Abstract PS4-12-26: Neosaci-io: neoadjuvant sacituzumab govitecan (sg) + pembrolizumab (pb) in patients (pts) with early-stage tnbc experiencing suboptimal response to keynote-522

Abstract Background: Pts with residual disease (non-pCR) after the KEYNOTE-522 regimen face a 30-40% risk of recurrence within 3 years, underscoring the urgent need for more effective therapies. In preliminary analyses, we identified that ≤80% tumor reduction after 4 cycles of paclitaxel+carboplatin (PC) + pembrolizumab (Pb) predicted a pCR rate of only ∼20%, defining a biologically aggressive subgroup at risk of early recurrence and reduced survival. SG has demonstrated superior clinical efficacy over conventional chemotherapy in metastatic TNBC and emerging data suggest that SG enhances the efficacy of anti-PD-(L)1 therapy. Given the paucity of available evidence regarding the effectiveness of SG with Pb in the neoadjuvant setting, particularly in pts with suboptimal response to PC+Pb, we conducted the first trial of SG+Pb as sequential neoadjuvant therapy (NAT) in pts with high-risk, early-stage TNBC (NCT05675579). Methods: Pts with stage II-III TNBC and suboptimal response to PC+Pb, defined as disease progression or a ≤80% reduction in tumor volume by breast imaging, were eligible. Pts received SG (10mg/kg IV, D1 & 8) + Pb (200mg IV, D1) every 21 days x 4 cycles as the second phase of NAT before undergoing surgery. Blood and tumor biospecimens were collected prior to initiating SG+Pb and at surgery for correlative studies. We employed the Bayesian Optimal Phase II design to detect an improvement in pCR rate from 20% to 45% in order to deem the regimen worthy of further study in a randomized, phase III trial. Success was defined as pCR in 9 out of 25 response-evaluable pts (alpha=4.6%, power=85.8%). Pts not evaluable for response were replaced to ensure N=25 response-evaluable pts. Results: 27 pts were enrolled from 6/22/2023-5/23/2025. All 27 pts were evaluable for safety, and 25 pts were evaluable for response (1 pt completed <2 cycles of study treatment due to an unrelated adverse event; 1 pt was found to have an ineligible histology at surgery). Among the 25 response-evaluable pts, the pCR rate was 48% (95% CI: 28-69%). Clinicopathological characteristics are described in Table 1. Treatment-related adverse events (TRAE, all grades) occurring in ≥20% of safety-evaluable pts included neutropenia (78%), fatigue (37%), leukopenia (30%), and anemia (26%). 16 pts (59%) experienced grade ≥3 neutropenia. Of the 27 safety-evaluable pts, 24 (89%) completed all 4 planned cycles of SG+Pb. The remaining 3 pts discontinued study treatment early due to TRAEs (n=1), AEs unrelated to study treatment (n=1), and disease progression (n=1). Conclusion: These data provide the first evidence of SG+Pb as an effective treatment option in pts with high-risk, early-stage TNBC experiencing poor response to PC+Pb (pCR=48% vs 20% in historical controls), with no new safety signals. Correlative proteomic (including TROP2 IHC), genomic, and immunological studies are ongoing. Citation Format: C. Yam, T. Iwase, B. Nelson, R. L. Bassett Jr, A. Singareeka, G. Whitman, M. Karuturi, B. Adrada, D. Kizub, M. Guirguis, A. Buzdar, T. Moseley, A. Nwosu-Iheme, M. Kapoor, J. Sukumar, P. Thomas, C. H. Barcenas, N. Ibrahim, G. Moscol, A. Nasrazadani, D. Ramirez, M. Wright, J. Lee, W. A. Woodward, J. K. Litton, K. K. Hunt, S. Giordano, D. Tripathy, V. Valero, L. Huo, G. M. Rauch, N. T. Ueno. Neosaci-io: neoadjuvant sacituzumab govitecan (sg) + pembrolizumab (pb) in patients (pts) with early-stage tnbc experiencing suboptimal response to keynote-522 [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 PS4-12-26.