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

“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 ESR1 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 ESR1-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.