Dr Zhang on the Rationale of Evaluating SIM0270/Everolimus in ER+/HER2– Advanced Breast Cancer

“After CDK4/6 inhibitors, we have a lot of options, such as mTOR inhibitors, [antibody-drug conjugates], and PARP inhibitors. However, everolimus has an indication in China, but some inhibitors, especially PIK3CA inhibitors, were not approved by our regulation, so we usually use rechallenge CDK4/6 inhibitors or everolimus [after progression in estrogen receptor–positive breast cancer].”

Jian Zhang, MD, of Fudan University Shanghai Cancer Center, details the rationale of evaluating SIM0270 plus everolimus (Afinitor) in patients with estrogen receptor (ER)–positive/HER2-negative advanced breast cancer in a phase 1b study (NCT05293964).

Treatment with endocrine therapy is especially important for patients with ER-positive/HER2-negative breast cancer, and the use of CDK4/6 inhibitors has altered the treatment paradigm for this patient population, Zhang began. He noted that following the use of frontline CDK4/6 inhibitors, other treatment options include mTOR inhibitors, antibody-drug conjugates (ADCs), and PARP inhibitors. However, although everolimus is approved in China, certain treatments, such as some PIK3CA inhibitors, have not yet been approved, he explained. Therefore, rechallenging with CDK4/6 inhibitors or using everolimus are common treatment approaches in the country, he said.

In the phase 1b study, the brain-penetrant oral selective estrogen receptor degrader (SERD) SIM0270 was investigated in combination with everolimus to determine the efficacy of the duo, Zhang continued. In the study, which included heavily pretreated patients with ER-positive/HER2-negative advanced breast cancer, the combination demonstrated a median progression-free survival (PFS) of 8.2 months (95% CI, 4.96-not estimable [NE]). The median PFS was also 8.2 months (95% CI, 3.71-NE) for patients with baseline ESR1 wild-type tumors, and the median PFS was not reached in those with ESR1-mutated tumors. Notably, patients achieved an objective response rate of 16.7% and a clinical benefit rate of 60%, which included complete responses, partial responses, and stable disease lasting at least 24 weeks.

Based on the efficacy shown in the phase 1b study, Zhang concluded that a phase 3 study is evaluating SIM0270 plus everolimus vs exemestane (Aromasin) plus everolimus in patients with ER-positive/HER2-negative advanced breast cancer after prior CDK4/6 inhibition.