Safety and toxicity of first-line combination therapy in patients with advanced renal cell carcinoma: A real-world retrospective study

Background. Preference regimens in line 1 therapy for advanced renal cell carcinoma (RCC) are combinations based on immuno-oncology (IO) drugs. The efficacy and safety of combination therapy have been demonstrated in large, randomized phase III clinical trials involving patients with satisfactory performance status and without severe organ dysfunction or comorbidities that could potentially impact treatment outcomes. The characteristics of patients receiving combination immunotherapy (IO-IO) or immunotargeted therapy with tyrosine kinase inhibitors (IO-TKIs) in real-world practice generally differ significantly from the profile of patients who meet the inclusion criteria for registration randomized clinical trials. The lack of comparative studies on IO-IO and IO-TKIs does not allow for a reasonable choice between these regimes in real-world practice, including from a safety perspective.

Aim. Comparative assessment of safety and toxicity of first-line combination therapy in patients with advanced RCC treated with IO-IO or IO-TKIs in real-world practice.

Materials and methods. A retrospective study conducted at the Moscow City Clinical Hospital named after S.S. Yudin from 07.07.2019 to 22.10.2024 included 194 patients ≥18 years old with verified advanced RCC who received first-line therapy with IO-IO [nivolumab with ipilimumab, 94 (48.5%) patients] or IO-TKIs [100 (51.5%) patients: pembrolizumab plus axitinib – 85 (43.7%), pembrolizumab plus lenvatinib – 10 (5.2%), nivolumab plus cabozantinib – 5 (2.6%)]. The median follow-up duration was 28.4 (1-63) months. In all patients during therapy, adverse events (AEs), dose reductions, interruptions in therapy, and discontinuations of therapy due to AEs were recorded.

Results. No new safety signals emerged at a median duration of line 1 therapy of 11.1 (1.0-55.9) months. The incidence of any AE was 88.1%, including severe AEs in 42.3% of patients. The most common grade ≥3 AEs were hypertension (HTN) at 10.8%, transaminase increased at 10.8%, diarrhea at 7.2%, and creatinine increased at 5.2%. Risk factors for severe toxicity are baseline hypertension (p=0.001) and the neutrophil-to-lymphocyte ratio (NLR) ≥3 (p=0.012). IO-TKIs compared to IO-IO were associated with a higher incidence of severe AEs (p=0.008), as well as skin and mucosal AEs (p=0.042), gastrointestinal AEs (p=0.015), and hypertension (p<0.0001), but a lower incidence of nephrotoxicity (p=0.045).

Conclusion. In real-world practice, in patients with advanced RCC treated with IO-IO and IO-TKIs as first-line therapy, the safety and toxicity of treatment regimens were comparable to the results of registration studies. IO-TKIs were associated with a higher incidence of severe AEs and certain types of AEs (skin, gastrointestinal, hypertension), but a lower incidence of nephrotoxicity compared to IO-IO.