Dynamic Changes in Serum Immunoglobulin G Predict Clinical Response and Prognosis in Metastatic Clear-cell Renal Cell Carcinoma

Background and objective: Systemic treatments involving immunotherapy-tyrosine kinase inhibitor (IO-TKI) combinations and TKI monotherapy have significantly improved outcomes for patients with metastatic clear-cell renal cell carcinoma (mccRCC). However, there are no biomarkers for predicting the efficacy of these treatments. Our aim was to investigate the prognostic and therapeutic significance of serum immunoglobulin G (IgG) in patients with mccRCC patients receiving systemic therapy. Methods: We included 318 patients with mccRCC who received TKI or IO-TKI therapy. Patients were classified into groups according to whether they had an increase or decrease in serum IgG after systemic treatment. The association between baseline serum IgG and the objective response rate (ORR) was compared between the groups using a t test. The association of the change in serum IgG with progression-free survival (PFS) and overall survival (OS) was evaluated via Cox proportional-hazards regression, and survival curves were generated using the Kaplan-Meier method. Key findings and limitations: Baseline serum IgG was not significantly associated with ORR (p = 0.055). After 3-mo systemic therapy, 133 patients (42%) exhibited an increase in serum IgG. The group with an IgG increase had significantly poorer median PFS (5.6 vs 16.2 mo; hazard ratio [HR] 3.36, 95% confidence interval [CI] 2.58-4.36; p < 0.001) and OS (26.0 vs 52.2 mo; HR 2.26, 95% CI 1.66-3.08; p < 0.001) than the group with an IgG decrease. Multivariable analysis revealed that an increase in serum IgG after 3-mo systemic therapy was an independent risk factor for both PFS (HR 3.28, 95% CI 2.51-4.30; p < 0.001) and OS (HR 1.94, 95% CI 1.41-2.68; p < 0.001). An increase in serum IgG after 1-mo treatment (n = 160) was also significantly associated with poorer median PFS (7.9 vs 13.7 mo; HR 1.62, 95% CI 1.13-2.32; p = 0.008) and OS (32.6 vs 50.5 mo; HR 1.68, 95% CI 1.09-2.59; p = 0.017). Conclusions and clinical implications: The change in serum IgG after 3-mo systemic therapy can predict the therapeutic effect and prognosis for patients with mccRCC. This predictive value was observed as early as 1 mo after treatment initiation. Our findings highlight the potential of serum IgG as a predictive biomarker in this setting. Further validation is required in large prospective studies.