Impact of safety parameters and toxicity profile on the efficacy of first-line combination therapy in patients with advanced renal cell carcinoma: a real-world study

Objective: To evaluate the impact of safety parameters and toxicity profile on the efficacy of first-line immuno-oncology (IO) — based therapy in patients with renal cell carcinoma (RCC) in real-world clinical practice. Materials and Methods: Inclusion criteria for this retrospective study were: age ≥ 18 years, histologically confirmed advanced RCC, and administration of first-line therapy with IO-based combination regimens. Exclusion criteria included contraindications to any combination therapy agents, lack of data on at least one administration of each combination agent, and absence of at least one follow-up examination after treatment initiation. All adverse events (AEs), their characteristics, and instances of treatment regimen modification due to AEs were documented, along with the best overall response to therapy, time to progression, time to death, and last follow-up. An analysis of the potential association between safety parameters and first-line therapy efficacy outcomes was performed. Results: Data from 194 patients were included, receiving either nivolumab with ipilimumab (IO — IO), 94 patients (48.5 %) or immuno-targeted therapy (IO — TKI) 100 patients (51.5 %). Median follow-up duration was 28.4 months (1–63 months). The objective response rate (ORR) in the entire population (IO — IO / TKI) was 36.6 %, disease control rate (DCR) was 79.4 %, median progression-free survival (PFS) was 20.0 months (95 % CI, 15.3–24.8), and median overall survival (OS) was 29.2 months (95 % CI, 24.4–34.0). In the IO — IO / TKI group, independent favorable prognostic factors for therapy efficacy were cutaneous AEs (risk ratio [RR] for ORR 5.9 [95 % confidence interval (CI): 3.1–38.4], p = 0.002; odds ratio [OR] for PFS 2.4 [95 % CI: 1.2–4.6], p = 0.011), endocrine AEs (RR for ORR 2.5 [95 % CI: 1.8–3.5], p = 0.021; OR for PFS 2.6 [95 % CI: 1.4–4.8], p = 0.002; OR for overall survival [OS] 2.6 [95 % CI: 1.5–4.6], p = 0.001), and gastrointestinal (GI) AEs (OR for PFS 1.8 [95 % CI: 1.1–3.2], p = 0.030). Independent unfavorable prognostic factors for OS were serious AEs (OR 24.9 [95 % CI: 4.7–130.5], p < 0.0001).Independent favorable prognostic factors in the IO — IO group were endocrine AEs (OR for PFS 2.1 [95 % CI: 1.1–4.1], p = 0.026; OR for OS 2.8 [95 % CI: 1.4–5.6], p = 0.003), while in the IO — TKI group, favorable prognostic factors included the occurrence of any AEs (OR for OS 2.9 [95 % CI: 1.1–7.5], p = 0.033), cutaneous AEs (RR for ORR 3.1 [95 % CI: 1.2–6.2], p = 0.04; OR for PFS 3.0 [95 % CI: 1.2–7.6], p = 0.021), GI AEs (OR for PFS 3.3 [95 % CI: 1.5–7.2], p = 0.002), and endocrine AEs (OR for PFS 3.3 [95 % CI: 1.6–6.7], p = 0.001). Conclusions: The development of AEs in patients with RCC is associated with improved efficacy outcomes of IO based combination therapy. The potential use of AEs as biomarkers of clinical benefit from IO-based combination therapy warrants confirmation in prospective studies.