Postdoctoral Research Fellow Mayo Clinic , Phoenix, Arizona Phoenix, Arizona, United States
Background: The efficacy of ICI-combination as 1L therapy across different subgroups remains unclear for patients with mRCC. Therefore, we assessed the efficacy of ICI-combination by different clinically relevant subgroups using evidence from up-to-date clinical trials.
Methods: MEDLINE and EMBASE were systematically searched to identify phase II/III randomized controlled trials (RCTs) assessing ICI-combination therapies in 1L mRCC and reporting efficacy by age ( < 65 y; >65 y), gender , PDL1 receptor status, and international mRCC database consortium (IMDC) risk categories (favorable; intermediate/poor [IP]). Main efficacy outcomes included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). A random-effects meta-analysis was conducted. A p-value of interaction < 0.1 indicated statistical significance.
Results: In a metanalysis of 6 trials with 5121 patients, ICI-combination improved OS compared to sunitinib in the overall population. ICI-combination therapy significantly improved OS compared to sunitinib in IP risk (hazard ratio: 0.67; 95% CI: 0.60-0.75) but not in the favorable risk (0.98;0.76-1.27). There was statistically significant effect modification by IMDC risk (P:0.01). Younger patients were observed to derive a significant OS benefit with ICI-combination compared to older ( < 65 years: 0.64; 0.57-0.73; >65 years: 0.84;0.69-1.01; P:0.02). Females appeared to derive greater benefit with ICI-combination therapy (females: 0.64;0.53-0.77; males: 0.77;0.69-0.86; P:0.09). No statistically significant difference in benefit was observed for PDL+ve compared to PDL-ve (PDL+ve: 0.74;0.64-0.85; PDL1-ve: 0.72;0.62-0.85; P:0.84). The results for PFS and ORR are provided in Figure. Post-hoc sensitivity analyses excluding CheckMate 274 trial showed a consistent direction of results. However, no significant effect modification was observed by age and sex.
Conclusions: Factors such as intermediate-poor risk disease, younger age ( < 65 years), and female gender may predict a higher magnitude of benefits for patients with mRCC contemplating treatment with immunotherapy combination with tyrosine kinase inhibitors.