A phase 1 clinical trial is evaluating SIM0270, a novel oral selective estrogen receptor (ER) degrader, as a potential treatment for patients with ER-positive/HER2-negative advanced breast cancer. The study, an open-label, multicohort trial, is exploring the use of SIM0270 as monotherapy. Previously, results from the phase 1a dose-escalation phase were presented, and now, data from the dose-expansion cohort utilizing the recommended doses are being shared.
The dose-expansion cohort of the trial specifically targeted patients with at least 1 previous endocrine therapy in the advanced setting, with no restrictions on the number of previous endocrine therapies. Previous treatment with fulvestrant or CDK4/6 inhibitors was permitted, and pre/perimenopausal women received ovarian function suppression treatment. Key endpoints of this study included safety, tolerability, and efficacy.
Per the phase 1a results already published, the recommended dose of SIM0270 is 60 mg taken orally once a day. As of October 8, 2024, 51 patients had been enrolled in the dose-expansion cohort, and were treated at this dose. The median age of the participants was 60 years, with most (90.2%) being postmenopausal. A significant proportion of the patients (74.5%) presented with visceral metastases, with the liver (35.3%) and lung (54.9%) being the most frequent sites. Furthermore, 23.5% of patients had an ESR1 mutation detected at baseline, and the patient population was heavily pretreated with a median of 1 prior chemotherapy and endocrine therapy received in the advanced setting.
The observed safety profile aligned with that of the earlier dose-escalation phase of the trial. All patients experienced treatment-emergent adverse events (TEAEs), but most were grade 1 or 2 in severity. The most frequently reported TEAEs included sinus bradycardia (51%), elevated liver enzymes alanine aminotransferase (31%) and aspartate aminotransferase (29%), hypertriglyceridemia (24%), and urinary tract infections (26%). Grade ≥3 TEAEs were reported in 24% of the patients, and grade ≥3 treatment-related adverse events (TRAEs) were reported in 14% of patients. Only 4 patients needed dose interruptions or reductions caused by TRAEs, and no patients stopped treatment because of TRAEs. There were no treatment-related serious adverse events observed.
SIM0270 also demonstrated promising clinical activity. The confirmed overall response rate (ORR) was 8.3% among the 48 patients who could be evaluated for response. The clinical benefit rate (CBR), which includes complete response, partial response, and stable disease, was 40% for patients with ESR1 mutations and 38.2% for patients with wild-type ESR1.
Adding to the positive findings, 17 patients were still on treatment at the time of data cutoff, suggesting that SIM0270 may lead to durable responses in certain individuals. The primary reason for treatment discontinuation was disease progression.
Researchers have concluded that SIM0270 monotherapy shows promise as a treatment for ER-positive/HER2-negative locally advanced or metastatic breast cancer, with particular benefit for patients with ESR1 mutations. The observed ORR and CBR compared favorably with historical controls, especially considering that the patients in this trial had received extensive previous treatments. Notably, SIM0270 demonstrated a manageable safety profile with a low incidence of treatment discontinuation because of adverse events. Further analysis is ongoing to gain a more comprehensive understanding of the efficacy and safety of SIM0270 for this patient population.
Zhang Q, et al. Updated analyses from a phase I study of the brain-penetrant oral SERD- SIM0270 in patients with ER-positive, HER2-negative advanced breast cancer. Presented at: San Antonio Breast Cancer Symposium. December 10, 2024; San Antonio, TX. Abstract SESS-1590.