Journal of Hematology & Oncology | Long-term follow-up study of anti-GDF-15 antibody visugromab combined with nivolumab for anti-PD-1/PD-L1 resistant solid tumors

This study elucidates the role of GDF-15 as a key immunosuppressive factor, providing new experimental design insights for resistance reversal strategies in non-small cell lung cancer, urothelial carcinoma, and hepatocellular carcinoma.

 

Literature Overview

This article, titled "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," published in the Journal of Hematology & Oncology, systematically explores the long-term efficacy and safety of reactivating immune responses by blocking the GDF-15 pathway after failure of anti-PD-1/PD-L1 therapy. The article reviews extended cohort data from the GDFATHER-01 trial, focusing on the objective response rate and progression-free survival of visugromab combined with nivolumab in heavily pre-treated patients with non-small cell lung cancer, urothelial carcinoma, and hepatocellular carcinoma. It further discusses the clinical translational value of this combination therapy in overcoming immune escape mechanisms.

Background Knowledge

This study primarily addresses the clinical challenge of primary or secondary resistance in solid tumor patients following treatment with PD-1 or PD-L1 inhibitors. Currently, GDF-15 is confirmed as a key cytokine overexpressed in the tumor microenvironment; it inhibits T-cell infiltration into tumor tissues by disrupting the connection between LFA-1 and the actin cytoskeleton, thereby forming an immunosuppressive microenvironment. However, regulation targeting single resistance factors has not yet achieved consistent efficacy revitalization across various solid tumors. This study selects GDF-15 as the entry point to verify whether neutralizing this factor can relieve immunosuppression, restore T-cell cytotoxic function, and provide a theoretical basis for subsequent combination immunotherapy.

 

 

Research Methods and Core Experiments

The authors utilized long-term follow-up data from the GDFATHER-01 Phase I/II clinical trial, enrolling 77 patients with non-small cell lung cancer, urothelial carcinoma, and hepatocellular carcinoma who were resistant to PD-1/PD-L1 therapy. The experimental protocol involved administering visugromab (10 mg/kg) in combination with nivolumab (240 mg) every two weeks until disease progression or unacceptable toxicity. Key evidence included the objective response rate (ORR) assessed by RECIST v1.1 criteria, metabolic response evaluation via FDG-PET/CT, monitoring of changes in serum GDF-15 levels, and assessment of treatment-related adverse events (TRAEs). The study also compared tumor shrinkage depth and duration in patients before and after receiving the combination therapy to verify its resistance-reversal effects.

Key Conclusions and Perspectives

• In the non-small cell lung cancer cohort, the objective response rate was 18.2%, with a median duration of response (DoR) of 32.2 months, significantly superior to historical data for PD-1 monotherapy, indicating that GDF-15 blockade can effectively prolong T-cell-mediated anti-tumor responses.
• The urothelial carcinoma and hepatocellular carcinoma cohorts showed objective response rates of 18.5% and 14.3%, respectively, with 46.2% of responders achieving deeper tumor shrinkage than with initial PD-1 therapy, suggesting this strategy can overcome the suppression of some refractory tumor microenvironments.
• Among responders, the proportion achieving complete response (CR) or complete metabolic response (CMR) reached 61.5%, with a median DoR of 28.8 months, confirming the potential of GDF-15 neutralizing antibodies to induce deep and durable remissions.
• In terms of safety, the combination therapy was generally well-tolerated. Although a few grade 3 or higher adverse events were observed, no new safety signals emerged, providing a safety basis for broader application in populations resistant to immune checkpoint inhibitors.

Research Significance and Prospects

From a research perspective, this finding has profound implications for drug development, confirming the feasibility of targeting GDF-15 as a combination immunotherapy strategy, particularly in scenarios of immunotherapy resistance. For clinical monitoring, GDF-15 levels may become an important biomarker for predicting PD-1 efficacy and guiding combination therapy. Furthermore, this study provides a new direction for disease modeling, suggesting that future animal model construction should consider GDF-15 high-expression models to simulate resistant states, thereby more accurately evaluating the efficacy of novel combination therapies.

 

 

Conclusion

Through long-term follow-up data, this study powerfully demonstrates the significant potential of the anti-GDF-15 antibody visugromab combined with the PD-1 inhibitor nivolumab in overcoming immune resistance in solid tumors. For patients with non-small cell lung cancer, urothelial carcinoma, and hepatocellular carcinoma previously resistant to PD-1/PD-L1 therapy, this combination regimen not only achieved a high objective response rate but also induced deep and durable complete remissions, with some patients even achieving long-term disease-free survival. This finding not only offers new therapeutic hope for patients with clinically refractory tumors but also builds an important bridge from laboratory mechanistic research to clinical translational application. In the future, combination therapy strategies based on the GDF-15 pathway are expected to become a cornerstone in the standard care system for patients with immunotherapy resistance, driving tumor immunotherapy into a new era of precision combination.

 

Ignacio Melero, María de Miguel, Elena Garralda Cabanas, Frank Hermann, and Eugen Leo. 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. Journal of Hematology & Oncology.