Dato-DXd Betters Progression-Free Survival in Metastatic Breast Cancer Group

Patients with hormone receptor-positive HER2-low or HER2-negative metastatic breast cancer tended to have improved progression-free survival when being treated with datopotamab deruxtecan.

Patients with hormone receptor-positive HER2-low or HER2-negative metastatic breast cancer tended to have improved progression-free survival (PFS; time from treatment until disease worsening or death) when being treated with datopotamab deruxtecan (Dato-DXd), compared to those being treated with chemotherapy, according to findings from the phase 3 TROPION-Breast-1 clinical trial.

The study findings were presented at the 2023 ESMO Congress.

“Overall results support Dato-DXd as a potential new therapeutic option for patients with metastatic hormone receptor-positive breast cancer,” Dr. Aditya Bardia, director of breast cancer research and medical oncology, Massachusetts General Hospital Cancer Center, and associate professor at Harvard Medical School, Boston, said during a presentation of the data.

Improved Survival With Dato-DXd

Median PFS with Dato-DXd was 6.9 months, compared with 4.9 months with investigator’s choice of chemotherapy (ICC), reducing the risk for disease progression by 37% and meeting the trial’s co-primary end point.

“After a small initial drop, there's a separation between the curves in favor of Dato-DXd, (PFS is) maintained over time and, if anything, increases over time,” Bardia said, adding that the nine-month PFS rates were almost double with Dato-DXd, compared with ICC. The 6-, 9- and 12-month PFS rates with Dato-DXd were 53.3%, 37.5% and 25.5%, respectively, compared with 38.5%, 18.7% and 14.6% with ICC.

PFS benefit was seen across all subgroups, including age, race, ECOG performance status, geographic region, number of previous lines of chemotherapy, prior use of CDK4/6 inhibitors, and prior use of taxane and/or anthracyclines.

Objective response rate, which describes the percentage of patients whose disease shrinks or disappears from treatment, was also superior with Dato-DXd at 36.4%, including 0.5% of complete responses (CRs; complete disappearance of cancer), compared with 22.9% in the ICC arm, which had no CRs.

While the overall survival (OS; time from treatment until death of any cause) data are not mature at a median follow-up of 9.7 months, there was a trend that favored Dato-DXd over ICC.

“The study is continuing to the next planned analysis for overall survival,” Bardia added.

Additional Findings

Median treatment duration was 6.7 months in the Dato-DXd arm and 4.1 months in the ICC arm.

After a median follow-up of 10.8 months, 93 patients in the Dato-DXd arm and 39 in the ICC arm were still ongoing with study treatment. In both arms, patients discontinued treatment as a result of progressive disease (267 vs 240), side effects (11 vs 10), patient decision (13 vs 32), death (two vs seven) or other (12 vs 23).

“Two important points to note in this slide. The first is that as of data cutoff, approximately three times the number of patients are still on Dato-DXd, as compared to the standard chemotherapy arm. And second is that majority of patients who discontinued the study had disease progression,” Bardia said.

Treatment-related side effects occurred in 94% and 86% of the Dato-DXd and ICC groups; however, the rate of grade 3 or higher side effects was less than half with the TROP2-directed antibody-drug conjugate (ADC) vs ICC (21% vs 45%, respectively).

Side effects led to dose reductions in 21% of the Dato-DXd arm, compared with 30% in the ICC arm, dose interruptions in 12% and 25%, respectively, and treatment discontinuation in 3% of each arm. One patient death occurred in the ICC group. Serious side effects occurred in 6% of the Dato-DXd arm and 9% of the ICC arm.

Bardia highlighted that most side effects were grade 1 or 2. In the Dato-DXd and ICC arms, side effects included anemia (11% vs 20%, respectively), neutropenia (11% vs 42%), dry eye (22% vs 8%), nausea (51% vs 24%), stomatitis (50% vs 13%), vomiting (20% vs 8%), constipation (18% vs 9%), fatigue (24% vs 18%) and hair loss (36% vs 21%). Bardia noted that one patient with oral mucositis/stomatitis and one patient with dry eye led to treatment discontinuation in the Dato-DXd group; however, adjudicated drug-related interstitial lung disease rate rates were low and mostly grade 1 or 2 in this arm.

“These statistically significant and clinically meaningful results from the TROPION-Breast01 trial support datopotamab deruxtecan as a new potential standard of care for patients with advanced HR-positive, HER2-low or negative breast cancer in the post-endocrine therapy setting,” Dr. Ken Takeshita, global head of research and development, Daiichi Sankyo, said in a press release. “The results further validate the portability of Daiichi Sankyo's DXd antibody drug conjugate technology to additional targets such as TROP2, and we look forward to potentially bringing our second antibody drug conjugate to patients with breast cancer.”

Addressing an Unmet Need

Bardia noted that, despite the availability of newer treatment options in breast cancer, an unmet need remains for those with endocrine-resistant, metastatic disease. In particular, while chemotherapy is widely used for this patient population, it is associated with a low response rate, poor prognosis and significant toxicity; similarly, TROP2-directed ADCs that are either approved or are in development have demonstrated efficacy but may lead to toxicity leading to treatment limitations.

“From a field perspective, there's an unmet need, both from an efficacy perspective, as well as a toxicity perspective. We need agents that are better and less toxic,” Bardia said, adding that Dato-DXd may have unique properties to address these needs.

Therefore, in the randomized, open-label, global, phase 3 TROPION-Breast01 trial, investigators randomized patients to receive either 6 mg/kg Dato-DXd IV every three weeks (365 patients) or ICC (367 patients). ICC was comprised of eribulin mesylate on days 1 and 8 every three weeks (220 patients), vinorelbine on days 1 and 8 every three weeks (38 patients); gemcitabine on days 1 and 8 every three weeks (76 patients), or capecitabine on days 1 through 14 every three weeks (33 patients). Treatment in both arms continued until progressive disease, unacceptable toxicity or other discontinuation criteria.

Patients were stratified by lines of chemotherapy, geographic location and previously received CEK4/6 inhibitor.

Patients were eligible for the trial if they had hormone receptor-positive, HER2-negative breast cancer, were previously treated with one to two lines of chemotherapy, had experienced progression on endocrine therapy (ET) or for those where ET was unsuitable and had an ECOG performance status of 0 or 1, which indicated that they can perform all of their daily tasks with little to no assistance.

Baseline characteristics were well balanced between arms. In the Dato-DXd arm, the median age was 56 years (range, 29-86), while the majority were White (49%). In total, 63% of patients had received prior lines of chemotherapy, 82% were previously given a CDK4/6 inhibitor, and 90% were previously administered a taxane and/or anthracycline.

“With these TROPION-Breast01 results, datopotamab deruxtecan has the potential to meaningfully improve treatment expectations for patients with HR-positive, HER2-low or negative metastatic breast cancer by offering them an effective and better tolerated treatment option after endocrine therapy and only 1 line of chemotherapy,” Susan Galbraith, executive vice president of oncology research and development, AstraZeneca, said the release. “We look forward to continuing discussions with regulatory authorities with the goal of bringing this TROP2-directed antibody drug conjugate to eligible patients as soon as possible.”

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