204P Phase Ib Study of Gedatolisib Plus Palbociclib and Endocrine Therapy in Women with Hormone Receptor Positive Advanced Breast Cancer: Updated Results in Treatment Naïve Patients

Treatment with a CDK4/6 inhibitor (CDK4/6i) combined with endocrine therapy (ET) is the front-line (1L) standard of care for HR+/HER2- advanced breast cancer (ABC). Resistance to a CDK4/6i can arise in a number of ways, including adaptive activation of the PI3K/mTOR pathway, which may be prevented by addition of a PI3K/mTOR inhibitor to the 1L CDK4/6i + ET regimen. To evaluate this hypothesis, we conducted a phase Ib study of gedatolisib, a pan-PI3K/mTOR inhibitor, palbociclib (palbo), a CDK4/6i, and ET (letrozole [LET] or fulvestrant) in 138 women with HR+/HER2- ABC. Promising preliminary antitumor activity was observed (Wesolowski, SABCS 2022). Here, we report updated baseline characteristics, safety, and efficacy data in treatment naïve patients (pts) treated with gedatolisib + palbo + LET. We analyzed the treatment naive subgroup of pts with HR+/HER2- ABC who were treated with gedatolisib + palbo + LET as 1L treatment (Escalation and Expansion Arms A; n=41). The primary endpoint was investigator assessed objective response rate (ORR). Secondary endpoints included safety, duration of response, and progression free survival (PFS). Of these 41 pts, 95% had Stage 4 disease, 37% had metastases to the liver, 17% had metastases to the lung, 93% had measurable lesions, and 24% had PIK3CA mutations. The most common Grade 3-4 adverse events (AE) in the treatment naïve subgroup were neutropenia (61%), rash (39%), stomatitis (29%), and leukopenia (22%). Five of 41 pts (12%) discontinued treatment due to an AE. As of December 12, 2022, for Expansion Arm A, median PFS was 48.6 months (n=30) and ORR was 85% (n=26, measurable and evaluable disease). When treatment naïve pts from both arms are combined, mPFS was 48.6 months (n=41) and ORR was 79% (n=33, measurable and evaluable disease). The gedatolisib + palbo + LET combination demonstrated promising activity in treatment-naïve pts with ABC. The safety profile of gedatolisib + palbo + LET was similar to palbo + LET. These encouraging results warrant further evaluation of gedatolisib in combination with a CDK4/6i + LET in the front-line setting.