Dr Han on the Investigation of Gedatolisib in HR+/HER2– Metastatic Breast Cancer

Heather Han, MD, research director, Department of Breast Oncology, Moffitt Cancer Center, discusses prior research with gedatolisib that provided the rationale for the phase 3 VIKTORIA-1 trial (NCT05501886) in patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer.

Patients with HR-positive, HER2-negative, metastatic breast cancer have effective frontline treatment options, including endocrine therapy combined with a CDK4/6 inhibitor, Han says. However, these patients often progress on or after their first-line treatment because of acquired resistance to endocrine therapy or CDK4/6 inhibitors, prompting investigations of more effective first- or second-line treatments that may overcome these resistance issues, Han explains.

Previously, a phase 1b study (NCT02684032) explored the clinical activity of gedatolisib, a dual small molecule inhibitor of PI3K and mTOR, in combination with the CDK4/6 inhibitor palbociclib (Ibrance) and the endocrine therapy fulvestrant (Faslodex), in patients with HR-positive, HER2-negative, advanced breast cancer with prior exposure to a CDK4/6 inhibitor. This triplet combination led to a median progression-free survival of 12.9 months in the second-line setting and an overall response rate of 63% in this population, regardless of PIK3CA mutation status.

Additionally, the combination was well tolerated, with 1 patient discontinuing treatment at the phase 3 dosing schedule because of treatment-related adverse effects (AEs). The incidence of grade 3/4 AEs typically associated with PI3K/mTOR inhibitors was low. In total, 7%, 6%, and 4% of patients experienced grade 3/4 hyperglycemia, diarrhea, and aspartate aminotransferase/alanine transaminase increase, respectively.

Based on the response rates and safety profile seen in this phase 1b trial, the registrational VIKTORIA-1 trial was designed, Han emphasizes. In this multinational trial, patients with HR-positive, HER2-negative, advanced breast cancer with prior exposure to a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor will be stratified by PIK3CA mutation status. Patients with PIK3CAmutations will be randomized to receive gedatolisib plus palbociclib and fulvestrant; alpelisib (Piqray) plus fulvestrant; or gedatolisib plus fulvestrant. Patients without PIK3CA mutations will be randomized to receive gedatolisib plus palbociclib and fulvestrant; gedatolisib plus fulvestrant; or fulvestrant alone.

Disclosures: Dr Han reports grants from/contracts with AbbVie, GSK, G1 Therapeutics, Quantum Leap Healthcare Collaborative, Pfizer, Zymeworks, Department of Defense, Arvinas, Celcuity, and Marker; consulting fees from Eli Lilly; institutional research funding from Mersana Therapeutics; and data safety monitoring board/advisory board roles with Novartis, AstraZeneca, and Gilead.