Abstract PS5-02-28: Safety analysis of phase 3 ASCENT-04 study of sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro for previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC)

Abstract Background: SG is a Trop-2-directed antibody-drug conjugate approved for patients (pts) with previously treated mTNBC. In PD-L1+ mTNBC, SG + pembro demonstrated statistically significant and clinically meaningful progression-free survival improvement vs chemo + pembro in the phase 3 ASCENT-04/KEYNOTE-D19 study; we report the first in-depth safety analysis. Methods: Pts were randomized 1:1 to SG (10 mg/kg IV, days 1 and 8) + pembro (200 mg, day 1, max 35 cycles) in 21-day cycles or chemo (gem + carbo, pac, or nab-pac) + pembro until disease progression or unacceptable toxicity. Exploratory analysis of exposure-adjusted incidence rates (EAIRs) was performed, defined as number of pts with ≥1 specified treatment-emergent adverse event (TEAE) per pt-year of exposure. Incidence, severity, time to onset, duration, and impact of AE management were assessed for select TEAEs for SG and/or pembro. Results: 441 pts (SG + pembro: 221; chemo + pembro: 220) were included in the analysis. EAIRs, time to onset and duration of TEAEs of interest, and immune-mediated (im)AE rates are summarized in the Table. G-CSF as primary prophylaxis was used in 43 (19%) and 20 (9%) pts in the SG + pembro and chemo + pembro arms, respectively; as secondary prophylaxis, G-CSF was used in 75/122 (61%) and 37/118 (31%) eligible pts. Incidence of grade ≥3 neutropenia was 35% with SG + pembro and 50% with chemo + pembro in pts who received G-CSF as primary prophylaxis; 50% and 45% in those who did not. Diarrhea was experienced by 155 (70%) and 63 (29%) pts in the SG + pembro and chemo + pembro arms, respectively; most cases were grade 1 (37% vs 17%) or 2 (24% vs 10%) diarrhea (60% vs 26% grade 1/2). The proportion of pts with diarrhea leading to dose reduction was similar in both arms (5% vs 1%) and there was no discontinuation due to diarrhea in the SG + pembro arm. Among pts with diarrhea, antidiarrheal treatment (tx) was used for 101 (65%) pts who received SG + pembro including loperamide (93%) and atropine (12%). The imAE of colitis occurred in 13 (6%) and 3 (1%) pts in the SG + pembro and chemo + pembro arms, respectively; one led to discontinuation in the SG + pembro arm. Colitis was managed according to pembro labeling guidance. Conclusions: In pts with previously untreated PD-L1+ mTNBC, EAIRs were generally similar between tx arms. With SG + pembro, there was a lower rate of TEAEs leading to dose reduction or discontinuation and a higher rate of any TEAEs; the rate of imAEs was lower vs chemo + pembro, although diarrhea and colitis were higher. Neutropenia, diarrhea, and colitis were manageable with supportive care. The overall safety profile was consistent with that of each agent, with no exacerbation of imAEs. Taken with previously reported efficacy benefit, these data support a favorable benefit/risk profile for SG + pembro vs chemo + pembro in this population. Citation Format: K. Kalinsky, P. Schmid, E. de Azambuja, S. Loi, S. Kim, C. Yam, B. Rapoport, S. Im, B. Pistilli, W. Mchayleh, D. W. Cescon, J. Watanabe, M. Bañuelas, R. Freitas-Junior, A. Lortholary, D. Gary, K. Caldwell, E. Harting, S. M. Tolaney. Safety analysis of phase 3 ASCENT-04 study of sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro for previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC) [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 PS5-02-28.