KEY TAKEAWAYS
- The Phase 1b study evaluated gedatolisib + palbo + LET in treatment-naïve subgroup of pts with HR+/HER2- ABC.
- The study’s primary endpoint was investigator-assessed ORR. Secondary endpoints were safety, duration of response, and PFS.
- Gedatolisib + palbo + LET showed promising activity in treatment-naïve ABC pts, with a safety profile similar to palbo + LET.
The primary treatment approach for HR+/HER2- advanced breast cancer (ABC) in the first-line (1L) setting involves using a CDK4/6 inhibitor (CDK4/6i) in combination with endocrine therapy (ET). However, resistance to CDK4/6 inhibitors can develop through various mechanisms, including the adaptive activation of the PI3K/mTOR pathway. One potential strategy to counteract this resistance is to include a PI3K/mTOR inhibitor alongside the 1L CDK4/6i + ET treatment regimen.
The phase Ib study involved 138 women with HR+/HER2- ABC and evaluated the use of gedatolisib, a pan-PI3K/mTOR inhibitor, in combination with palbociclib (palbo), a CDK4/6 inhibitor, and ET (specifically letrozole [LET] or fulvestrant) in treatment-naïve patients (pts). Preliminary findings showed promising antitumor activity (Wesolowski, SABCS 2022). In this update, researchers presented additional information on this treatment approach’s baseline characteristics, safety, and effectiveness in treatment-naïve pts receiving gedatolisib + palbo + LET.
Researchers conducted an analysis focusing on a subgroup of previously untreated pts with HR+/HER2- ABC. These pts received gedatolisib + palbo + LET as their first-line (1L) treatment, specifically in the Escalation and Expansion Arms A, which comprised 41 individuals. The primary goal of this analysis was to assess the objective response rate (ORR) as determined by the investigating healthcare professionals. Secondary endpoints included safety, the duration of response, and progression-free survival (PFS).
Of the 41 pts included in this analysis, 95% had Stage 4 disease, 37% had liver metastases, 17% had lung metastases, 93% had measurable lesions, and 24% had PIK3CA mutations. Among the treatment-naïve subgroup, the most frequently occurring Grade 3-4 adverse events (AE) were neutropenia (61%), rash (39%), stomatitis (29%), and leukopenia (22%). Five out of 41 pts (12%) discontinued their treatment due to AE. As of December 12, 2022, for Expansion Arm A, the median PFS stood at 48.6 months (with a sample size of 30 pts), and the ORR was 85% (based on 26 pts with measurable and evaluable disease). When considering treatment-naïve pts from both arms, the combined median PFS was 48.6 months (with 41 pts), and the combined ORR was 79% (based on 33 pts with measurable and evaluable disease).
The combination of gedatolisib, palbo, and LET showed encouraging effectiveness in previously untreated pts with ABC. The safety characteristics of gedatolisib + palbo + LET were comparable to those of palbo + LET. These positive findings indicated the need for additional investigation into using gedatolisib alongside a CDK4/6 inhibitor and LET as a first-line treatment approach.
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT02684032
Rugo, H.S., Wesolowski, R., Stringer-reasor, E., Han, H., Specht, J., Dees, C., Kabos, P., Vaishampayan, U.N., Wander, S.A., Lu, J., Gogineni, K., Spira, A., Schott, A., Abu-Khalaf, M., Mutka, S., Suzuki, S., Gorbatchevsky, I., Layman, R.M. 204P – Phase 1b study of gedatolisib plus palbociclib and endocrine therapy in women with hormone receptor positive advanced breast cancer: updated results in treatment naïve patients. Annals of Oncology (2023) 8 (1suppl_4): 101223-101223. 10.1016/esmoop/esmoop101223.
