University of Texas MD Anderson Cancer Center in Houston, Texas, said in a presentation of the data.

Dysregulation in the PI3K/AKT/mTOR signaling pathway is associated with endocrine therapy resistance. The addition of the mTOR inhibitor everolimus to endocrine therapy improved progression-free survival vs endocrine therapy alone in patients with metastatic hormone receptor–positive, HER2-negative breast cancer.

In the randomized, placebo-controlled S1207 trial, investigators evaluated the role of everolimus in the adjuvant setting in patients with hormone receptor–positive, HER2-negative breast cancer.

To be eligible for enrollment, patients at least 18 years of age needed to have histologically confirmed, invasive, high-risk hormone receptor–positive, HER2-negative breast cancer and have received prior chemotherapy.

Patients were stratified into 1 of 4 risk groups:

1. Tumor at least 2 cm; node-negative (or pN1mi); and Oncotype DX Recurrence Score (RS) of at least 25 or MammaPrint high-risk category (MP high; n = 158; 9%)
2. Between 1 and 3 positive nodes and either RS above 25, MP high or a pathological grade 3 tumor (n = 213; 12%)
3. At least 4 positive lymph nodes (n = 710; 40%)
4. Neoadjuvant chemotherapy and residual disease with at least 1 lymph node involvement (n = 711; 40%)

Per the study design, patients underwent either surgery or neoadjuvant chemotherapy first. Patients who underwent surgery first (risk groups 1-3) and those who received neoadjuvant chemotherapy first (risk group 4) proceeded to standard adjuvant chemotherapy and radiation afterward.

Following adjuvant chemotherapy and radiation, patients were randomly assigned 1:1 to receive physician’s choice of adjuvant endocrine therapy plus 1 year of everolimus 10 mg orally once daily (n = 971), or endocrine therapy plus placebo for 1 year (n = 968). A total of 896 patients from each arm were included in the analysis.

The primary end point of iDFS had 80% power to detect a hazard ratio (HR) of 0.75 in a sample size of 1900 patients, using a two-sided 5% level stratified log-rank test. The statistical power was changed from 90% in a sample size of 3500 patients to 80% in April 2016 to reflect the actual risk distribution of the enrolled population. No results were used to change the study design.

Secondary end points included OS, safety, and efficacy assessment by risk group.

Regarding baseline characteristics among all enrolled patients, the median age was 54 years (range, 22-86), and most patients were White (n = 1529; 85%) and postmenopausal (n = 1221; 68%). According to the study, menopause was defined as previous history of bilateral oophorectomy or last menstrual period greater than 12 months without any history of hysterectomy, MacGregor said.

Among patients who received everolimus, 48% (n = 428) completed treatment as planned, and 37% (n = 335) discontinued treatment due to an adverse effect (AE). Twenty-one patients (2%) experienced progression or relapse, and one (0.1%) death was reported. In the placebo arm, 73% (n = 651) of patients completed treatment as planned, and 10% (n = 86) stopped treatment due to an AE. A total of 43 patients (5%) had progressed or relapsed, and one death occurred. Refusal to complete treatment for reasons other than toxicity occurred in 9% (n = 84) of patients in both arms.

Additional results showed that the estimated 5-year iDFS rate was 74.9% with everolimus vs 74.4% with placebo. The estimated 5-year OS rates were 88.1% and 85.8%, respectively. “In the forest plot of the iDFS subgroup analysis, we did not observe any differences according to high-risk group category, or according to endocrine therapy received initially according to treatment arm. Similar to the iDFS subgroup analysis, the OS subgroup analysis demonstrated no differences according to treatment arm based on high-risk group category or based on treatment assigned,” MacGregor said.

Within the exploratory analysis by menopausal status, the estimated 5-year iDFS rate in the postmenopausal population was 72.0% with everolimus vs 74.3% with placebo. The estimated 5-year OS rates were 84.6% and 85.7%, respectively. In the premenopausal population, the estimated 5-year iDFS rate was 81.0% with everolimus vs 74.7% with placebo. The estimated 5-year OS rates were 95.7% and 86.0%, respectively.

A Cox regression model indicated that the treatment arm and menopausal status interaction had a hazard ratio of 1.67 for iDFS (95% CI, 1.07-2.60; P = .0241) and 2.41 for OS (95% CI, 1.27-4.57; P = .0072).

Regarding safety, grade 3/4 treatment-related AEs occurred in 35% of patients (n = 303) in the everolimus arm vs 7% (n = 59) in the placebo arm. These AEs included oral mucositis (7% vs 0%), lymphopenia (4% vs 1%), hypertriglyceridemia (4% vs 0%), hyperglycemia (4% vs 0%), fatigue (3% vs 1%), neutropenia (3% vs 0%), leukopenia (2% vs 0%), hypertension (2% vs 1%), diarrhea (1% vs 0%), anemia (1% vs 0%), hypercholesterolemia (1% vs 0%), and skin infection (1% vs 0%).

Reference

Chavez-MacGregor M, Miao J, Pusztai L, et al. Results from a phase III randomized, placebo-controlled clinical trial evaluating adjuvant endocrine therapy +/- 1 year of everolimus in patients with high-risk hormone receptor-positive, HER2-negative breast cancer: SWOG S1207. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2021. San Antonio, TX. Abstract GS1-07.