A phase Ib study of PI3Kα inhibitor risovalisib mesylate in combination with fulvestrant in patients with <i>PIK3CA</i>-mutated, HR+/HER2- advanced breast cancer.
Authors: Jiong Wu, Jian Zhang, Man Li, Li Cai, Tao Sun, Quchang Ouyang, Yanchun Meng, Yehui Shi, Chuan Wang, Qiang Liu, Yongkui Lu, Yongmei Yin, Qianjun Chen, Lilin Chen, Haitao Wang, Jiuwei Cui, Ning Liao, Shubin Wang, Yi Tu, Min Yan
Journal: Journal of Clinical Oncology (2024)

1047 Background: PIK3CAmutations represent a common mechanism of resistance to endocrine therapy (ET) ± CDK4/6 inhibitors (CDK4/6i) in patients (pts) with HR+/HER2– advanced breast cancer (ABC). Alpelisib (PI3Kα inhibitor) + fulvestrant has been approved for pts with PIK3CA-mutated HR+/HER2- ABC following progression on/after an ET-based regimen. Risovalisib Mesylate (CYH33) is a novel PI3Kα inhibitor with superior inhibitory activity to alpelisib in multiple cancer cell lines and tumor xenograft models, and it exhibited encouraging anti-tumor efficacy in solid tumors in the first-in-human study (NCT03544905). A multicenter, open-label, phase Ib study of CYH33 in combination with ET ± Palbociclib (CDK4/6i) is ongoing (NCT04856371). Here we only present data from the CYH33 + fulvestrant arm (Cohort 1). Methods: The safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (assessed every 8 weeks by RECIST v1.1) of CYH33 30/40mg administered orally once daily in combination with intramuscular fulvestrant 500mg on Day1 of every 28-day cycle with 1 additional dose on Day15 of Cycle 1 were assessed until disease progression, unacceptable toxicity, or withdrawal of consent in pts with PIK3CA-mutated, HR+/ HER2- ABC who progressed on/after ET ± CDK4/6i treatments. Results: From Jul 29, 2021 to Nov17, 2023 (data cutoff), a total of 52 pts were enrolled into Cohort 1 and followed up for at least 8 months. The recommended phase 2 dose (RP2D) was identified as CYH33 30mg QD + Fulvestrant 500mg. For all pts, no grade 4/5 treatment-related AEs (TRAEs) were observed and the most common grade 3 TRAEs (≥5%) were hyperglycaemia (17.3%), rash (15.4%), stomatitis (13.5%), weight decreased (7.7%), decreased appetite (5.8%), diarrhoea (5.8%) and hypokalaemia (5.8%). For pts receiving RP2D, the incidence of grade 3 TRAEs were lower, and the most common grade 3 TRAEs (≥5%) were rash (13.6%) and stomatitis (9.1%). In addition, the most common grade 1-2 TRAEs were hyperglycaemia, nausea, decreased appetite, rash, weight decreased, diarrhoea, vomiting, stomatitis, AST increased and ALT increased. There were 39 pts harboring PIK3CA-mutations without prior fulvestrant treatment, 90% had received ≥1 prior lines of systemic therapy, 41% were premenopausal, 74% had visceral metastases, 49% had received a prior CDK4/6i, and 31% had received systemic chemotherapy. Among these 39 pts, confirmed ORR was 17.9%, CBR was 41.0%, and median PFS (mPFS) was 10.91 months. For pts receiving RP2D (n=21), confirmed ORR was 9.5%, CBR was 47.6% and mPFS was 10.97 months. For pts with prior CDK4/6i treatment at RP2D, the mPFS was 7.92 months. Conclusions: CYH33 + fulvestrant exhibited a manageable safety profile and encouraging preliminary anti-tumor efficacy in pts with PIK3CA-mutated, HR+/HER2- ABC who progressed on/after ET ± CDK4/6i treatments. Clinical trial information: NCT04856371 .