Safety and preliminary activity results of the GATTO study, a phase Ib study combining the anti-TA-MUC1 antibody gatipotuzumab with the anti-EGFR tomuzotuximab in patients with refractory solid tumors
S Ochsenreither, W M Fiedler, G D Conte, M Macchini, I Matos, B Habel, I Ahrens-Fath, F Raspagliesi, D Lorusso, U Keilholz, C Rolling, M Kebenko, K F Klinghammer, O Saavedra, H Baumeister, A Zurlo, E Garralda, S Ochsenreither, W M Fiedler, G D Conte, M Macchini, I Matos, B Habel, I Ahrens-Fath, F Raspagliesi, D Lorusso, U Keilholz, C Rolling, M Kebenko, K F Klinghammer, O Saavedra, H Baumeister, A Zurlo, E Garralda
Abstract
Background: The phase I GATTO study (NCT03360734) explored the feasibility, tolerability and preliminary activity of combining gatipotuzumab, a novel humanized monoclonal antibody binding to the tumor-associated epitope of mucin 1 (TA-MUC1) and an anti-epidermal growth factor receptor (anti-EGFR) antibody in refractory solid tumors.
Patients and methods: Initially the study enrolled primary phase (PP) patients with EGFR-positive metastatic solid tumors, for whom no standard treatment was available. Patients received gatipotuzumab administered at 1400 mg every 2 weeks, 6 weeks after the start of the glyco-optimized anti-EGFR antibody tomuzotuximab at 1200 mg every 2 weeks. As this regimen was proven safe, enrollment continued in an expansion phase (EP) of patients with refractory metastatic colorectal cancer, non-small-cell lung cancer, head and neck cancer and breast cancer. Tomuzotuximab and gatipotuzumab were given at the same doses and gatipotuzumab treatment started 1 week after the first dose of the anti-EGFR antibody. Additionally, investigators could use a commercial anti-EGFR antibody in place of tomuzotuximab.
Results: A total of 52 patients were enrolled, 20 in the PP and 32 in the EP. The combined treatment was well tolerated and no dose-limiting toxicity was observed in the whole study, nor related serious adverse event or death. Preliminary activity of the combination was observed, with one and four RECIST partial responses in the PP and EP, all in colorectal cancer patients. The trial was accompanied by a comprehensive translational research program for identification of biomarkers, including soluble TA-MUC1 (sTA-MUC1) in serum. In the EP, patients with baseline sTA-MUC1 levels above the median appeared to have improved progression-free survival and overall survival.
Conclusions: Combination of a TA-MUC1-targeting antibody and an EGFR-targeting antibody is safe and feasible. Interesting antitumor activity was observed in heavily pretreated patients. Future studies should test this combination together with chemotherapy and explore the potential of sTA-MUC1 as a companion biomarker for further development of the combination.
Keywords: EGFR; TA-MUC1; colorectal cancer; lung cancer; monoclonal antibody; phase I.
Conflict of interest statement
Disclosure OS: advisory board participation, invited speaker or conference honoraria from: Merck Sarono, Merck Sharp & Dohme (MSD), Ipsen, AstraZeneca, Roche, Immunocore, CureVac, Glenmark and Bristol-Myers Squibb (BMS). FW: consultancy or advisory role for AbbVie, Amgen, ARIAD, Celgene, Jazz Pharmaceuticals, Novartis, MorphoSys and Pfizer; research funding from Amgen; patents, royalties or other intellectual property from a patent on immunotherapy in acute myeloid leukemia (AML) obtained together with Amgen; and travel support from Amgen, Daiichi Sankyo, Jazz Pharmaceuticals and Servier. DCG: advisory boards and travel expenses for conferences: Novartis, BMS, Astellas, Pfizer, Jannsen. MI: ESMO Research Fellowship sponsored by Roche; honoraria for serving as a speaker bureau for MSD. HB: employment with Glycotope GmbH. IAF: employment with Glycotope GmbH. RF: bureau, research collaboration and research support—AstraZeneca, GSK, MSD, Clovis, Roche. LD: consultant/advisor: AstraZeneca, GSK, MSD, Pharmamar, Clovis, Merck Serono, Novartis, Amgen, Eisai; promotional speaker: GSK, Clovis, AstraZeneca, Genmab, MSD; investigator/researcher: GSK, Clovis, MSD, AstraZeneca, Immonogen, Genmab, Corcept, Roche, Eisai; support for travel: AstraZeneca, GSK, Roche. KU: advisory boards, speaker bureau, trial support, research collaboration and research support; Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Glycotope, Innate, Lilly, Medimmune, Merck Serono, MSD/Merck, Novartis, Pfizer, Roche/Genentech, Sirtex. KK: advisory board participation, invited speaker or conference honoraria from: Merck, Sanofi, MSD, Glycotope, Roche, Novartis and BMS. BH: employment and shares with Glycotope GmbH. ZA: employment with Glycotope GmbH. GE: research: Novartis/Roche/Thermo Fisher/AstraZeneca/Taiho/BeiGene; consultant/advisor: Roche/Genentech–F.Hoffmann/La Roche–Ellipses Pharma–Neomed Therapeutics 1 Inc.–Boehringer Ingelheim–Janssen Global Services–SeaGen–TFS–Alkermes–Thermo Fisher–BMS–MabDiscovery–Anaveon; speakers bureau: MSD/Roche/Thermo Fisher/Lilly; clinical trials PI or Co-PI (Institution): Affimed GmbH–Amgen SA–Anaveon AG–AstraZeneca AB–BioNTech GmbH–CatalYm GmbH–Cytomx–F. Hoffmann La Roche Ltd–F-Star Beta Limited–Genentech Inc.–Genmab B.V.–Hutchison Medipharma Limited–Icon–Imcheck Therapeutics–Immunocore Ltd–Janssen-Cilag SA–Medimmune LLC–Merck KGaA–Novartis Farmacéutica, S.A.–Peptomyc–Ribon Therapeutics–Roche Farma SA–Seattle Genetics Inc.–Symphogen A/S–Taiho Pharma USA Inc. All other authors have declared no conflicts of interest.
Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.
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References
- Hollingsworth M.A., Swanson B.J. Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 2004;4(1):45–60.
- Nath S., Mukherjee P. MUC1: a multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med. 2014;20(6):332–342.
- Bozkaya G., Korhan P., Cokaklı M., et al. Cooperative interaction of MUC1 with the HGF/c-Met pathway during hepatocarcinogenesis. Mol Cancer. 2012;11:64.
- Singh P.K., Hollingsworth M.A. Cell surface-associated mucins in signal transduction. Trends Cell Biol. 2006;16:467–476.
- Dharmaraj N., Engel B.J., Carson D.D. Activated EGFR stimulates MUC1 expression in human uterine and pancreatic cancer cell lines. J Cell Biochem. 2013;114:2314–2322.
- Bitler B.G., Goverdhan A., Schroeder J.A. MUC1 regulates nuclear localization and function of the epidermal growth factor receptor. J Cell Sci. 2010;123:1716–1723.
- Engel B.J., Bowser J.L., Broaddus R.R., Carson D.D. MUC1 stimulates EGFR expression and function in endometrial cancer. Oncotarget. 2016;7:32796–32809.
- de Boer H.R., Pool M., Joosten E., et al. Quantitative proteomics analysis identifies MUC1 as an effect sensor of EGFR inhibition. Oncogene. 2019;38(9):1477–1488.
- Danielczyk A., Stahn R., Faulstich D., et al. PankoMab: a potent new generation anti-tumour MUC1 antibody. Cancer Immunol Immunother. 2006;55:1337–1347.
- Fiedler W., DeDosso S., Cresta S., et al. A phase I study of PankoMab-GEX, a humanised glyco-optimised monoclonal antibody to a novel tumour-specific MUC1 glycopeptide epitope in patients with advanced carcinomas. Eur J Cancer. 2016;63:55–63.
- Fiedler W., Cresta S., Schulze-Bergkamen H., et al. Phase I study of tomuzotuximab, a glycoengineered therapeutic antibody against the epidermal growth factor receptor, in patients with advanced carcinomas. ESMO Open. 2018;3(2)
- Shields R.L., Lai J., Keck R., et al. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J Biol Chem. 2002;277(30):26733–26740.
- Kellner C., Otte A., Cappuzzello E., Klausz K., Peipp M. Modulating cytotoxic effector functions by Fc engineering to improve cancer therapy. Transfus Med Hemother. 2017;44(5):327–336.
- Mauri G., Pizzutilo E.G., Amatu A., et al. Retreatment with anti-EGFR monoclonal antibodies in metastatic colorectal cancer: Systematic review of different strategies. Cancer Treat Rev. 2019;73:41–53.
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