A first-in-human study of cinrebafusp alfa, a HER2/4-1BB bispecific molecule, in patients with HER2-positive advanced solid malignancies Journal Article
| Authors: | Piha-Paul, S.; Olwill, S. A.; Hamilton, E.; Tolcher, A.; Pohlmann, P.; Liu, S. V.; Wurzenberger, C.; Hasenkamp, L. C.; Hansbauer, E. M.; Shroff, R.; Hurvitz, S.; Krishnamurthy, A.; Patnaik, A.; Hahn, N.; Kumar, R.; Duerr, M.; Zettl, M.; Aviano, K.; Matis, L.; Bruns, I.; Ku, G. |
| Article Title: | A first-in-human study of cinrebafusp alfa, a HER2/4-1BB bispecific molecule, in patients with HER2-positive advanced solid malignancies |
| Abstract: | Purpose: 4-1BB (CD137) is a costimulatory immune receptor expressed on activated T cells, activated B cells, NK cells, and tumor-infiltrating lymphocytes, making it a promising target for cancer immunotherapy. Cinrebafusp alfa, a monoclonal antibodylike bispecific protein targeting HER2 and 4-1BB, aims to localize 4-1BB activation to HER2-positive tumors. This study evaluated the safety, tolerability, and preliminary efficacy of cinrebafusp alfa in patients with previously treated HER2-positive malignancies. Patients and Methods: This was a multicenter dose-escalation study involving patients with HER2-positive malignancies who received prior treatment. The study assessed the safety and efficacy of cinrebafusp alfa across various dose levels. Patients were assigned to different cohorts, and antitumor responses were evaluated. The study aimed to determine the MTD and to observe any clinical activity at different dose levels. Results: Of 40 evaluable patients in the "active dose"efficacy cohorts, five showed an antitumor response, resulting in an overall response rate of 12.5% and a disease-control rate of 52.5%. Clinical activity was observed at the 8 and 18 mg/kg dose levels, with confirmed objective response rates of 28.6% and 25.0%, respectively. Cinrebafusp alfa was safe and tolerable, with grade ≤2 infusion-related reactions being the most frequent treatment-related adverse event. MTD was not reached during the study. Conclusions: Cinrebafusp alfa demonstrates promising activity in patients with HER2-positive malignancies who have progressed on prior HER2-targeting regimens. Its acceptable safety profile suggests it could be a treatment option for patients not responding to existing HER2-directed therapies. © 2024 The Authors. |
| Keywords: | immunohistochemistry; adult; cancer chemotherapy; clinical article; human tissue; aged; middle aged; young adult; drug tolerability; area under the curve; drug efficacy; drug safety; nuclear magnetic resonance imaging; colorectal cancer; cd8+ t lymphocyte; biological marker; melanoma; liver toxicity; neutrophil count; pharmacodynamics; breast cancer; image analysis; nausea; thrombocytopenia; vomiting; ca 19-9 antigen; carcinoembryonic antigen; epidermal growth factor receptor 2; cohort analysis; antineoplastic activity; drug screening; bladder cancer; biopsy; drug dose escalation; febrile neutropenia; fever; granzyme b; cytokine; gamma interferon; heart failure; multicenter study; immunogenicity; stomach cancer; pleura effusion; drug dose; physical examination; phase 1 clinical trial; ca 125 antigen; drug half life; disease control; heart left ventricle ejection fraction; alopecia; radiodiagnosis; biliary tract cancer; t lymphocyte activation; antibody titer; heart function; programmed death 1 receptor; interleukin 18; drug solubility; adverse event; drug disposition; cd56 antigen; cd137 ligand; response evaluation criteria in solid tumors; bispecific antibody; infusion related reaction; very elderly; human; male; female; article; obinutuzumab; solid malignant neoplasm; ecog performance status; maximum concentration; tumor necrosis factor receptor superfamily member 9; cinrebafusp alfa; electrochemiluminescence immunoassay |
| Journal Title: | Clinical Cancer Research |
| Volume: | 31 |
| Issue: | 2 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2025-01-15 |
| Start Page: | 288 |
| End Page: | 298 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-24-1552 |
| PUBMED: | 39235868 |
| PROVIDER: | scopus |
| PMCID: | PMC11739778 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
