Abstract PD7-02: Trastuzumab Deruxtecan in patients with Unstable Central Nervous System Involvement from HER2-Low Advanced Breast Cancer: The DEBBRAH Trial
Authors: Pérez-García José Manuel , Batista Marta Vaz , Cortez-Castedo Patricia , Borrego Manuel Ruiz , Cejalvo Juan Miguel , de la Haba-Rodríguez Juan , Garrigós Laia , Racca Fabriccio , Servitja Sonia , Blanch Salvador , Gión Maria , Nave Mónica , Fernández Adela , Martínez-Bueno Alejandro , Llombart-Cussac Antonio , Sampayo-Cordero Miguel , Malfettone Andrea , Cortés Javier , Braga Sofía 
Published: March 2023

Abstract
Background: The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) significantly improved survival outcomes of HER2-low advanced breast cancer (ABC) patients (pts) compared to standard chemotherapy in the DESTINY-Breast04 trial. DEBBRAH is assessing the efficacy and safety of T-DXd in HER2[+] and HER2-low ABC pts with a history of brain metastases (BM) and/or leptomeningeal carcinomatosis (LMC); here, we report results of HER-low ABC pts. Methods: DEBBRAH (NCT04420598) is a multicenter, open-label, five-cohort, non-comparative, phase 2 study across 18 hospitals in 2 countries. A total of 39 pts aged ≥18 years with pretreated HER2[+] or HER2-low ABC with stable, progressing, or untreated BM and/or LMC, were enrolled in 5 cohorts: (1) HER2[+] ABC with non-progressing BM after radiotherapy and/or surgery; (2) HER2[+] or HER2-low ABC with asymptomatic untreated BM; (3) HER2[+] ABC with progressing BM after local treatment; (4) HER2-low ABC with progressing BM after local treatment; (5) HER2[+] or HER2-low ABC with LMC. Pts received 5.4 mg/kg T-DXd intravenously once every 21 days until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint for cohorts 2 and 4 was intracranial overall response rate (ORR-IC) according to RANO-BM. Secondary endpoints included overall response (ORR) according to RECIST v1.1, progression-free survival (PFS), duration of response (DoR), clinical benefit rate (CBR); and safety and tolerability as per NCI-CTCAE v.5.0. Primary analysis is the estimation of ORR-IC (H0: ORR-IC ≤5%; H1: ORR-IC ≥40%) based on the one-sided binomial exact test. Sample size was planned to attain an 80% power at a nominal α level of 0.05 in each cohort. Results from cohort 2 should be considered descriptive since formal testing has to be performed in the whole cohort of pts with HER2[+] or HER2-low ABC and asymptomatic untreated BM. Results: From Oct 23, 2020, through Feb 15, 2022, 6 pts and 7 pts were allocated into cohorts 2 and 4, respectively. One patient with LMC included in cohort 4 was excluded from analysis. Median age was 54 (range 40–73) years. Median number of previous lines of therapy for advanced disease was 7 (range, 4-8) and 3 (range, 2-4) for cohorts 2 and 4, respectively. Median follow-up was 9.5 months (range, 1.6-15.7). At data cutoff (Apr 29, 2022), no patient of cohort 2 and 3 (50.0%) pts of cohort 4 remained on therapy. In cohort 2, ORR-IC was 66.7% (4 of 6 pts had intracranial partial response [PR]; 95% CI, 22.3–95.7). In cohort 4, ORR-IC was 33.3% meeting the primary endpoint (2 of 6 pts had intracranial PR; 95% CI, 4.3–77.7; P = .033). Overall, ORR-IC in all pts was 50% (6 of 12 pts; 95% CI, 21.1-78.9) and CBR was 66.7% (8 of 12 pts; 95% CI, 34.9-90.1). Combining pts with measurable intracranial or extracranial disease from cohorts 2 and 4, ORR, CBR and median DoR were 41.7% (5 of 12 pts; 95% CI, 15.2–72.3), 50.0% (6 of 12 pts; 95% CI, 21.1–78.9), and 7.2 months (95% CI, 2.5-16.4), respectively. Median PFS was 5.7 months (95% CI, 4.7-NA) among these pts. The most common treatment emergent adverse events (TEAEs) of any grade (G) were fatigue (58.3%; 8.3% G≥3) and nausea (50.0%; 0% G≥3). Two (16.7%; 0% G≥3) cases of interstitial lung disease/pneumonitis were reported. Serious unrelated TEAEs occurred in 2 (16.7%) of 12 pts; 1 case of general pain (G3) and 1 case of venous embolism (G5) that led to death. There were no drug-related deaths due to TEAEs. Conclusions: T-DXd showed a preliminary antitumor activity in pretreated HER2-low ABC pts with asymptomatic untreated or progressing BM after local treatment. The substantial response of BM to T-DXd in this setting is promising and warrants further investigation.
Citation Format: José Manuel Pérez-García, Marta Vaz Batista, Patricia Cortez-Castedo, Manuel Ruiz Borrego, Juan Miguel Cejalvo, Juan de la Haba-Rodríguez, Laia Garrigós, Fabriccio Racca, Sonia Servitja, Salvador Blanch, Maria Gión, Mónica Nave, Adela Fernández, Alejandro Martínez-Bueno, Antonio Llombart-Cussac, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortés, Sofía Braga. Trastuzumab Deruxtecan in patients with Unstable Central Nervous System Involvement from HER2-Low Advanced Breast Cancer: The DEBBRAH Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-02.