EC Decision for Datroway (datopotamab deruxtecan) and Enhertu (trastuzumab deruxtecan) indications in the HR+/HER2- metastatic breast cancer

Datroway has been approved for the treatment of adult patients with HR+/HER2- (IHC 0, 1+, or 2+/ISH-) mBC who have received prior endocrine therapy (ET) and at least one line of chemotherapy (CT)

• The EC approval follows the positive CHMP opinion given on January 30, 2025, and recent approvals in the US and JP for the same indication
• The approval is based on results from the Phase 3 TROPION-Breast01 trial that were presented at ESMO 2023 and published in the Journal of Clinical Oncology
• Dato-DXd demonstrated statistically significant positive PFS vs. investigator’s choice chemo (mPFS: 6.9mo vs 4.9mo; HR=0.63) but did not achieve statistical significance for its OS dual primary endpoint (mOS: 18.6mo vs 18.3mo; HR: 1.01)
• Though Dato-DXd demonstrated a numerically higher mPFS compared to Trodelvy in TROPICS-02 (mPFS: 6.9 mo vs 5.5 mo), this is likely due to the TROPION-Breast01 study population being less-heavily pre-treated as the hazard ratios were comparable (HR: 0.63 vs 0.66)

While not affecting regulatory approval, the lack of OS benefit may negatively impact future reimbursement in the EU; DSI also alluded in the press release that “subsequent ADC treatment” may have impacted the OS results

In their press release, DSI highlighted that this was the first EU approval for the Datroway but “ the second ADC approved for breast cancer based on DSI’s DXd technology...further underscoring our commitment to creating new medicines for patients with cancer” 

Enhertu, (T-DXd; HER2-ADC) is indicated as a monotherapy for the treatment of adult patients with HR+/HER2-low (IHC 1+ or ICH 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) mBC who have received at least one endocrine therapy (ET) in the metastatic setting and who are not considered suitable for ET as the next line of treatment]

• This EC approval follows the positive CHMP opinion in February 28, 2025, with a relatively short duration (~35 days) from positive opinion to approval
• The approval is based on results from the Phase 3 DESTINY-Breast06 trial that were presented at ASCO 2024 and published in The New England Journal of Medicine
• T-DXd showed a 38% reduction in the risk of disease progression or death versus chemotherapy (mPFS: 13.2 mo vs 8.1 mo; HR: 0.62) in patients with chemotherapy-naïve HR+/HER2-low mBC
• T-DXd’s EU label includes a specification “who are not considered suitable for endocrine therapy as the next line of treatment” which is not included in the FDA label
• T-DXd’s SmPc has not yet been updated to include the newly approved indication

In the PR, it is noted that T-DXd “continues to open up new approaches to diagnosis and treatment” and that this approval “underscores the importance of testing metastatic breast cancer tumours for any IHC staining” to identify patients eligible of T-DXd. AZ/DS continues to emphasize the importance of HER2-testing to push adoption of T-DXd in this newly defined HER2-ultralow population.

Nevertheless, France’s High Authority of Health (HAS) has refused to grant early access authorization to trastuzumab deruxtecan (Enhertu, T-DXd; HER2-ADC) in patients with HR+/HER2-low/ultralow mBC who have received at least one line of hormone therapy in the metastatic setting

• The HAS’s refusal follows a negative recommendation from the Technical Information Committee indicating that the therapeutic effect of T-DXd did not sufficiently support a benefit to patients within the context of current treatment options available 
• The Technical Information Committee also does not consider T-DXd to be innovative in the indication because, while it is a novel treatment modality, it is not considered likely to bring substantial change in patient management to this stage of treatment
  • T-DXd was considered to have demonstrated a PFS benefit in the Phase 3 DESTINY-Breast06 trial (mPFS: 13.2 vs 8.1 mo; HR: 0.62), however the immaturity of OS data has limited its impact
  • The toxicity profile was also concerning, with higher rates of grade ≥3 AEs in the T-DXd group compared to the CT control group (52.8% vs. 44.4%), serious AEs (20.3% vs. 16.1%), and treatment discontinuations (14.3% vs. 9.4%)
• The HAS’ innovation criteria are as follows: 
  • The disease constitutes a serious, rare, or disabling indication
  • No appropriate treatment exists
  • Treatment cannot be postponed
  • Clinical trials have demonstrated strong efficacy and safety data for the treatment
• This rejection suggests that it may face challenges in gaining reimbursement status across European countries