The HER2 eligibility spectrum: three tiers, one ADC
The traditional HER2 biomarker was binary: positive (IHC 3+ or IHC 2+/ISH+) or negative. That binary collapsed between 2022 and 2025 as trastuzumab deruxtecan generated registrational data in each successive tier below the old HER2-positive threshold.
Original target for trastuzumab (Herceptin), pertuzumab (Perjeta), and T-DM1 (Kadcyla). Standard of care: THP (docetaxel + trastuzumab + pertuzumab) in 1L, with T-DXd approved second-line. Multiple biosimilar trastuzumab programs and next-generation combination regimens in Phase 3.
Previously classified HER2-negative and excluded from HER2-directed therapy. DESTINY-Breast04 (NCT03734029) demonstrated T-DXd PFS benefit in HR+/HER2-low patients, leading to FDA approval in August 2022 — the first approval specifically for "HER2-low" as an indication. This doubled the HER2-targeted population in breast cancer overnight and catalyzed the current wave of HER2-low ADC programs.
The newest eligibility tier. DESTINY-Breast06 (NCT04494425) demonstrated T-DXd benefit even in this population previously classified as IHC 0 (HER2-negative). This further expands the eligible population. The practical implication: nearly all HR+/HER2-non-overexpressing metastatic breast cancers now fall within the T-DXd target population if the ultralow threshold is adopted.
This three-tier reclassification is the most consequential HER2 biomarker development since the original HER2+ definition. It has created a new class of competitive intelligence questions: which ADCs can replicate T-DXd's activity in low-expressing tumors, and which tumor types beyond breast cancer carry meaningful HER2-low prevalence?
Track HER2-low and HER2-targeted trial updates daily
Configure separate profiles for HER2+, HER2-low, and HER2-ultralow — each delivers a focused morning digest.
Start Free — No Credit CardT-DXd DESTINY series: 11 active Phase 3 programs across 5 tumor types
No single asset in oncology has more active Phase 3 trials than trastuzumab deruxtecan. Each represents a potential new indication or label expansion — and a competitive signal for companies with HER2-targeting assets.
| NCT ID | Indication | Eligibility Tier | Status |
|---|---|---|---|
| NCT04784715 | HER2+ Breast Cancer 1L (DESTINY-Breast09) | HER2+ | Recruiting |
| NCT04494425 | HER2-low/ultralow Breast Cancer (DESTINY-Breast06) | HER2-low/ultralow | Active |
| NCT05950945 | HR+/HER2-low Breast Cancer (DESTINY-Breast15) | HER2-low | Recruiting |
| NCT05113251 | HER2+ Breast Cancer Sequence (DESTINY-Breast11) | HER2+ | Recruiting |
| NCT04739761 | HER2+ Breast Cancer + Brain Mets | HER2+ | Active |
| NCT04704934 | HER2+ Gastric / GEJ Cancer 2L (DESTINY-Gastric02) | HER2+ | Active |
| NCT06899126 | HER2-overexpressing NSCLC 1L | HER2-overexp | Recruiting |
| NCT07022483 | HER2-overexpressing Endometrial Cancer | HER2+/overexp | Recruiting |
| NCT06989112 | Endometrial Cancer DESTINY-E01 | HER2+ | Recruiting |
| NCT06467357 | Biliary Tract Cancer (T-DXd + rilvegostomig) | HER2-overexp | Recruiting |
| NCT06819007 | Ovarian Cancer (T-DXd + bevacizumab) | HER2-expressing | Recruiting |
HER2-low in non-breast cancers: the next frontier
Gastric and gastroesophageal junction cancer
HER2 amplification/overexpression occurs in 15–20% of gastric/GEJ adenocarcinomas. Beyond the established HER2+ tier (where T-DXd is approved 2L and multiple frontline combinations are in Phase 3), HER2-low in gastric cancer is being systematically evaluated in early-phase ADC trials. Given that gastric cancer has high unmet need in the HER2-negative majority, ADC developers are designing eligibility criteria to capture IHC 1+ and IHC 2+/ISH- patients — paralleling the breast cancer HER2-low expansion thesis. The zanidatamab gastric Phase 3 (NCT05152147) and disitamab vedotin programs from HengRui represent the leading Chinese competition in this space.
HER2-low in colorectal cancer
HER2 amplification in colorectal cancer occurs in approximately 3–5% of cases and is enriched in RAS/BRAF wild-type disease. The conventional HER2+ threshold (IHC 3+ or IHC 2+/ISH+) defines the target population for tucatinib (NCT05253651, Pfizer Phase 3) and T-DXd combinations. Whether the HER2-low framework (IHC 1–2+) is actionable in colorectal cancer is under investigation in early-phase studies — important to monitor for companies evaluating pan-tumor ADC strategies.
HER2-mutant NSCLC: a distinct category
HER2 mutations (predominantly exon 20 insertions) are mechanistically distinct from HER2 overexpression and define a separate eligibility category. Both T-DXd and zongertinib (BI-1810631, Boehringer Ingelheim) are approved or registrational in this setting. The two active Phase 3 programs for zongertinib — Beamion LUNG-2 (NCT06151574) and Beamion LUNG-3 (NCT07195695) — represent the most watched HER2-mutant NSCLC programs in 2026, with potential to establish an oral TKI standard competing against the T-DXd IV infusion pathway.
Competitive landscape: next-generation HER2 ADCs racing T-DXd
The commercial success of T-DXd has triggered the most competitive HER2 ADC pipeline in oncology history. Five programs have advanced into Phase 3 or pivotal Phase 2 against a T-DXd benchmark:
| Agent | Sponsor | Key Phase 3 Trial | Differentiator | Status |
|---|---|---|---|---|
| SHR-A1811 | Jiangsu HengRui | NCT06057610 (HER2+ breast) | Chinese ADC, global Phase 3 | Recruiting |
| DB-1303/BNT323 | DualityBio/BioNTech | NCT06018337 (HER2-low breast) | Designed for HER2-low from Phase 1 | Recruiting |
| RO7771950 | Hoffmann-La Roche | NCT07413939 vs. tucatinib | Roche pipeline HER2 ADC | Recruiting |
| ARX788 | Ambrx / Johnson & Johnson | HER2+ breast pivotal cohort | Site-specific conjugation, DAR 1.9 | Active |
| Zanidatamab | Jazz Pharmaceuticals | NCT06435429 vs. trastuzumab 1L | HER2 domain II+IV bispecific | Recruiting |
Monitoring early-phase trial activity for these programs — Phase 1 dose-escalation updates, new cohort additions, enrollment holds — provides 12–24 months of lead time over published clinical data. A protocol amendment adding a HER2-low expansion cohort is a key intelligence signal that often precedes a public announcement of HER2-low strategy.
Why HER2 biomarker intelligence requires dedicated monitoring
The HER2 space has several characteristics that make manual monitoring inadequate for professional use:
- Multiple eligibility tiers: Trials now distinguish HER2+, HER2-low, HER2-ultralow, HER2-mutant, and HER2-overexpressing (the last being a looser definition used in non-breast tumors). A single search for "HER2" on ClinicalTrials.gov returns a mixed result set across all of these.
- Multi-tumor type coverage: Monitoring 7 tumor types with active HER2 Phase 3 programs simultaneously (breast, gastric, NSCLC, colorectal, endometrial, biliary, ovarian) requires seven separate search workflows — or a configurable multi-profile system.
- High amendment frequency: T-DXd trials frequently post protocol amendments as Daiichi Sankyo and AstraZeneca refine dosing, add biomarker substudies, or expand eligibility. These amendments contain competitive intelligence that is invisible to teams relying only on published data.
- Chinese ADC programs: SHR-A1811 (HengRui), RC48/disitamab vedotin (RemeGen/Seagen), DB-1303 (DualityBio), and KN026 (Jiangsu Kintor) are all advancing HER2 ADC programs with global registration strategies. These programs often register on ClinicalTrials.gov months before appearing in Western conference presentations.
Set up HER2 monitoring across all tiers and tumor types
Create separate profiles for HER2+, HER2-low, HER2-mutant NSCLC, and specific tumor types. free plan.
Start FreeHow to configure HER2 trial monitoring on DataLookout
Profile 1: HER2-low breast cancer (ADC focus)
Keywords: "HER2-low", "HER2 low", "IHC 1+", "HER2-ultralow", "HER2 ultralow", "DESTINY-Breast", "trastuzumab deruxtecan", "T-DXd", "DB-1303", "SHR-A1811". Condition filter: "breast cancer". Phase filter: Phase 2/3. This catches T-DXd DESTINY updates and all next-generation ADC competitors designing for HER2-low eligibility from Phase 1.
Profile 2: HER2+ traditional (multi-tumor)
Keywords: "HER2 positive", "HER2-positive", "ERBB2 amplification", "HER2 amplified", "zanidatamab", "pertuzumab", "trastuzumab", "tucatinib". Exclude breast-cancer-only studies to focus on gastric, CRC, endometrial, and biliary tract programs. This captures the T-DXd cross-tumor expansion and competing bispecifics.
Profile 3: HER2-mutant NSCLC
Keywords: "HER2 mutation", "HER2-mutant", "HER2 exon 20", "ERBB2 mutation", "zongertinib", "BI-1810631", "Beamion", "SHR-A1811 lung". Condition filter: "lung cancer" or "NSCLC". This is a narrower indication where two major Phase 3 programs (Beamion LUNG-2, LUNG-3) are the primary monitoring targets.
Frequently asked questions
What changed when T-DXd was approved for HER2-low breast cancer?
Before the DESTINY-Breast04 approval in August 2022, "HER2-low" was not a clinical category — IHC 1+ and IHC 2+/ISH- patients were classified as HER2-negative and received chemotherapy or endocrine therapy. The approval created a new biomarker tier that requires reflex IHC testing for patients who previously received no HER2 testing beyond the initial diagnosis. It also opened HER2 ADC development to the ~50% of metastatic breast cancer patients in the low-expression range, fundamentally changing the competitive landscape for next-generation ADC programs.
How many breast cancer patients are HER2-low vs. HER2-ultralow?
Retrospective reanalysis of clinical trial samples suggests approximately 45–55% of metastatic breast cancers are HER2-low (IHC 1+ or IHC 2+/ISH-). An additional 15–25% may qualify as HER2-ultralow (IHC 0 with any staining in ≤10% of cells), depending on the precise IHC scoring methodology and antibody clone. Combined, these two tiers bring the potentially T-DXd-eligible population to approximately 60–75% of all metastatic breast cancer patients — a profound expansion from the original 15–20% HER2+ target.
Does DataLookout cover international HER2 trials?
ClinicalTrials.gov captures international trials from all sponsors registering studies with US sites or meeting FDAAA 801 requirements, plus a large volume of voluntarily registered international studies from Japanese, Korean, Chinese, and European sponsors. The HER2 ADC space in particular has significant Chinese representation (HengRui's SHR-A1811, RemeGen's RC48, DualityBio's DB-1303) that is best tracked through ClinicalTrials.gov registration activity before conference presentations.
What is the difference between HER2-targeted and HER2-directed therapy?
"HER2-targeted" is the broader term — it includes any agent whose mechanism involves HER2 as a direct target, including monoclonal antibodies (trastuzumab), ADCs (T-DXd), bispecific antibodies (zanidatamab), TKIs (tucatinib, zongertinib, neratinib), and CAR-T cells targeting HER2. "HER2-directed" is sometimes used synonymously but can also specifically refer to antibody-based approaches. For clinical trial search purposes, both terms appear in trial descriptions, so running both as keyword variations increases coverage.
576 active trials, 298 recruiting. Phases: Early Phase 1: 8, Phase 1: 94, Phase 2: 299, Phase 3: 107, Phase 4: 14.
| Top sponsor | Trials |
|---|---|
| Daiichi Sankyo | 15 |
| AstraZeneca | 14 |
| Sichuan Baili Pharmaceutical Co., Ltd. | 11 |
| Pfizer | 9 |
| Shanghai JMT-Bio Inc. | 9 |
| Trial | Status | Latest tracked change | Seen |
|---|---|---|---|
| Disitamab Vedotin Combined With Sintilimab and Multimodal Radiotherapy for… NCT07490990 | Not Yet Recruiting | Trial arms changed: 0 → 1 | 2026-08-04 |
| HER-2 B Cell Peptide Vaccine NCT06414733 | Recruiting | Interventions modified | 2026-08-28 |
| A Phase 1/2a Study of DB-1303/BNT323 in Advanced/Metastatic Solid Tumors NCT05150691 | Recruiting | Primary completion pushed: 2026-04 → 2027-08 | 2026-08-28 |
| A Safety Extension Study of Trastuzumab Emtansine in Participants Previously… NCT00781612 | Active, Not Recruiting | Completion moved earlier: 2030-04-30 → 2026-11-28 | 2026-08-28 |
| Stage I HER2 Positive Invasive Breast Cancer De-escalation Study(IRIS) NCT04383275 | Active, Not Recruiting | Completion pushed: 2027-05-15 → 2031-07-06 | 2026-08-20 |
Each trial page shows every change DataLookout has recorded for that trial.
DataLookout checks ClinicalTrials.gov every day and records what changed on each trial: status, enrollment, phase, primary endpoint, completion dates, sites, sponsor, and the stated reason a trial stopped. Add a sponsor or a disease to your watchlist, or save any search, and the changes arrive in a daily or weekly email digest.
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