Trastuzumab Deruxtecan (Enhertu) and the Antibody-Drug Conjugate Boom

Trastuzumab deruxtecan, sold as Enhertu, is a HER2-directed antibody-drug conjugate (ADC) that carries a topoisomerase I inhibitor payload. It has become a benchmark for the ADC field because it works not only in HER2-positive disease but also in tumors with lower HER2 expression.

Mechanism at a glance

The drug links the HER2 antibody trastuzumab to a topoisomerase I inhibitor payload (deruxtecan) via a cleavable linker. After the conjugate binds HER2 and is internalized, the payload is released and kills the cell; some payload can also diffuse to neighboring tumor cells. Nausea, fatigue and low blood counts are common, and monitoring for interstitial lung disease is essential.

Why it changed practice

In breast cancer, trastuzumab deruxtecan was approved in HER2-positive disease and also in “HER2-low” disease, a category that did not meaningfully exist as a treatable group before. Since January 2025 the label also covers hormone receptor-positive “HER2-ultralow” disease after endocrine therapy. It has also been approved in HER2-mutant non-small cell lung cancer and in HER2-positive gastric cancer, and tumor-agnostic use in HER2-positive solid tumors has been recognized.

Features that set the bar

High drug-to-antibody ratio and a payload that can affect neighboring cells (the bystander effect).
Movement into earlier lines, which raises the stakes for later-line competitors.

Competitors and challenges

Other HER2 ADCs and rivals with different targets such as TROP2 and HER3.
Safety management: interstitial lung disease is a known risk that requires monitoring.
Combination regimens with immune checkpoint inhibitors and other agents.

What to watch

Early-stage trial results, head-to-head comparisons with other ADCs, new payloads and linkers, and biomarker approaches that define which patients benefit. The ADC pipeline is large enough that dedicated pipeline tracking is essential.

Recent developments

Updated October 8, 2026. Items are drawn from company announcements, regulators and trade press; links go to the sources.

Sep 14, 2026: At WCLC, DESTINY-Lung04 showed Enhertu beating platinum-pemetrexed plus pembrolizumab as first-line treatment of HER2-mutant NSCLC: median PFS of 14.3 vs 8.3 months (HR 0.63) and response rate of 70.0% vs 44.5%. Interstitial lung disease or pneumonitis occurred in 20.8%, including four grade 5 events (company-reported). (AstraZeneca)
Aug 25, 2026: FDA approved zanidatamab-based regimens for first-line HER2-positive gastric, GEJ and esophageal adenocarcinoma (HERIZON-GEA-01), a competing HER2 option: median overall survival of 26.4 vs 19.2 months and OS HR 0.72 with the triplet. (OncLive)
Jun 24, 2026: FDA approved a competing antibody-drug conjugate, Trodelvy, for first-line triple-negative breast cancer, alone (ASCENT-03) or with Keytruda (ASCENT-04). (CURE)
May 15, 2026: FDA approved two early breast cancer indications: neoadjuvant Enhertu followed by THP in HER2-positive stage II-III disease (DESTINY-Breast11; pCR 67.3% vs 56.3%) and adjuvant Enhertu for residual invasive disease (DESTINY-Breast05; three-year IDFS 92.4% vs 83.7%). The label carries a boxed warning for interstitial lung disease. (FDA)
Dec 15, 2025: FDA approved Enhertu with pertuzumab for first-line HER2-positive metastatic breast cancer (DESTINY-Breast09): median PFS of 40.7 vs 26.9 months (HR 0.56). Overall survival data were still immature. (FDA)
Oct 18, 2025: DESTINY-Breast05 was presented at ESMO 2025: Enhertu reduced the risk of invasive disease recurrence or death by 53% vs T-DM1 in high-risk residual HER2-positive early breast cancer (IDFS HR 0.47). (AstraZeneca)
Jan 27, 2025: FDA approved Enhertu for HR-positive HER2-low or HER2-ultralow metastatic breast cancer after endocrine therapy (DESTINY-Breast06): median PFS of 13.2 vs 8.1 months against chemotherapy (HR 0.62). (FDA)

Upcoming catalysts

Oct 23-27, 2026: ESMO Congress, Madrid. I could not confirm a list of Enhertu abstracts.
Pending: AstraZeneca says DESTINY-Lung04 data will be shared with regulators; no submission or decision date has been announced.
Ongoing: DESTINY-Gastric05 (first-line HER2-positive gastric cancer, Enhertu plus pembrolizumab regimen); no topline results yet.

Bottom line

Trastuzumab deruxtecan raised expectations for the whole ADC category. Any company developing a competing conjugate will be asked how its efficacy, safety and patient selection compare, so having a current side-by-side view is essential.

Want this kind of analysis for the cancer areas you compete in? Request information and we will share sample deliverables.

This article is for informational and competitive-intelligence purposes only and is not medical advice. Approvals, labels and trial results change; verify details against current prescribing information and primary sources.