Background: PIK3CA mutations, present in ̃40% of HR+, HER2– ABC, are associated with therapeutic resistance and shorter survival. Alpelisib (ALP) + fulvestrant (FUL) demonstrated efficacy in this population for which achieving long-term (LT) disease control is challenging. Here, we report on pts with HR+, PIK3CA-altered ABC who achieved LT disease control with ALP + FUL. Methods: SOLAR-1 was a phase 3, randomized, double-blind study of ALP (or placebo) + FUL in HR+, HER2– ABC that progressed on/after an aromatase inhibitor. CBYL719X2101 (X2101) was a phase 1, open-label study of escalating ALP doses ± FUL in advanced solid tumors that progressed on/after anti-estrogen therapy (ET) or relapsed after adjuvant anti-ET. A cut-off ≥ median (progression-free survival [PFS] + 2 SE) was chosen based on Kaplan-Meier curves from SOLAR-1 to define LT disease control as PFS (SOLAR-1) or time on treatment (X2101) ≥18 mo. Results: In SOLAR-1, 51 of 169 pts (30.2%) randomized to ALP + FUL achieved LT disease control with a median PFS of 33.5 mo (95% CI, 27.4 mo-not reached). Baseline characteristics of pts in SOLAR-1 are in the table below. In pts with LT disease control, adverse events (AEs) of special interest (combined preferred terms) of GI toxicity were observed in 47 pts (92.2%; grade ≥3: 11.8%, n=6), of hyperglycemia in 41 pts (80.4%; grade ≥3: 39.2%, n=20), and of rash in 28 pts (54.9%; grade ≥3: 19.6%, n=10). Median ALP relative dose intensity was 79.9% and 82.1% for pts with LT disease control (n=51) and the overall population (n=168), respectively. In X2101, 7 of 52 pts (13.5%) with ABC who received ALP+FUL achieved LT disease control up to 47.8 mo. Conclusions: In this subset of pts with hard-to-treat, endocrine-resistant disease, LT disease control ≥18 mo is meaningful considering median PFS of 4.6-9.3 mo or 9.5-16.4 mo with FUL alone or with cyclin-dependent kinase 4/6 inhibitors, respectively. Here, LT disease control was observed in 2 studies of HR+, PIK3CA-altered ABC, including in pts with poor prognosis, diabetes/pre-diabetes at baseline, and heavy pre-treatment. AE profile was consistent with prior reports and did not preclude LT disease control. Further work is needed to better understand factors influencing LT disease control. Clinical trial information: NCT01219699, NCT02437318.

^aPts with PIK3CA-mutated ABC in the ALP + FUL arm; ^bbased on American Diabetes Association guidelines.