Outcomes by lobular (lob) histology status at initial diagnosis in patients (pts) in the INAVO120 phase 3 trial with <i>PIK3CA</i> -mutated (mut), hormone receptor-positive (HR+), HER2-negative (HER2–), endocrine-resistant advanced breast cancer (aBC

1079 Background: INAVO (a highly potent and selective PI3Kα inhibitor that also promotes mut p110α degradation) + PALBO + FULV is approved for PIK3CA mut, HR+, HER2–, endocrine-resistant aBC based on statistically significant and clinically meaningful investigator-assessed progression-free survival (PFS) benefit over PBO + PALBO + FULV in INAVO120 (NCT04191499). We report exploratory analyses of treatment (tx) outcomes by lob histology status documented at initial diagnosis. Methods: Baseline characteristics, PFS, overall survival (OS), objective response rate (ORR), and duration of response (DoR) were evaluated for 53 pts with reported lob only and 64 with reported lob only or mixed lob (lob + ≥1 other selected subtype) histology at initial diagnosis. PIK3CA mut distribution, and association of histology and PFS with CDH1 alteration (alt) status, were also assessed. Results: At the clinical data cut-off for the updated PFS and final OS analyses (Nov 15, 2024), 24 and 29 pts with lob only histology, and 29 and 35 pts with mixed lob histology, were randomized to the INAVO and PBO arms, respectively. Baseline characteristics were balanced across tx arms. Median follow-up was 34.2 and 32.3 months (m) in the INAVO and PBO arms, respectively. Pathogenic CDH1 alts were more frequent in the lob only (65.2%) and mixed lob (58.9%) subgroups compared with no lob histology (6.3%). Efficacy by lob status is shown in the Table. PIK3CA mut distribution was similar across histologies. PFS benefit of INAVO over PBO was observed regardless of baseline CDH1 alt status (hazard ratio 0.3 for CDH1 alt and 0.5 for no alt detected). Conclusions: In this INAVO120 exploratory analysis, efficacy was improved with INAVO vs PBO, regardless of lob histology status at initial diagnosis and CDH1 alt status. This further supports the benefit of INAVO + PALBO + FULV in PIK3CA mut, HR+, HER2–, endocrine-resistant aBC. Clinical trial information: NCT04191499 . Lob only: INAVO n = 24 Non-lob: INAVO n = 137 Lob only: PBO n = 29 Non-lob: PBO n = 135 Mixed lob: INAVO n = 29 Non-mixed lob: INAVO n = 132 Mixed lob: PBO n = 35 Non-mixed lob: PBO n = 129 PFS, m (95% CI) 21.7 (9.3–25.8) 17.2 (11.6–24.3) 7.2 (3.7–9.4) 7.4 (5.8–9.7) 21.7 (11.3–27.9) 16.6 (11.2–24.2) 7.2 (3.8–9.4) 7.4 (5.8–9.7) OS, m (95% CI) NR (18.1–NR) 33.0 (27.1–44.8) 24.1 (11.1–NR) 27.0 (22.8–40.7) NR (28.4–NR) 33.0 (27.0–38.0) 24.1 (11.1–NR) 28.0 (22.8–40.7) ORR, n (%; 95% CI) 15 (62.5; 40.6–81.2) 86 (62.8; 54.1–70.9) 6 (20.7; 8.0–39.7) 40 (29.6; 22.1–38.1) 19 (65.5; 45.7–82.1) 82 (62.1; 53.3–70.4) 7 (20.0; 8.4–36.9) 39 (30.2; 22.5–38.9) DoR, m (95% CI) 21.2 (9.3–NR) 18.7 (12.2–28.3) 11.1 (8.5–NR) 10.7 (7.5–20.2) 20.3 (9.6–NR) 18.8 (11.1–28.7) 11.1 (3.1–NR) 11.1 (7.5–20.2) CI, confidence interval; NR, not reached.