datopotamab deruxtecan-dlnk — Drug Monograph

Datopotamab Deruxtecan (Dato-DXd) — TROP2 ADC Overview

Datopotamab deruxtecan (Datroway; Dato-DXd) is a TROP2-directed antibody-drug conjugate (ADC) that links an anti-TROP2 antibody to the topoisomerase I inhibitor DXd via a cleavable linker. TROP2 is broadly overexpressed across epithelial cancers, and after internalization the membrane-permeable DXd payload drives DNA damage plus a bystander killing effect. It is approved for HR-positive, HER2-negative breast cancer and for non-squamous NSCLC without actionable alterations. This monograph covers datopotamab deruxtecan dosing (6 mg/kg every 3 weeks), TROP2 ADC mechanism, line-of-therapy indications, and proactive management of stomatitis, interstitial lung disease (ILD), and ocular toxicity.

Indications (FDA / NCCN)

• HR-positive, HER2-negative metastatic breast cancer after endocrine therapy + ≥2 prior lines of chemotherapy (TROPION-Breast01)
• Metastatic non-squamous NSCLC without actionable alterations, after platinum chemotherapy and a checkpoint inhibitor (TROPION-Lung01)
• TROP2-directed ADC — no companion biomarker test required

Dosing

• Standard dose: 6 mg/kg IV every 3 weeks (21-day cycle)
• First infusion over 90 min; may shorten to 30 min if tolerated
• First dose reduction: 4 mg/kg; discontinue if further reduction needed
• Premedicate with antiemetics (5-HT3 + dexamethasone) and antihistamine

Monitoring

• Respiratory symptoms before each cycle; CT chest for suspected ILD/pneumonitis
• Oral mucosa for stomatitis — cryotherapy / steroid mouthwash prophylaxis
• Ocular symptoms and dry eye — prompt ophthalmology referral
• CBC with differential and LFTs

Brand names: Datroway

Drug class: Antibody-Drug Conjugate

Mechanism of Action

Anti-TROP2 (trophoblast cell-surface antigen 2) humanized monoclonal antibody conjugated to DXd (deruxtecan; an exatecan derivative, topoisomerase I inhibitor) via a tetrapeptide-based cleavable linker, with DAR ~4. TROP2 is broadly overexpressed in epithelial cancers. Upon internalization, DXd is released intralysosomally, inhibits topoisomerase I, causes DNA single-strand breaks, and induces S-phase arrest and apoptosis. The membrane-permeable DXd also exerts a bystander killing effect on adjacent tumor cells.

FDA Indications

• Unresectable or metastatic hormone receptor (HR)-positive, HER2-negative breast cancer in adults who received prior endocrine-based therapy and chemotherapy in the metastatic setting (≥2 prior lines) — approved February 2025 (TROPION-Breast01: PFS HR 0.63 vs investigator-choice chemotherapy)
• Unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) in adults with no actionable genomic alterations, after platinum-based chemotherapy and a checkpoint inhibitor — approved February 2025 (TROPION-Lung01: PFS HR 0.75 vs docetaxel)

Common Side Effects

• Stomatitis / oral mucositis (very common, nearly universal; often Grade 1–2)
• Nausea
• Fatigue
• Alopecia
• Constipation
• Decreased appetite
• Anemia
• Dry eye

Clinical Pearl

Dato-DXd is the first TROP2-targeting ADC approved in breast cancer and NSCLC. Its most critical differentiator from sacituzumab govitecan (another TROP2 ADC) is that stomatitis/oral mucositis is extremely common (and not typical with SG), while diarrhea and severe neutropenia are less prominent. Steroid mouthwash prophylaxis from Day 1 is standard practice and greatly reduces Grade 3 stomatitis. Vigilance for ILD is required throughout therapy — a hallmark of the DXd-payload class (shared…

Related Therapies & Mechanisms

• Trastuzumab deruxtecan (Enhertu) — Antibody-Drug Conjugate · Breast
• Sacituzumab govitecan (Trodelvy) — Antibody-Drug Conjugate · Breast
• Telisotuzumab vedotin (Emrelis) — Antibody-Drug Conjugate · NSCLC
• Trastuzumab Emtansine (T-DM1) (Kadcyla) — Antibody-Drug Conjugate · Breast