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SAN ANTONIO -- The investigational Trop2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) continued to best chemotherapy in new results from the phase III randomized TROPION-Breast01 trial.

Looking at progression-free survival (PFS) by blinded independent central review (BICR) in certain subgroups of patients with hormone receptor (HR)-positive, HER2-negative, endocrine-resistant metastatic breast cancer, those assigned to Dato-DXd had improvements compared with investigator's choice of chemotherapy, reported Aditya Bardia, MD, of Mass General Cancer Center and Harvard Medical School in Boston, during the San Antonio Breast Cancer Symposium.

Among patients with prior duration of CDK4/6 inhibitors ≤12 months, median PFS was 6.9 months with Dato-DXd versus 4.2 months with chemotherapy (HR 0.61, 95% CI 0.45-0.81), and for those with duration >12 months, median PFS was 7.1 months versus 5 months, respectively (HR 0.61, 95% CI 0.45-0.82).

Superior median PFS was also observed in the Dato-DXd arm in patients without brain metastases at entry (7.0 vs 4.9 months; HR 0.62, 95% CI 0.51-0.75), but the difference was not significant among those with brain metastases at entry (5.6 vs 4.4 months; HR 0.73, 95% CI 0.39-1.42).

The primary results, presented at this year's European Society for Medical Oncology meeting, demonstrated a hazard ratio of 0.63 (95% CI 0.52-0.76, P<0.0001) for PFS by BICR in favor of Dato-DXd over chemotherapy, and a trend favoring Dato-DXd for overall survival (OS), although these data were immature.

"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 said.

Patients who received Dato-DXd had a lower rate of grade ≥3 treatment-related adverse events (TRAEs) compared with chemotherapy (21% vs 45%). Similarly, the rates of dose reductions (21% vs 30%) and dose interruptions (12% vs 25%) due to TRAEs were lower with Dato-DXd versus chemotherapy. The rate of neutropenia was especially low in the Dato-DXd arm, at 11%, with only a 1% rate of grade ≥3 neutropenia.

The most common TRAEs leading to dose interruption in the Dato-DXd arm were fatigue, infusion-related reaction, interstitial lung disease (ILD), and stomatitis (1% each), whereas neutropenia (17%) and leukopenia (3%) were the most common reasons in the chemotherapy arm.

The frequency of any-grade stomatitis was higher with Dato-DXd versus chemotherapy (50% vs 13%). Most were low grade and manageable, and did not lead to treatment discontinuation, said Bardia. The incidence of grade ≥3 stomatitis was 6% versus 3%, respectively.

The confirmed time to deterioration in global health status/quality of life was delayed in the Dato-DXd arm compared with the chemo arm (9 vs 4.8 months; HR 0.76, 95% CI 0.58-0.98), "and this was maintained over time, at 3 months, 6 months, 9 months, 12 months, and beyond," Bardia said.

Median time to deterioration in the physical functioning and pain domains of the global health status/quality of life measure, whether first instance or confirmed, was also delayed in the Dato-DXd arm, though the difference was not always significant.

"One thing from the data reported today that makes Dato-DXd very favorable in my mind is that toxicity was actually less than that with chemotherapy," Jasmine Sukumar, MD, of the University of Texas MD Anderson Cancer Center in Houston, told 名媛直播. "Usually when we are looking at investigational agents, we find more toxicity, even with some of the other trials of ADCs. Dato-DXd had a lower risk of neutropenia and patients had better quality of life on this drug, so I would consider it a very important treatment option if it receives approval."

The 1% rates of grade ≥3 neutropenia and ILD were especially impressive, she said. Dose-limiting neutropenia appears to be much more common with sacituzumab govitecan, she noted, often requiring administration of growth factors, and the rate of ILD has been 10% to 15% in studies of other ADCs.

Patients randomized to Dato-DXd also had a longer median time to first subsequent therapy versus chemotherapy (8.2 vs 5.0 months; HR 0.53, 95% CI 0.45-0.64).

is a phase III, open-label study that enrolled 732 patients with HR-positive, HER2-negative breast cancer previously treated with one to two lines of chemotherapy in the metastatic setting, who experienced progression on endocrine therapy or for whom endocrine therapy was unsuitable. Median patient age was 54-56 years, and all patients had an Eastern Cooperative Oncology Group performance status score of 0 or 1.

Options in the chemotherapy arm were eribulin mesylate (Halaven), vinorelbine, gemcitabine, and capecitabine.

Prophylaxis for mucositis will likely be important if Dato-DXd is used in practice, Sukumar said, and low-grade ocular events (i.e., dry eyes) is another unique side effect with Dato-DXd that will require attention.

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