Editor’s note: Currently, antibody-drug conjugates (ADCs) have become “star drugs” in the field of cancer treatment. Dato-DXd is a novel ADC that consists of a humanized monoclonal antibody targeting Trop-2, connected through a cleavable linker to a topoisomerase I inhibitor. Early results indicate encouraging anti-tumor activity of Dato-DXd in triple-negative breast cancer (TNBC). At this year’s ESMO conference, multiple research data on its effectiveness in HR+ breast cancer and non-small cell lung cancer were disclosed. Professor Man Li from the Second Affiliated Hospital of Dalian Medical University, a guest speaker at the ESMO conference, provided an introduction.
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Oncology Frontier : The heavyweight study in the breast cancer field, TROPION-Breast 01, was officially released at this year’s ESMO conference. It is also the first Phase III study of the second Trop-2 ADC, Dato-DXd. Can you share your interpretation and thoughts on this study?
Professor Man Li: The TROPION-Breast 01 study is a global, randomized, multicenter, open-label Phase III clinical trial designed to evaluate the efficacy and safety of Dato-DXd compared to investigator’s choice of monotherapy (ICC: eribulin, capecitabine, vinorelbine, or gemcitabine) in patients with unresectable or metastatic HR-positive, HER2-low expression, or HER2-negative (IHC 0, 1+, or IHC 2+/ISH-) advanced breast cancer who have progressed on or are not suitable for endocrine therapy (having received at least one prior systemic treatment). The study enrolled over 700 patients from Asia, Europe, North America, South America, and Africa. It employs a dual primary endpoint design, namely, blinded independent central review (BICR)-assessed progression-free survival (PFS) and overall survival (OS). Key secondary endpoints include objective response rate (ORR), investigator-assessed PFS, and safety, among others.
From the results disclosed in the study, we can see that, compared to the ICC group, DATO-DXd achieved better PFS data. The median PFS for patients in the Dato-DXd group and the ICC group were 6.9 months and 4.9 months, respectively. Patients in the Dato-DXd group experienced a significant 37% reduction in the risk of disease progression or death compared to the ICC group (HR 0.63, 95% CI: 0.52–0.76; P < 0.0001). Although OS data is not yet mature, a favorable trend in benefit has been observed in the Dato-DXd group (HR 0.84, 95% CI: 0.62–1.14). We also look forward to the subsequent release of OS data results.
From the safety data disclosed in this announcement, we can observe that overall, the incidence of adverse reactions is similar between the two groups. However, in adverse reactions of grade ≥3, the Dato-DXd group had a lower incidence, at only 21%, compared to 45% in the ICC group. Additionally, in the Dato-DXd group, 9 cases (3%) experienced varying levels of interstitial lung disease (ILD), with only 1 case classified as grade 3 ILD.
From the results of the TROPION-Breast 01 study, we learn that for patients with advanced breast cancer who are HR-positive, HER2-low expression, or HER2-negative, treatment with Dato-DXd can achieve better short-term efficacy. Dato-DXd is the first Phase III clinical trial in the field of breast cancer, and the study has yielded positive results, which is uplifting news.
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Oncology Frontier: The release of the results from the TROPION-Breast 01 study is expected to bring about what changes in the treatment landscape for HR+/HER2- advanced breast cancer?
Professor Man Li: For advanced HR+/HER2- breast cancer, the emphasis in first-line treatment is on the crucial role of CDK4/6 inhibitors. The PALOMA, MONALEESA, and MONARCH series of clinical studies collectively established the standard position of CDK4/6 inhibitor combined with endocrine therapy in first-line treatment for HR+/HER2- advanced breast cancer. As patients progress in their disease, there is currently no standard treatment regimen for later lines of therapy. In clinical practice, physicians often choose subsequent treatment plans based on the patient’s sensitivity to endocrine therapy. For patients who have clearly benefited from first-line treatment, second-line treatment usually involves endocrine therapy. The selection of second-line treatment also emphasizes screening for different targets. If a patient has a PIK3CA mutation, the recommendation is PI3K inhibitors plus endocrine therapy. For patients with a BRCA gene mutation, PARP inhibitors are recommended. For patients who have previously benefited from CDK4/6 inhibitors and have an ESR1 mutation, oral SERD drugs (Elacestrant) can be considered. AKT inhibitors (Capivasertib) have also shown promising results in this population.
There are still some patients in clinical practice who are not sensitive to endocrine therapy, and their disease progresses rapidly. For this subset of patients, we should assess their HER2 expression status. For patients with low HER2 expression, based on the results of the DB-04 clinical study, T-DXd is preferred for treatment. For patients with HER2 0 expression, ADC drugs targeting Trop-2 seem to have better data in this population. Both trastuzumab deruxtecan and DATO-DXd have been tried in this subgroup of patients. We also look forward to more evidence-based medicine to guide treatment choices for populations with low HER2 expression and HER2 0 expression in the future.
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Oncology Frontier: In addition to advances in the breast cancer field, DATO-DXd has also presented multiple research data results in the field of lung cancer at this year’s ESMO conference. As someone who attended the conference, could you share your thoughts on the development prospects of DATO-DXd in the field of oncology, considering its structure and mechanism of action?
Professor Man Li: Dato-DXd is an ADC drug targeting Trop-2. Trop-2 is closely associated with the proliferation, migration, and invasion of tumor cells and is highly expressed in various solid tumors, including breast cancer. 85% of breast cancers show positive expression of Trop-2, and Trop-2 is even more highly expressed in HR-positive and triple-negative breast cancers. Currently, Trop-2 has become an important target for ADC drug development in breast cancer, and its mechanism of action involves specific binding to breast cancer cells expressing Trop-2. It enters tumor cells through receptor-mediated endocytosis and releases the payload, exerting an anti-tumor effect.
Dato-DXd has a structure similar to other ADC drugs, mainly composed of three parts. The antibody part is a humanized monoclonal antibody, and the linker is a cleavable tetrapeptide linker. The cytotoxic drug payload is a topoisomerase I inhibitor (derivative of exatecan, DXd). This structure gives it good stability. The drug-antibody ratio of Dato-DXd is 4:1, providing it with stronger anti-tumor activity.
At this year’s ESMO conference, in addition to announcing the PFS data of TROPION-Breast 01 in the breast cancer field, Dato-DXd also showed promising results in the treatment of non-small cell lung cancer. In the TROPION-Lung 01 study on advanced non-small cell lung cancer, the results indicated that in the intention-to-treat (ITT) population, the median PFS of the Dato-DXd group was extended by 0.7 months compared to the docetaxel group (4.4 months vs. 3.7 months). The risk of disease progression or death for patients in the Dato-DXd group was significantly reduced by 25% compared to the docetaxel group (HR 0.75, 95% CI: 0.62–0.91, P=0.004). This suggests that Dato-DXd has a promising outlook in different areas of oncology treatment.
Our center has had the privilege of participating in the clinical research of Dato-DXd for advanced triple-negative breast cancer, and we have witnessed its excellent short-term efficacy. We also look forward to Dato-DXd’s future expansion into different tumor types, hoping that it can bring hope for survival to more cancer patients.
Professor Man Li
Doctor of Medicine, Professor, Ph.D. Supervisor
Director of the Department of Oncology, Second Affiliated Hospital, Dalian Medical University
Liaoning Province’s Talents of a Hundred, Thousand, and Ten Thousand People – Hundred Talent Level
Director of the Chinese Society of Clinical Oncology
Standing Committee Member of the Breast Cancer Expert Committee of the Chinese Society of Clinical Oncology (CSCO)
Committee Member of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Oncology Branch of the Liaoning Medical Association
Vice Chairman of the Breast Cancer Professional Committee of the Liaoning Anti-Cancer Association
Incoming Chairman of the Tumor Metastasis Committee of the Liaoning Anti-Cancer Association
Chairman of the Oncology Branch of the Dalian Medical Association
