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Growth Differentiation Factor 15 (GDF-15) has been identified as a key resistance factor for anti\u2013PD-1\/PD-L1 immunotherapy. Visugromab, a neutralizing anti\u2013GDF-15 antibody, plus the anti\u2013PD-1 antibody nivolumab (V+N) was evaluated in the first-in-human phase 1\/2a GDFATHER-01 trial in heavily pretreated participants with locally advanced\/metastatic non-squamous non-small-cell lung cancer (nsq NSCLC), urothelial carcinoma (UC), or hepatocellular carcinoma (HCC), stringently defined as anti\u2013PD-1\/PD-L1-relapsed\/refractory, and showed encouraging objective responses. This analysis reports long-term follow-up of these three phase 2 expansion cohorts of the GDFATHER-01 trial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Seventy-seven participants with nsq NSCLC (N=22), UC (N=27), and HCC (N=28) received visugromab (10 mg\/kg) plus nivolumab (240 mg) every two weeks until disease progression or unacceptable toxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Objective response rates (RECIST v1.1) were 18.2% for nsq NSCLC (4\/22; 95%CI 5.2\u201340.3), 18.5% for UC (5\/27; 95%CI 6.3\u201338.1), and 14.3% for HCC (4\/28; 95%CI 4.0\u201332.7). Median duration of response (DoR) was 32.2 months (95%CI 5.5\u201338.0), 28.8 months (95%CI 7.4\u201339.4), and 19.4 months (95%CI 5.8\u201339.7; with protracted recruitment), respectively, with 7\/13 responses (53.8%) ongoing. Confirmed complete response or complete metabolic response (CR or CMR) among responders was 61.5% (8\/13), with 7\/8 ongoing. In addition, 46.2% (6\/13) of responders achieved a deeper response on V+N per RECIST v1.1 than with the prior anti\u2013PD-(L)1 therapy; median DoR on V+N was 28.8 months (95%CI 7.4\u201338.0) versus 12.0 months (95%CI 8.0\u201324.0) on initial anti\u2013PD-1\/PD-L1 treatment. V+N was generally well tolerated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In heavily pretreated, advanced\/metastatic participants with nsq NSCLC, UC, or HCC who were anti\u2013PD-1\/PD-L1-relapsed\/refractory, V+N achieved deep and durable objective responses. The observed DoR, depth of response, and CR+CMR rate among responders exceeded those reported for their initial anti\u2013PD-1\/PD-L1 therapy. These findings suggest that GDF-15 blockade with visugromab can overcome resistance and enhance the magnitude and durability of anti\u2013PD-1\/PD-L1 responses, and warrant further exploration in randomized trials.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Registry<\/jats:title>\n                    <jats:p>ClinicalTrials.gov, TRN: NCT04725474, Registration date: 25 January 2021; EudraCT, TRN: 2020-002103-19, Registration date 16 Dec 2020<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13045-026-01818-2","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T04:16:01Z","timestamp":1783570561000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Long-term follow-up of a phase 1\/2 trial of anti-GDF-15 antibody visugromab plus anti-PD-1 antibody nivolumab in anti-PD-1\/-L1 relapsed\/refractory solid 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All participants provided written informed consent.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"J.H. is a co-founder of the biotech company CatalYm GmbH, owner of GDF-15 related patents and stock owner of Catalym GmbH. C.S.W., J.A., F.L., A.A., M.F., K.K., P.F., M.L., A.A., S.S., F.H. and E.L. are current or former employees of CatalYm GmbH and\/or hold stock options of Catalym GmbH. J.W., I.M. and H.H. have received research funding or consulting and\/or advisory fees from Catalym GmbH. Several coauthors declare potentially competing interests (grants or contracts and\/or royalties or licenses, stock or stock options, consulting fees, honoraria, travel or meeting support, or advisory or data safety monitoring board participation) apart from their relationship with CatalYm GmbH: I.M. (research grants from Roche, Bristol-Myers Squibb, Genmab and AstraZeneca; honoraria from Genmab, Mestag, Flagship, Bright Peak, Curon, Pharmamar, AstraZeneca, Bioinvent, Warewolf, Qbiotics, AstraZeneca and Johnson & Johnson); E.G.C. (grants from Novartis, Roche, ThermoFisher, AstraZeneca, Taiho, BeiGene, Janssen, Anaveon; honoraria from Roche, Ellipses Pharma, Boehringer Ingelheim, Janssen Global Services, Seattle Genetics, SeaGen, Skypta, Sotio, Sanofi, Anaveon, Abbvie, Astex Therapeutics, Alentis Therapeutics, Marengo Therapeutics, Incyte, Lilly, Medpace, Pfizer, Amgen, GenMab, Genentech, GreyWolf, Gilead, Daiichi Sankyo, Takeda Pharmaceuticals, Pyramid Biosciences; stock options from 1TrialSP); G.d.V. (Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen Merck Sharp & Dohme, Merck Serono, Pfizer and Roche); M.J. (grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Immunophotonics, Innomedica, Lilly, Merck Sharp & Dohme, Novartis, Intensity Therapeutics, Roche, Sanofi, Takeda, Incyte, Debiopharm, Anaveon; honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Johnson & Johnson, Merck Sharp & Dohme, Roche, Sanofi); J.M.L. (grants and research contracts from Astellas, BMS, Highlight Therapeutics, Ipsen, Merck Serono, Merck Sharp & Dohme, Novartis, Roche, Pfizer, PharmaMar, Pierre Fabre, Regeneron, Sanofi and Trialing Health); M.R. (institutional research grants from Bayer and Ipsen; consultancy\/advisory roles for AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, Geneos, Ipsen, Merck, Roche, Universal DX, Boston Scientific, Engitix Therapeutics, Parabilis Medicines Inc, Boehringer Ingelheim); D.K. (grant from Geistlich-Stucki-Stiftung; honoraria\/fees from Amgen, AstraZeneca, Amgen, Bristol-Myers Squibb, Iaculis, Johnson & Johnson, Merck Serono, Merck Sharp & Dohme, Mirati, Novartis, PharmaMar, Roche and Sanofi); J.T. (AstraZeneca, Bristol Myers Squibb, Institut fur Qualitatssicherung und Transparenz im Gesundheitswesen, Merck Serono, Merck Sharp & Dome, Oncolytics Biotech, onkowissen.de, Roche); M.S. (grants from Bristol-Myers Squibb and Johnson & Johnson; honoraria\/consultancy from\/for Amgen, AstraZeneca, Bristol Myers Squibb, Gilead, GlaxoSmithKline, Johnson & Johnson, Lilly, Merck Sharp & Dohme, Novartis, Regeneron, Roche, Sanofi); R.D. (consultancy\/advisory roles for Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and Iovance, Oncobit. Derma2go); M.R.R. (AstraZeneca, Bristol-Myers Squibb, Roche); R.Y. (honoraria\/fees from Merck, Boehringer Ingelheim, Kura Oncology, BioNTech); G.P. (Roche and Pierre Fabre); J.E.V. (research funding and honoraria from Astellas Pharma); M.S.Z. (AstraZeneca, BTG, Captor, Bayer, Eisai-MSD, Roche); C.K. (honoraria\/fees from Ipsen, Astra Zeneca, StreamedUp, NeoConnect, Merck, Sharp & Dohme, Servier, Bristol-Myers Squibb, Incyte, Takeda, Amgen, BeiGene, Roche, Jazz Pharma, GI-OnkoNET Rhein Main, DGVS, Leo Pharma); C.S. (Bristol-Myers Squibb, Boehringer Ingelheim, Ipsen); E.R. (BMS, Eli Lilly, Kyowa Kirin, Leo Pharma, Merck Sharp & Dohme, Pierre Fabre and Sanofi); P.G. (Bayer, AstraZeneca, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche); A.N. (AstraZeneca, Merck Sharp & Dohme, Incyte, Bristol-Myers Squibb, Gilead Science, Seattle Genetics, Astellas, Geneta Science, Janssen, PeerView, PeerVoice, Merck Serono, Samsung Bioepis, Bicycle Therapeutics); M.R. (honoraria\/fees from Accord, Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Merck Serono, Merck Sharp & Dohme, Mirati, Novartis, Pfizer, Regeneron, Roche, Sanofi, Daiichi-Sankyo, Janssen); M.F. (Stock options from Thermo Fisher Scientific); P.F. (Stock options from Amgen and BionTech); C.S.W. (Stock options from Merck Sharp & Dohme and RNhale). M.d.M., M.E.G., G.A., K.L.K., P.S.V., H.L., T.G., Z.T., H.H., F.G., J.B. and T.S. disclosed no other relationships or conflicts of interest.","order":2,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"64"}}