Patritumab Deruxtecan (HER3-DXd / U3-1402) Clinical Trials (June 2026, post-ASCO) — First HER3 ADC in Phase 3
Last updated: June 9, 2026 — post-ASCO 2026 refresh
🗓️ Post-ASCO 2026 update (June 5–9, Chicago): Patritumab deruxtecan (HER3-DXd) was a featured topic in the ClinTrialFinder
ASCO 2026 wrap-up (takeaway #4). HER3-DXd is the
first HER3-targeted antibody-drug conjugate to reach Phase 3 in oncology. The registrational Phase 3 in HR+/HER2- metastatic breast cancer (
NCT07060807, MK-1022-016 — protocol short name HERTHENA-Breast04, widely referred to as HERTHENA-Breast03 at ASCO 2026) is actively recruiting. Companion ASCO-cited programs: HERTHENA-PanTumor01 solid-tumor Phase 2 (NCT06172478), HERTHENA-PanTumor02 GI basket Phase 1/2 (NCT06596694), and the HER3 PET/CT imaging companion (NCT06222489) — the latter tests whether HER3 imaging can guide patient selection without standardized IHC.
About Patritumab Deruxtecan
Drug profile:
Patritumab deruxtecan (HER3-DXd; development code U3-1402; Merck code MK-1022) is an investigational antibody-drug conjugate co-developed by Daiichi Sankyo and Merck (worldwide collaboration finalized in 2023, similar in structure to the AstraZeneca / Daiichi Sankyo co-promotion of T-DXd). It is the first HER3-targeted ADC to reach Phase 3 in oncology.
Mechanism of action:
HER3-DXd combines patritumab — a fully human anti-HER3 (ERBB3) monoclonal antibody — with deruxtecan, a potent topoisomerase I inhibitor payload (an exatecan derivative), via a tumor-selective cleavable tetrapeptide linker. The drug-to-antibody ratio is approximately 8 — the same DXd platform shared with trastuzumab deruxtecan (T-DXd / Enhertu) and datopotamab deruxtecan (Dato-DXd / Datroway, TROP2-targeted). After binding HER3-expressing tumor cells, HER3-DXd is internalized and releases the deruxtecan payload intracellularly, producing direct DNA damage. The payload is membrane-permeable, which creates a "bystander effect" — neighboring tumor cells are also killed even if they don't express HER3 themselves. HER3 (also called ErbB3) is broadly overexpressed across many cancer types — breast, lung (especially EGFR-mutant NSCLC after osimertinib resistance), gastrointestinal, head and neck, and others — making it a broad oncology target. The post-osimertinib NSCLC setting is the highest-leverage HER3 indication for HER2-naive patients because HER3 upregulation is a known EGFR-TKI resistance mechanism.
Regulatory status:
- FDA approvals: none yet. Patritumab deruxtecan is investigational.
- FDA designations: Breakthrough Therapy Designation in EGFR-mutant non-small cell lung cancer after EGFR-TKI and platinum-based chemotherapy progression (granted 2021 based on HERTHENA-Lung01 data).
- Registrational path (post-ASCO 2026): 1 Phase 3 trial actively recruiting — NCT07060807 (MK-1022-016; protocol short name HERTHENA-Breast04, widely cited as HERTHENA-Breast03 at ASCO 2026) in HR+/HER2- metastatic breast cancer. The HERTHENA-Lung02 Phase 3 in EGFR-mutant NSCLC has completed enrollment.
- Anticipated first approval window: 2026-2027 based on the Breast Phase 3 and/or HERTHENA-Lung02 readouts.
Active Research Directions (post-ASCO 2026)
- Registrational breast cancer Phase 3 (NCT07060807, MK-1022-016 — protocol short name HERTHENA-Breast04, widely cited as HERTHENA-Breast03 at ASCO 2026): HER3-DXd monotherapy vs. treatment of physician's choice in HR+/HER2- unresectable locally advanced or metastatic breast cancer. The lead registration path for the first anticipated FDA approval.
- HERTHENA-Breast03 neoadjuvant TNBC / HR-low Phase 2 (NCT06797635, MK-1022-010) — patritumab deruxtecan + pembrolizumab (with or without chemotherapy sequencing) compared with pembrolizumab + chemotherapy followed by surgery in high-risk early-stage TNBC or HR-low HER2-negative breast cancer. Tests whether HER3-ADC + checkpoint inhibition can deepen pathological complete response in the curative-intent setting.
- EGFR-mutant NSCLC post-osimertinib — HER3 is upregulated in EGFR-resistant NSCLC, making HER3-DXd a mechanism-rational post-osimertinib option for HER2-naive patients. HERTHENA-Lung01 Phase 2 data established proof of concept; the HERTHENA-Lung02 Phase 3 confirmatory study has reported topline results (not currently recruiting).
- HERTHENA-PanTumor01 solid-tumor Phase 2 (NCT06172478, U31402-277) — multi-cohort proof-of-concept basket in HER3-expressing locally advanced or metastatic solid tumors.
- HERTHENA-PanTumor02 GI basket Phase 1/2 (NCT06596694, MK-1022-011) — patritumab deruxtecan in gastrointestinal cancers, expanding the indication footprint beyond breast and lung.
- NRG1 fusion-positive solid tumors (NCT06383884) — a unique mechanism: NRG1 (neuregulin-1) is the natural HER3 ligand, so NRG1 fusions drive HER3 signaling directly. HER3-DXd is one of the few therapies designed for this rare-but-actionable fusion class (which occurs in some pancreatic, NSCLC, breast, and other cancers).
- HER2-positive metastatic breast cancer combinations (NCT06686394, MK-1022-009) — HER3-DXd with other anticancer agents in HER2-positive breast cancer that has spread and cannot be surgically removed. Tests cross-receptor combination strategies in the ErbB family.
- Advanced breast cancer after T-DXd progression (NCT06298084) — Phase 1b/2 dose-expansion of HER3-DXd monotherapy and combinations after T-DXd progression. Important because this defines whether HER3-DXd is a useful sequential ADC after the established HER2 ADC.
- Pediatric expansion (NCT06941272, LIGHTBEAM-U01) — patritumab deruxtecan in pediatric relapsed/refractory solid tumors. Notable for being one of the few HER3-targeted programs reaching pediatric oncology.
- HER3 PET/CT companion imaging (NCT06222489) — whole-body HER3 quantification with radiolabelled patritumab deruxtecan PET/CT. Tests whether HER3 imaging can guide patient selection without a standardized HER3 IHC companion diagnostic (HER3 IHC is not yet validated the way HER2 IHC is for T-DXd).
- Cross-platform / pembrolizumab combinations — HER3-DXd appears as a treatment arm in the I-SPY 2 neoadjuvant breast cancer platform trial (NCT01042379), KEYMAKER-U01 Substudy 01A pembrolizumab combinations in NSCLC (NCT04165070), KEYMAKER-U06 Substudy 06D in 2L gastroesophageal adenocarcinoma (NCT06445972), Substudy 06C with pembrolizumab + chemotherapy in 1L gastroesophageal (NCT06469944), and a broader pembrolizumab ± chemotherapy NSCLC platform (NCT06731907).
Recruiting Trials by Indication (post-ASCO 2026)
Breast Cancer — Lead Indication (Phase 3 registrational + Phase 2 + foundational)
- NCT07060807 — Registrational Phase 3 (MK-1022-016 — protocol short name HERTHENA-Breast04; widely cited as HERTHENA-Breast03 at ASCO 2026): patritumab deruxtecan monotherapy vs. treatment of physician's choice in HR+/HER2- unresectable locally advanced or metastatic breast cancer. The registrational Phase 3 — basis for the first anticipated FDA approval.
- NCT06797635 — HERTHENA-Breast03 (Phase 2, MK-1022-010): HER3-DXd + pembrolizumab (with or without carboplatin/paclitaxel + pembrolizumab sequencing) vs. pembrolizumab + chemotherapy followed by surgery in high-risk early-stage TNBC or HR-low / HER2-negative breast cancer (neoadjuvant setting).
- NCT04965766 — Patritumab Deruxtecan (U3-1402) in unresectable locally advanced or metastatic HER3-expressing breast cancer (Phase 2 foundational study).
- NCT06298084 — Phase 1b/2 dose-expansion of HER3-DXd monotherapy and combinations in advanced breast cancer after progression on T-DXd.
- NCT06686394 — (MK-1022-009) patritumab deruxtecan + other anticancer agents in HER2-positive metastatic breast cancer (cross-receptor ErbB combinations).
- NCT01042379 — I-SPY 2: patritumab deruxtecan is a treatment arm in this long-running neoadjuvant adaptive platform trial in breast cancer.
NSCLC after Osimertinib (EGFR-mutant resistance setting)
HER3 upregulation is a known EGFR-TKI resistance mechanism in EGFR-mutant NSCLC, making HER3-DXd a mechanism-rational post-osimertinib option for HER2-naive patients. The pivotal HERTHENA-Lung02 Phase 3 (NCT04619916) has completed enrollment and is not currently recruiting. NSCLC patients are currently accommodated through the broader pembrolizumab and basket platforms below, plus the HER3 PET/CT imaging companion.
HERTHENA-PanTumor Basket / Solid-Tumor Studies
- NCT06172478 — HERTHENA-PanTumor01 (Phase 2, U31402-277): multi-cohort proof-of-concept basket in HER3-expressing locally advanced or metastatic solid tumors.
- NCT06596694 — HERTHENA-PanTumor02 (Phase 1/2, MK-1022-011): patritumab deruxtecan in gastrointestinal cancers (GI basket).
NRG1 Fusion-Positive Solid Tumors (mechanism-specific)
NRG1 (neuregulin-1) is the natural HER3 ligand. NRG1 fusions drive HER3 signaling directly, making HER3-targeted therapy particularly mechanistically relevant. NRG1 fusions occur in some pancreatic, lung, breast, and other cancers (rare but actionable):
- NCT06383884 — Patritumab Deruxtecan in patients with solid tumors harboring an NRG1 fusion (Phase 2).
Pembrolizumab Combination Platforms (KEYMAKER / KEYNOTE program)
- NCT06731907 — MK-3475-01G / KEYMAKER-U01: Pembrolizumab ± chemotherapy + additional treatments for advanced NSCLC (HER3-DXd arms).
- NCT04165070 — KEYMAKER-U01 Substudy 01A: pembrolizumab combinations in treatment-naïve Stage IV NSCLC (includes HER3-DXd arms).
- NCT06469944 — KEYMAKER-U06 Substudy 06C: investigational agents (incl. HER3-DXd) with pembrolizumab + chemotherapy in 1L gastroesophageal adenocarcinoma.
- NCT06445972 — KEYMAKER-U06 Substudy 06D: combination therapies in 2L gastroesophageal adenocarcinoma (MK-1022 arm).
Pediatric (Relapsed / Refractory Solid Tumors)
- NCT06941272 — LIGHTBEAM-U01 (MK-9999-01C): patritumab deruxtecan in pediatric participants with relapsed or refractory solid tumors.
HER3 PET/CT Imaging Companion
- NCT06222489 — Whole-body HER3 quantification with radiolabelled patritumab deruxtecan PET/CT. Tests whether HER3 imaging can guide patient selection without standardized HER3 IHC — addressing a major patient-selection gap relative to T-DXd's validated HER2 IHC.
Trials listed above are actively recruiting in the ClinTrialFinder corpus as of June 9, 2026 (post-ASCO 2026 refresh). View the latest patritumab deruxtecan search on ClinicalTrials.gov. Note: HERTHENA-Lung02 (NCT04619916) — the EGFR-mutant NSCLC Phase 3 — has completed enrollment and is not currently recruiting (not in the CTF corpus); topline results have been reported. Naming caveat: NCT07060807's official protocol short name is "HERTHENA-Breast04", but the trial was widely referenced as "HERTHENA-Breast03" in ASCO 2026 coverage; NCT06797635 is the separate Phase 2 neoadjuvant study that carries the "HERTHENA-Breast03" name on ClinicalTrials.gov.
Patient Selection and HER3 Biomarker Testing
Patient selection for HER3-DXd is less standardized than for T-DXd (HER2 IHC). Key considerations:
- HER3 (ERBB3) expression by IHC — many trials enroll based on HER3 immunohistochemistry, but the optimal cutoff is still being defined. Patients with HER3-low tumors may still benefit because of the deruxtecan bystander effect.
- NRG1 fusion — detected on tumor next-generation sequencing or RNA-seq. NRG1 fusions are the most mechanistically clear-cut indication for HER3-DXd (NRG1 is the HER3 ligand; fusion drives HER3 signaling).
- EGFR mutation status (NSCLC) — EGFR-mutant NSCLC after EGFR-TKI (osimertinib) progression is the established setting. HER3 upregulation is a known EGFR-TKI resistance mechanism, making HER3-DXd mechanism-rational.
- HER3 PET/CT imaging (NCT06222489) — investigational imaging-based patient selection. Currently a research tool; could become a companion diagnostic if the registrational Phase 3 (NCT07060807) or HERTHENA-Lung02 readouts support PET-based selection.
- Prior treatment history — most trials enroll patients who have progressed on prior standard therapies for their cancer type. Specific prior-therapy requirements vary by trial.
- Comprehensive genomic profiling (e.g., Foundation Medicine, Tempus, Guardant360) — recommended to identify NRG1 fusions and to characterize the broader molecular context. Knowing your EGFR / HER2 / NRG1 status helps determine which HER3-DXd trial may best apply.
Side Effects and Practical Considerations
- ⚠️ Interstitial lung disease (ILD) / pneumonitis — the most important class-level safety concern for all deruxtecan-based ADCs (including T-DXd). Rare but potentially serious lung inflammation. Any new respiratory symptoms (cough, shortness of breath, fever) require immediate evaluation, treatment interruption, and (if confirmed) corticosteroid management. Patients with prior ILD, active pneumonia, or significant pulmonary impairment require careful pre-treatment evaluation.
- Nausea and vomiting — very common; standard practice is prophylactic antiemetic regimens.
- Fatigue — common throughout treatment.
- Alopecia — hair loss is common.
- Low blood counts — neutropenia, anemia, thrombocytopenia. Routine CBC monitoring; dose modifications per protocol if Grade 3+.
- Liver enzyme elevations — observed in some patients; routine LFT monitoring required.
- Decreased appetite and constipation — common; managed supportively.
- Combination-specific toxicities — HER3-DXd + pembrolizumab adds immune-related event risk. Combinations with chemotherapy add the toxicities of the partner regimen.
Frequently Asked Questions
What is patritumab deruxtecan (HER3-DXd)?
Patritumab deruxtecan (HER3-DXd; development code U3-1402; Merck code MK-1022) is an investigational antibody-drug conjugate co-developed by Daiichi Sankyo and Merck. It is the first HER3-targeted ADC to reach Phase 3 in oncology. Patritumab is a fully human anti-HER3 (ERBB3) monoclonal antibody; deruxtecan is the topoisomerase I inhibitor payload (the same DXd platform shared with T-DXd / Enhertu and datopotamab deruxtecan / Datroway). HER3 is broadly overexpressed across breast, lung (especially EGFR-mutant NSCLC after osimertinib resistance), GI, and other cancers. No FDA approvals yet; the registrational Phase 3 in HR+/HER2- metastatic breast cancer (NCT07060807, MK-1022-016 — protocol short name HERTHENA-Breast04, widely cited as HERTHENA-Breast03 at ASCO 2026) is recruiting.
What cancers is patritumab deruxtecan being tested in?
Breast cancer (lead indication: registrational Phase 3 NCT07060807 / MK-1022-016 in HR+/HER2- MBC; HERTHENA-Breast03 NCT06797635 Phase 2 in early-stage TNBC / HR-low; NCT04965766 Phase 2 in HER3-expressing metastatic breast; NCT06298084 Phase 1b/2 post-T-DXd; NCT06686394 in HER2+ MBC combinations; I-SPY 2 neoadjuvant arm NCT01042379), EGFR-mutant NSCLC after osimertinib failure (HERTHENA-Lung01 Phase 2 + HERTHENA-Lung02 Phase 3 — Lung02 has reported topline and is not recruiting), HERTHENA-PanTumor01 solid-tumor basket (NCT06172478), HERTHENA-PanTumor02 GI basket (NCT06596694 MK-1022-011), NRG1 fusion-positive tumors (NCT06383884 — unique mechanism), pembrolizumab combinations (KEYMAKER platforms NCT06731907 / NCT04165070 / NCT06469944 / NCT06445972), pediatric R/R solid tumors (NCT06941272 LIGHTBEAM-U01), and HER3 PET/CT imaging companion (NCT06222489).
How does HER3-DXd differ from T-DXd?
Both are deruxtecan-based ADCs from Daiichi Sankyo's DXd platform — same exatecan-derivative payload, same cleavable linker, same drug-to-antibody ratio (~8). The platform is also shared with datopotamab deruxtecan (Datroway, TROP2-targeted). The difference is the antibody backbone and its target: T-DXd uses an anti-HER2 antibody; HER3-DXd uses an anti-HER3 (ERBB3) antibody. HER3 has a distinct expression pattern — broadly overexpressed across many cancer types and especially upregulated in EGFR-mutant NSCLC after osimertinib resistance, making HER3-DXd a particularly relevant post-osimertinib option for HER2-naive patients. Co-development structure differs: T-DXd is co-promoted by AstraZeneca / Daiichi Sankyo; HER3-DXd is co-developed by Merck / Daiichi Sankyo (2023 deal). Patient selection also differs: T-DXd uses validated HER2 IHC scoring (positive, low, ultralow); HER3-DXd selection is less standardized — HER3 IHC is not yet a validated companion diagnostic, and a HER3 PET/CT imaging trial (NCT06222489) is testing imaging-based selection.
What are the main side effects of patritumab deruxtecan?
The class-level safety concern for all deruxtecan-based ADCs is interstitial lung disease (ILD) / pneumonitis — rare but potentially serious; close monitoring and prompt treatment interruption at any pulmonary symptom. Common side effects include nausea (very common; prophylactic antiemetics standard), vomiting, fatigue, alopecia, low blood counts (neutropenia, anemia, thrombocytopenia), liver enzyme elevations, decreased appetite, and constipation. Combination-specific toxicities depend on the partner regimen.
Find Patritumab Deruxtecan and HER3 ADC Trials Matched to Your Situation
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