PAM Inhibitor Approved for HR-Positive Breast Cancer

The FDA approved the kinase inhibitor gedatolisib (Revtorpyk) for treating hormone receptor (HR)-positive/HER2-negative breast cancer in patients whose disease has progressed on endocrine therapy in the metastatic setting.

Approval of the PI3K/AKT/mTOR (PAM) inhibitor stipulates use in combination with fulvestrant — with or without the CDK4/6 inhibitor palbociclib (Ibrance) — in adults without PIK3CA mutations.

PAM is a complex multi-node pathway that drives breast cancer growth and contributes to endocrine and CDK4/6 inhibitor resistance.

Efficacy was evaluated in Study 1 of the open-label VIKTORIA-1 trial, which demonstrated improvements in progression-free survival (PFS) and overall response with gedatolisib in this patient population.

“For patients with HR-positive/HER2-negative locally advanced or metastatic breast cancer, there is an urgent need for new treatment options that can meaningfully increase the likelihood of survival without disease progression or death,” said investigator Sara Hurvitz, MD, of Fred Hutchinson Cancer Center and the University of Washington in Seattle, in a press release from drugmaker Celcuity.

“With the approval of Revtorpyk, oncologists now have an effective new treatment option for these patients,” Hurvitz added.

In the multicenter trial, median PFS reached 9.3 months with the gedatolisib-based triplet regimen of gedatolisib plus fulvestrant and palbociclib and 7.4 months with the gedatolisib-fulvestrant doublet, as compared with 2 months with fulvestrant alone (P<0.0001 for both).

Overall response rates among the patients with measurable disease reached 32% with the triplet, 28% with the doublet, and 1% with fulvestrant alone. At the time of the PFS analysis, OS data were not mature.

Study 2 of VIKTORIA-1 has also shown benefit with the gedatolisib-based regimens in PIK3CA-mutant disease versus fulvestrant plus the PI3K inhibitor alpelisib (Piqray), and Celcuity said it intends to seek approval in that setting as well.

Adverse events (AEs) occurring in at least 20% of patients with the gedatolisib-based triplet included stomatitis; nausea and vomiting; fatigue; rash; constipation; diarrhea; musculoskeletal pain; decreases in white blood cells, neutrophils, hemoglobin, lymphocytes, platelets, and sodium; and increases in fasting glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and eosinophils.

With the gedatolisib-based doublet, common AEs included stomatitis; nausea and vomiting; rash; fatigue; musculoskeletal pain; pruritus; diarrhea; increases in glucose, eosinophils, ALT, and AST; and decreases in hemoglobin and lymphocytes.

Warnings and precautions in the labeling include potential risks for stomatitis, dermatologic AEs, hyperglycemia, and embryo-fetal toxicity.