Background: Patients (pts) with metastatic triple-negative breast cancer (mTNBC) who have brain metastases represent a poor prognosis cohort with a high unmet clinical need. Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, an active metabolite of irinotecan, via a unique hydrolyzable linker that allows for SN-38 release intracellularly and in the tumor microenvironment (bystander effect). SN-38 can cross the blood-brain barrier and is a drug partner in central nervous system (CNS) disease regimens (PMID: 18784279; PMID: 26080460). Although antibody-based therapy raises concerns regarding CNS penetration, activity with SG has been seen in intracranial xenograft models (Brenner Neurooncol Adv 2019). In a subgroup analysis from ASCENT, the efficacy and safety of SG were evaluated in pts with stable brain metastases.

Methods: In the phase 3 ASCENT study (NCT02574455), 529 pts with mTNBC refractory to or relapsing after at least 2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg IV on days 1 and 8 every 21 days) or single-agent treatment of physician’s choice (TPC; capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. Brain MRIs were required in pts with known brain metastases who were eligible if they had stable CNS disease for ≥4 wk by MRI. Per protocol, stable disease was defined as ≥2 wk from discontinuation of antiseizure medication and corticosteroid dose (≤20 mg prednisone equivalent) that was stable or decreasing for ≥2 wk before randomization. In these pts, brain MRIs were required throughout the study. The primary endpoint was progression-free survival (PFS) per independent central review (RECIST v1.1) in brain metastases-negative pts. Secondary endpoints included PFS per investigator assessment, PFS in the full population (in pts with/without brain metastases) by central review, objective response rate (ORR), overall survival (OS), and safety.

Results: Overall, 61 of 529 (12%) enrolled pts had stable brain metastases at screening and were randomized to SG (n=32) or TPC (n=29). Median age was 53 y for SG and 51 y for TPC; all pts were female and had a median of 5 prior anticancer regimens. In this subset, median PFS was 2.8 mo (95% CI, 1.5-3.9) for SG vs 1.6 mo (95% CI, 1.3-2.9) for TPC by central review, and median OS was 6.8 mo (95% CI, 4.7-14.1) for SG vs 7.5 mo (95% CI, 4.7-11.1) for TPC. ORR for SG vs TPC, respectively, was 3% (1/32) vs 0% by central review, with a clinical benefit rate of 9.4% vs. 3.4%. Stable disease was achieved in 15 (47%) pts with SG vs 9 (31%) pts with TPC. In 53 pts who received at least 1 dose of treatment (SG, n=30; TPC, n=23), any-grade treatment-emergent adverse events (>20% with SG) for SG vs TPC were fatigue (63% vs 52%), diarrhea (50% vs 13%), neutropenia (43% vs 35%), nausea (43% vs 26%), decreased appetite (30% vs 17%), decreased neutrophil count (33% vs 22%), anemia (23% vs 35%), alopecia (23% vs 13%), and constipation (23% vs 22%). There were no treatment-related deaths. Two pts treated with SG are continuing study treatment for 16.2 and 6.3 mo as of the data cutoff date.

Conclusions: Data interpretation in this population with poor prognosis is limited by the small sample size. In this exploratory analysis of pts with brain metastases from the phase 3 ASCENT study, SG was numerically better than TPC for tumor response and PFS but not OS. The safety profile was similar to that of the population without brain metastases for both study arms. SG is currently under clinical investigation for pts undergoing elective craniotomy for breast cancer with brain metastases or recurrent glioblastoma (NCT03995706) based on promising preclinical and intracranial clinical data.

Citation Format: Véronique Diéras, Robert Weaver, Sara M. Tolaney, Aditya Bardia, Kevin Punie, Adam Brufsky, Hope S. Rugo, Kevin Kalinsky, Tiffany Traina, Leonard Klein, Delphine Loirat, Filipa Lynce, Brooke Daniel, Foluso Ademuyiwa, Sara A. Hurvitz, David M. Goldenberg, Quan Hong, Martin Olivo, Loretta M. Itri, Lisa Carey. Subgroup analysis of patients with brain metastases from the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD13-07.