Patients with a/mTNBC have limited treatment options and a poor prognosis (objective response rate [ORR] of 37%, median duration of response of 6.5 months, and median overall survival [OS] of 15.5 months with 1L chemotherapy). Combining immune checkpoint inhibitors with 1L chemotherapy modestly improves outcomes but only in programmed cell death ligand-1 (PD-L1)–high a/mTNBC, emphasizing a critical unmet need for patients with PD-L1–low disease and for further improving outcomes in PD-L1–high disease. BEGONIA (NCT03742102) is an ongoing 2-part, open-label platform study, evaluating the safety and efficacy of durvalumab, an anti–PD-L1 antibody, combined with other novel therapies in 1L a/mTNBC, including Dato-DXd. Dato-DXd is an antibody-drug conjugate consisting of a humanized anti-TROP2 antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. Early data from BEGONIA arm 7 of durvalumab in combination with Dato-DXd were presented at ESMO Breast 2022 (n = 29) and showed promising responses.
The first 6 patients treated with Dato-DXd + durvalumab were evaluated for dose-limiting toxicities (DLTs), no DLTs were observed, and additional patients were enrolled in Part 1 (previously reported); Part 1 ORR evaluation confirmed before proceeding to Part 2 expansion. Tumors were assessed per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 every 6 weeks for the first 48 weeks, then every 12 weeks thereafter. PD-L1 was assessed using the VENTANA PD-L1 (SP263) Assay, and expression was defined as the percentage of the tumor area populated by tumor or immune cells with membranous staining (tumor area positivity [TAP]). A sample was considered PD-L1 high if it demonstrated ≥10% TAP PD-L1 expression. Confirmed response was assessed for patients who had the opportunity for ≥2 on-treatment disease assessments, progressed, or died; unconfirmed response was assessed for patients who had the opportunity for ≥1 on-treatment disease assessment.
As of 22 July 2022, 61 pts received Dato-DXd + D (45 ongoing) and 53 were included in the efficacy analysis. Median follow-up was 7.2 months (range 1–14) months. Pt age was median 53 years, 59% received prior treatment for early stage TNBC, and 57% had visceral metastases at baseline. Confirmed ORR was 39/53 (74%; 95% CI, 59.7%–84.7%) with 4 (7.5%) complete responses; and 35 (66%) partial responses). Responses were observed in PD-L1 high and low tumors; 82% of pts remained in response at data cutoff. Adverse events (AEs) were manageable and consistent with the known safety profiles of each agent, with treatment-related AEs occurring in 60 pts (98%), any-grade 3/4 AEs in 25 pts (41%), and any serious AEs in 10 pts (16%). The most common all-grade AEs were gastrointestinal (nausea, [n= 35; 57%]; stomatitis, [n = 34; 56%]). A low rate of diarrhea was reported (n = 8 [13%], 7 grade 1/2, 1 grade 3), and 2 (3.3%) pts had neutropenia (both grade 2). The adjudication committee confirmed 2 (3.3%) interstitial lung disease/pneumonitis cases. There were no deaths due to treatment-related AEs.
In this updated analysis with a median of 7 months follow-up, the combination of Dato-DXd + durvalumab in 1L a/ mTNBC demonstrated a tolerable and manageable safety profile. A compelling high response rate, with 4 patients having a complete response, was observed with Dato-DXd + durvalumab. Although subgroups were small, responses were observed in PD-L1–high and PD-L1–low tumors. While maturity is low, response durability is promising; longer follow-up will further inform efficacy results, including PFS. Further investigation of Dato-DXd + durvalumab is warranted in this patient population.
Jamil Asselah,1 Cynthia X. Ma,2 Zbigniew Nowecki,3 Robert Huisden,4 Ross Stewart,4 Petra Vuković,4 Peter Schmid5
1McGill University Health Centre, Montreal, Quebec, Canada.
2Washington University School of Medicine, St. Louis, MO.
3Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
4AstraZeneca, Cambridge, UK.
5Barts Cancer Institute, Queen Mary University of London, London, UK.