The 46th San Antonio Breast Cancer Symposium (SABCS), a prestigious academic event in the field of international breast cancer, was held from December 5th to 9th in San Antonio, Texas, USA. A Phase I clinical study of a new selective estrogen receptor degrader (SERD) led by Professor Jiong Wu and Professor Jian Zhang ‘s team from Fudan University Shanghai Cancer Center was selected for the SABCS Poster Spotlight and was orally presented by Professor Jian Zhang on December 7th, with Professor Wu Jiong answering questions on site. SIM0270, a novel SERD capable of crossing the blood-brain barrier, demonstrated good tolerability and antitumor activity in its first human Phase I clinical trial among patients with advanced or metastatic ER+/HER2- who had failed multiple lines of treatment.
Professor Jiong Wu (second from the left) answers questions at the SABCS conference.
Research Background: Estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) is the most common subtype of breast cancer, primarily treated with endocrine therapy. However, a significant number of patients develop resistance to treatment, leading to relapse, metastasis, and reduced survival. SIM0270, an orally administered selective estrogen receptor degrader (SERD) that can penetrate the blood-brain barrier, has shown to degrade ER and exhibit strong anti-tumor activity in various preclinical models, including intracranial xenografts. This makes it a promising option for offering more effective treatment with better tolerability, specifically targeting brain metastases in breast cancer patients.
Study Design: This ongoing Phase I clinical trial assesses the safety, pharmacokinetics, and preliminary anti-tumor activity of SIM0270, both as a monotherapy and/or in combination with ribociclib or everolimus, in patients with HR+/HER2- advanced or metastatic breast cancer. The Phase Ia part of the study is the dose-escalation phase for SIM0270 monotherapy, using a BOIN design to make dose escalation or de-escalation decisions. This phase observed dose-limiting toxicities (DLTs) across a range of 10mg to 300mg. Based on early data, doses of 60mg and 120mg were selected for dose optimization and expansion to provide a basis for further selecting the recommended Phase 2 dose (RP2D).
Phase I Study Design
Study Results: As of August 28, 2023, a total of 57 female patients received SIM0270 monotherapy at various dosages. The majority of these patients were in advanced stages and had undergone multiple lines of endocrine therapy and chemotherapy. 72% of the patients had visceral metastases, 16% had brain metastases, and 23% had ESR1 mutations detected at baseline.
In terms of safety: Most adverse events (AEs) were Grade 1 to 2, with the most common AE being sinus bradycardia, which was mostly asymptomatic Grade 1 and did not require dose adjustment or special treatment. Dose-limiting toxicity (DLT) events were observed in four patients, and the maximum tolerated dose (MTD) was determined to be 200 mg daily. Overall, the treatment was well tolerated, with only two patients discontinuing treatment due to treatment-related AEs.
Regarding efficacy: Among 50 patients evaluable for efficacy, four confirmed partial responses (PRs) were observed across various doses, including two cases with ESR1 mutations, resulting in an objective response rate (ORR) of 8%. In the 40 patients evaluable for clinical benefit rate (CBR, defined as CR + PR + stable disease ≥ 24 weeks), the CBR was 25%. Notably, among the seven patients with brain metastases, none discontinued treatment due to progression of brain lesions.
Best Tumor Response
Study Conclusions: SIM0270 demonstrated good safety and showed anti-tumor activity at all dosage levels in patients with ER+/HER2- advanced breast cancer who had previously received multiple lines of treatment. Based on preliminary data, 60mg was selected as the recommended Phase 2 dose (RP2D) for further enrollment to confirm its efficacy and safety. The cohorts combining SIM0270 with ribociclib and everolimus are currently enrolling participants. More data is anticipated to be shared in the future.
Professor Jian Zhang
Director of the Phase I Clinical Research Ward and Chief Oncologist at Fudan University Shanghai Cancer Center.
