patritumab deruxtecan (U3-1402) / Daiichi Sankyo, Merck (MSD) - LARVOL DELTA

HERTHENA-Breast01: A phase Ib/II, multicenter, open-label, dose-finding study to evaluate the safety and antitumor activity of patritumab deruxtecan (HER3-DXd) in HER2+ advanced breast cancer (BC) (ESMO Asia 2025) - P1/2 | "Background: Although HER2-targeted antibody-drug conjugates (ADCs) have improved outcomes in HER2+ advanced BC, safe and effective later-line therapies are needed for patients who have progressed on trastuzumab deruxtecan (T-DXd)...Pts in Arms 2 and 3 receive the same regimen as Arm 1, with either pertuzumab 840 mg IV followed by 420 mg IV Q3W (Arm 2) or tucatinib 300 mg orally BID (Arm 3)...Secondary endpoints are pharmacokinetics of HER3-DXd ADC, total HER3-DXd antidrug antibody and free DXd payload. Enrollment began in early 2025."

Clinical • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ERBB3 • HER-2

Collaborations Supporting Innovation in Breast Cancer ResearchCollaborations Supporting Innovation in Breast Cancer Research (Businesswire) - "Two spotlight poster presentations will report interim results from the HALLOW prospective observational trial (PD13-11) evaluating the efficacy and safety of ENHERTU in patients with HER2 low (IHC 1+ or 2+/ISH-) metastatic breast cancer with and without active brain metastases in Japan, and a post-hoc pooled efficacy analysis (PD13-10) from the TUXEDO-3 phase 2 trial of patritumab deruxtecan (HER3-DXd)...Two poster presentations will report on the intracranial and/or extracranial activity of ENHERTU and DATROWAY. A translational ctDNA analysis of intracranial and extracranial activity (PS2-08-20) of ENHERTU from the DEBBRAH phase 2 trial in patients with HER2 positive and HER2 low breast cancer with leptomeningeal disease will be highlighted, as well as results of intracranial activity (PS1-09-02) of DATROWAY from the DATO-BASE phase 2 trial in patients with HER2 negative breast cancer with leptomeningeal disease."

Clinical data • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer

The company has also presented a poster in a highlighted session regarding a sub-analysis of its TUXEDO-3 study… (PRNewswire) - "The results point towards a potential strategy of sequential antibody-drug conjugate treatment, by demonstrating the benefit of the use of HER3-DXd in these patients with a median overall survival of 8.1 months, as well as a median progression-free survival of 6.3 months evaluated for intracranial lesions, 11.3 months evaluated for extracranial lesions, and 6.3 months evaluated for combined lesions."

P2 data • HER2 Positive Breast Cancer • Lung Non-Small Cell Squamous Cancer

Herthena-breast04: a phase 3, randomized, open-label study evaluating the efficacy and safety of patritumab deruxtecan (HER3-DXd) versus treatment of physician's choice in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) unresectable locally advanced or metastatic breast cancer (SABCS 2025) - "Participants in Arm 1 will receive HER3-DXd 5.6 mg/kg IV on day 1 Q3W, and participants in Arm 2 will receive TPC consisting of 1 of the following options: 1) paclitaxel 80 mg/m2 IV on days 1, 8, 15, and 22 Q4W; 2) paclitaxel 90 mg/m2 IV on days 1, 8, and 15 Q4W; 3) nab-paclitaxel 100 mg/m2 IV on days 1, 8, and 15 Q4W; 4) capecitabine 1000 mg/m2 orally twice daily on days 1 to 14 Q3W; 5) liposomal doxorubicin 50 mg/m2 IV on day 1 Q4W; or 6) trastuzumab deruxtecan 5.4 mg/kg IV on day 1 Q3W. Imaging assessments occur Q6W from randomization through week 60 and Q12W thereafter. Enrollment is planned to begin in Q3 2025 across North America, Latin America, Europe, and Asia Pacific."

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ERBB3 • HER-2

Trials-in-Progress Across Breast Cancer Portfolio of Daiichi Sankyo (Businesswire) - "Additional externally sponsored trials for ENHERTU and DATROWAY include the PONTIAC phase 2 trial (PS5-07-15) evaluating ENHERTU versus CDK4/6 inhibitor-based endocrine therapy as a first-line treatment of non-luminal HR positive, HER2 low and HER2 ultralow advanced breast cancer; a phase 1b trial (PS5-09-22) evaluating ENHERTU in combination with valemetostat, an EZH1/2 inhibitor, in patients with HER2 low, HER2 ultralow and HER2 null metastatic breast cancer; and the TROPION-Breast06 phase 3b trial (PS5-07-21) of DATROWAY...Three additional trials-in-progress from the HERTHENA clinical development program of patritumab deruxtecan (HER3-DXd) also will be highlighted."

Trial status • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Triple Negative Breast Cancer

Herthena-breast01: a phase 1b/2, multicenter, open-label, dose-finding study to evaluate the safety and antitumor activity of patritumab deruxtecan (HER3-DXd) in HER2+ unresectable locally advanced or metastatic breast cancer (SABCS 2025) - P1/2 | "Background: Although HER2-targeted antibody-drug conjugates (ADCs) have improved outcomes in HER2+ advanced or metastatic breast cancer, safe and effective later-line therapies are needed for patients who have progressed on trastuzumab deruxtecan (T-DXd)...Participants in Arms 2 and 3 will receive the same regimen as Arm 1, with either pertuzumab 840 mg IV followed by 420 mg IV Q3W (Arm 2) or tucatinib 300 mg orally BID (Arm 3)...AEs are graded per National Cancer Institute Common Terminology Criteria for Adverse Events 5.0. Enrollment began in early 2025."

Clinical • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ERBB3 • HER-2

Outcome of patritumab deruxtecan (HER3-DXd) in patients with HER2-positive metastatic breast cancer and CNS involvement previously treated with T-DXd: A subanalysis of TUXEDO-3 (SABCS 2025) - P2 | "The number of previous treatment lines for advanced disease in the HER2-positive mBC population was 4.0 (range: 2.0-7.0); all patients had received prior T-DXd, three (30.0%) had additional T-DM1, and six (60%) tucatinib as well. In this post hoc analysis of the prospective TUXEDO-3 trial, HER3-DXd showed promising PFS and OS in patients with HER2-positive mBC and active BMs or LMD, previously treated with T-DXd. Despite the small sample size, these findings suggest a potential strategy for sequential ADC treatment in a patient population with no established standard of care. With a median PFS exceeding 6 months, further investigation of HER3-DXd in patients progressing on T-DXd is warranted."

Clinical • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ERBB3 • HER-2

Herthena-breast03: a phase 2, randomized, open-label study evaluating neoadjuvant patritumab deruxtecan (HER3-DXd) + pembrolizumab before or after pembrolizumab + chemotherapy for early-stage TNBC or HR-low+/HER2− breast cancer (SABCS 2025) - P2 | "There is a need for improved neoadjuvant therapy to increase the rate of pathological complete response (pCR), as patients who do not achieve pCR have a high risk of recurrence, and to reduce risk of long-term toxicities associated with cyclophosphamide and anthracyclines...This phase 2 study (NCT06797635) is evaluating neoadjuvant HER3-DXd + pembrolizumab administered before or after carboplatin + paclitaxel + pembrolizumab for early-stage TNBC or HR-low+/HER2− breast cancer. Eligible participants are adults (≥18 y) with untreated, locally advanced nonmetastatic (AJCC stage cT1c, N1-N2 or cT2-cT4, N0-N2) TNBC or HR-low+/HER2− breast cancer...Primary endpoints are safety (Part 1 and 2) and pCR (ypT0/Tis ypN0) rate (Part 2). Enrollment is ongoing."

Clinical • IO biomarker • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ERBB3 • HER-2 • PD-L1

Determinants of long-term response to patritumab deruxtecan in breast cancer patient-derived xenografts. (PubMed, NPJ Precis Oncol) - "Basal-like PAM50 intrinsic subtype, limited prior exposure to chemotherapy and intrinsic sensitivity to the TOP1i irinotecan were associated with long-term response. Long-term responders exhibited persistent DNA damage and lacked early transcriptional activation of the G2/M cell cycle checkpoint that allow for DNA repair and RNA-DNA hybrid (R-loop) resolution, in parallel resulting in immune pathways transcriptional activation. Notably, characteristics linked to long-term response were primarily associated with the TOP1i payload activity."

Journal • Breast Cancer • Oncology • Solid Tumor • BRCA1 • BRCA2 • ERBB3

Study of Patritumab Deruxtecan in Participants With Gastrointestinal Cancers (MK-1022-011) (HERTHENA-PanTumor02) (clinicaltrials.gov) - P1/2 | N=180 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Jul 2028 ➔ Dec 2028 | Trial primary completion date: Jul 2028 ➔ Dec 2028

Pan tumor • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Oncology • Solid Tumor

HERTHENA-breast03: A phase 2, randomized, open-label study evaluating neoadjuvant patritumab deruxtecan + pembrolizumab before or after pembrolizumab + chemotherapy for early-stage TNBC or HR-low+/HER2− breast cancer (ESMO 2025) - P2 | "Enrollment began Q1 2025. Table Table: 463eTiP Neoadjuvant cycles 1-4 Neoadjuvant cycles 5-8 Part 1 Arm A HER3-DXd 5.6 or 4.8 or 3.2 mg/kg Q3W + pembro a Carboplatin b + paclitaxel c + pembro a Part 2 Arm A HER3-DXd (selected dose from Part 1) + pembro a Carboplatin b + paclitaxel c + pembro a Part 2 Arm B Carboplatin b + paclitaxel c + pembro a HER3-DXd (selected dose from Part 1) + pembro a Part 2 Arm C Carboplatin b + paclitaxel c + pembro a Doxorubicin d OR epirubicin Legal entity responsible + cyclophosphamide f + pembro a a 200 mg Q3W; b AUC 1.5 mg/mL/min QW; c 80 mg/m 2 QW; d 60 mg/m 2 Q3W; Legal entity responsible 90 mg/m 2 Q3W; f 600 mg/m 2 Q3W"

Clinical • IO biomarker • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PD-L1

HERTHENA-Breast-01: Study of Patritumab Deruxtecan With Other Anticancer Agents in Participants With HER2 Positive Breast Cancer That Has Spread and Cannot Be Surgically Removed (MK-1022-009) (clinicaltrials.gov) - P1/2 | N=81 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Sep 2029 ➔ Apr 2030 | Trial primary completion date: Sep 2029 ➔ Apr 2030

Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

Patritumab deruxtecan (HER3-DXd) in patients with active brain metastases of breast cancer (TUXEDO-3): a multicentre, single-arm, phase 2 trial. (PubMed, Lancet Oncol) - "HER3-DXd showed promising clinical activity in patients with metastatic breast cancer and active brain metastases, and could offer a novel therapeutic option in this setting."

Journal • P2 data • Breast Cancer • Hematological Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Neutropenia • Oncology • Pneumonia • Solid Tumor • Triple Negative Breast Cancer • ERBB3 • HER-2

Patritumab deruxtecan (HER3-DXd) in patients with active brain metastases of non-small-cell lung cancer (TUXEDO-3): a multicentre, single-arm, phase 2 trial. (PubMed, Lancet Oncol) - "HER3-DXd showed promising clinical activity in patients with advanced NSCLC and active brain metastases, and could represent a novel treatment option in this setting."

Journal • P2 data • Febrile Neutropenia • Hematological Disorders • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ERBB3 • KRAS

Targeting Acquired Resistance to KRASG12DInhibitors: designing rationale synergistic treatments. (AACR-NCI-EORTC 2025) - "Interestingly, co-treatment of MRTX133 with MG-132 or bortezomib- potent proteasome inhibitors- or dactolisib -dual PI3K and mTOR inhibitor- increased cleaved PARP levels...Thus, drug resistant models were sensitive to dual MRTX1133 and patritumab deruxtecan inhibition...More importantly, these drug combinations were also effective in sensitive and de novo MRTX1133 resistant patient-derived organoids. Our findings emphasize the necessity to design combinatorial treatments to prevent and delay the acquisition of drug resistance in KRAS-driven cancers."

Preclinical • Colorectal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CD24 • ERBB3 • KRAS • STAR

Evaluation of HER3-targeting ADC patritumab deruxtecan in irinotecan-resistant colorectal cancer PDX models reveals resistance mechanisms and informs rational combination strategies (AACR-NCI-EORTC 2025) - "Phospho-proteomic data supported adaptive pathway rewiring following HER3 blockade. These findings highlight the complexity of HER3 signaling in chemotherapy-refractory mCRC and support the development of biomarker-driven combination strategies to enhance therapeutic efficacy of HER3-targeted ADCs (and conceivably other ADCs with topoisomerase inhibitor payload) in this setting."

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

Validation of HER2 Low/Ultralow breast cancer patient stratification strategy for neoadjuvant chemotherapy utilizing FOXC1 immunohistochemistry: Implications for neoadjuvant patritumab deruxtecan (HER3-DXd) [WITHDRAWN] (ESMO 2025) - No abstract available

Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ERBB3 • FOXC1 • HER-2

HERTHENA-PanTumor01: a phase II study of patritumab deruxtecan (HER3-DXd) in previously treated advanced solid tumors. (PubMed, Future Oncol) - P2 | "HER3-DXd has also shown preclinical antitumor efficacy in HER3-expressing cancers including cutaneous melanoma, gastric cancer, and prostate cancer, among others...Clinical trial registration: NCT06172478 (ClinicalTrials.gov); 2023-507641-29-00 (EudraCT); jRCT2031230575 (Japan Registry of Clinical Trials)."

Journal • P2 data • Pan tumor • Bladder Cancer • Breast Cancer • Cutaneous Melanoma • Esophageal Cancer • Gastric Cancer • Genito-urinary Cancer • Gynecologic Cancers • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ERBB3 • HER-2

Trials-in-Progress Across Daiichi Sankyo’s Oncology Portfolio (Businesswire) - "A trial-in-progress poster will highlight the design of the DESTINY-Endometrial01 phase 3 trial...Three phase 2 trials-in-progress will include the HERTHENA-Breast03 trial (463eTiP)...the REJOICE-GI01 trial (1001TiP)...and, the KEYMAKER-U01 sub-studies 01H/01I (2081eTiP) evaluating ifinatamab deruxtecan, raludotatug deruxtecan or docetaxel in patients with stage IV NSCLC...The design of two additional early phase trials will be shared, including the phase 1/2 trial (2792TiP) evaluating ifinatamab deruxtecan and gocatamig in patients with relapsed/refractory ES-SCLC and a phase 1b trial (977P) of valemetostat..."

pMMR • Trial status • Biliary Tract Cancer • Endometrial Cancer • Gastroesophageal Junction Adenocarcinoma • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Pancreatic Ductal Adenocarcinoma • Prostate Cancer • Renal Cell Carcinoma • Triple Negative Breast Cancer • Urothelial Cancer

Study of Patritumab Deruxtecan in Participants With Gastrointestinal Cancers (MK-1022-011) (HERTHENA-PanTumor02) (clinicaltrials.gov) - P1/2 | N=180 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | N=130 ➔ 180

Enrollment change • Pan tumor • Gastrointestinal Cancer • Oncology • Solid Tumor

KEYMAKER-U01 Substudy 01G: Pembrolizumab+Patritumab Deruxtecan±Chemotherapy in Previously Untreated Stage IV NSCLC (IASLC-WCLC 2025) - P, P2 | "Participants in Arm 1 will receive pembrolizumab 200 mg IV Q3W up to 35 cycles with carboplatin area under the curve 5 mg/ml/min (nonsquamous histology) or 6 (squamous) IV Q3W for 4 cycles, and either paclitaxel 200 mg/m 2 IV Q3W or nab-paclitaxel 100 mg/m 2 IV QW for squamous histology, or pemetrexed 500 mg/m 2 IV Q3W for nonsquamous histology. The secondary objectives are duration of response and PFS per RECIST v1.1 by BICR, and OS. Enrollment for this study will be ongoing globally."

IO biomarker • Metastases • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Solid Tumor • ALK • ERBB3 • HER-2 • PD-L1 • ROS1

ERBB3-BCAR4 Is a Recurrent and Oncogenic Fusion in Lung Adenocarcinoma Cases That Lack Other Driver Alterations (IASLC-WCLC 2025) - "The cells were then treated with lorlatinib to suppress growth of the parental cells, thereby testing if the ERBB3-BCAR4 fusion could function as a driver in a lung adenocarcinoma context...Use of patritumab deruxtecan in vitro, a HER3 antibody drug conjugate, reverses the growth advantage of ERBB3-BCAR4 , suggestive of a potential treatment option for patients with this rare fusion...Data suggestive that this fusion is functional include the lack of other driver alterations, the elevated RNA expression, and in vitro studies showing a growth advantage. Ongoing research includes additional work to define the signaling mechanisms of the fusion and potential therapeutic options to aid in the care of this rare patient population."

Clinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BCAR4 • EGFR • ERBB3

Incidence and Severity of Interstitial Lung Disease Associated With Antibody-Drug Conjugates in NSCLC and SCLC: A Meta-Analysis (IASLC-WCLC 2025) - "In NSCLC, the highest pooled incidence of any-grade ILD was seen with patritumab deruxtecan (23%) and trastuzumab deruxtecan (22%), followed by datopotamab deruxtecan (9%), telisotuzumab vedotin (7%), and sacituzumab govitecan (1%)...Treatment discontinuation due to ILD in NSCLC was highest with telisotuzumab vedotin combined with erlotinib (36%), followed by trastuzumab deruxtecan (9%) and patritumab deruxtecan (7%)...In SCLC, any-grade ILD incidence was 8% with rovalpituzumab tesirine, with no reported grade ≥3 ILD events...HER2/HER3-targeted, deruxtecan-containing ADCs demonstrated the highest ILD rates, while other ADCs such as sacituzumab govitecan had minimal reported toxicity. These findings highlight the need for agent-specific ILD monitoring and support the consideration of ADC design, including target and payload, when evaluating pulmonary safety and guiding clinical decision-making."

Retrospective data • Interstitial Lung Disease • Lung Cancer • Non Small Cell Lung Cancer • Pulmonary Disease • Respiratory Diseases • Small Cell Lung Cancer • Solid Tumor • ERBB3 • HER-2

Identification of asporin as a HER3 ligand exposes a therapeutic vulnerability in prostate cancer. (PubMed, JCI Insight) - "Antibody-drug conjugate (ADC) therapies designed to target HER2 (trastuzumab-deruxtecan) or HER3 (patritumab-deruxtecan) significantly diminished prostate cancer cell growth in vitro and tumor size in vivo, despite Aspn in the TME. Collectively, these findings indicate ASPN functions as a HER3 ligand to induce cellular migration, and inhibition with anti-HER2 or anti-HER3 ADC therapies highlights potential clinical utility for patients with metastatic castration-resistant prostate cancer that expresses HER2 or HER3."

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

Trials-in-Progress Across DXd ADC Portfolio…at WCLC (Daiichi Sankyo Press Release) - "DESTINY-Lung06 phase 3 trial evaluating the efficacy and safety of ENHERTU plus pembrolizumab; KEYMAKER-U01 substudy 01G phase 2 trial evaluating patritumab deruxtecan (HER3-DXd) in combination with pembrolizumab...and a phase 1b/2 trial evaluating ifinatamab deruxtecan and gocatamig...will be highlighted."

Trial status • Non Small Cell Lung Cancer • Small Cell Lung Cancer