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Daiichi Sankyo Korea has dismissed concerns about Dato-DXd (datopotamab deruxtecan), an antibody-drug conjugate (ADC) being developed as a follow-on to Enhertu (trastuzumab deruxtecan).
The company said the new predictive biomarker, developed after clinical failures, holds promise as a combination drug with targeted and immuno-oncology agents in the largest lung and breast cancer markets.
Daiichi Sankyo Korea’s Onco Medical Affairs Department Head Ko Hyung-mun
Daiichi Sankyo Korea’s Onco Medical Affairs Department Head Ko Hyung-mun
Daiichi Sankyo Korea’s Onco Medical Affairs Department Head Ko Hyung-mun said so at the recent “Science & Technology Day 2025” event, which was open to the media.
Dato-DXd is a DXd (deruxtecan) based ADC developed to target TROP2 on the surface of cancer cells.
It recently received initial approval from the U.S. Food and Drug Administration (FDA) under the name DATROWAY for treating patients with unresectable or metastatic hormone receptor-positive (HR+), HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer.
Daiichi Sankyo is developing Dato-DXd in collaboration with AstraZeneca.
Initially targeting an expanded indication for treating locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC), the companies recently modified their development strategy for Dato-DXd in lung cancer following the failure of the TROPION-Lung01 phase 3 trial.
The company voluntarily withdrew its license application from the U.S. FDA after the TROPION-Lung01 study failed to improve overall survival (OS), one of the primary efficacy endpoints.
Following the failure of the TROPION-Lung01 study, some have raised concerns that Dato-DXd may not be well-positioned to replicate Enhertu's success. These concerns quickly spread when it was realized that the TROP2 target was less established as a therapeutic target than Enhertu's HER2.
HER2 is a driver gene directly involved in cancer development, making it a reliable biomarker for predicting response to targeted therapies. TROP2, on the other hand, has not been linked to cancer development and lacks evidence as a predictor of treatment response.
While acknowledging TROP2's obvious limitations, Director Ko countered that the recent breakthrough in the failed TROPION-Lung01 trial was the discovery of a new biomarker that could predict treatment response to Dato-DXd.
“Our retrospective analysis of the TROPION-Lung01 study confirmed that the TROP2 Quantitative Continuous Score (QCS) is meaningful as a predictive biomarker of Dato-DXd treatment,” Ko said. “We plan to prospectively utilize the QCS to evaluate the efficacy of Dato-DXd treatment in future follow-up trials.”
The TROP2 QCS is a new type of biomarker developed based on digital pathology and is significant because it goes beyond the traditional IHC-based “positive/negative” dichotomy to a precision biomarker approach utilizing a quantitative, continuous score.
The companies plan to apply the QCS in the TROPION-Lung14 study, a phase 3 clinical trial evaluating the combination of Dato-DXd and Tagrisso (osimertinib) in the first-line treatment of patients with advanced or metastatic NSCLC with EGFR mutations.
The QCS will be used from patient screening to prospectively validate patients with high TROP2 expression by including them in the enrollment criteria or using them as a stratification analysis variable.
Patient selection has recently become an important issue in the field of EGFR tyrosine kinase inhibitor (TKI) monotherapy, chemotherapy (FLAURA2 study), and bispecific antibody (MARIPOSA study) combinations.
Although adding chemotherapy or bispecific antibodies to TKI monotherapy, which has been used as standard therapy, may provide survival benefits, there is not enough information to evaluate the risk-benefit ratio for each patient regarding “overtreatment” or “quality of life”.
There is some debate about the need for more intensified treatment in high-risk groups, such as those with brain metastases or metastases to other organs and those with TP53 mutations, but it is also unclear whether the combination should be chemotherapy or bispecific antibodies.
The strength of Dato-DXd's TROPION-Lung14 study is clear in this regard. By utilizing QCS to predict treatment effectiveness from the time of patient screening, more precise treatment strategies can be provided.
In addition, Director Koh emphasized Dato-DXd's potential in breast cancer.
According to Ko, Dato-DXd demonstrated a remarkable 79 percent overall response rate (ORR) in combination with the immuno-oncology drug Imfinzi (durvalumab) in an early clinical trial (BEGONIA study) in patients with metastatic triple-negative breast cancer.
“These results are particularly encouraging given that immuno-oncology monotherapy in triple-negative breast cancer has previously shown response rates of 20-30 percent,” he said.
The companies are conducting two phase 3 clinical trials (TROPION-Breast 02 and 03 studies) evaluating Dato-DXd in triple-negative breast cancer patients.
The TROPION-Breast02 study compares Dato-DXd to chemotherapy in patients with inoperable, locally recurrent, or metastatic breast cancer who are not candidates for anti-PD-L1 therapy and have not received prior treatment. Initial data are expected to be presented at the upcoming American Society of Clinical Oncology Annual Meeting (ASCO 2025).
The TROPION-Breast03 study will evaluate Dato-DXd ± Imfinzi vs. the investigator's choice of treatment in patients with residual disease after adjuvant therapy in stages 1-3, and Dato-DXd will be expanded to include all stages of triple-negative breast cancer.
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Kim Yun-mi kym@docdocdoc.co.kr
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