SIM0270 Demonstrates Early Antitumor Activity in ER+/HER2– Advanced/Metastatic Breast Cancer

The brain-penetrant oral selective estrogen receptor degrader (SERD) SIM0270 exhibited a favorable safety profile and early signals of antitumor activity in patients with estrogen receptor (ER)–positive, HER2-negative locally advanced or metastatic breast cancer, including those with ESR1 mutations, according to findings from phase 1 trial (NCT05293964) that were presented at the 2023 San Antonio Breast Cancer Symposium.¹

Based on findings derived from the first-in-human study, dose-limiting toxicities (DLTs) were reported in 4 patients. Two patients, 1 each in the 200 mg and 300 mg cohorts, had grade 3 QT prolongation, and 2 patients in the 300 mg cohort had grade 3 dizziness. All DLTs were resolved through dose interruptions and reductions.

Based on these safety data, 200 mg daily was determined to be the maximum tolerated dose (MTD) of SIM0270 monotherapy. Moreover, the improved safety profile and comparable efficacy in patients receiving the agent at 60 mg daily vs 120 mg daily established 60 mg daily as the recommended phase 2 dose (RP2D).

“We observed antitumor activity across all dose levels in heavily pretreated, ER-positive, HER2-negative advanced breast cancer patients, including those with ESR1 mutations and [those whose] ESR1 status [was] unknown,” lead study author Jian Zhang, MD, PhD, of Fudan University Shanghai Cancer Center, in China, stated in a presentation of the data.

The phase 1 trial is enrolling both female and male patients with breast cancer who are at least 18 years of age and present with histologically or cytologically confirmed metastatic or locally advanced ER-positive, HER2-negative breast cancer and have at least 1 measurable lesion per RECIST v1.1 criteria, as well as adequate bone marrow and organ function.² Exclusion criteria include proof of ongoing gastrointestinal disease or other malabsorption that may affect the absorption of SIM0270.

The phase 1a portion of the investigation includes dose-escalation and dose-expansion evaluation to examine the administration of single-agent SIM0270.1 In the dose-escalation cohort (n = 36), patients received once-daily doses of SIM0270 at 300 mg (n = 6), 200 mg (n = 5), 120 mg (n = 17), 90 mg (n = 6), 60 mg (n = 15), 30 mg (n = 4), or 10 mg (n = 4). Later optimization expansion doses included 60 mg and 120 mg daily.

The dose-expansion cohort (n = 80) plans to enroll patients for treatment with the selected RP2D. In the dose-expansion phase of the investigation, Cohort S1 will enroll patients with measurable lesions per RECIST v1.1 criteria, and Cohort S2 will enroll patients with measurable lesions per Response Assessment in Neuro-Oncology Brain Metastases criteria. As of a data cutoff of August 28, 2023, 57 patients have received at least 1 dose of SIM0270 monotherapy in the dose-escalation and dose-optimization portions.

The primary end points of this trial are the determination of the MTD, RP2D, and DLTs.2 Evaluation of adverse effects (AEs), the Cmax of SIM0270, the Tmax of SIM0270, the area under the curve of the plasma concentration of SIM0270, clinical benefit rate (CBR), disease control rate, duration of response, progression-free survival, time to progression, time to response, overall survival, and overall response rate (ORR) will all serve as secondary end points in this investigation.

Overall, patients had a median age of 55 years, 82% had an ECOG performance status (PS) of 1, and 68% were post-menopausal.1 Furthermore, 74% and 12% of patients had visceral metastases and brain metastases, respectively. Twenty-three percent, 40%, and 37% of patients, respectively, had ESR1-mutated disease, ESR1 wild-type disease, and disease with unknown ESR1 status. Evaluable patients had a median of 2 prior lines of endocrine therapy, and 65% had received prior chemotherapy. Prior endocrine therapies included aromatase inhibitors (AIs; 89%), CDK4/6 inhibitors (65%), and fulvestrant (Faslodex; 63%).

In the 200 mg cohort, patients had a median age of 54 years, 100% had an ECOG PS of 1, and 80% were post-menopausal. Furthermore, 80% of patients had visceral metastases, and none had brain metastases. Twenty percent, 60%, and 20% of patients, respectively, had ESR1-mutated disease, ESR1 wild-type disease, and disease with unknown ESR1 status. Patients had received a median of 2 prior lines of endocrine therapy, and 40% had received prior chemotherapy. Prior endocrine therapies included AIs (100%), CDK4/6 inhibitors (60%), and fulvestrant (40%).

In the 60 mg cohort, patients had a median age of 56 years, 87% had an ECOG PS of 1, and 67% were post-menopausal. Furthermore, 73% and 13% of patients had visceral metastases and brain metastases, respectively. Thirty-three percent, 40%, and 27% of patients, respectively, had ESR1-mutated disease, ESR1wild-type disease, and disease with unknown ESR1 status. Patients had received a median of 2 prior lines of endocrine therapy, and 60% had received prior chemotherapy. Prior endocrine therapies included AIs (93%), CDK4/6 inhibitors (80%), and fulvestrant (73%).

Notably, among the 7 patients with brain metastases, none discontinued treatment because of brain metastatic lesion progression.

Most treatment-emergent AEs (TEAEs) associated with SIM0270 were grade 1/2. In the total population (n = 57), the most reported TEAE was sinus bradycardia (58%). Seventy-nine percent of sinus bradycardia cases were grade 1 asymptomatic. Other common TEAEs included anemia (42%), asthenia (39%), hypertriglyceridemia (30%), hypoalbuminemia (28%), decreased appetite (26%), QT electrocardiogram (ECG) prolongation (26%), dizziness (25%), increased aspartate aminotransferase (AST; 23%), hypocholesterolemia (23%), urinary tract infection (21%), and decreased white blood cell (WBC) counts (21%).

In the 300 mg, 200 mg, 120 mg, 90 mg, 60 mg, 30 mg, and 10 mg cohorts, respectively, the most common TEAEs were sinus bradycardia (67%; 60%; 53%; 50%; 67%; 50%; 50%), anemia (50%; 80%; 29%; 33%; 33%; 25%; 100%), asthenia (50%; 60%; 41%; 17%; 33%; 0%; 75%), hypertriglyceridemia (50%; 20%; 24%; 17%; 40%; 25%; 25%), hypoalbuminemia (33%; 60%; 18%; 17%; 7%; 50%; 100%), decreased appetite (33%; 20%; 35%; 0%; 33%; 0%; 25%), ECG QT prolongation (67%; 20%; 18%; 17%; 27%; 25%; 25%), dizziness (67%; 20%; 35%; 17%; 7%; 0%; 25%), increased AST (50%; 0%; 6%; 17%; 13%; 50%; 100%), hypocholesterolemia (0%; 20%; 6%; 67%; 27%; 0%; 75%), urinary tract infection (17%; 20%; 18%; 50%; 13%; 0%; 50%), and decreased WBC counts (17%; 40%; 29%; 17%; 13%; 25%; 0%).

Among 50 patients who were evaluable for response per RECIST v1.1 criteria, 4 achieved a partial response (PR), including 1 confirmed PR each at 30mg, 120 mg, and 200 mg, and 1 unconfirmed PR at 120 mg in a patient with visceral disease. Two of the patients who achieved a confirmed PR had an ESR1 mutation, 1 of whom also had visceral disease and had received prior fulvestrant and a CDK4/6 inhibitor. The ORR was 8%. Furthermore, 21 patients each had stable disease and progressive disease.

Of the patients evaluable for CBR (n = 40), the CBR was 25% (n = 10).

“We look forward to sharing more comprehensive data from this cohort in the future, especially concerning endocrine-resistant populations [and] those with brain metastases,” Zhang concluded.

Trial enrollment with SIM0270 at the 60-mg dose is ongoing. The phase 1b portion of the trial is concurrently investigating SIM0270 in combination with palbociclib (Ibrance) or everolimus (Afinitor). 

Disclosure: Dr Zhang has no financial relationships to disclose.

References

1. Wu J, Zhang J, Zhang Q, et al. A first-in-human phase 1 study of SIM0270, a brain-penetrant oral selective estrogen receptor degrader (SERD), in patients with ER+/HER2- locally advanced or metastatic breast cancer. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX; Abstract PS15-01.
2. Phase 1 study to evaluate SIM0270 alone or in combination in ER+, HER2- locally advanced or metastatic breast cancer. ClinicalTrials.gov. Updated May 30, 2023. Accessed December 8, 2023. https://clinicaltrials.gov/study/NCT05293964