Meta-analysis of perioperative immune checkpoint inhibitors in urothelial and renal cell carcinoma: Data from the latest available evidence.
Authors: Esteban Villarrubia Jorge , Torres Jiménez Javier Torres , Ruiz Vico María , Alvarez-Ballesteros Pablo , Castellano Daniel , de Velasco Guillermo 
Published: June 2024

e16617

Background: Diverse trials using immune checkpoint inhibitors (ICI) in the adjuvant setting in urothelial carcinoma (UC) or in the peri-operative setting in renal cell carcinoma (RCC) have been recently published. However, conflicting results have been noted. Methods: A meta-analysis of the randomized phase 3 trials of peri-operative treatment with anti-PD-1/PD-L1 agents or anti-PD1/antiCTL4 in combination in RCC or UC was conducted. The primary outcomes of interest were disease-free survival (DFS) and overall survival (OS). Secondary outcomes of interest were the proportion of grade 3-4 adverse events (AE) according to CTCAE 5.0. Subgroup analyses were performed according to clinically relevant characteristics. Statistical heterogeneity assumption was evaluated by the χ²-based Cochran’s Q test and quantified with the I² statistic. All statistical analyses were performed using RevMan® (version 5.4, The Cochrane Collaboration, 2020). Results: Published results of 7 phase 3 trials were included, involving 4232 RCC patients and 2220 UC patients. 3425 patients received ICI (anti-PD1: 2018 patients; anti-PD-L1 796 patients, antiPD1/anti-CTLA4 611 patients) while 3027 received no active treatment (1861 placebo, 1166 observation). ICI did not show to increase DFS (Hazard ratio (HR) 0.85 95% CI 0.72 - 1.00, p 0.05) or OS (HR 0.77 95% CI 0.49 - 1.20, p 0.25) in RCC patients. ICI showed an increase in DFS (HR 0.76 95% CI 0.65 - 0.90, p 0.002) but not in OS (HR 0.91 95% CI 0.76 - 1.09, p 0.30) in UC patients. High-grade AEs were approximately 2 times more frequent in the immunotherapy arm in RCC (OR 2.48 95% CI 1.55 - 3.96, p < 0.001) and UC (OR 1.82 95% CI 1.27 - 2.60, p 0.001) patients compared to placebo or observation. Subgroup analyses showed statistically significant differences among selected subgroups. In RCC patients, an effect favoring experimental arm in patients with sarcomatoid differentiation (HR 0.57 95% CI 0.40 - 0.82, p 0.002) and PD-L1 positive tumors (HR 0.73 95% CI 0.61 - 0.89, p 0.001) was noted. In UC patients, a statistically significant difference was noted in patient that had received neoadjuvant chemotherapy (HR 0.69 95% CI 0.52 - 0.90, p 0.006) and, interestingly, in PD-L1 negative patients (HR 0.78 95% CI 0.64 - 0.94, p 0.009). PD-L1 positivity was not associated with a significant benefit in DFS (HR 0.74 95% CI 0.51 - 1.08, p 0.12). Upper tract showed a trend for inferior outcomes with adjuvant ICI (HR 1.19 95% CI[0.86 - 1.65, p 0.29). Conclusions: The introduction of anti-PD-(L)1 +/- anti-CTLA-4 agents in the adjuvant setting of RCC and UC might benefit some patients, although no currently available biomarker is available to select them. Concerns may also arise about a potential increase in toxicity. Longer follow-up of the conducted studies and data from studies pending publication is needed to establish a potential benefit in long-term survival.