The 2024 European Society for Medical Oncology Annual Meeting on Breast Cancer (ESMO BC) was held in Berlin, Germany from May 15 to 17. As a global international event in the field of breast cancer research held in Europe, ESMO BC covers the latest scientific research achievements and clinical treatment progress, and promotes in-depth exchanges and cooperation between global experts. In this conference, the new trophoblast cell surface antigen 2 (TROP2) antibody conjugate drug (ADC), Datopotamab deruxtecan (Dato-DXd), once again set off a boom in the field of breast cancer, and its TUXEDO-2 study1, which explores the therapeutic effect of brain metastases (BM) in triple-negative breast cancer (TNBC), announced the first phase results, showing good therapeutic potential; The TROPION-Breast01 study2, which focuses on the treatment of hormone receptor-positive (HR+) advanced breast cancer, is back with additional safety analysis results, injecting a cardiobolic agent into clinical use. Yimaitong has compiled the latest data disclosed in the two studies and information about Dato-DXd for readers.
TUXEDO - 2015: READ MORE ABOUTNBC Dato-DXde
BM is a common metastatic modality of TNBC and can increase morbidity and mortality. There is an urgent clinical need to provide effective strategies for intracranial and extracranial disease control in such patients. The TUXEDO-2 study is designed to explore the efficacy and safety of Dato-DXd in TNBC patients with active BM1. Studies primarily included patients with newly diagnosed, untreated BM or BM with TNBC for whom no immediate indication for topical therapy was conducted. Dato-DXd is administered at a dose of 6.0 mg/kg every 3 weeks. The primary endpoint of the study was intracranial response rate (RR) as assessed by the Neuro-Oncology Response Assessment (RANO) BM criteria. Secondary endpoints included extracranial RR, progression-free survival (PFS), overall survival (OS), safety, quality of life, and neurocognitive function. The study was based on a Simon two-stage design (RR >35% under alternative hypothesis; RR ≤11%) under the null hypothesis, and a total of 8 patients were enrolled in the first phase. If ≥ 2 responses are observed, an additional 12 patients will be enrolled in the study. At this congress, the researchers mainly reported the results of the first phase of the study.
- As of February 7, 2022, a total of 8 patients have been enrolled, of which 75% are newly diagnosed BM and 25% are progressive BM. Two patients had been previously treated with gosatuzumab (SG) and one patient had been treated with trastuzumab (T-DXd).
- At the time of data cut-off, 5 patients were evaluable for remission, of which 3 objective intracranial remissions were observed by the investigators, with an RR of 37.5%. One of the remaining patients died of intestinal perforation (not related to treatment), one died of extracranial disease progression, and one could not be assessed for intracranial remission. All cases of intracranial remission were in patients who had not received prior ADC therapy. Major adverse effects (AEs) included grade 1/2 fatigue. In addition, one patient was enrolled with grade 2 stomatitis and one was diagnosed with grade 3 interstitial lung disease (ILD).
Overall, a total of 3 intracranial responses were observed in the TUXEDO-2 study, with positive results in Phase I, and the study has progressed to Phase II. Dato-DXd treatment was generally well tolerated, and no new safety signals were observed. Therefore, Dato-DXd may provide an opportunity for systemic therapy in patients with active BM in TNBC.
TB-01 Study Update: Bright Safety Data, Dato-DXd Brings Peace of Mind to Patients with HR+ Advanced Breast Cancer
TB-01 is a global, randomized, multicenter, open-label, Phase III clinical study to evaluate the efficacy and safety of Dato-DXd versus investigator-selected single-agent chemotherapy (ICC) in patients with unresectable or metastatic HR+/HER2 low expression or negative (IHC 0,1+ or IHC 2+/ISH-) advanced breast cancer who have progressed on prior endocrine therapy or who are not candidates for endocrine therapy (must have received at least 1 systemic regimen)2. Additional safety analysis results were further reported at the conference.
- Previously published efficacy data3 from the TB-01 study showed a significant improvement in BICR-assessed PFS in patients in the Dato-DXd arm compared with the ICC arm (6.9 versus 4.9 months; HR=0.63; 95% CI, 0.52-0.76; p<0.0001), Dato-DXd reduced the risk of disease progression or death by 37% (Fig. 1). In terms of objective response rate (ORR), Dato-DXd achieved 36.4% compared to 22.9% in the ICC arm (Figure 2).
Fig.1 PFS results of TB-01 study
Fig.2 ORR and OS results of TB-01 study
- According to the data of this safety analysis, as of the data cut-off (July 2023), a total of 360 patients were treated with Dato-DXd and 351 patients were treated with ICC. ≥The incidence of G3 treatment-related adverse events (TRAEs) was lower in the Dato-DXd arm compared with the ICC arm (21 versus 45 percent). TRAEs (AESIs) of particular interest in the Dato-DXd arm include stomatitis/oral mucositis (OM), ocular events (OEs), and drug-related ILD. Among them, stomatitis/OM and OE, and drug-related ILD are mostly low-grade (asymptomatic/mild), and OE is mainly manifested as dry eye syndrome. In addition, AESIs typically occur in the first few treatment cycles: stomatitis/OM in cycle 2, OE in cycle 3, and drug-related ILD in cycle 4; The median resolution time of the above AESIs was 37, 67, and 28 days, respectively.
- The most prominent safety event in the ICC arm was high-grade neutropenia (31% ≥G3) and ultimately resulted in dose interruption in 17% of patients and dose reduction in 13% of patients. During the overall treatment period, both groups were well managed according to toxicity management guidelines (TMGs), with lower dose interruption rates (1% and 3%) and discontinuation rates (both 0.3%).
Data from this safety analysis show that AESIs in the Dato-DXd arm are typically low-grade and occur during the first few cycles of treatment, and can be well managed according to toxicity management guidelines. In addition, the incidence of G3 TRAEs ≥in the Dato-DXd group was less than half that of the ICC group, and treatment dose interruption/reduction due to TRAEs was rare. The results of this study showed that Dato-DXd was better tolerated than ICC and further highlighted the important potential of Dato-DXd as the best choice for clinical treatment.
The new TROP2 ADC treatment star is rising, and Dato-DXd continues to deploy breast cancer treatment
TROP2 is highly expressed in breast cancer and is associated with poor prognosis in breast cancer patients, making it an important research target in the field of breast cancer treatment4,5. Dato-DXd is an ADC consisting of three parts: a humanized IgG1 monoclonal antibody targeting TROP2, a tetrapeptide linker, and a topoisomerase I inhibitor payload (DXd), which can specifically bind to TROP2-expressing tumor cells and enter tumor cells under receptor-mediated endocytosis, thereby releasing the payload and exerting anti-tumor effects6.
The unique structure and design of ADC drugs play a decisive role in their efficacy and safety. The structural design of Dato-DXd drug is particularly exquisite, which provides unique mechanistic advantages for the treatment of TNBC BM and HR+ breast cancer patients: first, it has an excellent drug-to-antibody ratio (DAR). Based on the safety data from preclinical trials, Dato-DXd adjusts the drug-to-antibody ratio (DAR) to 4, which expands the therapeutic window while also improving safety7,8, and second, has a stable payload. DXd has 10-fold antitumor activity compared to similar TROP2 ADC SGs; Third, it has a cleavable linker, which is highly stable in plasma and can accurately deliver cytotoxic drugs to tumor cells8; Fourth, it can exert a bystander effect, and the killing effect is stronger.
Fig.3 Mechanism of action of Dato-DXd
As a new star in the field of breast cancer treatment, in addition to the TUXEDO-2 study and TB-01 study announced at the conference, Dato-DXd continues to carry out a series of studies to meet the treatment needs of more patients in the treatment exploration of TNBC and HR+ advanced breast cancer:
- TNBC的一线治疗：TROPION-Breast02研究、TROPION-Breast05研究
TROPION-Breast02 is an international multicenter, open-label, randomized controlled phase III study comparing the efficacy and safety of Dato-DXd versus chemotherapy in patients with locally advanced or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy.
TROPION-Breast05 is an international multicenter Phase III clinical study to explore the treatment of patients with PD-L1-positive locally recurrent, inoperable or metastatic TNBC with or without durvalumab versus chemotherapy in combination with pembrolizumab.
- TNBC的辅助治疗：TROPION-Breast03研究
TROPION-Breast03 is an international multicenter, open-label, 3-arm, randomized controlled phase III study of patients with TNBC with residual disease after neoadjuvant therapy comparing the efficacy and safety of Dato-DXd versus investigator's choice therapy (ICT).
- TNBC的新辅助治疗：TROPION-Breast04研究
TROPION-Breast04 is a two-arm, parallel-controlled, randomized, open-label, multicenter Phase III study to evaluate the efficacy of neoadjuvant Dato-DXd+ durvalumab followed by adjuvant therapy compared to current standard of care in patients with untreated early-stage TNBC or HR-low expression/HER2- breast cancer.
brief summary
The preliminary results of the TUXEDO-2 study presented at the ESMO BC meeting show that Dato-DXd can exert certain anti-tumor activity in patients with active BM of TNBC and has great potential for BM treatment. The additional safety analysis results of the TB-01 study reaffirm Dato-DXd's preferred position in the treatment of HR+ advanced breast cancer, and increase the confidence of doctors and patients in clinical use. It is expected that the results of the second phase of the TUXEDO-2 study will be published as soon as possible, which will further verify the efficacy and safety of T-DXd in the treatment of active BM and expand the beneficiaries of TNBC. It is also expected that the follow-up series of breast cancer studies can further enrich the evidence-based medical evidence chain and bring more optimized treatment strategies and more effective survival benefits to more breast cancer patients.
Bibliography:
1.Bartsch R, Furtner J, Marhold M, et al. 2024 ESMO BC. 187P.
2.Jhaveri K, Bardia A, Im S-A, et al. 2024 ESMO BC. LBA2.
3.Bardia A, Jhaveri K, Im S-A, et al. 2023 ESMO. LBA11.
4.Goldenberg D, et al. Oncotarget. 2018; 9(48): 28989-29006.
5.Cardoso F et al. Ann Oncol. 2020 (12); 1623-1649.
6. Li Bole, Feng Honglei, Wei Feng, et al. R&D Progress and Challenges of Tumor Antibody-Drug Conjugates[J]. Chin J Oncology Clin, 2022, 49(16):8.
7.Okajima D, Yasuda S, Maejima T, et al. Mol Cancer Ther. 2021 Dec; 20(12):2329-2340.
8.Liu X, Deng J, Yuan Y, et al. Pharmacol Ther. 2022 Nov;239:108296.
Editor: Tina
审校:Kino
Typesetting: KIKI
Execution: Uni
This platform aims to deliver more medical information to healthcare professionals. The content published on this platform should not be used as a substitute for professional medical guidance in any way, nor should it be regarded as diagnosis and treatment advice. If such information is used for purposes other than understanding medical information, the platform does not assume relevant responsibilities. This platform does not mean that it agrees with its descriptions and views on the published content. If copyright issues are involved, please contact us, and we will deal with it as soon as possible.