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

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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 .