SIM0270 is a new, brain-penetrating, oral selective estrogen receptor (ER) degrader currently being evaluated in the treatment of patients with ER-positive/HER2-negative advanced breast cancer. While monotherapy has been and is currently being explored, another phase 1b clinical trial is investigating the combination of SIM0270 plus everolimus, a mammalian target of the rapamycin inhibitor, in the same patient population. This combination aims to address the limited efficacy of current endocrine therapies and to leverage potential synergistic effects between the 2 drugs.
The study involved 2 phases: dose escalation and dose expansion (cohort B1 and cohort B2 for patients with measurable brain lesions). Inclusion criteria for all phases included patients with ER-positive/ HER2-negative advanced breast cancer who had developed secondary resistance to previous endocrine therapies and who had received ≤2 previous chemotherapy regimens and prior treatment with fulvestrant or CDK4/6 inhibitors in the advanced setting.
The dose-escalation cohort enrolled 8 patients who received 60 mg of SIM0270 orally, once daily combined with 10 mg of everolimus orally, once daily. The primary goal of this phase was to understand dose-limiting toxicities (DLTs). Cohort B1 enrolled 32 additional patients and cohort B2 plans to enroll 10 to 20 patients. The primary goal of cohort B1 included safety and tolerability, preliminary efficacy, and pharmacokinetics. Most patients in the dose-escalation cohort and cohort B1 (77.5%) presented with visceral disease, and 22.5% had detectable circulating tumor DNA ESR1 mutations at baseline. A majority had received previous endocrine therapies in the advanced setting, including 70.0% with aromatase inhibitors, 60.0% with fulvestrant, and 70.0% with CDK4/6 inhibitors. In addition, 27.5% of patients had received chemotherapy in the advanced setting, with 17.5% receiving ≥2 lines.
In the dose-escalation cohort, 2 of 8 patients experienced DLTs: grade 3 blood creatinine increase in 1 patient, and grade 3 hypertriglyceridemia and grade 2 interstitial lung disease in another patient. Based on these findings, further dose escalation was not recommended, and the 60 mg of SIM0270 plus 10 mg of everolimus combination was chosen.
Treatment-emergent adverse events (TEAEs) were observed in 97.6% of patients. The most frequent TEAEs (incidence ≥30%) were hypercholesterolemia (65%), hypertriglyceridemia (67.5%), anemia (55%), increased aspartate aminotransferase (50%), and increased alanine aminotransferase (50%). Grade ≥3 TEAEs occurred in 68.3% of patients, and grade ≥3 treatment-related adverse events occurred in 62.5%. Dose interruptions and reductions because of TEAEs were needed in 65.9% and 34.2% of patients, respectively. Four patients stopped treatment because of TEAEs: 1 each for hypertriglyceridemia, arrhythmia, rash, and interstitial lung disease.
Despite the high incidence of TEAEs, the combination therapy showed promising clinical activity. The confirmed objective response rate was 16.7% in the 36 response-evaluable patients, and the clinical benefit rate (CBR) was 60% in the 35 CBR-evaluable patients. The combination also showed encouraging activity in patients with brain metastases. Four patients with stable brain metastases were enrolled, with 2 achieving a confirmed complete response and 2 experiencing stable disease, based on RANO-BM criteria. Three of these 4 patients continued treatment at the time of data cutoff.
Pharmacokinetic analysis indicated that SIM0270 exposure was not significantly affected by coadministration with everolimus, both after the initial dose and after 15 days of daily dosing. Everolimus exposure was consistent with data reported for everolimus monotherapy.
The authors concluded that the SIM0270-plus-everolimus combination exhibited acceptable safety and tolerability. The combination also demonstrated promising clinical activity in patients with ER-positive/HER2-negative advanced breast cancer.
Zhang J, et al. SIM0270, a brain-penetrant oral SERD, in combination with everolimus in patients with ER+/HER2- advanced breast cancer: the phase 1b study. Presented at: San Antonio Breast Cancer Symposium. December 10, 2024; San Antonio, TX. Abstract SESS-1214.