PFS Significantly Improves With Dato-DXd in HR+, HER2- Metastatic Breast Cancer


Patients with metastatic hormone receptor-positive breast cancer treated with datopotamab deruxtecan experienced a statistically significant and clinically meaningful improvement in progression-free survival.

Aditya Bardia, MD, MPH

Aditya Bardia, MD, MPH

Patients with hormone receptor-positive, HER2-low or -negative metastatic breast cancer who were treated with datopotamab deruxtecan (Dato-DXd), when compared with chemotherapy, had a statistically significant and clinically meaningful improvement in progression-free survival (PFS), according to data from the phase 3 TROPION-Breast01 trial (NCT05104866) presented at ESMO Congress 2023.1,2

“Overall results support Dato-DXd as a potential new therapeutic option for patients with metastatic hormone receptor-positive breast cancer,” Aditya Bardia, MD, MPH, 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 (95% CI, 5.7-7.4), compared with 4.9 months (95% CI, 4.2-5.5) with investigator’s choice of chemotherapy (ICC), reducing the risk for disease progression by 37% (HR, 0.63; 95% CI, 0.52-0.76; P < .0001) 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 9-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 was also superior with Dato-DXd at 36.4%, including 0.5% of complete responses (CRs), compared with 22.9% in the ICC arm, which had no CRs.

While the overall survival (OS) data are not mature at a median follow-up of 9.7 months, there was a trend that favored Dato-DXd over ICC (HR, 0.84; 95% CI, 0.62-1.14). “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), AEs (11 vs 10), patient decision (13 vs 32), death (2 vs 7), or other (12 vs 23).

“Two important points to note in this slide. The first is that as of data cutoff, approximately 3 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 adverse events (TRAEs) occurred in 94% and 86% of the Dato-DXd and ICC groups; however, the rate of grade 3 or higher TRAEs was less than half with the TROP2-directed antibody-drug conjugate (ADC) vs ICC (21% vs 45%, respectively).

TRAEs 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 TRAEs occurred in 6% of the Dato-DXd arm and 9% of the ICC arm.

Bardia highlighted that most TRAEs were grade 1 or 2. In the Dato-DXd and ICC arms, TRAEs 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 alopecia (36% vs 21%). Bardia noted that 1 patient with oral mucositis/stomatitis and 1 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,” Ken Takeshita, MD, global head of research and development, Daiichi Sankyo, said in a press release.2 “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, such as its optimized drug-to-antibody ratio, its stable linker payload, its tumor-selective cleavable linker, and its bystander antitumor effect.

Therefore, in the randomized, open-label, global, phase 3 TROPION-Breast01 trial, investigators randomized patients 1:1 to receive either 6 mg/kg Dato-DXd IV every 3 weeks (n = 365) or ICC (n = 367). ICC was comprised of eribulin mesylate on days 1 and 8 every 3 weeks (n = 220), vinorelbine on days 1 and 8 every 3 weeks (n = 38); gemcitabine on days 1 and 8 every 3 weeks (n = 76), or capecitabine on days 1 through 14 every 3 weeks (n = 33). Treatment in both arms continued until progressive disease, unacceptable tolerability, 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 (defined as IHC 0/1+/2+; ISH negative) breast cancer, were previously treated with 1 to 2 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.

PFS by blind independent central review per RECIST v1.1 and OS served as the primary end points, while secondary end points included investigator-assessed PFS and safety.

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.

Of the 1003 patients screened, 732 underwent treatment randomization. “After screening about 1000 patients over the period of 1 year, the study enrolled rapidly. In a span of 1 year there were 732 patients who were randomized. It highlights the interest in the study and the unmet need,” Bardia highlighted.

“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.2 “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.”


1. Bardia A, Jhaveri K, Im SA, et al. Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer: Primary results from the randomized phase 3 TROPION-Breast01 trial. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA 11.

2. AstraZeneca press release. Datopotamab deruxtecan significantly extended progression-free survival vs. chemotherapy in patients with HR-positive, HER2-low or negative breast cancer in TROPION-Breast01 Phase III trial. Published: October 23, 2023. Accessed: October 23, 2023.

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