PIK3CA mutations are among the most frequent alterations in solid tumors, identified in 12% of ovarian cancer (OC), 27%-36% of breast cancer (BC), and 42% of cervical cancer. Targeting PI3Kα may be effective in those cancers harboring PIK3CA mutation. Here, we report the results from an ongoing phase Ia/Ib study of CYH33, a highly selective PI3Kα inhibitor, in advanced solid tumors.
This phase Ia trial had 2 parts: dose escalation and dose expansion. Pts with or without PIK3CA mutant were eligible for dose-escalation, but only pts with PIK3CA mutation were eligible for dose-expansion.
At data cut-off (31 Oct 2020), 39 pts had been enrolled (19 from dose escalation at 1-60 mg and 20 from dose expansion at 20-40 mg) including 4 pts with OC, 8 pts with BC. The most common (≥ 20%) any grade treatment-related adverse events included hyperglycemia (84.6%), decreased appetite (30.8%), nausea (30.8%), diarrhea (28.2%), weight decrease (25.6%), and vomiting (23.1%). Hyperglycemia was generally manageable with anti-hyperglycemic medications. Three pts had experienced dose-limiting toxicity (DLT): grade 3 hyperglycemia at 40 mg and 60 mg dose level, and grade 3 nausea at 60 mg dose level. Thus, the 40 mg dose was considered to be RP2D. AUC0-24h and Cmax increased in a dose-proportional manner. Median Tmax was 2-4 hours and half-life (t1/2) was about 20 hours. In 18 evaluable pts with PIK3CA hotspot mutations, 4 pts achieved best overall response. One OC pt (PIK3CA E545A mutation) who had received 2 lines of platinum-based chemotherapy achieved complete response (CR) per RECIST 1.1, and the duration of response had lasted more than 10 months as of data cut-off. Other 3 pts with partial response (PR) were found in 1 OC pt (PIK3CA E545K mutation), 1 BC pt (PIK3CA E545K mutation), and 1 gastric cancer (PIK3CA E542K mutation). In addition, 1 colorectal cancer pt (PIK3CA status unknown) in dose escalation part also achieved PR.
CYH33 demonstrates a manageable safety profile and linear pharmacokinetic characteristics. An encouraging preliminary anti-tumor efficacy in certain tumor types harboring PIK3CA mutation was observed.
NCT03544905.
Haihe Biopharma Co., Ltd.
Haihe Biopharma Co., Ltd.
Q-Q. Yu, Y-W. Du: Full/Part-time employment: Haihe Biopharma Co., Ltd. All other authors have declared no conflicts of interest.