Efficacy and safety of combined RANKL and PD-1 inhibitors in bone metastases: a retrospective study.

Background: RANKL inhibitors can inhibit the formation and functional activation of osteoclasts, providing osteoprotective effects. Recent findings indicate that RANKL inhibitors also exhibit immunomodulatory effects within the tumor microenvironment (TME). Both RANKL and programmed cell death protein 1 (PD-1) inhibitors modulate immune responses, raising concerns about the potential for overactivation of the immune system and increased adverse reactions when used together.We conducted a retrospective analysis to evaluate the safety and efficacy of combined RANKL and PD-1 inhibitor therapy in patients with bone metastases, and to explore its effects on immune response. Methods: This retrospective analysis included patients with bone metastases from malignant tumors who were treated with a combination of RANKL inhibitors and PD-1 inhibitors. Treatment response was evaluated using the RECIST 1.1 criteria, and toxicity was assessed using the CTCAE 5.0 criteria. Survival curves were plotted using the Kaplan-Meier method, and differences in survival between groups were compared using the Log-Rank test; Cox regression models were used to analyze prognostic risk factors; and the Kruskal-Wallis test, univariate analysis of variance, chi-square test, and Fisher's exact test were used to compare baseline characteristics among the complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) groups. Results: The combination demonstrated an acceptable safety profile, with grade ≥3 treatment-related adverse events (TRAEs) reported in 10 patients (11.4%), including one case of treatment-related immune-related encephalitis leading to death (1.1%). Among 88 patients included, the overall response rate (ORR) was 17.0%, and the disease control rate (DCR) was 53.4%. The median progression-free survival (PFS) was 5.90 months [95% confidence interval (CI): 5.13-6.67], and the median overall survival (OS) was 16.10 months (95% CI: 12.67-19.53). Conclusions: Overall, these findings indicate that the combined administration of RANKL and PD-1 inhibitors yields a manageable safety profile and preliminary signals of clinical activity in patients with bone metastases. These retrospective data are fundamentally hypothesis-generating, and rigorous prospective clinical trials remain imperative to validate the efficacy of this regimen. This study provides preliminary real-world evidence exploring the clinical feasibility of this combination therapy for advanced bone metastasis patients, though conclusions are inherently limited by its retrospective design.