Groundbreaking survival data from a Phase 1b trial of gedatolisib combination therapy in HR-positive, HER2-negative advanced breast cancer patients was presented at the 2024 San Antonio Breast Cancer Symposium (SABCS). The study revealed remarkable survival outcomes that could potentially reshape treatment approaches for advanced breast cancer.
The trial evaluated gedatolisib, a pan-PI3K/mTORC1/2 inhibitor, in combination with palbociclib and either letrozole or fulvestrant. In treatment-naïve patients, the combination achieved a median overall survival of 77.3 months (95% CI, 50.3 to 89.0). For patients previously treated with CDK4/6 inhibitors who received the Phase 3 dose, median overall survival reached 33.9 months (95% CI, 17.8 to 52.3).
Clinical Significance and Treatment Strategy
"These results highlight the promising clinical development strategy of simultaneously blocking the ER, CDK4/6, and PAM signaling pathways," explained Dr. Igor Gorbatchevsky, Chief Medical Officer of Celcuity. The data suggests superior efficacy compared to current standard-of-care treatments for HR+/HER2- advanced breast cancer.
Mechanism of Action and Differentiation
Gedatolisib distinguishes itself through its comprehensive targeting approach. As a potent, reversible inhibitor, it selectively targets all Class I PI3K isoforms and mTORC1/2, effectively blocking PI3K/AKT/mTOR signaling. This broad-spectrum inhibition may reduce the likelihood of drug resistance compared to more selective inhibitors.
Ongoing Clinical Development
The promising results have led to two pivotal Phase 3 trials:
- VIKTORIA-1: Currently enrolling patients to evaluate gedatolisib with fulvestrant with/without palbociclib in HR+/HER2- advanced breast cancer
- VIKTORIA-2: Planned to begin in Q2 2025, investigating gedatolisib plus CDK4/6 inhibitor and fulvestrant as first-line treatment
The FDA has granted Breakthrough Therapy designation to the gedatolisib combination for treating HR+/HER2- advanced breast cancer that has progressed following CDK4/6 inhibitor and aromatase inhibitor treatment.
Safety and Tolerability
The Phase 1b trial reported a manageable side effect profile alongside robust response rates, supporting the feasibility of this combination approach for long-term treatment in advanced breast cancer patients.
