emibetuzumab (LY2875358) / Eli Lilly, Innovent Biologics - LARVOL DELTA

Balise: A Study of LY2875358 in Participants With Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Eli Lilly and Company | Trial primary completion date: Mar 2016 ➔ Dec 2015

Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Balise: A Study of LY2875358 in Participants With Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations (clinicaltrials.gov) - P2 | N=150 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Dec 2022 ➔ Dec 2023

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Balise: A Study of LY2875358 in Participants With Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations (clinicaltrials.gov) - P2 | N=150 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • EGFR

Balise: A Study of LY2875358 in Participants With Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Balise: A Study of LY2875358 in Participants With Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations (clinicaltrials.gov) - P2 | N=150 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Balise: A Study of LY2875358 in Participants With Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations (clinicaltrials.gov) - P2 | N=150 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Jul 2020 ➔ Jul 2021

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • EGFR

Balise: A Study of LY2875358 in Participants With Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Eli Lilly and Company

New P2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • EGFR

Balise: A Study of LY2875358 in Participants With Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations (clinicaltrials.gov) - P2 | N=150 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Dec 2023 ➔ Dec 2024

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Balise: A Study of LY2875358 in Participants With Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations (clinicaltrials.gov) - P2 | N=150 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Jul 2021 ➔ Dec 2021

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Balise: A Study of LY2875358 in Participants With Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations (clinicaltrials.gov) - P2 | N=150 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Dec 2021 ➔ Dec 2022

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Balise: A Study of LY2875358 in Participants With Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations (clinicaltrials.gov) - P2 | N=168 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Anti-MET Antibody Therapies in Non-Small-Cell Lung Cancer: Current Progress and Future Directions. (PubMed, Antibodies (Basel)) - " Amivantamab, a bispecific EGFR/MET antibody was approved to treat EGFR exon 20 insertion and now has recently been extended to target classical EGFR mutations with progression on osimertinib. Other important anti-MET targeted therapies in development include antibody drug conjugates such as telisotuzumab vedotin, REGN5093-M114, and AZD9592 and emibetuzumab, which is a humanized immunoglobulin G4 monoclonal bivalent MET antibody...Future research should focus on developing novel MET antibody drugs and exploring new therapeutic combinations to enhance treatment efficacy and overcome resistance in NSCLC. Refining biomarker-driven approaches to ensure precise patient selection is also critical to optimizing treatment outcomes."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Evaluating the chaos game representation of proteins for applications in machine learning models: prediction of antibody affinity and specificity as a case study. (PubMed, J Mol Model) - "We then feed the resulting images to a convolutional neural network, built in Python 3.8.10, using TensorFlow 2.9.1, Keras 2.9.0, and the scikit-learn 1.1.1 packages. We select as case study a recently published dataset for the antibody emibetuzumab, with the objective of co-optimizing antibodies variants with both high affinity and low non-specific binding."

Journal • Machine learning

Position-Specific Enrichment Ratio Matrix scores predict antibody variant properties from deep sequencing data. (PubMed, Bioinformatics) - "We find that PSERM scores are much more reproducible and correlate more strongly with experimentally measured properties than frequencies or enrichment ratios, including for multiple antibody properties (affinity and non-specific binding) for a clinical-stage antibody (emibetuzumab)...All deep sequencing datasets and code to do the analyses presented within are available via https://github.com/Tessier-Lab-UMich/PSERM_paper. Supplementary data are available at Bioinformatics online."

Journal

Antitumor activity of MET antibody emibetuzumab (LY2875358) in combination with EGFR inhibitors in erlotinib resistant (ER) xenograft mouse models (AACR 2017) - P2; "...Combination of emibetuzumab with EGFR TKIs (erlotinib, AZD9291, CO1686) or EGFR Ab (necitumumab, cetuximab) was evaluated in 3 ER xenograft models...Model 2: ER cell line HCC827-A8 was derived from HCC827 parental xenograft tumor serially passed in vivo with long term treatment of gefitinib and erlotinib... The three erlotinib resistant models with MET amp and retaining sensitizing EGFRmt (ex19 del or L858R), and no acquired T790M were found resistant to other EGFR inhibitors (Abs and TKIs). Emibetuzumab in combination with either EGFR TKI or Ab showed anti-tumor activity in MET amp ER xenograft models including tumor regression in 2 out of 3 models. The combination of emibetuzumab with erlotinib is being evaluated in NSCLC patients with EGFR activating mutation (NCT01897480)."

Biosimilar • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Evaluation of single agent merestinib (LY2801653) or emibetuzumab (LY2875358) and the combination in a xenograft tumor model bearing MET exon 14 skipping (AACR 2017) - P2; "Merestinib (12 mg/kg) treatment resulted in durable and complete response in 6/7 mice bearing Hs746t tumors with MET ex14 skipping and MET amp. When used singly, merestinib (6 mg/kg) or emibetuzumab (10 mg/kg) resulted in only transient tumor regression in this model, while the combination resulted in substantial tumor regression while on treatment. This combination treatment was however, not as durable as was observed with single agent 12 mg/kg merestinib."

Biosimilar • Gastric Cancer • Gastrointestinal Cancer • Lung Cancer • Oncology

Characterization of the anti-angiogenic properties of merestinib (LY2801653), an oncokinase inhibitor (AACR 2017) - P1a/1b; "...In contrast, the MET-specific kinase inhibitor, PF04217903, only weakly inhibited cord formation and endothelial sprouting...In addition, while MET antibody emibetuzumab (human anti-MET antibody) plus ramucirumab (human anti-VEGFR2 antibody) decreased vascular density by 64%, merestinib plus ramucirumab decreased it by 92%...These data suggest that the anti-angiogenic activity of merestinib includes activities of other kinases targeted by merestinib. These data provide rationale and support for the clinical evaluation of combination of merestinib with ramucirumab (NCT02745769)."

Biosimilar • Gastric Cancer • Gastrointestinal Cancer • Oncology

A randomized, controlled, open label phase II study of erlotinib (E) with or without the MET antibody emibetuzumab (Emi) as first-line treatment for EGFRmt non-small cell lung cancer (NSCLC) patients who have disease control after an 8-week lead-in treatment with erlotinib. (ASCO 2017) - P2; "No statistically significant difference in PFS was noted in the ITT population.Exploratory analysis confirmed that high MET expression is a negative prognostic marker for pts treated with E and indicated that these pts may receive clinically meaningful benefit from Emi+E."

Biomarker • Clinical • P2 data • Biosimilar • Non Small Cell Lung Cancer

A phase 1b/2 study of ramucirumab in combination with emibetuzumab in patients with advanced solid tumors (AACR 2017) - "Abstract embargoed at this time."

Clinical • P1/2 data • Biosimilar • Oncology

Co-optimization of therapeutic antibody affinity and specificity using machine learning models that generalize to novel mutational space. (PubMed, Nat Commun) - "Here we evaluate the use of machine learning to simplify antibody co-optimization for a clinical-stage antibody (emibetuzumab) that displays high levels of both on-target (antigen) and off-target (non-specific) binding...Notably, models trained with deep learning features enable prediction of novel antibody mutations that co-optimize affinity and specificity beyond what is possible for the original antibody library. These findings demonstrate the power of machine learning models to greatly expand the exploration of novel antibody sequence space and accelerate the development of highly potent, drug-like antibodies."

Journal

A Randomized, Open-Label Phase II Study Evaluating Emibetuzumab Plus Erlotinib and Emibetuzumab Monotherapy in MET Immunohistochemistry Positive NSCLC Patients with Acquired Resistance to Erlotinib. (PubMed, Clin Lung Cancer) - "Acquired resistance to erlotinib in MET diagnostic (+) patients was not reversed by emibetuzumab plus erlotinib or emibetuzumab monotherapy, although a subset of patients obtained clinical benefit."

Journal • Monotherapy • P2 data • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MET

"Capmatinib? Tivantinib? Emibetuzumab ? Onartuzumab?" (,@EnriquedeAlava)

Targeted Therapy Approaches for MET Abnormalities in Non-Small Cell Lung Cancer. (PubMed, Drugs) - "Following the discovery of MET as a potential therapeutic target, extensive clinical studies have proposed three approaches to targeting MET: (1) MET tyrosine kinase inhibitors (TKIs), including crizotinib, capmatinib, tepotinib, savolinitib, and cabozantinib; (2) MET or HGF monoclonal antibodies, including emibetuzumab and ficlatuzumab; and (3) MET or HGF antibody drug conjugates, including telisotuzumab. Herein, we discuss the relevant clinical trials, particularly focusing on the efficacy as well as the safety and tolerability of the treatment options, in the promising field of targeting MET in NSCLC."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

MARCH Proteins Mediate Responses to Antitumor Antibodies. (PubMed, J Immunol) - "We report that MET surface expression is reduced by MARCH1, 4, or 8-mediated ubiquitination and that emibetuzumab-induced MET ubiquitination contributes to its capacity to downregulate MET and inhibit human tumor cell proliferation. Thus, MARCH E3 ligases can act as cofactors for antitumor Abs that target cell surface proteins, suggesting that the MARCH protein repertoire of cells is a determinant of their response to such Abs."

Journal • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • HGF • MET • SLC3A2

A Phase 1b/2 Study of Ramucirumab in Combination with Emibetuzumab in Patients with Advanced Cancer. (PubMed, Clin Cancer Res) - "Ramucirumab plus emibetuzumab was safe and exhibited cytostatic antitumor activity. MET expression may help to select patients benefitting most from this combination treatment in select tumor types."

Clinical • Combination therapy • Journal • P1/2 data • Esophageal Cancer • Fatigue • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Hepatology • Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Thoracic Cancer