187P Stage I results of a phase II study of datopotamab deruxtecan (DATO-DXd) in triple-negative breast cancer (TNBC) patients (pts) with active brain metastases (TUXEDO-2)

Brain metastases (BM) are a common site of progression in TNBC increasing morbidity and mortality. Strategies providing both intra- and extracranial disease control are urgently required. Dato-DXd is a Trop2-directed antibody-drug conjugate (ADC) with activity in TNBC. Here we report results of the first stage of the prospective single-arm phase II TUXEDO-2 trial investigating activity and safety of Dato-DXd in TNBC pts with active BM. TUXEDO-2 includes adult TNBC pts with newly diagnosed untreated or progressing BM and no indication for immediate local treatment. Dato-DXd is administered at a dose of 6.0 mg/kg once every 3 weeks. The primary endpoint is intracranial response rate (RR) centrally assessed by Response Assessment in Neuro-Oncology (RANO) BM criteria. Secondary endpoints consist of extracranial RR, progression-free survival, overall survival, safety, quality-of-life, and neurocognitive function. Based on a Simon's two-stage design (RR under alternative hypothesis >35%; RR under null hypothesis ≤11%), 8 patients were accrued in the first stage. If ≥2 responses are observed, the trial will accrue an additional 12 pts. As of February 7th, 2022, 8 pts have been accrued; 75% had newly diagnosed BM and 25% progressive BM. Two pts had received prior sacituzumab govitecan and one pt prior T-DXd as well. At the data cut-off, 5 pts were evaluable for response. We observed 3 objective intracranial responses, corresponding to a RR of 37.5%. One pt died from intestinal perforation (not related) and one pt died from extracranial disease progression, each before the first restaging; one pt is not yet evaluable for response. All responses were observed in ADC-naïve pts. Main toxicities consisted of grade 1/2 fatigue. One pt had grade 2 stomatitis and one case of grade 3 interstitial lung disease was detected. With three intracranial responses, the first stage of TUXEDO-2 is positive, and the trial has progressed to the second stage. Treatment was generally well tolerated, and no new safety signals were observed. Dato-DXd may thus provide an opportunity for successful systemic therapy of active BM in TNBC.