Effects of neutralization of tumor-derived immunosuppressant GDF-15 on anti-PD-1 activity in anti-PD-(L)1 relapsed/refractory non-squamous NSCLC, urothelial, and hepatocellular cancer.
Authors: Melero Bermejo Ignacio , de Miguel Maria J. , de Velasco Guillermo , Garralda Elena , Martin-Liberal Juan , Joerger Markus , Alonso Guzman , Goebeler Maria-Elisabeth , Schuler Martin H. , König David , Reig Maria , Rodriguez-Ruiz Maria E. , Calvo Emiliano , Esteban Villarrubia Jorge , Sàbat Paula , Koster Kira-Lee , Sayehli Cyrus , Gromke Tanja , Klar Kathrin , Leo Eugen 
Published: June 2024

2513

Background: Growth and Differentiation Factor 15 (GDF-15) plays a critical role as potent, local immunosuppressant during pregnancy. Here we report for the first time data identifying GDF-15 as immunosuppressant in non-sq NSCLC, urothelial (UC) and hepatocellular (HCC) cancer and provide clinical evidence that GDF-15 blockade with visugromab can restore anti-PD1 activity in last-line, anti-PD1-(L)1 r/r patients with these tumors. Methods: A large translational research program, analyzing > 11.000 tumors in The Cancer Genome Atlas (TCGA) and paired serum/tumor samples for GDF-15 impact on the tumor microenvironment was conducted. In the GDFather ph2a first-in-human visugromab trial, subjects with advanced-stage, anti-PD1/PD-L1 relapsed/refractory (r/r) last-line solid tumors received the GDF-15 neutralizing antibody visugromab (CTL-002) at 10 mg/kg Q2W in combination with nivolumab 240 mg Q2W om three defined expansion cohorts (NSCLC:n=5 2, UC :n=34, HCC: n=16). All patients were either (1) primary refractory to or (2) relapsed on continued checkpoint inhibitor (CPI) therapy after initial response, with all patients having received minimum of 12 weeks of continuous prior anti-PD-1/-L1 exposure. Primary endpoint was ORR. Results: In in-silico TCGA analyses, an inverse correlation between GDF-15 mRNA expression and key immune-related signatures revealed potent immunosuppression of several solid tumors including non-sq NSCLC and UC by GDF-15. In addition, in newly diagnosed, early-line UC patient samples, correlation of GDF-15 serum levels with reduced density of CD8+ T cells and immune cell proliferation (CD45+ki67+) was demonstrated. In the ph2a trial, visugromab + nivolumab showed excellent overall tolerability in heavily pre-treated patients, with just 6.9% of patients experiencing CTCAE Grade ≥ 3 treatment-related adverse events across these three indications. The observed ORR as per RECIST v1.1 criteria was 13.5% (5/37, 4PR, 1CR) in non-sq NSCLC, and 0% (0/15) in sq-NSCLC, in line with the translational research data. In UC, ORR was 17.6% (6/34, 5 PR, 1CR), and in HCC 18.8% (3/16, 2PR, 1CR); with 25 pts continuing on treatment, respectively. Duration of response (DoR) is surpassing 12 months for non-sq and UC lead cohort patients (N = 27 each) already, and 10/14 responses are ongoing. Conclusions: These analyses presented identify GDF-15 as novel, potent immunosuppressant in the tumor microenvironment of non-sq NSCLC, UC and HCC and identify it as potential key cause for CPI resistance. In heavily pretreated, by strict criteria anti-PD-1/-L1 r/r, late/last-line patients with NSCLC, UC and HCC, neutralization of GDF-15 by visugromab in combination with nivolumab resulted in an ORR of 16.1% (14/87; 11 PR and 3 CR) across these indications and long durability. Clinical trial information: NCT04725474 .