Implementing Datopotamab Deruxtecan in Practice: TROPION Insights

Datopotamab deruxtecan (Dato-DXd; Datroway; AstraZeneca) is a trophoblast cell surface antigen 2 (TROP2)–directed antibody-drug conjugate (ADC) consisting of a humanized anti–TROP2-directed immunoglobulin G1 monoclonal antibody, which is attached to a highly potent topoisomerase I inhibitor payload via a plasma-stable, tumor-selective, cleavable linker. The phase 3 TROPION-Breast01 trial (NCT05104866) demonstrated a clinically meaningful progression-free survival (PFS) benefit of Dato-DXd when compared with chemotherapy in patients with inoperable/metastatic hormone receptor–positive (HR+), HER2-negative (HER2–) breast cancer who had progressed on endocrine therapy, if suitable, and received at least 1 prior line of therapy.^1,2

The phase 3 TROPION-Lung01 and phase 2 TROPION-Lung05 trials (NCT04656652, NCT04484142)^3,4 demonstrated meaningful clinical activity of Dato-DXd in patients with EGFR-mutated advanced or metastatic non–small cell lung cancer (NSCLC) who progressed on prior EGFR-directed therapies and chemotherapy.⁵ For oncology pharmacists, implementation of this regimen into practice requires attention to premedication, supportive care, and toxicity monitoring. In this article, we highlight portions of the TROPION trials in breast cancer and NSCLC that are important when designing supportive care regimens for patients receiving Dato-DXd.

TROPION-Breast01 Trial Overview

Study Design and Population

TROPION-Breast01 was a global, phase 3, open-label, randomized trial that enrolled 1003 patients across 166 centers in 20 countries.¹ Patients were eligible for inclusion if they were 18 years or older with an ECOG status of 0 or 1 and inoperable or metastatic HR+/HER2– breast cancer (HER2– is defined as immunohistochemistry 0, 1+, or 2+/in situ hybridization negative). Eligibility criteria also included patients who progressed on endocrine therapy, if endocrine treatment was suitable, and received 1 or 2 previous lines of chemotherapy in the inoperable or metastatic setting. Patients treated with a chemotherapeutic agent targeting topoisomerase 1 and previous TROP2-targeted therapy were not eligible. Patients were randomly assigned 1:1 to either of the following:

1. Experimental arm: Dato-DXd
2. Control arm: Single-agent investigator’s choice chemotherapy (ICC)
   1. Eribulin
   2. Capecitabine
   3. Vinorelbine
   4. Gemcitabine

The primary end points were PFS, defined as time from assignment to progression, and overall survival (OS). Secondary end points included PFS by investigator assessment and response outcomes, including objective response rate (ORR) and disease control rate at 12 weeks.

• PFS: Dato-DXd achieved a 37% reduction in risk of progression or death compared with ICC (hazard ratio, 0.63; 95% CI, 0.52-0.76; P < .0001), with median PFS for Dato-DXd vs ICC of 6.9 months (95% CI, 5.7-7.4) vs 4.9 months (95% CI, 4.2-5.5), respectively.
• OS: The data were immature at the time of this analysis, but the observed trend in the Dato-DXd arm was favorable (hazard ratio, 0.84; 95% CI, 0.62-1.14).
• Mean duration of response was 6.7 months (95% CI, 5.6-9.8) in the Dato-DXd arm compared with 5.7 months (95% CI, 4.9-6.8) in the ICC arm.
• The most common treatment-related adverse events (TRAEs) in the Dato-DXd arm were nausea (51.1%), stomatitis (50%), alopecia (36.4%), and neutropenia (10.8%).

TROPION-Lung01 and -Lung05 Pooled Analysis Overview

Study Design and Population

TROPION-Lung01 was a phase 3, randomized, open-label trial comparing the safety and efficacy of Dato-DXd with docetaxel in previously treated advanced or metastatic NSCLC.⁵ TROPION-Lung05 was a single-arm phase 2 study assessing the safety and efficacy of Dato-DXd in patients with previously treated advanced or metastatic NSCLC with actionable genomic mutations.⁵ A pooled analysis of these 2 global trials was conducted to examine the efficacy of Dato-DXd specifically in patients with EGFR mutations. In both studies, patients with advanced or metastatic NSCLC with disease progression on prior targeted therapy (for those with driver mutations) and platinum-based chemotherapy, measurable disease per RECIST 1.1, and ECOG performance status 0 or 1 were eligible.

• Experimental arm (for pooled analysis): Dato-DXd

Design of pooled analysis: Data were retrospectively pooled from patients with at least 1 common or uncommon mutation in EGFR who received at least 1 dose of Dato-DXd in either trial. EGFR mutational status was tested locally using blood or tumor tissue.

ORR was the primary end point of TROPION-Lung05 and the secondary end point of TROPION-Lung01. PFS was defined as time to progression or death from start of treatment in TROPION-Lung05 and time from randomization in TROPION-Lung01. OS was defined as time to death from the same respective starting points.

• Confirmed ORR in the pooled population: 43% (95% CI, 34%-52%)
• Median duration of response in the pooled population: 7.0 months (95% CI, 4.2-9.8)
• Median PFS in the pooled population: 5.8 months (95% CI, 5.4-8.2)
• Median OS in the pooled population: 15.6 months (95% CI, 13.1-19.0)
• The most common TRAEs included stomatitis (69%), alopecia (49%), nausea (46%), and ocular surface events (32%)

Dosing, Administration, and Adjustments

Treatment Schedule and Administration

In both trials, Dato-DXd was administered intravenously in 21-day cycles at a dose of 6 mg/kg (maximum dose, 540 mg for patients ≥ 90 kg). Treatment continued until disease progression or intolerable adverse effects.^1,5

Premedication and Supportive Care

• Emetogenicity: high
  • Administer your institution’s preferred prophylaxis regimen for highly emetic chemotherapy (eg, NK1 receptor antagonist, 5-HT3 serotonin receptor antagonist, dexamethasone, and olanzapine) before each infusion.
• Infusion reactions
  • Administer diphenhydramine (25-50 mg) and acetaminophen (650-1000 mg) 30 to 60 minutes before each infusion.
  • The first infusion should be administered over a period of 90 minutes. Subsequent infusions may be administered over 30 minutes if prior infusions were tolerated.
• Stomatitis
  • Administer steroid-containing mouthwash (dexamethasone oral solution 0.1 mg/mL) 4 times daily and additionally as needed throughout the duration of treatment.
  • Patients should be instructed to hold ice chips or ice water in the mouth throughout the duration of each infusion.
• Ocular prophylaxis
  • Administer preservative-free lubricant eye drops at least 4 times a day and additionally as needed throughout the duration of treatment.
  • Patients should be instructed to avoid wearing contact lenses throughout the duration of treatment.

Dose modifications are provided in the labeling of Dato-DXd for the following adverse reactions⁶:

• Interstitial lung disease/pneumonitis
  • Withhold until completely resolved for grade 1.
    • If resolved within 28 days, restart at previous dose.
    • If resolved in more than 28 days, restart at 1 reduced dose level.
  • Permanently discontinue for grade 2 or greater.
  • Administer corticosteroid treatment as soon as suspected.
• Keratitis
  • Withhold for confluent superficial keratitis, cornea epithelial defect, or 3-line-or-more loss in best corrected visual acuity
    • Once improved or resolved, can restart at previous dose or consider reduction.
  • Withhold for corneal ulcer or stromal opacity or best corrected distance visual acuity 20/200 or worse.
    • Once improved or resolved, reduce dose by 1 level.
  • Permanently discontinue for corneal perforation.
• Stomatitis
  • Withhold for grade 2 until resolved to grade 1 or higher, then restart at the same dose level if the first occurrence. If recurrent, consider dose-level reduction.
  • Withhold for grade 3 until improvement to greater than or equal to grade 1, then restart at reduced dose level.
  • Permanently discontinue for grade 4.
• Infusion-related reactions
  • If grade 1, reduce infusion rate by 50%.
  • If grade 2, interrupt infusion and administer supportive care medications; restart at 50% of the infusion rate if resolved or improved to grade 1. All subsequent infusions should be administered at the 50% infusion rate..
  • If grade 3 or 4, permanently discontinue
• Other nonhematologic adverse reactions
  • Withhold for grade 3 until resolved to less than or equal to grade 1 or baseline, then restart at a reduced dose level.
  • Permanently discontinue for grade 4.

Recommended dose reductions for adverse reactions⁶

1. First: 4 mg/kg (up to a maximum of 360 mg for patients > 90 kg)
2. Second: 3 mg/kg (up to a maximum of 270 mg for patients > 90 kg)
3. Third: permanently discontinue

Baseline Organ Dysfunction

• Renal impairment
  • No dose adjustments are recommended by manufacturer labeling; however, higher rates of interstitial lung disease (ILD)/pneumonitis were observed in patients with mild and moderate renal impairments (creatinine clearance [CrCl] 30-90 mL/min). The effect of severe renal impairment (CrCl < 30 mL/min) is unknown. Use with caution.
• Hepatic impairment
  • No dose adjustments are recommended by manufacturer labeling; however, limited data exist for patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 times upper limit of normal [ULN], and any aspartate aminotransferase elevation). Patients should be monitored closely for potentially increased risk of adverse reactions. The effect of severe hepatic impairment (total bilirubin > 3 times ULN) is unknown. Use with caution.

Drug-Drug Interactions

Dato-DXd is not a strong CYP inducer or inhibitor, but pharmacists should be attentive to potentially overlapping toxicity risks.

Treatment Monitoring Requirements

Monitoring for significant AEs of Dato-DXd is essential for its safe administration. Pharmacists play a key role in developing monitoring protocols that include appropriate monitoring for infusion-related reactions, pneumonitis, and ocular AEs.

Key Points:

• Infusion-related reactions: Patients should be monitored for at least 1 hour for the first 2 cycles of infusions, then for at least 30 minutes for all subsequent infusions if no reactions are observed.
• Pneumonitis: Monitor for any signs and symptoms of ILD or pneumonitis. If suspected, stop Dato-DXd and start corticosteroids.
• Ocular AEs: A baseline ophthalmic exam should be conducted prior to initiation, annually while on treatment, at the end of treatment, and as clinically indicated.

Conclusion

Results from TROPION-Breast01 and the pooled analysis of TROPION-Lung01 and TROPION-Lung05 demonstrate the efficacy of Dato-DXd in both settings that led to its FDA approval and inclusion in treatment guidelines. These trials helped establish an additional option for therapy for pre-treated patients in the metastatic setting with certain genomic profiles.

For oncology pharmacists, successful incorporation of Dato-DXd will rely on the ability to effectively manage premedications and supportive care. Although the regimen itself is not operationally challenging, the high emetogenicity and significant risk of stomatitis and ocular AEs require pharmacological management. Pharmacy teams will continue to play an integral role in monitoring these patients and ensuring safe and effective delivery of treatment.

REFERENCES

1. Bardia A, Jhaveri K, Im S, 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

2. A phase-3, open-label, randomized study of Dato-DXd versus investigator's choice of chemotherapy (ICC) in participants with inoperable or metastatic HR-positive, HER2-negative breast cancer who have been treated with one or two prior lines of systemic chemotherapy (TROPION-Breast01). Clinicaltrials.gov. Updated April 14, 2025. Accessed October 16, 2025. https://clinicaltrials.gov/study/NCT05104866

3. Study of DS-1062a versus docetaxel in previously treated advanced or metastatic non-small cell lung cancer with or without actionable genomic alterations (TROPION-LUNG01). Clinicaltrials.gov. Updated August 27, 2025. Accessed October 16, 2025. https://clinicaltrials.gov/study/NCT04656652

4. Study of DS-1062a in advanced or metastatic non-small cell lung cancer with actionable genomic alterations (TROPION-Lung05). Clinicaltrials.gov. Updated October 15, 2025. Accessed October 16, 2025. https://clinicaltrials.gov/study/NCT04484142

5. Ahn M, Lisberg A, Goto Y, et al. A pooled analysis of datopotamab deruxtecan in patients with EGFR-mutated NSCLC. J Thor Oncol. Published online June 12, 2025. doi:10.1016/j.jtho.2025.06.002

6. Datroway (datopotamab deruxtecan). Package insert. Daiichi Sankyo. 2025.