patritumab (U3-1287) / Amgen, Daiichi Sankyo - LARVOL DELTA

Clinical implications of HER3 overexpression in a diverse patient cohort with prostate cancer. (ASCO 2025) - "Additionally, we found that by inhibiting HER3 signaling (patritumab, erlotinib, trastuzumab, capivasertib) PCa cells become more sensitized to enzalutamide(p≤0.01), suggesting a role for dual AR and HER3 targeting in PCa treatment. Our clinical and translational data supports the role of HER3 overexpression as a novel and targetable prognostic marker in diverse patients with PCa. Future studies should further evaluate HER3 inhibition in combination with AR targeted therapies to improve therapy sensitivity and reduce development of resistant disease."

Clinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • ERBB3

Antitumor effect and underlying mechanism on DNA damage response in breast cancer cells treated with HER3-DXd (AACR 2025) - "HER3-DXd is an antibody-drug conjugate (ADC) that combines patritumab, an anti-HER3 antibody and DXd, a topoisomerase I inhibitor, which is linked via a peptide-cleavable linker. HER3-DXd induces DNA damage, apoptotic cell death, and micronuclei formation in sensitive breast cancer cells, but not in insensitive cells. Thus, the induction of DNA damage, rather than protein expression levels of HER3 or internalization rates of HER3-DXd, may be associated with sensitivity to HER3-DXd in these cell lines, suggesting the payload could be particularly important for HER3-DXd activity in these models."

Late-breaking abstract • Breast Cancer • Colorectal Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ANXA5 • CASP3 • ERBB3 • H2AX • HER-2

Targeting mechanisms of adaptive resistance to the PI3Kαmutant selective inhibitor RLY-2608 in HR+/PIK3CA mutant breast cancer (AACR 2025) - "Alpelisib and inavolisib are currently FDA approved for treatment of PIK3CA-mutant breast cancers, although neither is selective for mutant PIK3CA...To identify the ERBB RTKs causing this adaptation, we tested the TKIs erlotinib, neratinib, and tucatinib, and the HER3 antibodies patritumab and zenocutuzumab, each in combination with RLY-2608...Other upregulated Hallmark pathways in both cell lines included Myogenesis, Hypoxia, and KRAS signaling down. These findings suggest that, in addition to RTK activation, adaptive resistance to RLY-2608 may involve metabolic reprogramming, increased oxidative stress, and hypoxia signaling, highlighting the need for combination strategies to overcome resistance and enhance treatment efficacy."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • EGFR • ERBB3 • ERBB4 • KRAS • PIK3CA

HERTHENA-PanTumor01: A global, multicohort, phase 2 trial of HER3-DXd in relapsed/refractory metastatic solid tumors. (ASCO 2024) - P2 | "HER3-DXd is a potential first-in-class HER3-directed antibody-drug conjugate (ADC) composed of a fully human anti-HER3 monoclonal antibody (patritumab) covalently linked to a potent topoisomerase I inhibitor payload via a tumor-selective cleavable linker. The primary endpoint for each cohort is ORR by investigator per RECIST version 1.1. Secondary endpoints include safety and tolerability, DOR, DCR, PFS, overall survival, pharmacokinetics, and the correlation between HER3 IHC protein expression and efficacy."

Clinical • Metastases • P2 data • Pan tumor • Breast Cancer • CNS Disorders • Cutaneous Melanoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Interstitial Lung Disease • Lung Cancer • Melanoma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • BRAF • ERBB3 • HER-2

ERBB3 overexpression is enriched in diverse patient populations with castration-sensitive prostate cancer and is associated with a unique AR activity signature. (PubMed, Clin Cancer Res) - "In diverse CSPC patient populations, ERBB3 OE was associated with high AR signaling despite low intraprostatic androgen. Mechanistic studies demonstrated a direct link between HER3 and enzalutamide resistance. ERBB3 OE as a biomarker could thus stratify patients for intensification of therapy in castration-sensitive disease, including targeting HER3 directly to improve sensitivity to AR-targeted therapies."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ERBB3

A phase 2 study of HER3-DXd in patients (pts) with metastatic breast cancer (MBC). (YIR 2024) - P2 | "Background: HER3-DXd is an antibody drug conjugate (ADC) comprised of a fully human anti-HER3 IgG1 monoclonal antibody (patritumab), attached to a topoisomerase 1 inhibitor via a tetrapeptide-based cleavable linker that has shown promising efficacy in pts with HER3-expressing MBC (Krop, 2022). HER3-DXd had an acceptable safety profile, and the data further confirm the clinical activity in MBC in heavy pre-tx MBC across the broad range of HER3 expression levels. Parts B and Z are ongoing and data from this report support the potential entry of HER3-DXd into the therapeutic paradigm in MBC"

Clinical • Metastases • P2 data • Alopecia • Anemia • Breast Cancer • Fatigue • Hematological Disorders • Immunology • Inflammation • Interstitial Lung Disease • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Thrombocytopenia • Triple Negative Breast Cancer • ERBB3 • HER-2

A multivariate biomarker to guide antibody-drug conjugate selection and provide insight on response differences across breast cancer subtypes (SABCS 2023) - P=N/A | "Background: Antibody-drug conjugates (ADCs), including trastuzumab deruxtecan (T-DXd; targeting HER2) and sacituzumab govitecan (SG; targeting TROP2), have transformed the management of metastatic breast cancer, with additional ADCs approved in other solid tumors or in late-stage development...TRS was then validated using held out SG ORRs from nine tumor types in the IMMU-132-01 basket trial and two ADC ORRs from ASCO 2023 abstracts (enfortumab vedotin [EV; targeting NECTIN-4] in head and neck cancer and patritumab vedotin [targeting HER3] in breast cancer), with TRS predictive biomarker positivity rates again being more significantly correlated vs. observed ORRs than target expression alone (n=11, TRS r=0.91, p=0.0001; target expression alone r=44, p=0.17)...Across the 21 tumor types in the Strata Trial dataset, breast cancer had the highest percentage (76%) of patients predicted positive for at least one ADC, with 23% and 55% positive for the approved ADCs..."

Biomarker • IO biomarker • Tumor mutational burden • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • ERBB3 • FOLR1 • HER-2 • TMB

A phase 2 study of HER3-DXd in patients (pts) with metastatic breast cancer (MBC). (ASCO 2023) - P2 | "Background: HER3-DXd is an antibody drug conjugate (ADC) comprised of a fully human anti-HER3 IgG1 monoclonal antibody (patritumab), attached to a topoisomerase 1 inhibitor via a tetrapeptide-based cleavable linker that has shown promising efficacy in pts with HER3-expressing MBC (Krop, 2022). HER3-DXd had an acceptable safety profile, and the data further confirm the clinical activity in MBC in heavy pre-tx MBC across the broad range of HER3 expression levels. Parts B and Z are ongoing and data from this report support the potential entry of HER3-DXd into the therapeutic paradigm in MBC. Clinical trial information: NCT04699630."

Clinical • Metastases • P2 data • Alopecia • Anemia • Breast Cancer • Fatigue • Hematological Disorders • Inflammation • Interstitial Lung Disease • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Thrombocytopenia • Triple Negative Breast Cancer • ERBB3 • HER-2

The impact of HER3 dynamics on the efficacy of HER3-DXd, a novel HER3 directed antibody-drug conjugate (AACR 2023) - "HER3-DXd, a novel antibody-drug conjugate (ADC) composed of a human anti-HER3 IgG1 monoclonal antibody (patritumab) covalently linked to a topoisomerase I inhibitor payload (DXd), is currently being studied in clinical trials for breast cancer and NSCLC...NSCLC cell lines harboring EGFR activating mutations, ROS1 fusions, or ALK fusions were used to evaluate the effect of osimertinib, lorlatinib, or ceritinib on cell surface HER3 expression and payload release (osimertinib only). HER3-DXd was rapidly transferred to early endosomes after binding to HER3... HER3 expression was dynamically changed by HER3-DXd dosing regimen and by RTKi treatment, resulting in a substantial impact on payload release. These findings support our strategy of clinical studies using HER3-DXd after drugs that increase HER3 expression including EGFR TKI and indicate that HER3 dynamics may play a key role in achieving optimal efficacy of HER3-DXd."

Clinical • Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • ROS1

HERTHENA-Lung02: A randomized Phase 3 study of patritumab deruxtecan vs platinum-based chemotherapy in locally advanced or metastatic EGFR-mutated NSCLC after progression with a third-generation EGFR tyrosine kinase inhibitor (AACR 2023) - P1, P3 | "Patients are randomized 1:1 to receive either HER3-DXd 5.6 mg/kg every 3 weeks or 4 cycles of PBC containing pemetrexed (can be continued as maintenance) with cisplatin or carboplatin. Patients are stratified by prior third-generation EGFR TKI treatment (osimertinib vs other), line of prior third-generation EGFR TKI use (first vs second line), region (Asia vs rest of world), and presence of stable brain metastases (yes vs no)...Other secondary endpoints include investigator-assessed progression-free survival, objective response rate, duration of response, clinical benefit rate, disease control rate, time to response (all assessed by investigator and BICR per RECIST 1.1), safety, and patient-reported outcomes. Enrollment began May 2022 and is ongoing, with sites in Asia, Australia, Europe, and North America."

Clinical • Metastases • P3 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2

Targeting ATR enhances the antitumor efficacy of patritumab deruxtecan (HER3-DXd)in tamoxifen-resistant ER+ breast cancer cells by inducing DNA damage and apoptosis (AACR 2023) - "Background: HER3, a member of the ERBB family of receptor tyrosine kinases that activates multiple oncogenic signaling pathways, is overexpressed in 50-70% of breast cancers (BC). The combination of HER3-DXd plus ATR inhibitors has therapeutic potential for overcoming tamoxifen resistance in HER3+/ER+ BC."

Clinical • Late-breaking abstract • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ANXA5 • CCNA2 • CDK2 • CHEK1 • ERBB3 • H2AX • TOP1

Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL (SABCS 2017) - "...For patients with HR+ HER2- tumors, only 70-gene (Mammaprint) high-risk patients are enrolled. To date, 1200+ patients have been randomized to one of 14 arms: control (paclitaxel followed by AC); veliparib/carboplatin; neratinib; MK2206; trebananib; trastuzumab/pertuzumab; ado-trastuzumab emtansine/pertuzumab; pembrolizumabx4; ganitumab/metformin; ganetespib; PLX-3397. 7 agents graduated in at least one signature (> 85% probability of success in a 300-patient phase III confirmatory trial); 2 did not graduate; 1 stopped for toxicity, and 3 are enrolling (patritumab/trastuzumab, talazoparib/irinotecan, pembrolizumabx8)... The first long-term efficacy results from the I-SPY2 TRIAL demonstrate that achieving pCR is a very strong surrogate endpoint for improved EFS and DDFS in a high-risk population, across all treatment arms, regardless of subtype. I-SPY2 shows substantially lower estimated EFS hazards for patients achieving pCR, compared to the 5 yr EFS hazard ratio for pCR...

Retrospective data • HER2 Breast Cancer • Hormone Receptor Breast Cancer

Correlation between antibody-drug conjugate (ADC) targetable antigen expression and occurrence of interstitial lung disease (ILD) (ESMO-TAT 2023) - "Data was abstracted for incidence of ILD from publically available trial results of phase I-II clinical trials of ADCs in non-small cell lung cancer (NSCLC) targeting antigens: ERBB2 (trastuzumab deruxetecan), ERBB3 (patritumab deruxetecan), TROP2 (datopotamab deruxetecan), CEACAM5 (tusamitamab ravtansine), and MET (Telisotuzumab Vedotin). This may imply and further provide support to ILD being a bystander effect rather than true on-target toxicity with ADCs. Further ADC development should focus on reducing bystander effects via selection of linker and payload classes least likely to cause ILD while optimizing dose and drug-to-antibody ratio."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CEACAM5 • ERBB3 • HER-2 • TROP2

[VIRTUAL] HER3-targeting antibody-drug conjugate, U3-1402, induces tumor regression in a variety of xenograft models and exerts enhanced antitumor activity by combining with PI3K inhibition (AACR-II 2020) - P1, P1/2 | "We have developed a HER3-targeting antibody-drug conjugate U3-1402, which consists of a fully human anti-HER3 antibody patritumab, cleavable peptide-based linker, and DNA topoisomerase I inhibitor DXd...Combination treatment of U3-1402 with PI3K inhibitor, alpelisib, was evaluated in human breast cancer MDA-MB-453 cells harboring PIK3CA mutation... U3-1402 may exert potent antitumor activity in various human cancer cells expressing HER3, and its efficacy is likely to be enriched by HER3 expression. A combination strategy with agents that upregulate HER3 expression, such as PI3K inhibitors, should be explored further given this observed benefit over monotherapy."

Preclinical • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • ERBB3 • PIK3CA

Phase 1 Study of the Anti-HER3 Antibody Drug Conjugate U3-1402 in Metastatic or Unresectable EGFR-Mutant NSCLC (WCLC 2017) - P1; "...U3-1402 is a novel antibody-drug conjugate (ADC) comprised of a recombinant fully human anti-HER3 antibody (patritumab) covalently conjugated via a cleavable peptide linker to a derivative of the topoisomerase I inhibitor exatecan...Trial Design: This is a multicenter, open-label Phase 1 study of U3-1402 in metastatic or unresectable non-squamous NSCLC subjects harboring EGFR-activating mutation who (a) are T790M mutation-negative after disease progression during treatment with erlotinib, gefitinib, or afatinib or (b) develop disease progression while on osimertinib...Section not applicable"

Clinical • P1 data • Non Small Cell Lung Cancer

[VIRTUAL] EGFR inhibition enhances the cellular uptake and antitumor activity of the novel HER3 antibody drug conjugate U3-1402 (AACR-II 2020) - P1 | "HER3 is frequently over expressed in EGFR-mutant NSCLC.U3-1402 is an antibody-drug conjugate (ADC) comprised of HER3-targeting antibody (patritumab) linked to a topoisomerase I inhibitor (DX-8951 derivative, or DXd)...We aimed to develop a preclinical strategy to enhance the efficacy of U3-1402.Pre-treatment with EGFR TKIs (gefitinib or osimertinib) increased HER3 membrane levels in six different EGFR-mutant cell lines by increasing both the amount of HER3 positive cells and the intensity of HER3 expression...In vivo experiments evaluating the antitumor efficacy of the combination of osimertinib and U3-1402 are currently underway.Our studies reveal that EGFR inhibitor treatment increased membrane expression of HER3 which was associated with enhanced internalization of U3-1402 in EGFR-mutant NSCLC. The combination of osimertinib and U3-1402 may be an effective treatment approach and should be evaluated in future clinical trials in patients with EGFR-mutant NSCLC."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • ERBB3 • HER-2

Dual-targeting therapy against HER3/MET in human colorectal cancers. (PubMed, Cancer Med) - "We established HER3-and/or MET-KO SW1116 cell lines, and HER3/MET-double KO resulted in the inhibition of in vitro cell proliferation and in vivo tumor growth in nude mice by SW1116 cells. Furthermore, the combination of patritumab, an anti-HER3 fully human mAb, and PHA665752, a MET inhibitor, markedly inhibited in vitro cell proliferation, 3D-colony formation, and in vivo tumor growth in nude mice by SW1116 cells The dual targeting of HER3/MET has potential as CRC therapy."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • ERBB3 • FOXM1 • HGF • NRG1

Pharmacokinetics, efficacy, and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) (ESMO 2022) - P1 | "The primary objective of cohort 4 is to evaluate the PK of this formulation during the first treatment cycle. Secondary objectives include the evaluation of PK, safety, tolerability, immunogenicity, and efficacy."

Clinical • PK/PD data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ERBB3 • HER-2

HERTHENA-Lung02: A randomized phase III study of patritumab deruxtecan vs platinum-based chemotherapy in locally advanced or metastatic EGFR-mutated NSCLC after progression with a third-generation EGFR TKI (ESMO 2022) - P1, P3 | "Pts are randomized 1:1 to receive either HER3-DXd 5.6 mg/kg every 3 weeks or 4 cycles of PBC containing pemetrexed (can be continued as maintenance) with cisplatin or carboplatin. Pts are stratified by prior 3rd-gen EGFR TKI treatment (osimertinib vs other), line of prior 3rd-gen EGFR TKI use (first vs second line), region (Asia vs rest of world), and presence of stable brain metastases (yes vs no)...Other secondary endpoints include investigator-assessed PFS, objective response rate, duration of response, clinical benefit rate, disease control rate, time to response (all per BICR per RECIST v1.1), safety, and patient-reported outcomes. Enrollment into the trial is starting in Q2 2022."

Clinical • P3 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2

Targeting nuclear HER3-AKT cascade improves radiotherapy of non-small cell lung cancer (AACR-NCI-EORTC 2022) - "In line with the role of AKT1 in DSB repair, the HER3 neutralizing antibody patritumab as well as HER3-siRNA diminished DSB repair in vitro... IR-induced activation of nuclear AKT occurs in the nucleus that is mainly dependent on HER3 expression in NSCLC. Thus, targeting HER3 in combination with radiotherapy may provide a logical treatment option for investigation in selected NSCLC patients. No"

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • ERBB3

A Phase II Study of HER3-DXD in Patients (pts) with Metastatic Breast Cancer (MBC) (ESMO-BC 2022) - P2 | "HER3-DXd is an antibody drug conjugate (ADC) comprised of a fully human anti-HER3 IgG1 monoclonal antibody (patritumab), covalently linked to a topoisomerase 1 inhibitor payload, an exatecan derivative (DXd), via a tetrapeptide-based cleavable linker. Part B will enroll ∼60 pts (20 pts in up to 3 subgroups) as defined from the biomarker expression pattern and preliminary efficacy findings from Part A. Pts from the same biomarker subgroups in Parts A and B will be pooled for the final efficacy analysis. Enrollment to Part A was initiated in November 2020."

Clinical • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • ERBB3 • HER-2 • PGR

HERTHENA-Lung02: A Randomized Phase 3 Study of Patritumab Deruxtecan vs Platinum-Based Chemotherapy in Locally Advanced or Metastatic EGFR-Mutated NSCLC After Progression with a Third-Generation EGFR TKI (IASLC-NACLC 2022) - P1, P3 | "Pts are randomized 1:1 to receive either HER3-DXd 5.6 mg/kg every 3 weeks or 4 cycles of PBC containing pemetrexed (can be continued as maintenance) with cisplatin or carboplatin. Pts are stratified by prior 3rd-gen EGFR TKI treatment (osimertinib vs other), line of prior 3rd-gen EGFR TKI use (first vs second line), region (Asia vs rest of world), and presence of stable brain metastases (yes vs no)...Enrollment began May 2022 and is ongoing, with sites in the US, Canada, EU, Asia, and Australia. This trial in progress was previously presented at ESMO 2022."

Clinical • P3 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2

Targeting HER3-dependent activation of nuclear AKT improves radiotherapy of non-small celllung cancer. (PubMed, Radiother Oncol) - "IR-induced activation of nuclear AKT occurs inside the nucleus that is mainly dependent on HER3 expression in NSCLC. These findings suggest that targeting HER3 in combination with radiotherapy may provide a logical treatment option for investigation in selected NSCLC patients."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • ERBB3

"Wont Patritumab work in these?" (@RenoHemonc)

"Third instalment of a triple whammy, after patritumab and Enhertu. $DSNKY making a bid to consolidate its status as the winner of #ASCO22" (@JacobPlieth)