A randomized, open-label, phase 3 study of gedatolisib + fulvestrant ± palbociclib vs standard of care in HR+/HER2−/ <i>PIK3CA</i> -mutant (MT) advanced breast cancer (VIKTORIA-1 Study 2).

Abstract

LBA1008 Background: Current standard treatment (tx) for patients (pts) with HR+/HER2-/ PIK3CA -MT advanced breast cancer (ABC) includes selective inhibitors of the PI3K/AKT/mTOR (PAM) pathway, which induce class-effect toxicities (e.g., hyperglycemia, diarrhea). Gedatolisib (geda) is a highly potent, IV-administered, comprehensive inhibitor of the PAM pathway that targets all class I PI3K isoforms, mTORC1, and mTORC2. Geda has superior preclinical potency and cytotoxicity compared to alpelisib, capivasertib, and everolimus and demonstrated activity in PIK3CA- MT and wild-type (WT) breast cancer cell lines. The randomized, open-label phase 3 VIKTORIA-1 clinical trial evaluated, in 2 cohorts by PIK3CA status, geda regimens in HR+/HER2- ABC that progressed during/after CDK4/6i + aromatase inhibitor (AI). In the PIK3CA -WT cohort, geda/fulv +/- palbo significantly improved PFS (HR vs. fulv, 0.24; 95% CI, 0.17-0.35; P&lt;0.001, and 0.33; 95% CI, 0.24-0.48; P&lt;0.001, respectively). We now present primary findings of the PIK3CA -MT cohort. Methods: Eligible pts had HR+/HER2- ABC with prior CDK4/6i + AI, no chemotherapy for advanced disease, no prior PAMi, measurable disease (RECIST v1.1), and HbA1c &lt;6.5%. Pts with PIK3CA -MT disease were randomized 3:3:1 to geda/palbo/fulvestrant, alpelisib/fulv or geda/fulv in 28-day cycles of geda 180 mg IV weekly for 3 weeks on/1 week off; palbo 125 mg daily for 21 days with 7 days off; fulv 500 mg IM every 2 weeks in cycle 1 then every 4 weeks; alpelisib 300 mg per day. Response was assessed per RECIST v1.1 by blinded independent central review. The primary endpoint was PFS for the geda triplet vs. alpelisib/fulv. Secondary endpoints include PFS for the geda doublet vs. alpelisib/fulv, OS, safety, ORR, DOR, TTR, CBR, QOL, and geda PK. Statistical comparisons were performed by stratified log-rank test. Results: At data cut-off (3/09/2026; N=362), median follow-up for PFS was 11.0 mos. The trial met its primary endpoint. Median PFS for geda triplet (n=155) vs alpelisib/fulv (n=155) was 11.1 vs. 5.6 mos (HR, 0.50; 95% CI, 0.37-0.68; P&lt;0.0001). Median PFS for the geda doublet (n=52) vs alpelisib/fulv was 11.3 vs. 5.6 mos (HR, 0.51; 95% CI, 0.33-0.79; P&lt;0.0013). Safety was generally consistent with the individual agents, with low rates of D/C of assigned therapy due to tx-related adverse events (2.6% for geda triplet; 3.8% for geda doublet; 7.1% for alpelisib/fulv). All-grade tx-related hyperglycemia was 15.0%, 11.5%, 57.9% (grade 3: 2.6%, 0%, 13.8%), and all-grade tx-related stomatitis was 61.4%, 61.5%, and 34.2% (grade 3: 16.3%, 5.8%, and 5.3%), respectively, for geda triplet, geda doublet, and alpelisib/fulv. Conclusion: These data demonstrate that gedatolisib combination therapies offer a potential new standard of care as 2L treatment of HR+/HER2- ABC, irrespective of PIK3CA mutation status. Clinical trial information: NCT05501886 .