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Funda Meric-Bernstam, MD, on Dato-DXd in Advanced Breast Cancer

– Novel antibody-drug conjugate selectively targets TROP2


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Medical Today

Based on promising clinical data in patients with advanced, heavily pretreated breast cancer, a novel antibody-drug conjugate (ADC) has been submitted for FDA approval and continues to be evaluated in phase III trials.

In a recently published phase I trial of 41 patients with HR+/HER2- cancer treated with datopotamab deruxtecan (Dato-DXd), the objective response rate was 26.8%, and the median progression-free survival was 8.3 months, Funda Meric-Bernstam, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues reported in the .

In 44 patients with triple-negative breast cancer (TNBC), the objective response rate was 31.8% and progression-free survival was 4.4 months.

"In this first-in-human phase I study of Dato-DXd, encouraging antitumor activity and a manageable safety profile were observed in patients with heavily pretreated advanced HR1/HER2– BC and TNBC," the researchers concluded.

In the following interview, Meric-Bernstam, who is chair of the Department of Investigational Cancer Therapeutics Phase I Program at MD Anderson, elaborated on details of the novel ADC and clinical trial results.

The mode of action of Dato-DXd allows for more selective targeting and potentially lower systemic exposure. Can you explain how this drug works?

Meric-Bernstam: Dato-DXd is a new antibody drug conjugate consisting of a humanized monoclonal antibody targeting TROP2, a commonly expressed target, and linked with a selectively cleavable linker to deruxtecan, a potent topoisomerase I inhibitor. Therefore, the drug works by binding the cancer cell surface, being internalized and releasing its cytotoxic payload. However, it is thought that deruxtecan may also have substantial "bystander effect," allowing for cancer cells with lower expression to also benefit from therapy.

What did you find in terms of safety and adverse events in your trial?

Meric-Bernstam: We demonstrated that Dato-DXd has a manageable safety profile; stomatitis was the most common treatment-emergent adverse event.

What did you find in your subgroup of topo-1 naïve patients, and what does this suggest?

Meric-Bernstam: In our study, the HR+ cohort excluded prior topo-1 payload ADCs but the TNBC cohort did not. The objective response rate in the TNBC cohort was 31.8% overall, and was 40% among patients who were topo-1 naïve. This suggests there may be some cross resistance with prior topo-1 exposure.

Further study is needed to determine the best sequencing of available and emerging therapies, mechanisms of intrinsic and acquired resistance, and how to overcome them.

The FDA has accepted a biologics license application [BLA] for Dato-DXd based on preliminary phase III trial data. What can you tell us about this phase III data?

Meric-Bernstam: The BLA was based on the phase III data from TROPION-Breast01 in HR+ HER2-negative breast cancer. This data was presented by Dr. Aditya Bardia at ESMO last year, demonstrating no new safety signals and a statistically significant and clinically relevant improvement of progression-free survival compared with investigator-choice chemotherapy.

How do results with Dato-DXd compare with the recently approved sacituzumab govitecan (Trodelvy), another TROP2-targeting conjugate?

Meric-Bernstam: It is not appropriate to make cross trial comparisons for efficacy. Interestingly Dato-DXd has a different adverse events [AE] profile than what is seen with sacituzumab govitecan, and its AE profile was favorable compared with the standard-of-care arm in TROPION-Breast01.

Read the study here.

The study was supported by Daiichi Sankyo, which is developing Dato-DXd in collaboration with AstraZeneca.

Meric-Bernstam reported consulting for Daiichi Sankyo/AstraZeneca and other pharmaceutical companies. Other study authors are also consultants for or employees of Daiichi Sankyo.

Primary Source

Journal of Clinical Oncology

Source Reference:

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ASCO Publications Corner