Editor’s Note: At the recent San Antonio Breast Cancer Symposium (SABCS), Professor Jiong Wu from Fudan University Shanghai Cancer Center presented the latest findings from a Phase I study on SIM0270 (Abstract Number: PS14-03). SIM0270, an innovative brain-penetrant oral selective estrogen receptor degrader (SERD), demonstrated significant clinical efficacy and excellent tolerability in patients with ER+/HER2- advanced breast cancer. Oncology Frontier invited the study’s leading investigator, Dr. Qingyuan Zhang from Harbin Medical University Cancer Hospital, to provide an in-depth interpretation of the results and share insights on future research directions.

Oncology Frontier: Could you please summarize the key findings and content of the Phase I study on SIM0270 that you reported at this year’s SABCS?

Dr. Qingyuan Zhang:This research is a multicenter, open-label Phase I clinical trial. At the 2023 SABCS, we shared data from the dose-escalation stage of the Phase Ia study focusing on SIM0270 monotherapy. This year, we presented updated findings from the dose-expansion stage (Cohort S1), where SIM0270 was administered as a single-agent treatment at the recommended dose (60 mg orally, once daily).

As of June 17, 2024, a total of 51 patients were enrolled and treated. The median patient age was 60, with 90.2% being postmenopausal women. At baseline, 23.5% of patients had ESR1 mutations, and 74.5% had visceral metastases (35.3% liver, 54.9% lung). Patients had undergone a median of one line of chemotherapy and one line of endocrine therapy in the metastatic setting. Notably, 45.1% had prior exposure to fulvestrant, and 39.2% had received CDK4/6 inhibitors. The study primarily evaluated safety, tolerability, and efficacy.

The median treatment duration was 16.3 weeks (range: 0.3–70.7 weeks). Overall safety was consistent with the dose-escalation phase. Treatment-emergent adverse events (TEAEs) occurred in 100% of patients, but most were mild to moderate (Grade 1–2). The most common TEAEs (≥20% incidence) included sinus bradycardia, elevated ALT and AST levels, urinary tract infections, and hypertriglyceridemia. Notably, most cases of sinus bradycardia were asymptomatic and Grade 1. No patients discontinued treatment due to treatment-related serious adverse events (SAEs).

In terms of efficacy, after a median follow-up of 10.2 months, the median progression-free survival (PFS) was 5.5 months (95% CI: 3.48–7.56).

• Confirmed objective response rate (ORR): 8.3%
• 24-week clinical benefit rate (CBR): 37.8% ESR1-mutant subgroup: 40.0% ESR1 wild-type subgroup: 38.2%

Treatment duration was illustrated in a swimmer plot, with the longest duration reaching 16.5 months.

Oncology Frontier: The study highlights promising clinical activity in patients with ESR1 mutations. Could you elaborate on SIM0270’s efficacy in this specific subgroup?

Dr. Qingyuan Zhang:SIM0270 exhibited remarkable clinical activity in patients with ESR1 mutations, a group that often demonstrates resistance to endocrine therapies and has limited treatment options. Despite poorer baseline characteristics, SIM0270 delivered notable benefits in this subgroup.

• ESR1-mutant patients had a median PFS of 3.7 months compared to 5.5 months in ESR1 wild-type patients.

These findings provide new hope for advanced breast cancer patients with ESR1 mutations who are resistant to conventional endocrine therapies.

Oncology Frontier: While TEAEs were observed in all patients, the study notes that most were mild or moderate, with no SAEs leading to treatment discontinuation. What factors do you think contributed to this favorable tolerability profile, and what strategies did your team implement to manage these adverse events?

Dr. Qingyuan Zhang:The favorable tolerability of SIM0270 can largely be attributed to its unique pharmacological mechanism and well-considered dosing regimen. As a selective estrogen receptor degrader, SIM0270 specifically targets estrogen receptors, minimizing off-target effects on other tissues. Moreover, thorough safety evaluations during the dose-escalation phase helped establish an optimal dose for the expansion phase, ensuring patient safety.

Our team employed several strategies to effectively manage adverse events:

1. Rigorous Screening: We carefully screened all participants to ensure they met the eligibility criteria and could tolerate SIM0270 treatment.
2. Close Monitoring: Patients’ vital signs and adverse events were closely monitored throughout the study. Any abnormalities were addressed promptly.
3. Interventions: For patients experiencing adverse events, we implemented dose adjustments or temporary treatment interruptions as needed to mitigate side effects.

Oncology Frontier: Based on current results, what do you envision as SIM0270’s potential applications in the treatment of ER+/HER2- advanced breast cancer? Are there plans to explore combinations with other therapies, such as immunotherapy or targeted agents, to enhance its efficacy?

Dr. Qingyuan Zhang:SIM0270 holds great promise as a treatment for ER+/HER2- advanced breast cancer. Beyond its demonstrated efficacy as a monotherapy, there is significant potential to enhance its therapeutic impact through combination therapies. In addition to the monotherapy cohort, our study also included two combination cohorts:

• SIM0270 with the CDK4/6 inhibitor palbociclib.
• SIM0270 with the mTOR inhibitor everolimus.

Preliminary results from the everolimus combination cohort were also presented at this year’s conference.

Looking ahead, the development of oral SERDs is exploring diverse directions, such as:

• Early-stage breast cancer in the adjuvant setting.
• Combination with HER2-targeted therapies in HER2+ breast cancer.
• Integration with PARP inhibitors.

Although these avenues remain in the exploratory stage, we are optimistic that oral SERDs like SIM0270, as a new generation of endocrine therapy, will bring meaningful benefits to a broader patient population.

About Dr. Qingyuan Zhang:

• Chief Physician, Professor, and PhD Advisor
• Leader of the National Key Specialty in Oncology
• Recipient of the National Hundred-Thousand-Talent Project
• National Outstanding Young and Middle-aged Expert
• Vice Chair of the Breast Cancer Committee, Chinese Anti-Cancer Association
• Vice Chair of the Breast Cancer Expert Committee, Chinese Society of Clinical Oncology
• Vice Chair of the Chemotherapy Committee, Chinese Anti-Cancer Association