Datopotamab Deruxtecan Wins CHMP Positive Opinion for Previously Treated HR+ Breast Cancer

The Committee for Medicinal Products for Human Use (CHMP), of the European Medicines Agency (EMA), has recommended the approval of datopotamab deruxtecan for use in adult patients with unresectable or metastatic hormone receptor–positive, HER2-negative breast cancer who have previously received endocrine therapy and 1 or more lines of chemotherapy in the advanced setting.1

The positive opinion was based on findings from the phase 3 TROPION-Breast01 study (NCT05104866) in which the antibody-drug conjugate (ADC; n = 365) led to a median progression-free survival (PFS) of 6.9 months (95% CI, 5.7-7.4) by blinded independent central review (BICR) vs 4.9 months (95% CI, 4.2-5.5) with investigator’s choice of chemotherapy (n = 367), translating to a 37% reduction in the risk of disease progression or death (HR, 0.63; 95% CI, 0.52-0.76; P < .0001).2

“Disease progression after endocrine and initial chemotherapy is common in patients with metastatic HR positive, HER2-negative breast cancer,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, stated in a news release.1 “This positive recommendation by the CHMP for datopotamab deruxtecan, which follows recent approvals in the United States and Japan, underscores the potential of this TROP2-directed ADC to offer a new treatment option to patients in the European Union with this type of breast cancer.”

Taking a Closer Look at TROPION-Breast01

The global, open-label, phase 3 study enrolled patients with inoperable or metastatic hormone receptor–positive, HER2-negative breast cancer who received 1 or 2 prior lines of chemotherapy in the inoperable or metastatic setting.2 They were at least 18 years of age and had an ECOG performance status of 0 or 1. Notably, those with stable brain metastases were permitted, but those who had prior exposure to a chemotherapy agent targeting topoisomerase I, including ADCs, or a prior TROP2-targeted therapy were not.

Study participants were randomized 1:1 to receive datopotamab deruxtecan at 6 mg/kg given intravenously (IV) and once every 3 weeks (Q3W) or single-agent chemotherapy per investigator choice. Those in the control arm could have received IV eribulin at 1.4 mg/m2 on days 1 and 8 Q3W, oral capecitabine at 1000 mg/m2 or 1250 mg/m2 twice daily on days 1 to 14 Q3W, IV vinorelbine at 25 mg/m2 on days 1 and 8 Q3W, or IV gemcitabine at 1000 mg/m2 on days 1 and 8 Q3W.

They were stratified by number of prior lines of chemotherapy (1 vs 2), geographic region (United States/Canada/Europe vs other regions of the world), and prior exposure to a CDK4/6 inhibitor (yes vs no). Treatment continued until radiologic progression was confirmed by investigator assessment and RECIST 1.1 criteria, intolerable toxicity, withdrawn consent, or other discontinuation criteria were met.

The dual primary end points of the study were PFS by BICR and RECIST criteria and overall survival (OS). Key secondary end points included investigator-assessed PFS, objective response rate (ORR), 12-week disease control rate (DCR), duration of response (DOR), time to first subsequent therapy or death (TFST), time to second subsequent therapy or death (TSST), and time to second progression or death (PFS2). Safety was also examined.

Additional Efficacy Findings

The median follow-up on the study was 10.8 months. Although immature at the time of the analysis published in Journal of Clinical Oncology, a trend in interim OS data favored the ADC arm vs the chemotherapy arm, with a hazard ratio of 0.84 (95% CI, 0.62-1.14).

Datopotamab deruxtecan elicited an ORR of 36.4% by BICR vs 22.9% with chemotherapy (OR, 1.95; 95% CI, 1.41-2.71). The median DOR with the ADC was 6.7 months (95% CI, 5.6-9.8) vs 5.7 months (95% CI, 4.9-6.8) with chemotherapy; the respective DCRs at 12 weeks were 75.3% and 63.8%. Moreover, TFST, TSST, and PFS2 were all prolonged with the ADC vs single-agent chemotherapy.

Safety Insights

The median duration of treatment with datopotamab deruxtecan was 6.7 months (range, 0.7-15.6) vs 4.1 months (range, 0.2-17.4) with chemotherapy. Treatment-related adverse effects (TRAEs) were experienced by 93.6% of those on the ADC and 86.3% of those on chemotherapy; they were grade 3 or higher for 2.8% and 44.7% of patients, respectively. Serious TRAEs were reported in 5.8% of those on the investigative arm and 9.1% of those on the control arm.

Additionally, TRAEs led to dose reductions or interruptions in 20.8% and 11.9% of those who received datopotamab deruxtecan vs 30.2% and 24.5% of those who were given chemotherapy. TRAEs led to discontinuation for 2.5% of those in the ADC arm vs 2.6% of those on the chemotherapy arm.

In the ADC Arm, the most common TRAEs experienced by at least 10% of patients included nausea (any grade, 51.1%; grade ≥3, 1.4%), stomatitis (50%; 6.4%), alopecia (36.4%; 0%), fatigue (23.6%; 1.7%), dry eye (21.7%; 0.6%), vomiting (19.7%; 1.1%), constipation (18.1%; 0%), keratitis (14.4%; 0.6%), decreased appetite (13.9%; 0.8%), asthenia (12.5%; 0.8%), anemia (11.1%; 1.1%), neutropenia (10.8%; 1.1%), increased aspartate aminotransferase level (8.6%; 0.6%), diarrhea (7.5%; 0%), leukopenia (7.2%; 0.6%), Palmar-plantar erythrodysesthesia syndrome (1.9%; 0%), and decreased platelet count (1.9%; 0%).

Looking Ahead

The European Commission will now review the recommendation.1

Earlier this month, the FDA approved datopotamab deruxtecan-dlnk (Datroway) for use in adult patients with unresectable or metastatic, hormone receptor–positive, HER2-negative breast cancer who had prior exposure to endocrine-based therapy and chemotherapy for unresectable or metastatic disease.3 The decision was based on data from this trial.

References

1. Datopotamab deruxtecan recommended for approval in the EU by CHMP for patients with previously treated metastatic HR positive HER2 negative breast cancer. News release. Daiichi Sankyo. January 31, 2025. Accessed January 31, 2025. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202501/20250131_E3.pdf
2. Bardia A, Jhaveri K, Im S-A, et al. Datopotamab deruxtecan versus chemotherapy in previously treated inoperable/metastatic hormone receptor–positive Human Epidermal Growth Factor Receptor 2–negative breast cancer: primary results from TROPION-Breast01. J Clin Oncol. 2025;43(3):285-296. doi:10.1200/JCO.24.00920
3. FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer. FDA. January 17, 2025. Accessed January 31, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-datopotamab-deruxtecan-dlnk-unresectable-or-metastatic-hr-positive-her2-negative-breast