M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with heavily pretreated CRC: Preliminary results from a phase I trial
| Autor: | Michael S. Wertheim, Petros Nikolinakos, Isabelle Dussault, Benjamin R. Tan, Edward J. Kim, Christoph Helwig, Patricia Rich, Heinz-Josef Lenz, Scott Kopetz, James L. Gulley, David Smith, Alexander I. Spira, Laureen S. Ojalvo |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research biology business.industry Ligand (biochemistry) Fusion protein 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Oncology chemistry 030220 oncology & carcinogenesis PD-L1 biology.protein Cancer research Medicine In patient Programmed death 1 Bifunctional business MSB0011359C Transforming growth factor |
| Zdroj: | Journal of Clinical Oncology. 36:764-764 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2018.36.4_suppl.764 |
| Popis: | 764 Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which plays a key role in tumor immunosuppression, may enhance the response to programmed death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs). M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, which serves as a TGF-β “trap.” We report results in patients (pts) with heavily pretreated colorectal cancer (CRC), an area of high unmet need since these pts no longer respond to standard therapies. Methods: In this expansion cohort of the ongoing, phase 1, open-label trial NCT02517398, pts with heavily pretreated (≥3rd line) advanced CRC receive M7824 1200 mg q2w until confirmed progressive disease (PD), unacceptable toxicity or trial withdrawal. The primary objective is best overall response (BOR) per RECIST v1.1; secondary objectives include safety/tolerability. Results: As of 28 June 2017, 32 heavily pretreated pts with advanced CRC (87.5% had ≥3 prior therapies) received M7824 for a median duration of 7.1 (range: 2-38) weeks; 2 pts remained on treatment. Among the 29 evaluable pts, 1 had a confirmed partial response (PR; ongoing at 8 months), 1 had stable disease (SD) and 27 had PD as BOR per independent read. The pt with a PR had CRC that was microsatellite stable (MSS), consensus molecular subtype (CMS) 4, KRAS mutant (mt) and PD-L1+; this pt had the highest tumor cell PD-L1 expression in our cohort (20%; PD-L1 expression was generally low among the other 24 pts with available results). 4 pts (12.5%) experienced 5 different grade 3 treatment-related adverse events (AEs; adrenal insufficiency, anemia, blood bilirubin increased, enteritis [leading to discontinuation] and fatigue); there were no grade ≥4 treatment-related AEs or treatment-related deaths. Conclusions: In heavily pretreated pts with advanced CRC, 1 pt (MSS, CMS 4, KRAS mt and PD-L1+) had a durable PR, 1 had SD and 27 had PD as BOR. M7824 showed a manageable safety profile. Updated data – including PD-L1, TGF-β and CMS results – will be presented. A study in pts with CMS 4 is in preparation. Clinical trial information: NCT02517398. |
| Databáze: | OpenAIRE |
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