Document resource
Background Growth and Differentiation Factor 15 (GDF-15) has emerged as resistance factor to immune checkpoint inhibition (ICI). 1 The GDFATHER-01 trial (NCT04725474) investigates visugromab (V; anti-GDF-15) in combination with nivolumab (N; anti-PD-1) in heavily pretreated, by strict criteria anti-PD1/PD L1-relapsed/refractory (r/r) patients (pts) with locally advanced/metastatic non-squamous (nsq) NSCLC, UC and HCC, and reported notable response rates previously.2 This long-term follow-up analysis now reveals an unparalleled depth and durability of response by V+N, with a substantial number of late onset complete (CR) and complete metabolic responses (CMR).Methods V (10mg/kg) combined with N (240mg) was administered Q2W in ph1 and disease-specific ph2a expansion cohorts to a total of 77 pts with advanced/metastatic, by strict criteria anti-PD1/PD-L1 r/r nsq NSCLC (22), UC (27) and HCC (28).Results The Objective Response Rate (ORR) for V+N treatment was 18.2%, 18.5% and 14.3% in nsq-NSCLC, UC and HCC, respectively (data cut-off 30Apr2025). 61.5% (8/13) of responders achieved a confirmed CR (5/13) or CMR (3/13; as assessed by PET-CT) ( figure 1). 8/13 (61.5%) experienced a deeper response level as compared with their initial, approved 1st or 2nd line ICI treatment regimen. The median duration of response (DoR) surpassed 28.4 and 26.3 mo.for nsq NSCLC and UC, and 15.6 mo. for HCC (protracted enrolment), respectively. 69.2% of responses (including all CR+CMR) are still ongoing and 46.2% continue with treatment. The safety profile of V+N was favorable, treatment-related adverse events ≥ Grade 3 were reported in 10/77 (13.0%) pts, only.Conclusions In 77 heavily pre-treated, by strict criteria anti-PD-1/-L1 relapsed/refractory nsq NSCLC, UC and HCC pts, V+N treatment induced very durable and deep long-term response, with 8/13 (61.5%) of responders achieving confirmed CR or CMR. GDF-15 neutralization by V may overcome ICI resistance and enable long-term immunologic tumor control in metastatic nsq NSCLC, UC and HCC.Acknowledgements The authors wish to thank all participating patients and their relatives.Trial Registration NCT04725474References Haake M, Haack B, Schäfer T. Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment. Nat Commun. 2023 Jul 20;14(1):4253.Melero I, de Miguel Luken M, de Velasco G. Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours. Nature 2025 Jan;637(8048):1218–1227.Ethics Approval The study was conducted following the Declaration of Helsinki and according to the Good Clinical Practice ICH guidelines in the timely applicable version. Besides approval of the competent authorities of the enroling countries Germany, Switzerland and Spain, ethics committee approvals have been granted by the lead ethic committee for Germany (Essen) as well as Swissethics for Switzerland (Zurich) and the ethics committee in Pamplona for Spain. The approval letters are on file and are available for review by the Editor of this journal.Consent Written informed consent was obtained from the participants for publication of this abstract and any accompanying images. A blinded copy of the written informed consent is available for review by the Editor of this journal.Abstract 519 Figure 1Waterfall plot: BoR in nsqNSCLC, UC and HCC. BoR as per RECIST 1.1 in 77 advanced/metastatic nsq-NSCLC, UC and HCC patients that had exhausted available treatment options including an approved anti-PD1/PD-L1 treatment and received the experimental anti-GDF-15 antibody visugromab and nivolumab