Background Trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in pretreated patients with HER2-positive advanced breast cancer (ABC), but its efficacy has not yet been evaluated in patients with active brain metastases (BMs). DEBBRAH aims to assess T-DXd in patients with HER2-positive or HER2-low ABC and central nervous system involvement. Methods This ongoing, five-cohort, phase II study (NCT04420598) enrolled patients with pretreated HER2-positive or HER2-low ABC with stable, untreated, or progressing BMs and/or leptomeningeal carcinomatosis. Here, we report findings from HER2-positive ABC patients with non-progressing BMs after local therapy (n=8; cohort 1), asymptomatic untreated BMs (n=4; cohort 2), or progressing BMs after local therapy (n=9; cohort 3). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was 16-week progression-free survival (PFS) for cohort 1 and intracranial overall response rate (ORR-IC) for cohorts 2 and 3. Results As of October 20, 2021, 21 patients received T-DXd. In cohort 1, 16-week PFS rate was 87.5% (95%CI, 47.3–99.7; P<.001). ORR-IC was 50.0% (95%CI, 6.7–93.2) in cohort 2 and 44.4% (95%CI, 13.7–78.8; P<.001) in cohort 3. Overall, the ORR-IC in patients with active BMs was 46.2% (95%CI, 19.2–74.9). Among patients with measurable intracranial or extracranial lesions at baseline, the ORR was 66.7% (12 out of 18 patients; 95%CI, 41.0–86.7), 80.0% (95%CI, 28.4–99.5) in cohort 1, 50.0% (95%CI, 6.7–93.2) in cohort 2, and 66.7% (95%CI, 29.9–92.5) in cohort 3. All responders had partial responses. The most common adverse events included fatigue (52.4%; 4.8% grade≥3), nausea (42.9%; 0% grade≥3), neutropenia (28.6%; 19% grade≥3), and constipation (28.6%; 0% grade≥3). Two (9.5%) patients suffered grade 1 interstitial lung disease/pneumonitis. Conclusions T-DXd showed intracranial activity with manageable toxicity and maintained quality of life in pretreated HER2-positive ABC patients with stable, untreated, or progressing BMs. Further studies are needed to validate these results in larger cohorts.

Background: Approximately 30% to 40% of patients (pts) with HER2[+] advanced breast cancer (ABC) will develop brain metastases (BM) during the course of their disease. Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate containing an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In the phase 2 DESTINY-Breast01 trial, T-DXd showed efficacy in the subgroup of HER2[+] ABC pts with stable BM at baseline. DEBBRAH is assessing the efficacy and safety of T-DXd in HER2[+] and HER2-low-expressing ABC pts with a history of BM and/or leptomeningeal carcinomatosis (LMC). Here, we report primary results from cohorts A and C. Methods: This is an ongoing, multicenter, open-label, 5-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-expressing ABC with stable, progressing, or untreated BM and/or LMC are being enrolled in 5 cohorts: (A) HER2[+] ABC with non-progressing BM after radiotherapy and/or surgery; (B) HER2[+] or HER2-low-expressing ABC with asymptomatic untreated BM; (C) HER2[+] ABC with progressing BM after local treatment; (D) HER2-low-expressing ABC with progressing BM after local treatment; (E) HER2[+] or HER2-low-expressing ABC with LMC. In cohorts A and C, pts must have received prior taxane and ≥1 HER2-targeted therapy for ABC. Pts received 5.4 mg/kg T-DXd intravenously on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint for cohort A is 16-week progression-free survival (PFS) per local assessment using RANO-BM for central nervous system (CNS) lesions and RECIST v.1.1 for extracranial lesions (H0: 5%); for cohort C, CNS overall response rate (ORR; H0: 10%). A single-arm binomial design is used for cohorts A and C. A futility interim analysis has been planned in cohort A after accrual of 4 pts. Sample size was planned to attain an 80% power at nominal level of one-sided α of 0.05 in each cohort. Results: Between Jun 29, 2020, and Feb 18, 2021, 26 pts were allocated in the study. Enrollment is complete in cohorts A (n=8 pts) and C (n=9 pts), and ongoing in the remaining cohorts. At data cutoff (May 21, 2021), median follow-up for the cohort A was 5.5 months (IQR 4.4-6.9) and 6.2 months (IQR 5.1-6.4) for the cohort C. In the cohort A, 6 (75.0%) of 8 pts were alive without disease progression at 16 weeks, reaching the primary endpoint (p<0.01). In the cohort C, the CNS ORR was 55.6% (5 pts with partial response), also meeting the primary endpoint (p<0.01). At the time of this analysis, 75.0% of pts of the cohort A and 55.6% of the cohort C remained on therapy. The most frequent adverse events of any grade in 26 pts who received at least 1 dose of T-DXd were fatigue (11 [42.3%]; 3.8% of grade 3), nausea (10 [38.5%]), a decreased neutrophil count (9 [34.6%]; 11.5% of grade 3), and anemia (6 [23.1%]). Treatment-related serious adverse events occurred in 1 (3.8%) of 26 pts due to grade 1 pneumonitis. No treatment-related deaths were reported. Conclusions: T-DXd demonstrated preliminary efficacy with manageable toxicity in pretreated pts with HER2[+] ABC with stable and progressing BM after local treatment. Further investigation is required in larger cohorts to validate these findings. The assessment of the T-DXd antitumor activity in cohorts B, D, and E is currently ongoing. Citation Format: Marta Vaz Batista, Patricia Cortez, Manuel Ruiz, Juan Miguel Cejalvo, Juan de la Haba, Laia Garrigós, Fabricio Racca, Sonia Servitja, Salvador Blanch, Iris Teruel, José Manuel Pérez-García, María Gion, Monica Nave, Antonio Llombart-Cussac, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortes, Sofia Braga. Trastuzumab deruxtecan in patients with HER2[+] or HER2-low-expressing advanced breast cancer and central nervous system involvement: Preliminary results from the DEBBRAH phase 2 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-06.

Background: Endocrine therapy (ET) is the preferred therapy option for patients (pts) with hormone receptor-positive (HR[+]) advanced breast cancer (ABC), except for pts with visceral crisis who often receive chemotherapy to achieve rapid symptom control. Cyclin-dependent kinases 4/6 inhibitors have improved the effectiveness of ET across all subgroups of pts with ABC by targeting potential mechanisms of resistance. An exploratory analysis revealed that the addition of abemaciclib to ET conferred the largest benefit in pts with poor prognostic characteristics (liver metastases, high grade tumors, or progesterone receptor-negative status) [Di Leo, NPJ Breast Cancer 2018; 4: 41]. ABIGAIL aims to provide consistent evidence that abemaciclib plus ET is superior or non-inferior to paclitaxel in terms of early overall response as first-line regimen in HR[+], HER2-negative ABC pts with poor prognosis. Trial Design: This is a multicenter, randomized, open-label, phase 2 trial. Eligible participants are men and women of any menopausal status aged ≥18 years with HR[+], HER2-negative ABC who had no prior systemic therapy in the advanced setting and at least one of the following aggressive disease criteria: (i) Visceral disease; (ii) High histological grade and/or progesterone receptor-negative status; (iii) Lactate dehydrogenase >1.5 × the upper limit of normal; (iv) Relapse while on or within 36 months of completing adjuvant ET. Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease as per RECIST 1.1, and adequate organ function are also required. A total of 160 pts will be randomly assigned (1:1) to receive abemaciclib (300 mg/day orally during each 28-day cycle) plus ET as per investigator’s criteria (either letrozole [2.5 mg/day orally] or fulvestrant [500 mg intramuscularly on days 1, 15 of cycle 1, and on day 1 thereafter], or paclitaxel (90 mg/m² intravenously on days 1, 8, 15). Men and pre-/peri-menopausal women will receive a gonadotropin-releasing hormone agonist if randomized to abemaciclib plus ET. At investigator’s discretion, pts in the paclitaxel arm could receive abemaciclib plus ET at any point after the first 12 weeks or extend chemotherapy for a total of 6 cycles. Randomization will be stratified according to the presence of visceral disease and endocrine therapy. The primary endpoint is 12-week overall response rate (ORR) as per RECIST 1.1. Key secondary endpoints include ORR, clinical benefit rate, 12-week progression-free survival, progression-free survival, time to response, duration of response, overall survival, time to first subsequent therapy, time to second subsequent therapy, and time to first chemotherapy for pts in abemaciclib plus ET arm, patient-reported outcomes, and safety as per NCI-CTCAE 5.0. The sample size assumes the comparison of two proportions in an asymptotical normal test. We expect that 12-week ORR will be higher in the abemaciclib plus ET arm than paclitaxel arm (30% vs. 15%), with the assumption of a 5% non-inferiority margin. Based on a 10% dropout rate, a sample size of 160 pts is necessary to attain 80% power at nominal level of two-sided alpha of 0.05. We will test the superiority of abemaciclib plus ET as compared with paclitaxel if the non-inferiority is achieved. Both analyses, will be conducted with the Newcombe hybrid score method for confidence intervals. This trial was opened to accrual in May 2021. Citation Format: Antonio Llombart-Cussac, Joseph Gligorov, Serena Di Cosimo, Cinta Albacar, Patricia Cortez, Eduardo Martinez-De Dueñas, Ana López, Vicente Carañana, Jacques Medioni, Luigi Cavanna, Marina Elena Cazzaniga, Sofia Braga, Passos Coelho, Miguel Sampayo-Cordero, Andrea Malfettone, José Manuel Pérez-García, Javier Cortes. Phase 2 study of abemaciclib in combination with endocrine therapy with or without paclitaxel induction in patients with hormone receptor-positive, HER2-negative advanced breast cancer and aggressive disease criteria: ABIGAIL [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-19-06.