Abstract PS1-10-07: Progression free survival and exploratory endpoints from PALVEN: a phase 1b study of palbociclib, letrozole and venetoclax in ER and BCL2-positive metastatic breast cancer

Abstract Background: CDK4/6 inhibitors induce growth arrest/senescence in breast cancer cells, which reduces their susceptibility to apoptotic cell death. In preclinical models, the BCL2 inhibitor venetoclax augmented tumor response to endocrine and CDK4/6 inhibitor (CDK4/6i) therapy by triggering apoptosis. PALVEN is a phase 1b dose escalation study in patients (pts) with ER+ and BCL2+ metastatic breast cancer (MBC). The maximum tolerated and recommended phase 2 dose was defined as letrozole 2.5 mg (d1-28), palbociclib 75 mg (d1-21) and venetoclax 400 mg (d1-21). Here, we report the progression free survival (PFS), overall survival (OS), updated treatment-related toxicity and exploratory endpoints at 48 wks. (NCT03900884) Methods: Postmenopausal women with ER+/HER2- (ASCO/CAP) and BCL2+ MBC who had received ≤2 prior lines of systemic therapy for MBC were included. Tumor assessment occurred every 8 wks (every 12 wks after 24 wks). Secondary endpoints were analyzed once the final pt had been on the study for 48 wks and included PFS and OS. Pre-defined exploratory endpoints included Clinical Benefit Rate (CBR) for: 1st vs 2nd/3rd line metastatic therapy; visceral vs non-visceral metastases; disease-free interval (DFI) following adjuvant endocrine therapy (ET) (relapse on or within 12 mo vs ≥12 mo following completion of ET). Adverse events (AEs) were reported using CTCAE v5.0. Tumor biopsies were collected at baseline and on day 15 of triplet therapy. Results: As of 31 January 2025, 16 pts had received venetoclax, palbociclib and letrozole treatment and 15 were DLT-evaluable (median age 50 yrs [range 36-67]), with a median follow-up of 37.6 months. Eight pts had de novo MBC and 8 pts had relapsed MBC. Seven pts had previously received adjuvant ET with 3 pts having primary endocrine resistance. Four pts had received prior therapy in the metastatic setting; 1st line aromatase inhibitor (3 pts) and chemotherapy and tamoxifen (1 pt). Five pts had visceral metastases and 11 pts had non-visceral or bone-only metastases. The CBR (rate of confirmed complete or partial response or stable disease at 24 wks) was 93% (14/15 pts). CBR for pts treated in the 1st line setting was 12/12 vs 2/3 for pts treated in the ≥2nd line; CBR for pts with visceral disease was 5/5 vs 9/10 for non-visceral disease; 3/3 for pts with primary endocrine resistance versus 3/3 for pts who relapsed >12 mo post-adjuvant ET. Median PFS was 29.2 mo (95% CI: 18.4-not estimable). OS was not mature. Seven pts remained on study therapy including 4 pts who had completed ≥32 months of triplet therapy. Paired tumor samples were available for 6 pts. Following 14 days of triplet therapy all tumors retained ER and BCL2 positivity however a reduction or loss in PR staining was observed in all samples. Ki67 was reduced by at least 50% for all samples with a baseline Ki67 of ≥10%. No additional TRAEs were observed from those previously reported at 24 wks. Grade ≥3 hematological TRAEs were decreased neutrophil count (63%), reduced white cell count (44%) and decreased lymphocyte count (19%). G3 neutropenia (without associated infections) was the main dose-limiting feature of combination therapy. Conclusion: Promising clinical activity has been observed using triplet therapy with palbociclib, letrozole and venetoclax in pts with ER+ MBC selected for BCL2-positive tumor expression. Studies combining ET with potent inhibitors of BCL2 and CDK4/6 (or a CDK4 inhibitor to mitigate CDK6i-associated neutropenia) merit further investigation. Citation Format: F. C. Martin, C. Muttiah, L. Lal, M. Christie, S. Dawson, J. Desai, A. Grobler, K. Moodie, A. Murugasu, P. Phan, M. R. Rosenthal, A. Travers, J. E. Visvader, J. Whittle, B. Yeo, G. J. Lindeman. Progression free survival and exploratory endpoints from PALVEN: a phase 1b study of palbociclib, letrozole and venetoclax in ER and BCL2-positive metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-10-07.