datopotamab deruxtecan (DS-1062a)

P2, N=531, Recruiting, AstraZeneca | Trial completion date: Mar 2025 --> Aug 2026 | Trial primary completion date: Mar 2025 --> Aug 2026

P1/2, N=240, Recruiting, AstraZeneca | Trial completion date: Aug 2024 --> Nov 2024 | Trial primary completion date: Aug 2024 --> Nov 2024

In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.

In lung cancer, trastuzumab deruxtecan (T-DXd) is approved in human epidermal growth factor receptor 2 (HER2)-mutated, unresectable or metastatic non-small cell lung cancer, with ADCs targeting HER3 (patritumab deruxtecan), trophoblast cell-surface antigen 2 (datopotamab deruxtecan and sacituzumab govitecan [SG]) and mesenchymal-epithelial transition factor (telisotuzumab vedotin) in late-stage clinical development. In breast cancer, several agents are already approved and widely used, including trastuzumab emtansine, T-DXd and SG, and multiple late-stage trials are ongoing...The ETOP IBCSG Partners Foundation are driving strong collaborations in this field and promoting the generation/sharing of databases, repositories and registries to enable greater access data. This will allow the most important research questions to be identified and prioritised, which will ultimately accelerate progress and help to improve patient outcomes.

P3, N=740, Recruiting, Daiichi Sankyo | Trial completion date: Jun 2026 --> Apr 2028 | Trial primary completion date: Jun 2026 --> Feb 2028

P1, N=140, Recruiting, Daiichi Sankyo | Trial completion date: Feb 2029 --> Nov 2028 | Trial primary completion date: Feb 2029 --> Nov 2028

P3, N=675, Not yet recruiting, AstraZeneca

P2, N=137, Active, not recruiting, Daiichi Sankyo | Trial completion date: May 2026 --> Dec 2024

P1, N=140, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

P3, N=582, Not yet recruiting, AstraZeneca

P2, N=137, Active, not recruiting, Daiichi Sankyo | Trial completion date: May 2024 --> May 2026

P1/2, N=490, Recruiting, AstraZeneca | Trial primary completion date: Apr 2025 --> Jan 2026

This article summarizes the incidence of AESIs among patients with HR+/HER2- BC, TNBC, and NSCLC reported in TROPION-PanTumor01. We report our recommendations for AESI prophylaxis, early detection, and management, using experience gained from treating AESIs that occur with Dato-DXd in clinical trials.

P2, N=58, Recruiting, Sarah Sammons, MD | Not yet recruiting --> Recruiting | Initiation date: May 2024 --> Dec 2023

P=N/A, N=0, Available, Daiichi Sankyo

P2, N=248, Active, not recruiting, AstraZeneca | Trial completion date: Nov 2025 --> May 2025 | Trial primary completion date: Nov 2025 --> May 2025

P2, N=490, Recruiting, AstraZeneca | N=350 --> 490

P1, N=140, Not yet recruiting, Daiichi Sankyo, Inc.

P1, N=145, Active, not recruiting, Daiichi Sankyo, Inc. | Phase classification: P1b --> P1 | Trial completion date: Oct 2024 --> Jun 2025 | Trial primary completion date: Dec 2023 --> Jun 2025

From the first-generation ADC, trastuzumab emtansine (T-DM1), approved in 2013 for HER2+ breast cancer, to next generation ADCs such as sacituzumab govitecan and trastuzumab deruxtecan, to emerging ADCs on the horizon, we continue to see unparalleled efficacy compared to traditional chemotherapy...Highlighting emerging ADCs and ongoing clinical trials, we will anticipate the changes in the breast cancer treatment paradigm. Lastly, we will outline the available data and current approaches for adverse event management and sequencing strategies for ADCs in clinical practice, including proposed mechanisms of resistance.

P1; Phase classification: P1b --> P1 | N=232 --> 321

P2, N=58, Not yet recruiting, Sarah Sammons, MD

P3, N=590, Active, not recruiting, Daiichi Sankyo, Inc.

P3; N=740; Recruiting; Sponsor:Daiichi Sankyo, Inc.

P1/2, N=490, Recruiting, AstraZeneca | N=270 --> 490 | Trial primary completion date: Sep 2024 --> Apr 2025

In heavily pretreated pts with a/m urothelial cancer, Dato-DXd demonstrated a tolerable and manageable safety profile with encouraging antitumor activity. Dato-DXd is being evaluated in pts with urothelial cancer as part of the phase 1/2 TROPION-PanTumor02 (NCT05460273) and the phase 2 TROPION-PanTumor03 (NCT05489211) studies. Clinical trial information: NCT03401385.*Stomatitis (n=2), lymphocyte count decreased (n=1).

P3, N=1728, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P3; N=975; Recruiting; Sponsor:Daiichi Sankyo, Inc.

P3; Not yet recruiting --> Recruiting

P2, N=250, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

P1/2, N=804, Recruiting, AstraZeneca | N=604 --> 804

P2, N=137, Active, not recruiting, Daiichi Sankyo, Inc. | Trial primary completion date: Sep 2023 --> Mar 2023

BEGONIA is an ongoing Simon 2-stage, multicenter, multi-arm platform study evaluating the safety and efficacy of durvalumab (D), an anti–PD-L1 monoclonal antibody, with or without paclitaxel, in combination with novel oncology therapies as first-line treatment for a/mTNBC (NCT03742102). TROP2 expression will be assessed by IHC. Enrollment is ongoing.

Pts were randomized 1:1 to Dato-DXd (6 mg/kg Q3W) or ICC (eribulin, vinorelbine, capecitabine, or gemcitabine) until progression or unacceptable toxicity. TROPION-Breast01 met its dual primary endpoint of PFS, demonstrating statistically significant and clinically meaningful improvement in PFS with Dato-DXd compared with ICC across all subgroups. Overall, the safety profile and QoL with Dato-DXd was favorable compared with ICC. These data support Dato-DXd as a potential new therapeutic option for pts with inoperable or metastatic HR+/HER2‒ BC who have received 1‒2 prior lines of CT.

P3, N=1728, Not yet recruiting, AstraZeneca

P2, N=350, Recruiting, AstraZeneca | Trial completion date: Mar 2026 --> Dec 2028 | Trial primary completion date: Mar 2026 --> Dec 2028

P3; N=625; Not yet recruiting; Sponsor:AstraZeneca

Methods Adult pts with inoperable or metastatic HR+/HER2-BC, who had experienced progression on endocrine therapy (ET) and for whom ET was unsuitable, and who had received 1-2 prior lines of systemic chemotherapy (CT), were randomised 1:1 to Dato-DXd (6 mg/kg Q3W) or investigator's choice of CT (ICC; eribulin, vinorelbine, capecitabine, or gemcitabine) until progression or unacceptable toxicity. Results support Dato-DXd as a novel treatment option for pts with inoperable or metastatic HR+/HER2-BC who have received 1–2 prior lines of CT. Table: LBA11 Dato-DXd ICC Efficacy N=365 N=367 PFS Median PFS (BICR), mo (95% CI) 6.9 (5.7‒7.4) 4.9 (4.2‒5.5) HR (95% CI) 0.63 (0.52‒0.76); p<0.0001 Median PFS (investigator assessed), mo (95% CI) 6.9 (5.9‒7.1) 4.5 (4.2‒5.5) HR (95% CI) 0.64 (0.53‒0.76) PFS rate (BICR), % (95% CI)6 mo 9 mo 53.3 (47.7‒58.5)37.5 (31.9‒43.2) 38.5 (32.8‒44.1)18.7 (13.8‒24.3) OS* HR (95% CI) 0.84 (0.62‒1.14) Response Confirmed ORR (BICR), % (n) 36.4 (133) 22.9 (84) Safety N=360 N=351 TRAEs, %Any grade Grade ≥3 93.620.8 86.344.7 AEs associated with dose reduction/discontinuation, % 23.1/3.1 32.2/2.8 ∗23% maturity.AEs, adverse events; mo, months; ORR, objective response rate; TRAEs, AEs possibly related to study treatment.

P3, N=590, Active, not recruiting, Daiichi Sankyo, Inc. | Trial primary completion date: Sep 2023 --> Jan 2024

P1b; Trial completion date: Feb 2025 --> Jan 2026 | Trial primary completion date: Feb 2025 --> Jan 2026

Primary end points are progression-free survival and overall survival; secondary end points include objective response rate, duration of response, safety and presence of antidrug antibodies. Clinical trial registration: NCT05215340 (ClinicalTrials.gov).