Alpelisib in combination with everolimus ± exemestane in solid tumours: Phase Ib randomised, open-label, multicentre...

Area of Science:

• Oncology
• Pharmacology

Background:

• Preclinical studies suggest synergistic efficacy between mTORC1 inhibitor everolimus (EVE) and PI3K inhibitor alpelisib (ALP).
• This supports clinical investigation of the ALP and EVE combination.

Purpose of the Study:

• Determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) of ALP in combination with EVE, and with EVE and exemestane (EXE).
• Assess safety, preliminary efficacy, and drug-drug interactions between ALP and EVE.

Main Methods:

• Dose escalation studies in patients with advanced solid tumors and HR+, HER2- advanced breast cancer (ABC).
• Dose expansion in pancreatic neuroendocrine tumors, renal cell carcinoma (RCC), mTOR inhibitor-pretreated solid tumors, and HR+, HER2- ABC.
• Evaluation of dose-limiting toxicities (DLTs), adverse events, progression-free survival, and pharmacokinetics.

Main Results:

• The MTD/RDE for ALP + EVE in advanced solid tumors was determined to be 250 mg + 2.5 mg.
• The MTD/RDE for ALP + EVE + EXE in advanced HR+, HER2- BC was 200 mg + 2.5 mg + 25 mg.
• Common adverse events included hyperglycemia, stomatitis, and diarrhea. Sixteen-week progression-free survival rates varied by cohort.
• No clinically relevant drug-drug interactions were observed between ALP and EVE.

Conclusions:

• The combination of alpelisib, everolimus, and exemestane demonstrates a manageable and reversible safety profile.
• Pharmacokinetics of the individual drugs remained largely unchanged when administered in combination.
• No unexpected safety signals emerged compared to individual drug profiles.