▎WuXiEdited by Kant Content Team

Today, the U.S. FDA announced the approval of Datroway (datopotamab deruxtecan or Dato-DXd), an antibody-drug conjugate (ADC) jointly developed by AstraZeneca and Daiichi Sankyo, for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-negative breast cancer who have previously received endocrine therapy and chemotherapy.Phase 3 trial results show that Datroway reduced the risk of disease progression or death by 37% compared to chemotherapy.According to the AstraZeneca press release, this is the first approval of Datroway in the United States.It is worth mentioning that this ADC was listed by the industry media Evaluate asTop 10 Potential Blockbuster R&D Projects in 2024One of.

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In the United States alone, more than 300,000 breast cancer cases are confirmed each year. While patients with early-stage breast cancer have a relatively high survival rate, only about 30% of patients with metastatic breast cancer or those whose condition has progressed to the metastatic stage survive five years after diagnosis. Statistics show that approximately 70% of breast cancers are defined as HR-positive, HER2-negative breast cancer (HER2 scored as IHC 0, IHC 1+, or IHC 2+/ISH-). Endocrine therapy is widely used in the early treatment of HR-positive metastatic breast cancer. However, after initial treatment, the efficacy of endocrine therapy is often limited. The current standard treatment after endocrine therapy is chemotherapy, but the response rate and therapeutic effects of chemotherapy are relatively poor.

This U.S. FDA approval is primarily based on the results of the TROPION-Breast01 trial. The trial is a global, multicenter, randomized, open-label Phase 3 study designed to evaluate the efficacy and safety of Datroway (6 mg/kg) administered intravenously every 21 days compared to investigator’s choice of single-agent chemotherapy (irinotecan, capecitabine, vinorelbine, or gemcitabine). The enrolled patients were adults with unresectable or metastatic HR-positive, HER2-negative breast cancer who, in the investigator's assessment, did not respond to endocrine therapy and were unsuitable for continued treatment, having already received at least one chemotherapy regimen for unresectable or metastatic disease.

The primary efficacy endpoint of the trial wasAssessed by the blinded independent central review (BICR) based on RECIST v1.1 criteriaProgression-Free Survival (PFS) and Overall Survival (OS). Other efficacy evaluation indicators include the Objective Response Rate (ORR) and Duration of Response (DOR) confirmed by BICR.

The analysis shows,The median PFS in the Datroway treatment group was 6.9 months (95% CI: 5.7, 7.4), compared to 4.9 months (95% CI: 4.2, 5.5) in the chemotherapy group, with a hazard ratio (HR) of 0.63 (95% CI: 0.52, 0.76) and a two-sided p-value <0.0001.The median OS in the Datroway treatment group was 18.6 months (95% CI: 17.3, 20.1), compared to 18.3 months (95% CI: 17.3, 20.5) in the chemotherapy group, with a hazard ratio (HR) of 1.01 (95% CI: 0.83, 1.22). The bilateral p-value did not reach statistical significance.The confirmed ORR was 36% (95% CI: 31, 42) and 23% (95% CI: 19, 28), with a median DOR of 6.7 months (95% CI: 5.6, 9.8) and 5.7 months (95% CI: 4.9, 6.8), respectively.

DatrowayIncluding abnormal laboratory test indicatorsThe most common adverse reactions (≥20%) include stomatitis, nausea, fatigue, leukopenia, hypocalcemia, alopecia, lymphocytopenia, anemia, constipation, neutropenia, dry eye, vomiting, increased alanine aminotransferase (ALT), keratitis, increased aspartate aminotransferase (AST), and increased alkaline phosphatase.

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Datroway is an ADC generated by conjugating a humanized, Trop2-targeting monoclonal antibody with an innovative DNA topoisomerase I inhibitor (DXd) through a cleavable tetrapeptide linker.DXd has a unique mechanism of action, with 10 times higher activity compared to the common chemotherapy drug irinotecan. Moreover, this drug has a strong ability to penetrate cell membranes, allowing them to kill neighboring cancer cells after destroying ADC-ingesting cancer cells, producing a "bystander effect."Trop2 is a protein widely expressed in various solid tumors, including HR-positive, HER2-low or negative breast cancer.AstraZeneca and Daiichi Sankyo reached an agreement in July 2020 to jointly develop this ADC. Currently, the marketing application of Datroway for breast cancer treatment is under review in the EU, China, and other countries and regions.

In December 2024, Datroway was approved in Japan.Global First Approval, for the treatment of adult patients with hormone receptor (HR)-positive, HER2-negative unresectable or recurrent breast cancer who have received chemotherapy. Datroway was granted by the U.S. FDA in the same month.Breakthrough Therapy Designation(BTD), for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) whose disease has progressed after receiving EGFR tyrosine kinase inhibitors (TKI) and platinum-based chemotherapy. This month, the U.S. FDA granted DatrowayPriority Review StatusFor the treatment of the same patient population, the FDA is expected to complete its review in the third quarter of 2025.

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References:

[1] FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer. Retrieved January 17, 2025 from https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-datopotamab-deruxtecan-dlnk-unresectable-or-metastatic-hr-positive-her2-negative-breast

[2] Datroway (datopotamab deruxtecan) approved in the US for patients with previously treated metastatic HR-positive, HER2-negative breast cancer. Retrieved January 17, 2025 from https://www.astrazeneca.com/media-centre/press-releases/2025/dato-dxd-approved-in-us-for-hr-p-breast-cancer.html

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