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AstraZeneca, Daiichi Sankyo Unveil First Datopotamab Deruxtecan TNBC Data at SABCS

NEW YORK – Daiichi Sankyo and AstraZeneca's anti-TROP2 antibody-drug conjugate datopotamab deruxtecan (dato-DXd) has shown promising efficacy in triple-negative breast cancer patients, according to preliminary results from a Phase I trial presented at the San Antonio Breast Cancer Symposium.

The drug is in the same class as trastuzumab deruxtecan (Daiichi Sankyo/AstraZeneca's Enhertu) and sacituzumab govitecan (Gilead's Trodelvy). The latter is already approved to treat unresectable or metastatic TNBC in the US and Europe.

The Phase I TROPION-PanTumor01 study of dato-DXd included several tumor types. The initial cohorts involved patients with advanced or metastatic TNBC and unresectable, advanced non-small cell lung cancer. The expansion cohorts enrolled patients with other advanced solid tumors. As of the data cutoff on July 30, there were 44 TNBC patients evaluable for response.

Among these patients, the overall response rate was 34 percent, with 14 confirmed responses and one unconfirmed response. The disease control rate, which included confirmed responses and patients with stable disease, was 77 percent.

The researchers, led by Ian Krop, associate chief of the division of breast oncology at Dana-Farber's Susan F. Smith Center for Women's Cancers, noted at the meeting that patients who had previous treatment with a topoisomerase antibody-drug conjugate, or ADC, had worse responses than those who did not. Ten patients in the cohort had received treatment with a topoisomerase ADC, specifically sacituzumab govitecan. When researchers excluded patients who had this earlier treatment, the overall response rate increased to 52 percent, Krop said.

In the study, the researchers did not limit enrollment to patients with TROP2 expression because TROP2 is widely expressed in TNBC patients, explained Krop. He added that the researchers will retrospectively consider patients' responses based on TROP2 expression and conduct further efficacy analysis in patients with brain metastases.

"Given this is a first study and previous data from sacituzumab govitecan suggested there wasn't a big difference in efficacy based on TROP2, we felt it was better to enroll all patients and then go back and look at efficacy based on TROP2 expression," Krop said, noting that the lung cancer cohort in the TROPION-PanTumor01 study did not show a strong relationship between TROP2 expression and efficacy. "There are more data to come and it should be explored."

Daiichi Sankyo and AstraZeneca are planning further studies of dato-DXd in this setting, including a Phase III study in TNBC. Krop, however, did not elaborate on the design of the Phase III trial or which therapy dato-DXd would be compared to because it is not finalized.

"The comparator depends on what line of therapy is explored," Krop said. "There is potential room for looking at this drug both in pretreated patients as well as in earlier lines of therapy, given that there may be a potential decrease in efficacy among patients who have had a prior topoisomerase ADC treatment."

In the TROPION-PanTumor01 study, Krop said the HR-positive, HER2-negative breast cancer cohort is now fully enrolled and all patients are receiving treatment. The researchers will continue enrolling patients with other solid tumors in this trial, including those with bladder, gastric, esophageal, and small cell lung cancer.

Another trial of dato-DXd, the Phase I/II BEGONIA study, is also underway, in which researchers are evaluating dato-DXd in combination with the anti- PD-L1 drug durvalumab (AstraZeneca's Imfinzi) as a first-line treatment for metastatic TNBC. There is also a Phase III trial comparing dato-DXd to chemotherapy in previously treated patients with HR-positive, HER2-negative breast cancer.

Although topoisomerase ADCs have had slower development in metastatic breast cancer, Krop noted that several studies involving dato-DXd, trastuzumab deruxtecan, and sacituzumab govitecan will read out soon and add knowledge that will advance the use of these drugs.

"There are other conjugates being evaluated in this space, and one [that is] already approved with sacituzumab," Krop said. "We've come a long way in triple-negative breast cancer when we're talking about comparing different targeted therapies because up until a few years ago there were no targeted therapies at all. This is good progress."