Pharmacist's Application to Practice: Datopotamab deruxtecan-dlnk

FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer

What is the potential role for datopotamab deruxtecan-dlnk in the treatment of unresectable/metastatic HR+, HER2- breast cancer?

• Datopotamab deruxtecan-dlnk (Dato-DXd) is an antibody-drug conjugate (ADC) that combines a humanized IgG1 monoclonal antibody targeting Trop2 with deruxtecan, a topoisomerase I inhibitor. The deruxtecan component is composed of a cleavable linker and the topoisomerase I inhibitor, DXd. Upon binding to Trop2 on tumor cells, datopotamab deruxtecan undergoes internalization and intracellular linker cleavage by lysosomal enzymes, releasing DXd and resulting in DNA damage and apoptotic cell death.1
• Dato-DXd is recommended in the National Comprehensive Cancer Network (NCCN) guidelines as second-line therapy for unresectable or metastatic hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer in adults who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease.2
• Approval for the above indication was based on the TROPION-Breast01 trial.
  • The TROPION-Breast01 trial evaluated the efficacy and safety of Dato-DXd compared to single-agent chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with unresectable or metastatic HR+ and HER2- breast cancer who had disease progression on endocrine therapy and one to two previous lines of chemotherapy.
  • Median progression-free survival (PFS) was higher in patients who received Dato-DXd at 6.9 months compared to 4.9 months in patients who received single-agent chemotherapy (p<0.0001).
  • The most common adverse events were nausea (51.1%), stomatitis (50%), alopecia (36.4%), fatigue (23.6%), and dry eye (21.7%).
  • The incidence of neutropenia was 10.8% in the Dato-DXd group compared to 42.5% in patients who received single agent chemotherapy.
  • TROPION-Breast01 did not meet the secondary endpoint of overall survival (OS). However, due to its favorable safety profile and other positive secondary endpoints, Dato-DXd may still be a valuable treatment option for patients with HR+, HER2- breast cancer. Further clinical trials are ongoing to determine the future of Dato-DXd.3,4
• Other available agents recommended per NCCN guidelines in this setting include fam-trastuzumab deruxtecan, targeted therapy, sacituzumab govitecan, or systemic chemotherapy.
  • Fam-trastuzumab deruxtecan is another ADC which consists of humanized IgG1 monoclonal antibody targeting HER2 with deruxtecan, a topoisomerase I inhibitor. To be eligible for this therapy, patients must have some expression of HER2 defined by HER2 IHC 0+, 1+, or 2+/ISH negative.
  • There are a few targeted therapies recommended in this setting, but options will depend on the tumor’s genomic profile.2
  • Sacituzumab govitecan (SG) is an option in patients who are not candidates for fam-trastuzumab deruxtecan. SG is an ADC which consists of humanized IgG1 monoclonal antibody targeting Trop-2 with SN-38, a topoisomerase I. This medication has the same target as datopotamab deruxtecan-dlnk but the payload is ten-times more potent than SG, and it has a longer half-life; therefore, it can be dosed once every 21 days.5 This dosing of SG is 10 mg/kg intravenous on days 1 and 8 every 21 days which requires the patient to travel to clinic more frequently than Dato-DXd, increasing the cost of care. SG has a linker with a lower serum stability, whereas Dato-DXd has a linker that exhibits high serum stability and only releases a low level of payload in plasma, which may decrease toxicity. As a result, the side effect profile of these agents differ as SG has a higher incidence of neutropenia, nausea or vomiting, and diarrhea whereas Dato-DXd has a higher incidence of ocular toxicity and stomatitis. Additionally, Dato-DXd was studied after one to two previous lines of chemotherapy, and SG was studied after two to four previous lines of chemotherapy, which should be considered when choosing between the two agents. It is also important to note that SG has data to support improvement in OS, but Dato-DXd has failed to meet OS endpoint.
    • SG was studied in the TROPiCS-02 trial in patients with metastatic HR+, HER2- breast cancer after disease progression on a CDK4/6 inhibitor, endocrine therapy, and a taxane in any setting and two to four previous chemotherapy regimens for metastatic disease. SG was compared to physician’s choice of single agent chemotherapy and showed an improvement in PFS and OS.6,7
    • It is important to note that the patient population received at least two prior chemotherapies in the metastatic setting. NCCN lists this agent as a second-line option but per clinical trial design, it should be a second line agent in patients who have progressed within 1 year of receiving a taxane as neoadjuvant or adjuvant therapy. It should also be considered in patients after treatment with endocrine therapy, a CDK 4/6 inhibitor, and at least 2 prior systemic chemotherapies.
  • Systemic chemotherapy such as doxorubicin, paclitaxel, capecitabine, gemcitabine, and vinorelbine are options; however, these agents are often discontinued due to unacceptable toxicity.2

What role can the pharmacist play in the management of patients on datopotamab deruxtecan-dlnk?

• Pharmacists play an integral role in the management of patients on ADCs, such as Dato-DXd, including ensuring appropriateness of therapy, dosing, prophylactic supportive care management, and toxicity management.
• Appropriateness of therapy
  • Patients are eligible to receive Dato-DXd for metastatic HR+, HER2- breast cancer after failure on endocrine therapy and one to two prior lines of chemotherapy.
  • It is important to note the treatment landscape of endocrine-refractory metastatic HR+, HER2- breast cancer changed during the study period with the publications of TROPiCS-Breast02 and Destiny-Breast06.
  • Further studies are required to determine the appropriate sequencing of ADCs in this setting.
• Dosing and Administration
  • The recommended dose is 6 mg/kg administered intravenously every 3 weeks with a maximum dose of 540 mg for patients ≥ 90 kg.
  • It is recommended to give the first infusion over 90 minutes followed by an observation period for at least 1 hour. In subsequent cycles, if well tolerated, the infusion can be administered over 30 minutes followed by an observation period of at least 1 hour.
    • If prior infusions were well-tolerated, administer all subsequent infusions over 30 minutes and observe patients for at least 30 minutes following infusion.
  • There are no recommended renal or hepatic dose adjustments.
  • If dose reductions are required:
    • First dose reduction: 4 mg/kg intravenous every 3 weeks.
      • There is a maximum of 360 mg for patients ≥90 kg.
    • Second dose reduction: 3 mg/kg intravenous every 3 weeks.
      • There is a maximum of 270 mg for patients ≥90 kg.
    • Third dose reduction: permanently discontinue.
• Prophylactic supportive care management
  • Infusion
    • It is recommended to premedicate with antihistamines and antipyretics 30-60 minutes prior to each infusion.
  • Ocular care
    • Advise patients to use preservative-free lubricant eye drops at least 4 times daily and as needed.
    • Refer patients to an eye care professional (optometrist or ophthalmologist) for an ophthalmic exam at treatment initiation, annually while on treatment, at end of treatment, and as clinically indicated. Exam should include visual acuity testing, slit lamp examination (with fluorescein staining), intraocular pressure, and fundoscopy.
    • Advise patients to avoid using contact lenses during treatment unless directed by an eye care professional.
  • Stomatitis prophylaxis
    • Advise patients to use dexamethasone oral solution 0.1 mg/mL (or a similar steroid-containing mouthwash) 4 times daily and as needed for prophylaxis. Patient should swish for 1-2 minutes then spit out the solution.
    • Instruct the patient to hold ice chips or ice water in the mouth throughout the infusion if feasible.
    • Encourage patients to brush with a soft bristle toothbrush and continue flossing if already part of their routine.
  • Nausea and Vomiting
    • Categorized as moderately emetogenic so patients should receive appropriate anti-emetic premedication and take-home antiemetics per NCCN nausea/vomiting guidelines.
• Toxicity management
  • Stomatitis
    • Treatment should be held for grade 2 and 3 stomatitis with grade 4 warranting discontinuation.
  • Ocular adverse reactions
    • Patients should be monitored for mild ocular disorders (nonconfluent superficial keratitis).
    • Treatment should be held in the event of the following ocular adverse effects: cornea epithelial defect, confluent superficial keratitis, or decreased visual acuity (defined by 3-line or more loss).
  • Infusion-related reactions
    • For mild (grade 1 or 2) infusion reactions, the PI recommends resuming the infusion at half of the original rate. The infusion should be stopped and appropriate supportive care medications administered.
    • If the patient experiences a moderate or severe (grade 3 or 4) infusion reaction, the infusion should not be rechallenged.

Clinical Pearls

• Dato-DXd can cause severe, life-threatening, or fatal cases of interstitial lung disease (ILD) or pneumonitis. In TROPION-Breast01 trial, the incidence of ILD/pneumonitis was low at 3.3%. It is recommended to monitor for new symptoms of ILD/pneumonitis such as shortness of breath or new onset cough. It is particularly important to monitor in patients with kidney impairment. If a patient develops any grade ILD/pneumonitis, it is recommended to hold Dato-DXd and consider corticosteroids.
• Do not re-escalate the dose after a dose reduction.1
• In TROPION-Breast01, patients were allowed on trial if they were endocrine-naïve due to endocrine therapy being classified as unsuitable, and they also allowed patients with clinically stable brain metastasis.4
• Stability and Safe Handling
  • Stability
    • Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Store in the original carton to protect from light until time of reconstitution. Do not shake the reconstituted or diluted solution.
    • If not used immediately, store solutions diluted for infusion at room temperature at up to 25°C (77°F) for up to 4 hours (including preparation time) or in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours; do not freeze; protect from light.
  • Safe Handling
    • If refrigerated, allow diluted infusion solution to reach room temperature prior to administration.
    • Administer only with an infusion set made of polyvinyl chloride, polybutadiene, or low-density polyethylene and a 0.2-micron in-line polytetrafluoroethylene, polyethersulfone, or nylon 66 filter.
    • The maximum time from vial reconstitution through the completion of administration should not exceed 24 hours; discard the infusion bag if storage time exceeds the limit. Cover infusion bag during infusion to protect from light.
• Embryo-fetal toxicity: Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.1
• Patient Access
  • Patient savings program: Eligible patients may pay as little as $0 per prescription. The annual benefit can be used for the cost of the drug itself and may cover up to $100 in infusion costs per administration. There are no income requirements to participate in the program.
  • There is also patient assistance program for uninsured or underinsured patients who meet the financial requirements.8

References

1.Datroway (datopotamab deruxtecan) [prescribing information]. Basking Ridge, NJ: Daiichi Sankyo; January 2025.

2.National Comprehensive Cancer Network. Breast Cancer (Version 1.2025). https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed February 28, 2025.

3.U.S. Food and Drug Administration. FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer. January 2025. Accessed January 31, 2025.

4.Bardia A, Jhaveri K, Im SA, 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

5.Schipilliti FM, Drittone D, Mazzuca F, La Forgia D, Guven DC, Rizzo A. Datopotamab deruxtecan: A novel antibody drug conjugate for triple-negative breast cancer. Heliyon. 2024;10(7):e28385. Published 2024 Mar 22. doi:10.1016/j.heliyon.2024.e28385

6.Rugo HS, Bardia A, Marmé F, et al. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022;40(29):3365-3376. doi:10.1200/JCO.22.01002

7.Rugo HS, Bardia A, Marmé F, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;402(10411):1423-1433. doi:10.1016/S0140-6736(23)01245-X

8.Access & Support: DATROWAY® (datopotamab deruxtecan-dlnk) for hcps. https://datrowayhcp.com/support-resources/access-support. Accessed February 28, 2025.