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

Study of Patritumab Deruxtecan in Participants With Gastrointestinal Cancers (MK-1022-011) (clinicaltrials.gov) - P1/2 | N=130 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P1/2 trial • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor

HERTHENA-PanTumor01: A global phase II trial of HER3-DXd in metastatic solid tumors (ESMO 2024) - P2 | "Study sites are in Asia, Australia, Europe, and the US. Table: 690TiP"

Clinical • Metastases • P2 data • Pan tumor • Breast Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor • ERBB3 • HER-2

Intracranial response in patients (pts) with baseline (BL) brain metastases (BM) and extensive-stage (ES) small cell lung cancer (SCLC) treated with ifinatamab deruxtecan (I-DXd) in the IDeate-Lung01 study (ESMO 2024) - P2 | "Antibody–drug conjugates (ADCs) containing the DXd payload (T-DXd, HER3-DXd, and Dato-DXd) have shown encouraging intracranial responses. CNS responses with I-DXd appear consistent with those seen with other DXd ADCs, with promising intracranial efficacy in ES-SCLC pts who have a poor prognosis."

Clinical • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CD276 • ERBB3

Efficacy, safety and biomarker analysis of ICARUS-BREAST01: A phase II study of patritumab deruxtecan (HER3-DXd) in patients (pts) with HR+/HER2- advanced breast cancer (ABC) (ESMO 2024) - P2 | "HER3-DXd showed clinically meaningful activity and manageable safety profile in patients with HR+/HER2- ABC progressing after 2 or more lines of therapy. Further studies are warranted to confirm the role of HER3-DXd in this setting."

Biomarker • Clinical • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ERBB3 • HER-2 • TOP1

Patritumab Deruxtecan: “HER3-Dxd showed clinically meaningful activity and manageable safety profile in patients with HR+/HER2 – ABC progressing after 2 or more lines of therapy including CDK4: 6inh”; Advanced/metastatic breast cancer (Daiichi Sankyo) - ESMO 2024: “ORR 53.5% [95% Cl, 43.2; 63.6]; mDoR 8.7 [8.1; 12.5]; m PFS 9.4mos [95% Cl, 8.1; 13.4]”

P2 data • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology

Is knowledge of HER3 as a prospective therapeutic biomarker necessary for pathologists? (ECP 2024) - "We detected membrane expression of HER3 in HER2- overexpressing and Luminal-A/B breast cancer cell lines and used immunohistochemistry to qualitative and localization detection of HER3. In HER2-overexpressing (HER2 3+) tumour tissues, we found a potential correlation between HER3 overexpression and HER2 overexpression. However, whether HER3 expression is associated with disease progression and poor prognosis requires further in-depth analysis."

Biomarker • Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • ERBB3 • HER-2

Patritumab Deruxtecan Demonstrated Statistically Significant Improvement in Progression-Free Survival Versus Doublet Chemotherapy in Patients with Locally Advanced or Metastatic EGFR-Mutated Non-Small Cell Lung Cancer in HERTHENA-Lung02 Phase 3 Trial (Merck (MSD) Press Release) - P3 | N=586 | HERTHENA-Lung02 (NCT05338970) | Sponsor: Daiichi Sankyo | "The HERTHENA-Lung02 phase 3 trial evaluating patritumab deruxtecan in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) who received prior EGFR tyrosine kinase inhibitor (TKI) treatment met its primary endpoint of progression-free survival (PFS), demonstrating a statistically significant improvement versus platinum plus pemetrexed induction chemotherapy followed by pemetrexed maintenance chemotherapy. Overall survival (OS) data were immature at the time of the analysis and the trial will continue to further assess OS, a secondary endpoint....Data from the HERTHENA-Lung02 trial will be presented at an upcoming medical meeting and shared with global regulatory authorities."

P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Antibody–drug conjugates offer hope for patients with breast cancer including patients with brain metastases (Daily Reporter) - P2 | N=170 | ICARUS-BREAST (NCT04965766) | "At the data cut-off, 99 patients had received treatment and at a median follow-up of 15.3 months, the confirmed objective response rate was 53.5% and median PFS was 9.4 months...Around half of patients (50.1%) had treatment-related grade ≥3 adverse events; the most frequently reported events, regardless of grade, were fatigue, nausea and diarrhoea...'We have clinical experience of managing adverse events like these pre-emptively, therefore based on the early data available, the tolerability of patritumab deruxtecan would be manageable in a clinical setting.'"

P2 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Antibodies to watch in 2024. (PubMed, MAbs) - "In this installment, we discuss key details for 16 antibody therapeutics granted a first approval in 2023, as of November 17 (lecanemab (Leqembi), rozanolixizumab (RYSTIGGO), pozelimab (VEOPOZ), mirikizumab (Omvoh), talquetamab (Talvey), elranatamab (Elrexfio), epcoritamab (EPKINLY), glofitamab (COLUMVI), retifanlimab (Zynyz), concizumab (Alhemo), lebrikizumab (EBGLYSS), tafolecimab (SINTBILO), narlumosbart (Jinlitai), zuberitamab (Enrexib), adebrelimab (Arelili), and divozilimab (Ivlizi))...These nearly 50 product candidates include numerous innovative bispecific antibodies, such as odronextamab, ivonescimab, linvoseltamab, zenocutuzumab, and erfonrilimab, and antibody-drug conjugates, such as trastuzumab botidotin, patritumab deruxtecan, datopotamab deruxtecan, and MRG002, as well as a mixture of two immunocytokines (bifikafusp alfa and onfekafusp alfa)...Our analyses indicate that these molecules have approval success rates in the range of 14-32%, with higher rates..."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases

Opportunities for ADC Development in 2L NSCLC Leveraging Predictive Biomarkers (IASLC-WCLC 2024) - "In the P1b TROPION-LUNG02 trial, Dato-DXd combined with pembrolizumab proved effective regardless of PD-L1 expression. While T-DXd and HER3-DXd have been tested in HER2 and EGFR mutated cohorts, respectively, Dato-DXd use has not shown to be impacted by any specific biomarker. These results indicate the need to identify predictive biomarkers of response for improved patient population selection."

Biomarker • IO biomarker • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • ERBB3 • HER-2 • PD-L1

Merck to Present Survival Data and New Research on 10 Investigational or Approved Medicines at ESMO Congress 2024 (Businesswire) - "Additionally, new data on investigational candidates from Merck’s pipeline will be presented at the Congress, including for: patritumab deruxtecan (HER3-DXd), a HER3-directed antibody-drug conjugate (ADC), and ifinatamab deruxtecan (I-DXd; also known as MK-2400) being developed in collaboration with Daiichi Sankyo; sacituzumab tirumotecan (sac-TMT; also known as MK-2870/SKB264), an investigational anti-TROP2 ADC being developed in collaboration with Kelun-Biotech; and opevesostat (also known as MK-5684/ODM-208), an investigational steroid synthesis inhibitor in collaboration with Orion."

Clinical data • Cervical Cancer • Endometrial Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor

U31402-A-U103: HER3-DXd (Patritumab Deruxtecan; U3-1402) in Combination With Osimertinib in Subjects With Locally Advanced or Metastatic EGFR-mutated Non-Small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=280 | Active, not recruiting | Sponsor: Daiichi Sankyo | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Targeting NSCLC with Precision: Evaluation of the Emerging Role of Antibody-Drug Conjugates : Episode 17: Patient Selection and Sequencing of NSCLC ADCs (OncLive) - "The panel examines which patient populations might benefit most from treatment with datopotamab deruxtecan (Dato-DXd), sacituzumab govitecan, and patritumab deruxtecan (HER3-DXd). Additionally, they explore potential sequencing strategies for these antibody-drug conjugates in second-line and later treatment settings."

Video

HERTHENA-Lung01: Patritumab Deruxtecan in Subjects With Metastatic or Locally Advanced EGFR-mutated Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=277 | Active, not recruiting | Sponsor: Daiichi Sankyo | Trial completion date: Nov 2024 ➔ Jan 2026

Metastases • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • ROS1

Targeting NSCLC with Precision: Evaluation of the Emerging Role of Antibody-Drug Conjugates : Episode 16: Mitigating Toxicities of Dato-DXd, Sacituzumab Govitecan, and HER3-DXd (OncLive) - "Benjamin Levy, MD, compares the common toxicities associated with datopotamab deruxtecan (Dato-DXd), sacituzumab govitecan, and patritumab deruxtecan (HER3-DXd), and shares practical tips for managing these toxicities in the clinical setting to optimize patient care and minimize adverse effects."

Video

Novel antibody-drug conjugates based on DXd-ADC technology. (PubMed, Bioorg Chem) - "This review provides a comprehensive assessment of drugs developed with DXd-ADC technology, with a focus on mechanisms of action, pharmacokinetics studies, preclinical data, and clinical outcomes for DS-8201a, U3-1402, DS-1062a, DS-7300a, DS-6157a, and DS-6000a. By integrating existing data, we aim to provide valuable insights into the current therapeutic status and future prospects of these novel agents."

Journal • Review • Oncology

Consolidated Financial Results for the First Three Months of the Year Ending (Daiichi Sankyo Press Release) - "Research and development expenses increased by JPY23.5 billion, or 30.5% year on year, to JPY100.7 billion due to increased R&D investment in 5DXd ADCs (trastuzumab deruxtecan, datopotamab deruxtecan: Dato-DXd/DS-1062, patritumab deruxtecan: HER3-DXd/U3-1402, ifinatamab deruxtecan: I-DXd/DS-7300, DS-6000)....The negative effect on core operating profit from foreign exchange was JPY2.0 billion in total...Revenue from the Unit increased by JPY35.8 billion, or 50.7% year on year, to JPY106.4 billion and the revenue in local currency increased by USD169 million, or 32.8%, to USD683 million due to growth of Enhertu in the U.S. and Europe."

Commercial • Sales • Breast Cancer • Colorectal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Head and Neck Cancer • Non Small Cell Lung Cancer

Patritumab deruxtecan in HER2-negative breast cancer: part B results of the window-of-opportunity SOLTI-1805 TOT-HER3 trial and biological determinants of early response. (PubMed, Nat Commun) - "Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft  models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer."

Journal • 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 • CCNE1 • ERBB3 • HER-2 • SLC39A6 • TP53

Spotlight on Patritumab Deruxtecan (HER3-DXd) from HERTHENA Lung01. Is a Median PFS of 5.5 Months Enough in Light of FLAURA-2 and MARIPOSA? (PubMed, Lung Cancer (Auckl)) - "This prioritization by the FDA is grounded in compelling results from the global Phase II HERTHENA-Lung01 trial, wherein HER3-DXd exhibited clinically meaningful efficacy, achieving a median progression-free survival (mPFS) of 5.5 months in patients with heavily treated EGFR-mutated NSCLC. A pivotal question remains: Is a mPFS of 5.5 months sufficient in the context of the evolving first-line landscape observed in the FLAURA-2 and MARIPOSA trials?"

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

Patritumab deruxtecan in HER2-negative breast cancer: part B results of the window-of-opportunity SOLTI-1805 TOT-HER3 trial and biological determinants of early response (Nature) - P1 | N=80 | TOT-HER3 (NCT04610528) | "In the SOLTI-1805 TOT-HER3 trial, a single HER3-DXd dose was administered to 98 patients across two parts: 78 patients received 6.4 mg/kg (Part A), and 44 received a lower 5.6 mg/kg dose (Part B)....RNA analyses show significant correlations between CelTIL responses, high proliferation genes (e.g., CCNE1, MKI67), and low expression of luminal genes (e.g., NAT1, SLC39A6). DNA findings indicate that CelTIL response is significantly associated with TP53 mutations, proliferation, non-luminal signatures, and a distinct DNA-based subtype (DNADX cluster-3)."

P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor

Real-World Treatment Patterns and Clinical Outcomes Among Patients with Metastatic or Unresectable EGFR-Mutated Non-Small Cell Lung Cancer Previously Treated with Osimertinib and Platinum-Based Chemotherapy. (PubMed, Adv Ther) - P2 | "The treatment landscape for this heavily pretreated population of patients with EGFRm mNSCLC is fragmented, with no uniformly accepted standard of care. A high unmet need exists for therapeutic options that provide meaningful improvements in clinical benefit."

Clinical data • HEOR • Journal • Metastases • Real-world • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • ERBB3

Patritumab Deruxtecan BLA Submission Receives Complete Response Letter from FDA Due to Inspection Findings at Third-Party Manufacturer (Businesswire) - "The U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) for the Biologics License Application (BLA) seeking accelerated approval of Daiichi Sankyo...and Merck’s...patritumab deruxtecan (HER3-DXd) for the treatment of adult patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) previously treated with two or more systemic therapies. The CRL results from findings pertaining to an inspection of a third-party manufacturing facility. The CRL did not identify any issues with the efficacy or safety data submitted....The BLA is based on the primary results from the HERTHENA-Lung01 pivotal phase 2 trial..."

CRL • Non Small Cell Lung Cancer

Garon Discusses the Standing and Future of ADCs, Targeted Therapies in NSCLC (OncLive) - "'Lung cancer has been considered an area where the therapies are somewhat marginal and maybe not impacting sort of meaningful benefit for the patient,' Garon said in an interview with OncLive. 'There's been a major change within the subdivision of patients based on driver mutations based on advances in targeted therapies and immunotherapies. I would encourage practitioners to be hopeful in patients with NSCLC. This is still a very difficult disease, but many of the treatments that we have now can lead to substantial benefits for patients.'"

Interview

Long road towards effective HER3 targeting in breast cancer. (PubMed, Cancer Treat Rev) - "In this review, we discuss the HER3 role in the pathogenesis of breast cancer and its relevance across all subtypes. We also explore the new anti-HER3 treatment strategies, calling into question the significance of HER3 detection as crucial information in breast cancer treatment."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • ERBB3 • HER-2

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