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Dato-DXd Phase III Data Shows Promising Efficacy, Safety Profile in Competitive Breast Cancer Market

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NEW YORK – Updated results from the TROPION-Breast01 trial confirmed earlier benefits seen with AstraZeneca and Daiichi Sankyo's Trop2-directed antibody-drug conjugate datopotamab deruxtecan, or Dato-DXd, in patients with previously treated, hormone receptor (HR)-positive, HER2-negative or -low metastatic breast cancer.

At the San Antonio Breast Cancer Symposium on Thursday, Aditya Bardia, a medical oncologist at the Massachusetts General Hospital Cancer Center, reported that investigator-assessed median progression-free survival for patients on Dato-DXd within the Phase III trial was 6.9 months compared to 4.5 months for those on investigator's choice of chemotherapy, which included eribulin mesylate, vinorelbine, gemcitabine, or capecitabine.

The patients in the trial had to have progressed on prior endocrine therapy and received one to two lines of chemotherapy. They also had to have inoperable or metastatic disease that was HER2 negative or low, defined as having immunohistochemistry scores of 0, 1+, or 2+ and in situ hybridization negative.

In October, at the European Society for Medical Oncology Congress, AstraZeneca reported the same median progression-free survival on Dato-DXd according to blinded independent central review, 6.9 months versus 4.9 months on chemotherapy. This translated to a 37 percent lower risk of progression or death for those on the antibody-drug conjugate versus the comparator arm. In the Dato-DXd arm, 36 percent of patients saw their tumors shrink compared to 23 percent of patients on chemo. While overall survival data weren't mature, there was a trend favoring Dato-DXd.

AstraZeneca in September announced that this trial had met its primary endpoint and said it planned to share the data with health authorities. In AstraZeneca's last earnings call, Susan Galbraith, executive VP of oncology R&D, noted that the data from this and another study in non-small cell lung cancer suggests that Dato-DXd can replace backbone chemotherapy in these settings, but its efficacy and safety profile also makes it a good agent to combine with other agents in earlier lines of care.

If regulators approve Dato-DXd based on data from TROPION-Breast01, it will compete most directly with Gilead Sciences' Trop2-directed antibody-drug conjugate Trodelvy (sacituzumab govitecan), which was approved earlier this year in the US and Europe as a treatment for patients with previously treated, HR-positive, HER2-negative or -low metastatic breast cancer. In order to receive Trodelvy, patients also must have HER2 expression immunohistochemistry scores of 0, 1+, or 2+ and ISH negative.

The FDA last year also approved AstraZeneca and Daiichi Sankyo's HER2-targeted antibody-drug conjugate Enhertu (trastuzumab deruxtecan) for previously treated patients with unresectable or metastatic HER2-low breast cancer, defined as having a HER2 IHC score of 1+, or IHC 2+ and ISH negative.

Since Dato-DXd stands to enter a competitive market in HR-positive HER2-negative/low breast cancer, oncologists are eager to better understand the agent's activity in different patient subgroups, as well as the quality of life it provides patients and the toxicities it could cause. At SABCS, Bardia provided further insight into these aspects of the drug.

When researchers segmented patients based on whether they had received a CDK4/6 inhibitor previously, for example, they found that the progression-free survival advantages with the antibody-drug conjugate remained. In patients who received a CDK4/6 inhibitor for 12 months or less, the median progression-free survival by blinded independent central review was 6.9 months on Dato-DXd versus 4.2 months on chemotherapy. In patients who received a CDK4/6 inhibitor for more than a year, median progression-free survival was 7.1 months versus 5.0 months, respectively.

Although HR-positive breast cancer infrequently metastasizes to the brain, when it does, patients have poor outcomes. Dato-DXd showed in TROPION-Breast01 that it could benefit these patients as well. Among patients who had brain metastases upon entering the study, the median progression-free survival was 5.6 months on Dato-DXd versus 4.4 months on chemo. In patients without brain metastases, the median progression-free survival was 7.0 months compared to 4.9 months, respectively.

Bardia noted that although chemotherapy is widely prescribed for patients with HR-positive, HER2-negative metastatic breast cancer patients who have become resistant to endocrine therapy, patients tend to have lackluster responses and experience significant toxicities such as myelosuppression or peripheral neuropathy. "Clinically, there's a need for better therapies," he said.

Dato-DXd comprises an anti-Trop2 IgG1 monoclonal antibody and a Topo I inhibitor. The antibody portion attaches to Trop2 receptors on tumor cells, allowing the Topo I inhibitor to be released directly into them, reducing off-target toxicities. The drug also has a "bystander effect," Bardia highlighted, meaning that after the molecule attaches to Trop2 receptors on cancer cells, it can diffuse into nearby cancer cells killing even those that are Trop2-negative.

In terms of safety, there were fewer grade 3 or higher adverse events on Dato-DXd than on chemo, 21 percent and 45 percent, respectively, and there were fewer dose interruptions or reductions with the antibody-drug conjugate. "We saw [safety] results that are a bit different than other trials," Bardia said. "In general, in clinical trials, we see that … in the intervention arm, the frequency of grade 3 or higher adverse events is higher … compared to the control arm. But in this study, it was opposite."

Neutropenia was the most common adverse event experienced by patients in the chemotherapy arm and caused one patient's death. Although more patients experienced grade 3 stomatitis on Dato-DXd than with chemo, these were generally low-grade and manageable.

Patients also had better quality of life on Dato-DXd than on chemo. Bardia reported that Dato-DXd delayed deterioration of patients' physical function and pain parameters for a longer time than did chemo.

"Looking at the totality of the data, not just efficacy but also the safety profile and impact on quality of life, the results support Dato-DXd as a potential new therapeutic option for patients with endocrine-resistant metastatic HR-positive, HER2-negative breast cancer," Bardia concluded.

At SABCS, oncologists listening to Bardia's presentation wondered whether his team had identified any additional biomarkers that could help them identify with even more precision the patients that should receive Dato-DXd.

Bardia said that TROPION-Breast01 investigators are currently evaluating biomarkers in the study, including the relationship between Trop2 expression and patients' progression-free survival and response to Dato-DXd. He pointed out, however, that other trials involving the other Trop2-directed drug, Trodelvy, had not shown a strong correlation between Trop2 expression and treatment outcomes.

Bardia added that researchers are also looking at how HER2 expression might impact outcomes on Dato-DXd, especially given the availability of Enhertu for treating HER2-low metastatic breast cancer.