EMA Validates MAAs for Datopotamab Deruxtecan in NSCLC and HR+ Breast Cancer


MAAs for datopotamab deruxtecan in non–small cell lung cancer and hormone receptor–positive, HER2-negative breast cancer have been validated by the EMA.

Ken Takeshita, MD

Ken Takeshita, MD

The European Medicines Agency (EMA) has validated 2 marketing authorization applications (MAAs) seeking the approval of the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) for the treatment of patients with locally advanced or metastatic nonsquamous non–small cell lung cancer (NSCLC) requiring systemic therapy after prior treatment; and those with hormone receptor (HR)–positive, HER2-negative breast cancer who have progressed on or are not eligible for endocrine therapy and have received 1 or more prior systemic therapies.1

The MAAs were supported by findings from the pivotal phase 3 TROPION-Lung01 (NCT04656652) and TROPION-Breast01 (NCT05104866) trials, respectively, which were presented during the 2023 ESMO Congress.1 In TROPION-Lung01, treatment with Dato-DXd (n = 299) led to a median progression-free survival (PFS) of 4.4 months (95% CI, 4.2-5.6) vs 3.7 months (95% CI, 2.9-4.2) with docetaxel (n = 305) in patients with locally advanced or metastatic NSCLC with or without actionable genomic alterations who required systemic therapy after prior treatment (HR, 0.75; 95% CI, 0.62-0.91; P = .004).1,2

In TROPION-Breast01, Dato-DXd (n = 365) generated a median 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 single-agent chemotherapy (n = 367) in patients with unresectable or metastatic HR-positive, HER2-negative breast cancer who had progressed on and were not eligible for endocrine therapy and who had received 1 or more prior systemic therapies for unresectable or metastatic disease (HR, 0.63; 95% CI, 0.52-0.76; P < .0001).1,3

“The EMA validation is an important first step toward bringing this TROP2-directed ADC to eligible patients in Europe with nonsquamous lung cancer and HR-positive, HER2-negative breast cancer,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, stated in a news release.1 “This news builds on our recent regulatory progress in the US, where our lung cancer application has been accepted and our breast cancer application is underway, underscoring our commitment to changing the standard of care by developing new medicines to help as many patients worldwide as possible.”

In TROPION-Lung01, patients with actionable genomic alternations needed to have received prior platinum-based chemotherapy and an approved targeted therapy.1 Patients without known actionable genomic alterations were previously treated with platinum-based chemotherapy and a PD-L1/PD-1 inhibitor, either in combination or sequentially. PFS by BICR and overall survival (OS) served as the dual primary end points of the trial. Key secondary end points included investigator-assessed PFS, objective response rate (ORR), duration of response (DOR), time to response, disease control rate (DCR), and safety. The median OS was 12.4 months (95% CI, 10.8-14.8) with Dato-DXd vs 11.0 months (95% CI, 9.8-12.5) with docetaxel (HR, 0.90; 95% CI, 0.72-1.13).2

Treatment-related adverse effects (TRAEs) of grade 3 or higher were observed in 25% of patients in the Dato-DXd arm vs 41% of those in the docetaxel arm. The most common grade 3 or higher TRAEs in the Dato-DXd arm were stomatitis (6%), anemia (4%), asthenia (3%), and nausea (2%).

The dual primary end points of TROPION-Breast01 were PFS by BICR and OS.1 The key secondary end points were ORR, DOR, investigator-assessed PFS, DCR, time to first subsequent therapy, and safety. At a median follow-up of 9.7 months, the OS data were immature, but investigators observed a trend favoring Dato-DXd (HR, 0.84; 95% CI, 0.62-1.14).3

Grade 3 or higher TRAEs were observed in 21% of patients in the Dato-DXd arm vs 45% of those in the chemotherapy arm. The most common grade 3 or higher TRAEs in the Dato-DXd arm were stomatitis (6%) and fatigue (2%).

In February 2024, the FDA accepted for review a biologics license application (BLA) seeking the approval of Dato-DXd for patients with locally advanced or metastatic nonsquamous NSCLC who had received prior systemic therapy.4 This BLA was based on findings from TROPION-Lung01.

“Our ambition is for Dato-DXd to improve upon and replace conventional chemotherapy in the treatment of multiple cancer types,” Susan Galbraith, MBBChir, PhD, executive vice president of Oncology R&D at AstraZeneca, added in the news release.1 “Today’s dual validation of our applications in lung and breast cancers brings this potential medicine a meaningful step closer to redefining treatment expectations for patients with 2 of the most common cancers in Europe.”


  1. Two datopotamab deruxtecan applications validated in the EU for patients with advanced nonsquamous non-small cell lung cancer or HR-positive, HER2-negative breast cancer. News Release. AstraZeneca. March 4, 2024. Accessed March 4, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/ema-validates-dato-dxd-maas-for-nsq-nsclc-and-bc.html
  2. Ahn MJ, Lisberg A, Paz-Ares L, et al. Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): results of the randomized phase III study TROPION-Lung01. Ann Oncol. 2023;34(suppl 2):1305-1306. doi:10.1016/j.annonc.2023.10.061
  3. 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 (BC): primary results from the randomised phase III TROPION-Breast01 trial. Ann Oncol. 2023;34(suppl 2):1264-1265. doi:10.1016/j.annonc.2023.10.015
  4. Datopotamab deruxtecan biologics license application accepted in the US for patients with previously treated advanced nonsquamous non-small cell lung cancer. News release. AstraZeneca. February 19, 2024. Accessed March 4, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/fda-accepts-dato-dxd-bla-for-nonsquamous-nsclc.html
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