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Background <p>Resistance to anti–PD-1/PD-L1 therapy is a major unmet need. Growth Differentiation Factor 15 (GDF-15) has been identified as a key resistance factor for anti–PD-1/PD-L1 immunotherapy. Visugromab, a neutralizing anti–GDF-15 antibody, plus the anti–PD-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–PD-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.</p> Methods <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.</p> Results <p>Objective response rates (RECIST v1.1) were 18.2% for nsq NSCLC (4/22; 95%CI 5.2–40.3), 18.5% for UC (5/27; 95%CI 6.3–38.1), and 14.3% for HCC (4/28; 95%CI 4.0–32.7). Median duration of response (DoR) was 32.2 months (95%CI 5.5–38.0), 28.8 months (95%CI 7.4–39.4), and 19.4 months (95%CI 5.8–39.7; 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–PD-(L)1 therapy; median DoR on V+N was 28.8 months (95%CI 7.4–38.0) versus 12.0 months (95%CI 8.0–24.0) on initial anti–PD-1/PD-L1 treatment. V+N was generally well tolerated.</p> Conclusions <p>In heavily pretreated, advanced/metastatic participants with nsq NSCLC, UC, or HCC who were anti–PD-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–PD-1/PD-L1 therapy. These findings suggest that GDF-15 blockade with visugromab can overcome resistance and enhance the magnitude and durability of anti–PD-1/PD-L1 responses, and warrant further exploration in randomized trials.</p> Registry <p>ClinicalTrials.gov, TRN: NCT04725474, Registration date: 25 January 2021; EudraCT, TRN: 2020-002103-19, Registration date 16 Dec 2020</p>

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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 tumors

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  • 发表日期：

    2026年7月9日

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  • Ignacio Melero,
  • María de Miguel,
  • Elena Garralda Cabanas,
  • Guillermo de Velasco,
  • Markus Joerger,
  • Juan Martín-Liberal,
  • Maria Reig,
  • David König,
  • Joerg Trojan,
  • Maria-Elisabeth Goebeler,
  • Martin Schuler,
  • Guzman Alonso,
  • Reinhard Dummer,
  • Maria E. Rodríguez-Ruiz,
  • Ramón Yarza,
  • Giulia Pretelli,
  • Jorge Esteban-Villarubia,
  • Kira-Lee Koster,
  • Paula Sabat Viltro,
  • Marco Sanduzzi-Zamparelli,
  • Heinz Läubli,
  • Christine Koch,
  • Cyrus Sayehli,
  • Tanja Gromke,
  • Fabricio Racca,
  • Egle Ramelyte,
  • Peter R. Galle,
  • Andrea Necchi,
  • Martin Reck,
  • Zlatko Trajanoski,
  • Hubert Hackl,
  • Falk Gogolla,
  • Jaclyn Billing,
  • Teresa Sattmann,
  • Jörg Wischhusen,
  • Christine Schuberth-Wagner,
  • Julia Akdemir,
  • Felix S. Lichtenegger,
  • Alexandra Auckenthaler,
  • Marlene Fox,
  • Kathrin Klar,
  • Petra Fettes,
  • Mara Liebig,
  • Aasim Amin,
  • Sheena Sachdeva,
  • Frank Hermann,
  • Eugen Leo

摘要

Background

Resistance to anti–PD-1/PD-L1 therapy is a major unmet need. Growth Differentiation Factor 15 (GDF-15) has been identified as a key resistance factor for anti–PD-1/PD-L1 immunotherapy. Visugromab, a neutralizing anti–GDF-15 antibody, plus the anti–PD-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–PD-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.

Methods

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.

Results

Objective response rates (RECIST v1.1) were 18.2% for nsq NSCLC (4/22; 95%CI 5.2–40.3), 18.5% for UC (5/27; 95%CI 6.3–38.1), and 14.3% for HCC (4/28; 95%CI 4.0–32.7). Median duration of response (DoR) was 32.2 months (95%CI 5.5–38.0), 28.8 months (95%CI 7.4–39.4), and 19.4 months (95%CI 5.8–39.7; 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–PD-(L)1 therapy; median DoR on V+N was 28.8 months (95%CI 7.4–38.0) versus 12.0 months (95%CI 8.0–24.0) on initial anti–PD-1/PD-L1 treatment. V+N was generally well tolerated.

Conclusions

In heavily pretreated, advanced/metastatic participants with nsq NSCLC, UC, or HCC who were anti–PD-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–PD-1/PD-L1 therapy. These findings suggest that GDF-15 blockade with visugromab can overcome resistance and enhance the magnitude and durability of anti–PD-1/PD-L1 responses, and warrant further exploration in randomized trials.

Registry

ClinicalTrials.gov, TRN: NCT04725474, Registration date: 25 January 2021; EudraCT, TRN: 2020-002103-19, Registration date 16 Dec 2020