Gedatolisib Combined with Palbociclib and Letrozole in Patients with No Prior Systemic Therapy for Hormone Receptor Positive, HER2 Negative Advanced Breast Cancer.

Purpose: Nonclinical evidence demonstrating that estrogen receptor (ER), CDK4/6, and PI3K/AKT/mTOR (PAM) pathways cross-promote tumor proliferation in HR+/HER2- breast cancer cell lines led to development of CDK4/6 inhibitors and agents inhibiting single PAM pathway nodes to treat HR+/HER2- advanced breast cancer (ABC). Simultaneous blockade of ER, CDK4/6 and PAM pathways may optimize anti-tumor control in the treatment-naïve ABC setting. Gedatolisib, a pan-PI3K/mTOR inhibitor, was evaluated as first-line therapy, combined with standard-of-care palbociclib and letrozole, for patients with HR+/HER2- ABC.

Patients And Methods: Treatment-naïve patients from a phase 1b study with HR+/HER2- ABC treated with gedatolisib plus palbociclib and letrozole were analyzed. The primary endpoint of the overall study was investigator-assessed objective response. Secondary endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Results: Of 41 patients, all had stage IV disease, 93% measurable disease, 78% visceral metastases, and 22% detectable PIK3CA mutations. The overall response rate (ORR) was 79% in patients with evaluable disease (N=33). Median DOR was 48 months for confirmed responders. Median PFS was 48.4 months and median OS was 77.3 months. ORR and PFS were comparable in patients with and without PIK3CA mutations. Fewer than 10% discontinued treatment due to treatment-related adverse events. The most frequent grade 3/4 adverse events were neutropenia (61%), rash (39%), and oral stomatitis (29%).

Conclusions: Gedatolisib plus palbociclib and letrozole demonstrated preliminary efficacy in patients with no prior systemic therapy for ABC. These results warrant further evaluation of gedatolisib added to standard-of-care, first-line therapy for HR+/HER2- ABC.