Background: Sacituzumab govitecan (SG), a novel antibody-drug conjugate in which the topoisomerase 1 inhibitor SN-38 (active metabolite of irinotecan) is linked to a humanized monoclonal antibody targeting the tumor antigen Trop2, is currently approved for treatment of patients (pts) with pre-treated metastatic triple negative breast cancer (TNBC). We conducted a phase 2 study evaluating neoadjuvant (NA) SG as upfront therapy for pts with localized TNBC (NCT04230109). The primary objective was to assess pathological complete response (pCR) rate in breast and lymph nodes (ypT0/isN0) with SG. Secondary objectives included assessment of radiological response rate, evaluation of the safety and tolerability (CTCAE v5.0) and event-free survival (EFS). Methods: Patients with localized TNBC (tumor size ≥1cm, or any size if node positive) with no prior treatment were eligible. SG was administered IV on Days 1, 8 of each 21-day cycle at a starting dose of 10 mg/kg for 4 cycles. After 4 cycles, patients with biopsy-proven residual disease, considered as no pCR for primary endpoint, had the option to receive additional NA therapy at the discretion of the treating physician. Radiologic response (US or MRI) was defined by RECIST version 1.1 using a composite response of CR & PR. Standard descriptive statistics were utilized, including 95% binomial confidence intervals for all rates estimated. Results: From 7/14/20 – 8/31/21, 50 pts were enrolled (median age = 48.5; 11 stage I disease, 24 stage II, 11 stage III, 4 unknown; 62% node negative). The majority (98%; n = 49) of pts completed 4 cycles of SG. Overall, the radiological response rate with SG alone was 62% (n = 31, 95% CI 48%, 77%). 26 pts proceeded directly to surgery after SG. Overall, the pCR rate with SG alone was 30% (n = 15/50, 95% CI 18%, 45%). The other 11 pts had RCB-1 (n = 3), RCB-2 (n = 5), and RCB-3 (n = 3) disease, respectively. Of the 24 pts who received additional NA therapy, 6 had a pCR (3 received anthracycline-based regimen, 2 carboplatin/taxane, and 1 docetaxel/cyclophosphamide). Among pts with a germline BRCA mutation (n = 8), 7 proceeded directly to surgery after SG and 6 had a pCR (86%, 95% CI 42%, 99%). The most common AEs with SG were nausea (82%, n = 41), fatigue (78%, n = 39), alopecia (76%, n = 38), neutropenia (58%, n = 29), anemia (36%, n = 18), and rash (48%, n = 24). 6% of pts required dose-reduction. No pts discontinued SG therapy due to disease progression or AEs; 1 discontinued due to minimal response per investigator preference. At the time of data cut-off (1/18/22), no pts experienced disease recurrence. Updated biomarker and EFS results will be presented at the meeting. Conclusions: In the first neoadjuvant trial in TNBC with an ADC, SG demonstrated single agent efficacy in localized TNBC. Further research on optimal duration of SG as well as NA combination strategies, including immunotherapy, are needed. Clinical trial information: NCT04230109.