seribantumab (MM-121) / Elevation Oncology, Merrimack - LARVOL DELTA

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

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."

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

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

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: 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: 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

Preclinical in vitro and in vivo evaluation of seribantumab, a human epidermal growth factor receptor-3 antibody, combined with standard therapies in hormone receptor-positive and human epidermal growth factor receptor-2-negative breast cancer models (SABCS 2018) - P2; "...In a randomized Phase 2 trial in hormone-positive (HR+) and human epidermal growth factor receptor-2-negative (HER2–) metastatic breast cancer (mBC), HRG+ patients appeared to have shortened progression free survival when receiving exemestane monotherapy and benefited from addition of seribantumab to this regimen...We investigated the role of HRG-HER3 in mediating resistance to CDK4/6 inhibitors (i.e., palbociclib) alone or in combination with fulvestrant... HRG-HER3 signaling impairs the activity of CDK4/6 inhibitors alone or in combination with fulvestrant in preclinical HR+ HER2– breast cancer models. HER3 blockade by seribantumab restores the drug sensitivity. This study provides rationale for the ongoing SHERBOC study (NCT03241810) testing seribantumab in combination with fulvestrant in postmenopausal women with HRG+ HR+ HER2– mBC who have received prior CDK4/6 inhibitor. "

Preclinical • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

MODULE 4: Integration of Targeted Therapy into the Management of Advanced BTCs (ASCO-GI 2023) - "CME Provider and Supporter(s): This event is organized and accredited by Research to Practice and supported through educational grants provided by AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, Eisai Inc, Exelixis Inc, Genentech, a member of the Roche Group, Incyte Corporation, and Merck. Spectrum and frequency of molecular alterations in cholangiocarcinoma and other BTCs; optimal timing and type of genomic analysis to identify actionable abnormalities Principal findings with pemigatinib, infigratinib and futibatinib for patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or other rearrangements Published outcomes from the Phase III ClarIDHy study of ivosidenib for cholangiocarcinoma with an IDH1 mutation; FDA approval and optimal incorporation into clinical practice Ongoing research evaluating targeted therapies (eg, FGFR inhibitors, ivosidenib) for patients with newly diagnosed..."

Metastases • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2 • HER-2 • IDH1 • NRG1

Elevation Oncology Reports Fourth Quarter and Full Year 2022 Financial Results (PRNewswire) - "Expected Upcoming Milestones and Operational Objectives: Present preclinical proof-of-concept data of EO-3021 at a major medical meeting in the first half of 2023; Initiate Phase 1 clinical trial of EO-3021 in the US in the second half of 2023; Report additional interim data of seribantumab from the CRESTONE study in the first half of 2023; Ongoing target evaluation for future pipeline expansion."

P2 data • Preclinical • Trial status • Biliary Tract Cancer • Bladder Cancer • Breast Cancer • Cholangiocarcinoma • Colorectal Cancer • Esophageal Cancer • Gallbladder Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Head and Neck Cancer • Kidney Cancer • Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Sarcoma • Solid Tumor • Uterine Cancer

Merrimack Reports Full Year 2022 Financial Results (Businesswire) - "In February 2023 Ipsen provided guidance to investors that it intends to file a supplemental New Drug Application with the U.S. Food and Drug Administration during the first half of 2023 following the Fast Track Designation granted in 2020 for the use of Onivyde in combination with oxaliplatin plus 5-fluorouracil/leucovorin for the treatment of patients with previously untreated mPDAC....Elevation also announced that it intends to present additional interim data from its study of seribantumab in the first half of 2023."

P2 data • sNDA • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

[VIRTUAL] Preclinical activity of seribantumab in gastrointestinal cancers with NRG1 fusions (AACR 2021) - "There was no shrinkage of afatinib-treated pancreatic PDX tumors.Our results here suggest that seribantumab is effective at reducing tumor growth in preclinical models of gastrointestinal cancers with NRG1 fusions. These data support the use of seribantumab to treat GI and other cancers with NRG1 fusions in the ongoing phase 2 CRESTONE study (NCT#04383210)."

Preclinical • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • ATP1B1 • EGF • NRG1 • SLC3A2

CRESTONE: Initial Efficacy and Safety of Seribantumab in Solid Tumors Harboring NRG1 Fusions (IASLC-ACLC 2022) - P2 | "Initial efficacy and safety data will be presented and was previously presented at ASCO 2022.Conclusions : Initial data indicate seribantumab induced durable responses in advanced solid tumors harboring NRG1 fusions with a favorable safety profile. These data support the 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

Evaluation of fixed-dose regimens of seribantumab in patients with solid tumors. (ASCO 2018) - "The recommended dose of seribantumab is 3 g Q3W+docetaxel in NSCLC and 3 g Q2W+fulvestrant in mBC. The fixed dose of seribantumab allows acceptable concentrations and safety profiles and potentially reduces drug waste and dosing errors."

Clinical • Hematological Malignancies • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Non Small Cell Lung Cancer

NRG1 Fusions in Non-Small Cell Lung Cancer (NSCLC) (IASLC-TTLC 2023) - "Agents targeting the HER2/HER3 pathway have shown early clinical promise in NRG1 fusion-positive cancers: both zenocutuzumab and seribantumab have FDA Fast Track Designation for tumors with NRG1-fusions. CONCLUSION NRG1 fusions are rare but actionable genomic events in NSCLC but there is striking heterogeneity within this family of alterations. The clinical impact of this heterogeneity on response to targeted agents warrants close attention."

IO biomarker • Tumor mutational burden • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ARID2 • CD74 • ERBB3 • GNAS • HER-2 • NRG1 • PD-L1 • SDC4 • SLC3A2 • TMB • TP53

Feasibility of Co-Targeting HER3 and EpCAM Using Seribantumab and DARPin-Toxin Fusion in a Pancreatic Cancer Xenograft Model. (PubMed, Int J Mol Sci) - "An experimental therapy study using Ec1-LoPE and MM-121 in mice bearing EpCAM- and HER3-expressing BxPC3 xenografts demonstrated the feasibility of the therapy. Further development of the co-targeting approach using HER3 and EpCAM could therefore be justified."

Journal • Preclinical • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • EPCAM • ERBB3 • HER-2

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 | Recruiting ➔ Active, not recruiting | Trial primary completion date: Dec 2022 ➔ Jun 2023

Enrollment closed • Metastases • 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