Jian Zhang, MD, is a professor at Fudan University Shanghai Cancer Center in China. 

Jian Zhang, MD, details the rationale of evaluating SIM0270 plus everolimus in patients with ER-positive/HER2-negative advanced breast cancer. 

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 

 wild-type tumors, and the median PFS was not reached in those with 

-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.

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Jian Zhang, MD, discusses SIM0270, a brain-penetrant oral SERD, in combination with everolimus, in ER-positive, HER2-negative advanced breast cancer.

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“I should point out that in four patients with brain metastases, two of the patients achieved confirmed CR per BM criteria, which I think is very important for this special drug.”

Jian Zhang, MD, Fudan University Shanghai Cancer Center, discusses results from the phase Ib trial (NCT05293964) evaluating SIM0270, a brain-penetrant oral selective estrogen receptor degrader (SERD), in combination with everolimus (Afinitor) in patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer, including those with brain metastases.

The trial enrolled heavily pretreated patients who received SIM0270 60 mg once daily in combination with everolimus 10 mg once daily. Efficacy outcomes assessed included progression-free survival (PFS), response rates, and safety/tolerability.

In the overall population, the combination demonstrated a median PFS of 8.2 months (95% CI, 4.96-not estimable [NE]). For patients with baseline 

wild-type tumors, the median PFS was also 8.2 months (95% CI, 3.71-NE), whereas the PFS was not reached for those with 

-mutated tumors, suggesting enhanced efficacy in this subgroup. The confirmed objective response rate was 16.7%, and the clinical benefit rate, defined as complete response (CR), partial response, or stable disease lasting at least 24 weeks, was 60%. Among four patients with brain metastases, two (50%) achieved confirmed CRs per RANO-BM criteria.

Safety findings were consistent with the profiles of similar agents. Dose-limiting toxicities included grade 3 blood creatinine increase and hypertriglyceridemia, as well as grade 2 interstitial lung disease. Most treatment-emergent adverse effects were grade 1 or 2, with hypertriglyceridemia and hypercholesterolemia being the most common. Sinus bradycardia occurred in 42.5% of patients, and all events were grade 1 or 2. 

Grade 3 or greater treatment-related adverse effects (TRAEs) occurred in 62.5% of patients, most frequently hypertriglyceridemia and hypokalemia. One grade 4 event, hypokalemia, was resolved with potassium supplementation. TRAEs led to dose reductions in 42.5% of patients for everolimus and 12.5% for SIM0270; treatment discontinuations were reported in two patients. 

A phase 3 trial will compare SIM0270 plus everolimus with treatment of physician’s choice in patients with ER-positive, HER2-negative advanced breast cancer previously treated with CDK4/6 inhibitors. These findings aim to clarify the role of SIM0270 in the therapeutic landscape, particularly for subpopulations such as those with brain metastases.

Jian Zhang, MD

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

Dr Zhang on the Efficacy of SIM0270 Plus Everolimus in ER+/HER2− Advanced Breast Cancer