4 Datopotamab Deruxtecan (Dato-DXd) + Durvalumab (D) as First-Line (1L) Treatment for Unresectable Locally Advanced/ Metastatic Triple-Negative Breast Cancer (a/mTNBC): Updated Results From BEGONIA, a Phase 1b/2 Study

Background

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.

Materials and Methods

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.

Results

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.

Conclusions

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.

AFFILIATIONS:

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.