Promising Efficacy, Manageable Safety Are Observed for CYH33 in Solid Tumors

A PI3Kα inhibitor, CYH33, demonstrated positive clinical activity in an ongoing phase 1a trial (NCT03544905) at the European Society for Medical Oncology Targeted Anticancer Therapies Virtual Congress 2021 by lead investigator Xiao-Li Wei, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China.

“Objective tumor responses were observed in 5 patients, including 1 complete response (CR) in 1 patient with ovarian cancer and 4 partial responses (PRs), 1 each in patients with colorectal cancer, breast cancer, ovarian cancer, and gastric cancer,” Wei said, during a virtual presentation of the findings.

The study was composed of 2 stages—a dose-escalation phase and a dose-expansion phase. In the dose-escalation phase, patients received 1 mg, 5, mg, 10 mg, 20 mg, 40 mg, and 60 mg of the agent. Dose expansion occurred at 20 mg, 30 mg, and 40 mg. Patients with or without PIK3CA mutations were eligible for dose escalation, but only patients with PIK3CA mutations were eligible for dose expansion.

The trial’s primary end points were safety, tolerability, and maximum tolerated dose of the oral monotherapy. The secondary end points were preliminary efficacy and pharmacokinetics, objective response rate (ORR), progression-free survival, duration of response, disease control rate, and the clinical benefit rate.

Thirty-nine patients, about evenly divided between male and female, were enrolled between July 2018 and November 2020.

Their median age was 54 years, and 21 (53.8%) harbored a PIK3CA mutation. Twenty-one patients (53.8%) had an ECOG performance status of 1, and the majority (71.8%) of patients had received 2 or more lines of prior therapy.

The most common treatment-related adverse effect (TRAE) was any-grade hyperglycemia, affecting 84.6% of patients. Grade 3 hyperglycemia affected 51.3% of patients.

“Hyperglycemia was manageable and reversible, effectively controlled by antihyperglycemic medication or insulin,” said Wei.

Subsequent any-grade TRAEs observed were decreased appetite (33.3%), nausea (33.3%), and diarrhea (28.2%), on-target effects that were expected, Wei noted. Peripheral and facial edema each affected 15.4% of patients, which clinicians should keep in mind, added Wei. She said that no grade 4 or 5 TRAEs were reported.

Investigators reported that 3 patients had experienced dose-limiting toxicity: grade 3 hyperglycemia at the 40-mg and 60-mg dose level, and grade 3 nausea at the 60-mg dose level. Ultimately, the 40-mg dose was deemed to be the recommended phase 2 dose.

Overall, 17 of 33 patients whose tumors harbored PIK3CA mutations were identified, and the ORR in this subpopulation was 23.5%. There were 4 patients on treatment as of the data cutoff date of November 15, 2020, Wei said.

“The main reason for stopping treatment was disease progression [56.4%] or subject withdrawal [17.9%],” Wei said. In patients with disease control, the median treatment duration was 16.4 weeks and the longest treatment duration time was 51 weeks in 1 patient with ovarian cancer.

In the dose-escalation phase, investigators reported 1 CR, 4 PRs, and 11 patients with stable disease. At the 40-mg dose, the overall ORR was 25.0%, and in the PIK3CA-mutation population, the ORR was 33.3%.

A total of 4 PI3K inhibitors have been approved by the FDA: idelalisib (Zydelig), copanlisib (Aliqopa), and duvelisib (Copiktra), all in hematologic malignancies; and alpelisib (Piqray), approved for hormone receptor–positive, HER2-negative breast cancer.

Studies involving CYH33 as monotherapy and in combination with other antitumor agents are ongoing to further explore the safety and efficacy in larger populations, concluded Wei.

_References:

_{Wei X-L, Liu J-H, Zhao H, et al. 33O: A phase I study to evaluate safety, pharmacokinetics (PK), and preliminary efficacy of CYH33, a phosphatidylinositol 3-kinase α (PI3Kα) inhibitor, in patients (pts) with advanced solid tumours. Ann Oncol. 2021;32(suppl 1):S14. doi:10.1016/annonc/j.annonc.2021.01.048}