Sacibertinib Plus Endocrine Therapy Shows Early Safety, Activity in ER+/HER2+ Breast Cancer

Sacibertinib (Hemay022) plus endocrine therapy demonstrated acceptable safety with early clinical activity in patients with estrogen receptor (ER)–positive/HER2-positive metastatic breast cancer, according to data from a phase 1b study (NCT02476539) presented at the 2023 San Antonio Breast Cancer Symposium.

In the 51 patients total patients, the overall response rate was 31.4%; this was comprised of a complete response (CR) rate of 2.0%, a partial response (PR) rate of 29.4%, and a stable disease (SD) rate of 51.0%; 17.6% of patients experienced progressive disease (PD). Moreover, the disease control rate (DCR) was 82.4%, and the clinical benefit rate (CBR) was 60.8%. The median progression-free survival (PFS) was 9.0 months (95% CI, 5.5~11.0).

“Sacibertinib plus endocrine therapy in this chemotherapy-free strategy had a favorable safety profile and antitumor activity in patients with ER-positive/HER2-positive metastatic breast cancer,” Huiping Li, MD, of Peking University Cancer Hospital and Institute, in China, and colleagues, wrote in a poster of the data. “The 400-mg to 500-mg daily [dose] showed more efficacy, supporting further assessment in randomized studies.”

Current treatment guidelines for this patient population call for HER2-targeted therapy in combination with chemotherapy; however, resistance to anti-HER2 treatments underscores the need for novel strategies that are safe and effective. Preclinical data have indicated that the crosstalk between the HER2 and ER signaling pathways could contribute to resistance and encourage disease progression. Because those with ER-positive/HER2-positive disease are not as likely to respond to standard HER2-targeted therapies plus chemotherapy, it is hypothesized that simultaneously blocking the HER2 and ER pathways could help overcome the resistance.

In preclinical studies and a phase 1a trial (NCT02476539), single-agent use of the oral EGFR/HER2 TKI, sacibertinib, has been shown to have acceptable tolerability with signals of antitumor activity. Investigators launched the phase 1b study to explore the safety and efficacy of the agent in combination with chemotherapy in patients ER-positive/HER2-positive metastatic breast cancer.

The study enrolled patients with relapsed disease who cannot be cured with standard-of-care therapy. They were required to have ER-positive disease characterized by immunochemistry of greater than 1% and HER2-positive disease characterized by immunochemistry of 3+ or 2+ confirmed by fluorescent in situ hybridization. Premenopausal patients were not eligible for enrollment.

This phase 1b study utilized a 3+3 dose-escalation and -expansion design. Patients were treated with sacibertinib at daily doses of 200 mg (n = 3), 300 mg/d (n = 7), 400 mg (n = 31), or 500 mg (n = 12) with endocrine therapy. Those in the 200-mg, 300-mg, and 500-mg cohorts received sacibertinib plus exemestane, and those in the 400-mg cohort received the agent paired with letrozole (n = 6), fulvestrant (n = 5), or exemestane (n = 18).

Investigators assessed patients for safety and clinical efficacy, which included ORR, CBR, DCR, and PFS.

In the total population (n = 55), the median patient age was 55 years (range, 34-69). The majority (90.9%) of patients had an ECOG performance status of 0. Regarding tumor site, 18.2% of patients had visceral disease and 81.8% had nonvisceral disease. All patients had ER-positive/HER2-positive disease. Moreover, 76.4%, 98.2%, and 100% of patients had received prior treatment with endocrine therapy, chemotherapy, or anti-HER2 therapy, respectively.

When broken down by cohort, those in the 200-mg cohort experienced an ORR of 0%, with 66.7% achieving SD and 33.3% experiencing PD. In this group, the DCR was 66.7%, the CBR was 33.3%, and the median PFS was 3.6 months (95% CI, 1.8~not available [NA]). In the 300-mg cohort, the ORR was 28.6%, with CR and PR rates of 14.3%; 42.9% of patients had SD and 28.6% experienced PD. Here, the DCR was 71.4%, the CBR was 42.9%, and the median PFS was 5.4 months (95% CI, 1.7~9.5). In the 500-mg cohort, the ORR was 25.0%; no patients had a CR, 25% experienced a PR, 75.0% achieved SD, and no patients experienced PD. In this group, the DCR was 100.0%, the CBR was 50.0%, and the median PFS was 9.0 months (95% CI, 2.1~NA).

Within the 400-mg cohort who also received exemestane, the ORR was 38.9%; no patients experienced a CR, 38.9% had a PR, 33.3% had SD, and 27.8% had PD. Here, the DCR was 72.2%, the CBR was 66.7%, and the median PFS was 8.9 months (95% CI, 2.7~16.4). In the subgroup that received letrozole, the ORR was 50.0%; no patients achieved a CR, 50.0% had a PR, 33.3% had SD, and 16.7% experienced PD. The DCR was 83.3%, the CBR was 83.3%, and the median PFS was 12.7 months (95% CI, 1.7~NA). In the subgroup that were given fulvestrant, the ORR was 100.0%; no patients achieved a CR, 20.0% had a PR, 80.0% achieved SD, and no patients experienced PD. The DCR was 100.0% and the CBR was 80.0%. In this group, the median PFS was 13.3 months (95% CI, 5.7~NA).

Safety was evaluated in all 55 patients enrolled. The most frequent grade 3 treatment-emergent adverse effect (TEAE) was diarrhea, which occurred in 9.1% of patients. One patient experienced grade 4 abnormal liver function.

The safety and efficacy of sacibertinib at 500 mg daily plus endocrine therapy in patients with ER-positive/HER2-positive metastatic breast cancer is under further exploration in the ongoing phase 3 Fillful-03 study (NCT05122494).

Reference

Li H, Zhang Q, Zhang R, et al Antitumor efficacy and safety of sacibertinib (Hemay022) in combination with endocrine therapy in patients with ER+/ HER2+ metastatic breast cancer: A phase Ib study. Presented at: San Antonio Breast Cancer Conference; December 5-9, 2023; San Antonio, TX. Poster PO2-27-11.