Key Phase 3 HER2 Trials
| Trial | Regimen | Sponsor | Setting | Status |
|---|---|---|---|---|
| NCT06731478 | T-DXd + chemo + pembrolizumab + trastuzumab | Daiichi Sankyo | 1L HER2+ mBC | Recruiting Phase 3 |
| NCT04784715 DESTINY-Breast09 | T-DXd ± pertuzumab vs taxane + HP | AstraZeneca | 1L HER2+ mBC | Active Phase 3 |
| NCT04494425 DESTINY-Breast06 | T-DXd vs chemotherapy | AstraZeneca | HER2-low/ultralow mBC | Active Phase 3 |
| NCT04739761 DESTINY-Breast12 | T-DXd vs chemotherapy (brain mets) | AstraZeneca | HER2+ mBC with brain metastases | Active Phase 3 |
| NCT05253651 MOUNTAINEER-03 | Tucatinib + trastuzumab + mFOLFOX6 vs SoC | Seagen/Pfizer | 1L HER2+ mCRC | Recruiting Phase 3 |
| NCT06282575 HERIZON-BTC-02 | Zanidatamab + SoC vs SoC | Jazz Pharmaceuticals | HER2+ biliary tract cancer | Recruiting Phase 3 |
| NCT06151574 Beamion LUNG-2 | Zongertinib vs SoC | Boehringer Ingelheim | HER2-mutant advanced NSCLC | Recruiting Phase 3 |
| NCT07195695 Beamion LUNG-3 | Zongertinib vs SoC | Boehringer Ingelheim | Adjuvant HER2-mutant NSCLC | Recruiting Phase 3 |
| NCT06899126 | T-DXd + pembrolizumab + plat-chemo | Daiichi Sankyo | 1L HER2+ gastric/GEJ cancer | Recruiting Phase 3 |
| NCT07022483 | T-DXd vs chemotherapy | Daiichi Sankyo | HER2-expressing solid tumors (tumor-agnostic) | Recruiting Phase 3 |
T-DXd: Reshaping the HER2 Landscape
Trastuzumab deruxtecan (T-DXd, Enhertu) — co-developed by Daiichi Sankyo and AstraZeneca — has become the defining oncology story of this decade. Its mechanism combines the tumor-targeting precision of trastuzumab with a highly potent topoisomerase I inhibitor payload (DXd), and critically, a bystander killing effect that enables activity even in HER2-heterogeneous tumors. This bystander mechanism is what makes T-DXd effective in HER2-low disease, where conventional HER2-directed therapies fail.
The DESTINY-Breast program now spans seven trials, covering every stage of HER2+ and HER2-low breast cancer:
- DESTINY-Breast09 (NCT04784715): Testing T-DXd ± pertuzumab vs HP+taxane as first-line therapy for HER2+ metastatic breast cancer. A positive result displaces pertuzumab+trastuzumab+docetaxel — the standard since 2012 — and restructures the entire HER2+ treatment algorithm.
- DESTINY-Breast06 (NCT04494425): HER2-low (IHC 1+ or IHC 2+/ISH-) and HER2 ultralow (IHC 0 with faint membranous staining) — extending eligibility to an estimated ~60% of all HR+/HER2- metastatic breast cancer patients.
- DESTINY-Breast12 (NCT04739761): Addressing the underserved brain metastasis population, where HER2+ patients have historically had poor outcomes with systemic therapy.
The strategic implication: HER2-low is not a niche subgroup. It is potentially the majority of metastatic breast cancer. If DESTINY-Breast06 reads out positively in the ultralow cohort, the HER2-positive/negative binary that has governed breast oncology for 25 years effectively collapses.
Bispecific antibodies represent the next competitive wave. Zanidatamab (Zymeworks/Jazz, HER2×HER3 bispecific) and amivantamab (Janssen, EGFR×MET) are both entering Phase 3, each exploiting receptor crosstalk that monoclonal antibodies cannot address simultaneously.
Zongertinib and the Next-Generation HER2 TKI Race
The HER2 TKI landscape has three distinct generations: lapatinib (pan-HER, high GI toxicity), neratinib (pan-HER, pan-HER toxicity), and tucatinib plus zongertinib (selective HER2, improved tolerability). The selectivity question matters because EGFR wild-type inhibition is responsible for the grade 3+ diarrhea that limits dose intensity for older agents.
Zongertinib (BI 1810631, Boehringer Ingelheim) is a covalent, selective HER2 inhibitor designed from the outset to spare EGFR wild-type activity. Early clinical data in HER2-mutant NSCLC showed compelling response rates, positioning it as a potential challenger to T-DXd in this subgroup:
- Beamion LUNG-2 (NCT06151574): Phase 3, zongertinib vs chemotherapy or docetaxel in HER2-mutant advanced NSCLC — the definitive regulatory trial.
- Beamion LUNG-3 (NCT07195695): Phase 3, adjuvant setting in resected HER2-mutant NSCLC — a market with no approved standard of care.
Tucatinib (Tukysa, Seagen/Pfizer) established the HER2-selective TKI proof of concept through HER2CLIMB (2020), showing OS benefit in heavily pretreated HER2+ mBC when combined with trastuzumab and capecitabine. The MOUNTAINEER-03 trial now tests tucatinib in first-line HER2+ metastatic colorectal cancer — a tumor type where HER2 amplification occurs in 3-5% of patients but has no approved HER2-directed standard.
HER2 in Solid Tumors Beyond Breast: The Expansion Frontier
HER2 targeting began in breast cancer but has expanded to five major tumor types, each with distinct HER2 biology and competitive dynamics:
- Gastric/GEJ cancer: ToGA (2010) established trastuzumab+chemotherapy as 1L standard for HER2+ tumors (IHC 3+ or IHC 2+/ISH+). T-DXd received accelerated approval based on DESTINY-Gastric01/02 data. A Phase 3 trial (NCT06899126) now combines T-DXd + pembrolizumab + chemotherapy in first-line HER2+ gastric/GEJ — building on ToGA's foundation with checkpoint immunotherapy.
- Biliary tract cancer: Zanidatamab (a HER2×HER3 bispecific from Zymeworks, partnered with Jazz Pharmaceuticals) is in Phase 3 HERIZON-BTC-02 (NCT06282575) for HER2+ biliary tract cancer. This is an orphan-disease-sized market (~15,000 US cases/year) where HER2 amplification occurs in 15-20% of patients and no HER2-directed therapy is approved.
- Colorectal cancer: MOUNTAINEER-03 (NCT05253651) tests tucatinib+trastuzumab+mFOLFOX6 as first-line therapy for HER2+ mCRC (~3-5% of all CRC). DESTINY-CRC01 established T-DXd activity; the question now is whether a TKI+antibody combination can compete.
- NSCLC: HER2-mutant (primarily exon 20 insertions) and HER2-amplified are biologically distinct. T-DXd received accelerated approval in HER2-mutant NSCLC (DESTINY-Lung02); zongertinib is now mounting a Phase 3 challenge. The Beamion LUNG-2 vs T-DXd question — TKI vs ADC in HER2-mutant NSCLC — will be a defining data readout of 2027-2028.
- Tumor-agnostic: NCT07022483 (Daiichi Sankyo) tests T-DXd vs chemotherapy in HER2-expressing solid tumors across histologies — a tumor-agnostic strategy that, if successful, would give T-DXd the broadest HER2+ label in oncology history.
Related Pages
- Breast Cancer Clinical Trials — Full Pipeline
- Gastric Cancer Clinical Trials
- Antibody-Drug Conjugate (ADC) Clinical Trials
- HER2-Positive Cancer Clinical Trials
- HER2-Mutant NSCLC Clinical Trials
- Non-Small Cell Lung Cancer Clinical Trials
- Bispecific Antibody Clinical Trials
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Start Free Trial →Frequently Asked Questions
How many HER2-targeted cancer clinical trials are currently active?
As of March 2026, there are 378 active HER2-targeted trials on ClinicalTrials.gov — 251 actively recruiting and 127 active but not yet recruiting. AstraZeneca leads with 26 active trials, driven primarily by the DESTINY-Breast program with trastuzumab deruxtecan (T-DXd/Enhertu), followed by NCI (19), Roche (15), Novartis (14), Daiichi Sankyo (8), and Seagen/Pfizer (8). There are 84 Phase 3 trials in active or recruiting status.
What is HER2-low and why does it matter for clinical trials?
HER2-low refers to tumors with IHC 1+ or IHC 2+/ISH-negative staining — previously considered HER2-negative under the traditional binary classification. The DESTINY-Breast04 trial established T-DXd as the first approved therapy for HER2-low metastatic breast cancer in 2022, dramatically expanding the HER2-targetable population. DESTINY-Breast06 extends this further to HER2 ultralow (IHC 0 with faint staining), potentially covering ~60% of all HR+/HER2- breast cancers. This reclassification is arguably the most significant HER2 paradigm shift since trastuzumab's approval.
What is zongertinib and how is it different from tucatinib and neratinib?
Zongertinib (BI 1810631, Boehringer Ingelheim) is a next-generation covalent, selective HER2 TKI designed to spare EGFR wild-type signaling — the mechanism responsible for diarrhea and skin toxicity seen with older HER2 TKIs like neratinib (pan-HER) and lapatinib. Tucatinib (Tukysa, Pfizer/Seagen) also achieves HER2 selectivity but through a different binding approach. Zongertinib is currently in Phase 3 trials in HER2-mutant advanced NSCLC (Beamion LUNG-2, NCT06151574) and adjuvant HER2-mutant NSCLC (Beamion LUNG-3, NCT07195695).