HER2-Low Breast Cancer Clinical Trials Recruiting Now (October 2026): T-DXd, Next-Gen HER2 ADCs, HER2-Ultralow

Last updated: October 21, 2026

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What "HER2-Low" (and "HER2-Ultralow") Means

A breast tumor is HER2-low when it makes some HER2 protein, but not enough to be called HER2-positive. On the standard immunohistochemistry (IHC) test it scores IHC 1+, or IHC 2+ with a negative ISH (FISH) test. For years these tumors were lumped in with "HER2-negative" disease — until the antibody-drug conjugate trastuzumab deruxtecan (T-DXd / Enhertu) showed it could treat them, turning HER2-low into its own treatable category. About half of all breast cancers that are not HER2-positive are HER2-low.

HER2-ultralow goes one step further: a tumor scoring IHC 0 but with faint, incomplete membrane staining in some cells. The DESTINY-Breast06 trial extended T-DXd's benefit into this ultralow group — so the exact wording of your HER2 pathology report matters. This page focuses on the HER2-low / HER2-ultralow setting; for the full disease picture see the main breast cancer trials page, or, if your tumor is HER2-positive (IHC 3+ or 2+/ISH-positive), the HER2-positive breast cancer page.

Approved Options Today (Before or Alongside a Trial)

Knowing the current standard of care helps you weigh a trial against it. In HER2-low disease, the right sequence depends heavily on your hormone-receptor (ER/PR) status.

Trastuzumab deruxtecan (T-DXd / Enhertu) — the defining HER2-low drug. A HER2-directed antibody-drug conjugate approved for HER2-low metastatic breast cancer. In the DESTINY-Breast04 trial it improved survival versus chemotherapy, and DESTINY-Breast06 extended its use to HER2-ultralow disease and to the chemotherapy-naive, post-endocrine setting. This is why knowing your HER2 IHC score matters so much (see the evidence below).
For hormone-receptor-positive (HR+) HER2-low disease: endocrine therapy, usually with a CDK4/6 inhibitor (palbociclib, ribociclib, abemaciclib), is typically used first; T-DXd generally follows after endocrine options are exhausted. Elacestrant is an option for ESR1-mutated HR+ disease.
For hormone-receptor-negative (triple-negative-like) HER2-low disease: chemotherapy and the TROP2 ADC sacituzumab govitecan (Trodelvy) are standard options, with T-DXd also approved in the HER2-low setting.

The Evidence Behind T-DXd in HER2-Low Disease

Two trials created and then expanded the HER2-low category:

DESTINY-Breast04 (Phase 3, the trial that created the category) — T-DXd vs. physician's-choice chemotherapy in HER2-low metastatic breast cancer (mostly hormone-receptor-positive), previously treated with chemotherapy:

Overall survival: median 23.4 vs. 16.8 months (hazard ratio 0.64)
Progression-free survival: median 9.9 vs. 5.1 months (hazard ratio 0.50)
The first time a HER2-directed therapy extended survival in HER2-low disease — establishing HER2-low as a treatable entity.

DESTINY-Breast06 (Phase 3, expansion) — T-DXd vs. chemotherapy in hormone-receptor-positive disease that was chemotherapy-naive (after endocrine therapy), and which notably included HER2-ultralow tumors. It showed a progression-free-survival benefit for T-DXd over chemotherapy and extended the T-DXd opportunity both to an earlier line and to the HER2-ultralow group.

Sources: DESTINY-Breast04 (Modi et al., N Engl J Med 2022, NCT03734029); DESTINY-Breast06 (NCT04494425). T-DXd is FDA-approved for HER2-low metastatic breast cancer; eligibility depends on a HER2 IHC test. Trial results describe specific HER2-low / HR-status / prior-treatment populations and may not apply to every patient. Exact figures for DESTINY-Breast06 should be confirmed with the primary publication and your oncologist.

Biomarkers That Open Trial Doors

Most HER2-low trials enroll by a specific combination of markers. Ask your oncologist which of these you have been tested for — they determine which trials below you can join.

HER2 IHC score (1+, 2+/ISH-negative, or 0-with-staining). This is the gatekeeper. HER2-low is IHC 1+ or 2+/ISH-negative; HER2-ultralow is IHC 0 with faint staining. Because the 1+ vs 0 call can be subtle between pathologists, some trials require central re-testing. Knowing your exact score is the single most important test for HER2-low trial eligibility.
Hormone-receptor (ER / PR) status. HR-positive vs HR-negative splits HER2-low into two different treatment worlds and determines which trials (and which arms) apply to you.
ESR1 mutation. In HR-positive disease, an ESR1 mutation (often found on a blood ctDNA test after endocrine therapy) opens elacestrant and several endocrine-combination trials, including with T-DXd.
BRCA / HRD and PIK3CA. Relevant in HR-positive and triple-negative-like disease for PARP inhibitor and PI3K/AKT-pathway trials; useful to have tested even though they are not HER2-specific.

Recruiting Trials by Mechanism

The HER2-low landscape in 2026 is dominated by antibody-drug conjugates — T-DXd in new settings and combinations, and a wave of next-generation HER2 ADCs. Trials below are recruiting; phase is noted for each. Confirm current status and eligibility with the study team — a trial's status and locations can change.

Trastuzumab Deruxtecan (T-DXd) — New Settings & Combinations

NCT06486883 — T-DXd vs. CDK4/6-inhibitor-based endocrine therapy as first-line treatment of HR-positive, HER2-low metastatic breast cancer (Phase 2)
NCT05950945 — T-DXd in hormone-receptor-negative (and HR-low), HER2-low metastatic breast cancer (Phase 3)
NCT07198724 — ERADICATE: elacestrant + T-DXd in HER2-low disease after a CDK4/6 inhibitor (Phase 1b/2)
NCT07150208 — T-DXd with or without bevacizumab for HER2-low breast cancer with brain metastases (Phase 2)
NCT06832202 — HLX22 (anti-HER2 antibody) + T-DXd in HR-positive, HER2-low breast cancer (Phase 2)
NCT06331169 — Anlotinib (anti-angiogenic) + T-DXd in previously-treated HER2-low advanced breast cancer (Phase 1)

Next-Generation HER2 Antibody-Drug Conjugates

New HER2 ADCs with different payloads and linkers, several already in Phase 3 head-to-head against chemotherapy.

NCT05904964 — Disitamab vedotin (RC48) in HR-positive, HER2-low metastatic breast cancer (Phase 3)
NCT06957886 — BL-M07D1 (HER2 ADC) vs investigator's-choice chemotherapy in HER2-low recurrent/metastatic breast cancer (Phase 3)
NCT07203729 — Trastuzumab rezetecan (SHR-A1811, HER2 ADC) in HER2-low unresectable/metastatic breast cancer (Phase 2)
NCT06224673 — ARX788 (HER2 ADC) in HER2-low locally advanced/metastatic breast cancer (Phase 2)
NCT06642545 — Disitamab vedotin + RC148 vs. albumin-paclitaxel ± toripalimab in HER2-low breast cancer (Phase 2)
NCT05831878 — RC48-ADC (disitamab vedotin) in HER2-low advanced breast cancer

ADC Sequencing & ADC-Refractory Disease

A fast-growing question in HER2-low: what works after one ADC, and how to sequence them.

NCT06533826 — TRADE DXd: datopotamab deruxtecan (Dato-DXd) or T-DXd in ADC-refractory breast cancer (Phase 2)
NCT06665178 — Predictors of sacituzumab govitecan sensitivity after T-DXd in ER-positive / HER2-low metastatic breast cancer (Phase 2)
NCT07037199 — Trastuzumab rezetecan followed by CDK4/6 inhibitor + endocrine therapy in HR-positive, HER2-low disease (Phase 2)

This is a curated snapshot, not the full list. There are 120+ HER2-low breast cancer trials recruiting (view all on ClinicalTrials.gov), and which ones fit depends on your HER2 IHC score, hormone-receptor status, prior lines of therapy, and country. Run a personalized match to see the trials you actually qualify for.

Frequently Asked Questions

What does HER2-low breast cancer mean?

HER2-low breast cancer is a tumor that has some HER2 protein but not enough to be called HER2-positive. On the standard test it scores IHC 1+, or IHC 2+ with a negative ISH (FISH) test. It used to be grouped with "HER2-negative" disease, but the drug trastuzumab deruxtecan (T-DXd / Enhertu) changed that — HER2-low is now its own treatable category. Roughly half of all breast cancers that are not HER2-positive are HER2-low.

What is HER2-ultralow breast cancer?

HER2-ultralow means a tumor that scores IHC 0 but with faint, incomplete membrane staining in some cells — just below the HER2-low threshold. The DESTINY-Breast06 trial extended T-DXd's benefit into this HER2-ultralow group, so the exact wording of your HER2 IHC report (including "IHC 0 with staining") can matter for both treatment and trial eligibility. Ask your oncologist or pathologist how your tumor was scored.

What trials are open for HER2-low breast cancer?

HER2-low is one of the most active breast-cancer trial areas, led by antibody-drug conjugates. Recruiting examples include T-DXd in new settings and combinations (vs CDK4/6-based endocrine therapy first-line, NCT06486883; elacestrant + T-DXd in ERADICATE, NCT07198724; T-DXd ± bevacizumab for brain metastases, NCT07150208; T-DXd in hormone-receptor-negative HER2-low, NCT05950945), next-generation HER2 ADCs (disitamab vedotin RC48, NCT05904964; trastuzumab rezetecan SHR-A1811, NCT07203729; ARX788, NCT06224673; BL-M07D1, NCT06957886), and ADC-sequencing studies (TRADE DXd, NCT06533826). Which ones fit depends on your HER2 IHC score, hormone-receptor status, and prior treatment — paste your summary into ClinTrialFinder for a personalized match.

What is the standard treatment for HER2-low metastatic breast cancer?

Trastuzumab deruxtecan (T-DXd / Enhertu) is approved for HER2-low metastatic breast cancer and, in the DESTINY-Breast04 trial, improved survival over chemotherapy. For hormone-receptor-positive disease, endocrine therapy (often with a CDK4/6 inhibitor) is typically used first, with T-DXd after endocrine options; for hormone-receptor-negative (triple-negative-like) HER2-low disease, chemotherapy and sacituzumab govitecan are also used. Your exact sequence depends on hormone-receptor status, prior lines, and symptoms. A clinical trial is a reasonable option to consider at any point.

Why does my HER2 IHC score (1+ vs 2+ vs 0) matter for trials?

The HER2 immunohistochemistry (IHC) score decides which category you fall into — HER2-positive (3+, or 2+/ISH-positive), HER2-low (1+, or 2+/ISH-negative), HER2-ultralow (0 with faint staining), or HER2-0 — and that category determines which drugs and trials you qualify for. Because scoring 1+ vs 0 can be subtle, some trials enroll by central re-testing. If you don't know your exact IHC score, ask your oncologist; it is the single most important test for HER2-low trial eligibility.

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