Impact of sex on the efficacy of immune checkpoint inhibitors in kidney and urothelial cancers: a systematic review and meta-analysis

Abstract

Purpose To analyze and summarize the efficacy of immune checkpoint inhibitor (ICI) alone or in combination therapy for renal cell carcinoma (RCC) and urothelial carcinoma (UC) stratified by sex. Methods Three databases were queried in October 2022 for randomized controlled trials (RCTs) analyzing RCC and UC patients treated with ICIs. We analyzed the association between sex and the efficacy of ICIs in RCC and UC patients across several clinical settings. The outcomes of interest were overall survival (OS) and progression-free survival for the metastatic setting and disease-free survival (DFS) for the adjuvant setting. Results Overall, 16 RCTs were included for meta-analyses and network meta-analyses. In the first-line treatment of metastatic RCC (mRCC) and UC (mUC) patients, ICI-based combination therapies significantly improved OS compared to the current standard of care, regardless of sex. Adjuvant ICI monotherapy reduced the risk of disease recurrence in female patients with locally advanced RCC (pooled hazard ratio [HR]: 0.71, 95% confidence interval [CI] 0.55–0.93) but not in male patients, and, conversely, in male patients with muscle-invasive UC (pooled HR: 0.80, 95%CI 0.68–0.94) but not in female patients. Treatment ranking analyses in the first-line treatment of mRCC and mUC showed different results between sexes. Of note, regarding adjuvant treatment for RCC, pembrolizumab (99%) had the highest likelihood of improved DFS in males, whereas atezolizumab (84%) in females. Conclusions OS benefit of first-line ICI-based combination therapy was seen in mRCC and mUC patients regardless of sex. Sex-based recommendations for ICI-based regimens according to the clinical setting may help guide clinical decision-making.

Sex differences in cancer and immunotherapy outcomes: the role of androgen receptor

“…There are no sex differences in the superior OS benefits from first-line ICI-based combination therapies in metastatic renal cell carcinoma (RCC) or metastatic urothelial carcinoma (UC) ( 133 ). In locally advanced RCC, however, adjuvant I/O monotherapy reduces recurrence risk in female patients (HR=0.71, 95% CI 0.55–0.93) but not in male patients ( 133 ). On the other hand, males with muscle-invasive bladder cancer have better DFS on adjuvant I/O compared to females ( 133 ).…”

“…In locally advanced RCC, however, adjuvant I/O monotherapy reduces recurrence risk in female patients (HR=0.71, 95% CI 0.55–0.93) but not in male patients ( 133 ). On the other hand, males with muscle-invasive bladder cancer have better DFS on adjuvant I/O compared to females ( 133 ). A meta-analysis on HCC shows single-agent I/O exhibits less OS benefit in females than males.…”

Sex and survival outcomes in patients with renal cell carcinoma receiving first-line immune-based combinations

“…A retrospective analysis performed in patients with metastatic RCC (mRCC) revealed no difference between nivolumab and everolimus among the two sexes, although the small sample size limits clear conclusions [ 14 ]. The CheckMate-214 trial on nivolumab plus ipilimumab versus sunitinib in the first-line treatment of intermediate/poor-risk mRCC patients showed a wider OS advantage from ICI-combination among females (HR, 0.52; 95% CI, 0.34–0.78) compared to males (HR, 0.71; 95% CI, 0.55–0.92) [ 2 ], while inconsistent conclusions derived in mRCC population from a following meta-analysis [ 15 ].…”