seribantumab (MM-121) / Merrimack, Concentra Biosciences - LARVOL DELTA

CRESTONE: Initial efficacy and safety of seribantumab in solid tumors harboring NRG1 fusions. (ASCO 2022) - P2 | "Initial data indicate seribantumab induced durable responses in advanced solid tumors harboring NRG1 fusions and has a favorable safety profile. These data support the continued evaluation of seribantumab in NRG1 fusion-positive solid tumors in the ongoing CRESTONE study."

Clinical • Fatigue • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ATP1B1 • CD74 • ITGB1 • NRG1 • SDC4 • SLC3A2

CRESTONE: Study of Seribantumab in Adult Patients With NRG1 Gene Fusion Positive Advanced Solid Tumors (clinicaltrials.gov) - P2; N=75; Recruiting; Sponsor: Elevation Oncology; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Colorectal Cancer • Esophageal Cancer • Gallbladder Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hepatology • Kidney Cancer • Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Sarcoma • Solid Tumor • Uterine Cancer • NRG1

CRESTONE: Study of Seribantumab in Adult Patients With NRG1 Gene Fusion Positive Advanced Solid Tumors (clinicaltrials.gov) - P2 | N=75 | Recruiting | Sponsor: Elevation Oncology | Trial primary completion date: Aug 2022 ➔ Dec 2022

Trial primary completion date • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Colorectal Cancer • Esophageal Cancer • Gallbladder Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hepatology • Kidney Cancer • Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Sarcoma • Solid Tumor • Uterine Cancer • NRG1

CRESTONE: Study of Seribantumab in Adult Patients With NRG1 Gene Fusion Positive Advanced Solid Tumors (clinicaltrials.gov) - P2; N=75; Not yet recruiting; Sponsor: Elevation Oncology

Clinical • New P2 trial • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Colorectal Cancer • Esophageal Cancer • Gallbladder Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hepatology • Kidney Cancer • Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Sarcoma • Solid Tumor • Uterine Cancer • NRG1

Tumor Microenvironmental NRG1 Drives Resistance to PI3K/AKT Pathway Inhibition in Prostate Cancer (AUA 2026) - " A library of 297 secreted factors was generated and screened for effects on response to GDC-0941, Capivasertib, or Sapanisertib ± enzalutamide in LNCaP, 22Rv1, and VCaP prostate cancer cell lines...In 22RV1 cell line xenografts, combination therapy with seribantumab, enzalutamide, and pictilisib significantly suppressed tumor growth compared to enzalutamide and pictilisib alone (Figure 1D)... The TME-derived secretome plays a critical role in modulating resistance to targeted therapies in prostate cancer. NRG1 in the PCa TME activates HER3/HER2 signaling and promotes resistance to both AR and PI3K pathway inhibitors. Targeting HER3 in combination with PI3K inhibitors represents a promising therapeutic strategy to overcome NRG1-mediated resistance mechanisms in advanced prostate cancer."

Biomarker • Tumor microenvironment • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Urology • NRG1

Leukemia Cutis at Initial Diagnosis of Acute Myeloid Leukemia Consistent With Therapy-Related Disease After Lung Cancer Chemotherapy: A Case Report. (PubMed, Case Rep Hematol) - "A 78-year-old woman with Stage IV NSCLC (adenocarcinoma, no actionable mutations, PD-L1 negative) initially received carboplatin, pemetrexed, and pembrolizumab, complicated by neutropenic fever. She later enrolled in the SHERLOC trial (MM-121 + docetaxel), discontinued due to colitis and neutropenia...The patient received hydroxyurea, transfusion support, and tumor lysis prophylaxis...LC at the time of initial AML diagnosis is uncommon and portends poor prognosis. Clinicians should remain vigilant for new skin lesions and cytopenias in cancer survivors previously exposed to chemotherapy, as early recognition of extramedullary AML may expedite timely diagnosis and care planning."

IO biomarker • Journal • Acute Myelogenous Leukemia • Fatigue • Febrile Neutropenia • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Lung Adenocarcinoma • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thrombocytopenia • CD4 • CD68 • DNMT3A • PD-L1 • PPM1D • SPN • U2AF1

Therapeutic potential of a HER3 antibody-drug conjugate for the treatment of HER3-expressing cancers (AACR 2024) - " HER3-ADC1 was evaluated in vitro and in vivo, with patritumab deruxtecan (patri-DXd) as a comparator. HER3-ADC1 demonstrated target-dependent in vitro cytotoxicity and in vivo anti-tumor activity in a HER3-expressing pancreatic cancer PDX model. Results from in vitro and in vivo studies highlight the promising therapeutic potential of a seribantumab-based ADC for patients with HER3-expressing cancers. Additional results on the optimization and characterization of HER3-ADC1 will be presented."

ADC • Breast Cancer • Gastrointestinal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Preclinical discovery and characterization of EO-1022, a site-specific glycan-conjugated anti-HER3 vc-MMAE ADC for treating solid tumors (AACR 2025) - "EO-1022 is comprised of the highly selective and clinically validated HER3 antibody, seribantumab, that is site-specifically glycan-conjugated with a cleavable valine-citrulline linker and monomethyl auristatin E (MMAE) payload to give a drug-to-antibody ratio (DAR) of 4. EO-1022 was evaluated in vitro and in vivo, with patritumab deruxtecan (patri-DXd) as a comparator. EO-1022 demonstrated target-dependent in vitro cytotoxicity and in vivo anti-tumor activity in a HER3-expressing breast cancer CDX model. Additional results on the optimization and characterization of EO-1022 will be presented, including bystander effect assays and in vivo models of HER3-positive breast cancer and EGFR mutant NSCLC. Results from preclinical studies highlight the therapeutic potential of EO-1022 for patients living with HER3-expressing cancers."

ADC • Late-breaking abstract • Preclinical • Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Determining the molecular and biologic effects of HER3 and IDH1 antagonism on liver endothelium-PDAC crosstalk (AACR 2024) - "HER3-specific antibody Seribantumab, HER3 inhibitor Sapitanib, and IDH1 inhibitor ivosidenib were used to block HER3 and/or IDH1. Our results demonstrated a paracrine role of liver ECs in promoting cell growth via activating HER3 in PDAC cells as well as reprograming cellular metabolism from OXPHOS towards glycolysis. Identification of the metabolic shift that takes place in metastatic PDAC to the liver due to HER3 activation gives way for the development of a potentially lethal drug combination."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • ERBB3 • IDH1

Tumor microenvironmental NRG1 activation of HER3 as a driver of resistance to PI3K pathway inhibition in prostate cancer. (ASCO-GU 2026) - "Cells were treated with PI3K pathway inhibitors (GDC-0941, Capivasertib, Sapanisertib) alone and in combination with enzalutamide, an androgen receptor inhibitor...NRG1-mediated resistance requires ligand activation and phosphorylation of the HER3 receptor as well as phosphorylation activity of HER2, and can be abrogated by treatment with anti-HER3 antibody seribantumab, knockdown with HER3 siRNA, or treatment with anti-HER2 inhibitor lapatinib. In 22RV1 cell line xenografts, combination therapy with seribantumab, enzalutamide, and pictilisib significantly suppressed tumor growth compared to enzalutamide and pictilisib alone... The TME-derived secretome plays a critical role in modulating resistance to targeted therapies in prostate cancer. NRG1 in the PCa TME, activates HER3 signaling and promotes resistance to both AR and PI3K pathway inhibitors. Targeting NRG1-HER2/3 signaling in combination with PI3K inhibitors represents a promising therapeutic strategy to overcome..."

Biomarker • Tumor microenvironment • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ERBB3 • NRG1

ERBB3 blockade sensitizes HCC to regorafenib after first-line TKI resistance by inhibiting HIF1A-ABCB1 signaling. (PubMed, Clin Mol Hepatol) - "Seribantumab, an ERBB3-targeting monoclonal antibody, inhibited ERBB3-HIF1A-ABCB1 cascade, and its combination with regorafenib exerted marked synergistic anti-tumor effects on ERBB3-high tumors resistant to sorafenib or lenvatinib both in vitro and in vivo. This study revealed that ERBB3 was a key resistance factor driving limited efficacy to sequential regorafenib, but also an effective therapeutic target whose inhibition enhanced regorafenib sensitivity after sorafenib or lenvatinib resistance."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • ABCB1 • ERBB3 • HIF1A

CRESTONE: A Phase II Study of the Efficacy and Safety of the HER3 Monoclonal Antibody, Seribantumab, in Solid Tumors With Neuregulin-1 (NRG1) Fusions. (PubMed, JCO Precis Oncol) - P2 | "These results support the antitumor activity and safety of seribantumab in patients with advanced solid tumors harboring NRG1 fusions."

Journal • P2 data • Fatigue • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NRG1

Tumor Microenvironmental NRG1 Drives Resistance to PI3K Pathway Inhibition in Prostate Cancer (SUO 2025) - "Cells were treated with PI3K pathway inhibitors (GDC-0941, Capivasertib, Sapanisertib) alone and in combination with enzalutamide, an androgen receptor inhibitor...In 22RV1 cell line xenografts, combination therapy with seribantumab, enzalutamide, and pictilisib significantly suppressed tumor growth compared to enzalutamide and pictilisib alone ( Figure 1D )... The TME-derived secretome plays a critical role in modulating resistance to targeted therapies in prostate cancer. NRG1 in the PCa TME, activates HER3 signaling and promotes resistance to both AR and PI3K pathway inhibitors. Targeting HER3 in combination with PI3K inhibitors represents a promising therapeutic strategy to overcome NRG1-mediated resistance mechanisms in advanced prostate cancer."

Biomarker • Tumor microenvironment • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • NRG1

CRESTONE: Study of Seribantumab in Adult Patients with NRG1 Gene Fusion Positive Advanced Solid Tumors (clinicaltrials.gov) - P2 | N=54 | Terminated | Sponsor: Elevation Oncology | Trial completion date: Mar 2025 ➔ Feb 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jan 2025 ➔ Feb 2024; Business decision

Metastases • Trial completion date • Trial primary completion date • Trial termination • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Colorectal Cancer • Esophageal Cancer • Gallbladder Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hepatology • Kidney Cancer • Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Sarcoma • Solid Tumor • Uterine Cancer • NRG1

Seribantumab Results in Robust and Durable Responses in NRG1 Fusion-Positive Non-Small Cell Lung Cancer: A Multi-Center Case Series (IASLC-WCLC 2024) - "Targeted agents, such as the pan-ERBB kinase inhibitor afatinib, fare slightly better, with an ORR in the eNRGy1 registry of 25%...Following four cycles of neoadjuvant intent cisplatin/pemetrexed/durvalumab therapy, resection was aborted when pleural studding was noted intraoperatively, pathologically confirmed as adenocarcinoma...He was initially treated with dual immunotherapy (nivolumab/ipilimumab), then an investigational PGE2-receptor antagonist in combination with pembrolizumab...Patient three was a 59-year-old woman with bilateral metastatic recurrence of NSCLC, ITGB1-NRG1 fusion, previously treated with multiple resections, radiation, and systemic therapy including carboplatin/pemetrexed and nivolumab with progression...Conclusions : NRG1 fusion-positive lung cancer remains a challenging clinical entity, with poor response to standard-of-care therapy in the advanced and metastatic setting. In patients with lung cancer positive for various NRG1-fusions with..."

Clinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD74 • ERBB3 • ERBB4 • ITGB1 • NRG1 • SLC3A2

Immune checkpoint inhibitors in cancer: the increased risk of atherosclerotic cardiovascular disease events and progression of coronary artery calcium. (PubMed, BMC Med) - "Treatment with ICIs was associated with a higher rate of ASCVD events and a noticeable increase in CAC progression."

Checkpoint inhibition • Journal • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

The Therapeutic Significance of HER3 in Non-small Cell Lung Cancer (NSCLC): A Review Study. (PubMed, Curr Med Chem) - "Monoclonal antibodies such as lumretuzumab, seribantumab, and patritumab have shown potential in targeting HER3 to overcome resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Additionally, antibody-drug conjugates (ADCs) like HER3-DXd (patritumab deruxtecan) are new drug candidates that have demonstrated selective delivery of cytotoxic chemicals to NSCLC cells by exploiting HER3's widespread expression, minimizing cytotoxicity. This review aims to evaluate the efficacy of current HER3 therapeutics in development and their therapeutic potential in NSCLC, incorporating evidence from clinical trials."

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

ErbB3 Governs Endothelial Dysfunction in Hypoxia-Induced Pulmonary Hypertension. (PubMed, Circulation) - "MM-121, a human anti-ErbB3 monoclonal antibody, exhibited both preventive and therapeutic effects against hypoxia-induced PH. Our study reveals, for the first time, that ErbB3 serves as a novel biomarker and a promising target for the treatment of PH."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • ERBB3 • HER-2 • HIF1A • POSTN • YBX1

CRESTONE: Study of Seribantumab in Adult Patients With NRG1 Gene Fusion Positive Advanced Solid Tumors (clinicaltrials.gov) - P2 | N=75 | Active, not recruiting | Sponsor: Elevation Oncology | Trial completion date: Jun 2023 ➔ Mar 2025 | Trial primary completion date: Jun 2023 ➔ Jan 2025

Metastases • Trial completion date • Trial primary completion date • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Colorectal Cancer • Esophageal Cancer • Gallbladder Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hepatology • Kidney Cancer • Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Sarcoma • Solid Tumor • Uterine Cancer • NRG1

Cisplatin-induced increase in heregulin 1 and its attenuation by the monoclonal ErbB3 antibody seribantumab in bladder cancer. (PubMed, Sci Rep) - "Seribantumab also prevented tumor growth in both the chemosensitive BL0440 and chemoresistant BL0269 models. Our data demonstrate that cisplatin-associated increases in Akt and ERK phosphorylation is mediated by an elevation in HRG1, suggesting that inhibition of ErbB3 phosphorylation may be a useful therapeutic strategy in BlCa with high phospho-ErbB3 and HRG1 levels."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • EGFR • ERBB3 • HER-2 • NRG1

Elevation Oncology Reports First Quarter 2023 Financial Results and Highlights Recent Business Achievements (PRNewswire) - "Expected Upcoming Milestones and Operational Objectives: Initiate Phase 1 clinical trial of EO-3021 in the US in the second half of 2023; Ongoing target evaluation for future pipeline expansion....Research and development expenses for the first quarter 2023 were $7.3 million, compared to $13.6 million for the first quarter 2022. The decrease in R&D expense in the first quarter of 2023 was primarily related to the decrease in costs related to manufacturing clinical supply of seribantumab for use in the CRESTONE clinical trial. The Company prioritized its pipeline and realigned resources to advance its EO-3021 product candidate."

Commercial • New P1 trial • Pipeline update • Oncology • Solid Tumor

CRESTONE: A Phase 2 study of seribantumab in adult patients with neuregulin-1 (NRG1) fusion positive locally advanced or metastatic solid tumors (AACR 2023) - P2 | "Seribantumab has an acceptable safety and tolerability profile as a single agent in pts with solid tumors harboring NRG1 fusions. Updated efficacy data indicate seribantumab has robust and durable clinical activity, including CRs, across different tumor types harboring an NRG1 fusion and is a promising treatment option."

Clinical • Metastases • P2 data • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD74 • NRG1 • SLC3A2

Elevation Oncology to Present at the American Association of Cancer Research (AACR) Annual Meeting 2023 (PRNewswire) - "Elevation Oncology... announced that preclinical proof-of-concept data for EO-3021 will be highlighted in an oral presentation at the New Drugs on the Horizon special session at the American Association for Cancer Research (AACR) Annual Meeting 2023, being held April 14-19, 2023 in Orlando, Florida. A poster highlighting the preclinical data for EO-3021, a potential best-in-class antibody-drug conjugate (ADC) designed to target Claudin 18.2, will also be presented at the conference....Elevation Oncology will also present two posters on NRG1 fusions, including updated data from the Phase 2 CRESTONE study evaluating seribantumab in patients with solid tumors harboring NRG1 fusions."

P2 data • Preclinical • Oncology • Solid Tumor • CLDN18 • NRG1

SHERBOC: A double-blind, placebo-controlled, phase 2 trial of seribantumab (MM-121) plus fulvestrant in postmenopausal women with hormone receptor-positive, heregulin positive, HER2 negative metastatic breast cancer whose disease progressed after prior systemic therapy (SABCS 2017) - "Previously, seribantumab was tested in combination with exemestane in a placebo-controlled, Phase 2 study in post-menopausal women with ER/PR+, HER2 negative metastatic breast cancer (mBC). Safety will also be assessed. Enrollment is expected to begin in 2017 at approximately 80 sites globally."

P2 data • Retrospective data • Head and Neck Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Non Small Cell Lung Cancer • Ovarian Cancer

Randomized Phase 2 Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer (IASLC-WCLC 2018) - P2; "However, pre-defined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial is validating this finding in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216). "

Clinical • Combination therapy • P2 data • Non Small Cell Lung Cancer