OBJECTIVES

PD-1/PD-L1 inhibitors are immunotherapies widely used in the treatment of metastatic renal cell carcinoma (mRCC) and other cancers. There is a lack of understanding regarding which factors predict response to such therapies. To address this gap, a systematic review and meta-analysis was conducted.

METHODS

An electronic search was performed on Tuesday September 3^rd, 2019 to identify studies published in English from 2006 onwards, within the MEDLINE and COCHRANE databases. We included all phase II/III randomized trials that provided subgroup analyses of any baseline characteristics regarding the effect of PD-1/PD-L1 inhibitors, alone or as part of a combination therapy, with respect to overall or progression-free survival among patients with mRCC. We developed a novel quantitative approach to synthesize subgroup findings across trials. The ratio of the subgroup-specific hazard ratios (HRs) from each study were pooled using a random effects meta-analysis whereby ratios of 1.00 would indicate that the subgroup-specific HRs were equal in magnitude.

RESULTS

From an initial 662 studies, five trials were judged to be eligible for inclusion. Variables that were commonly reported in these trials included the IMDC risk score, the MSKCC risk score, PD-L1 expression, age, geographic region, sex, and the presence of bone metastases, liver metastases, lung metastases, or a sarcomatoid tumour. Meta-analyses suggested that the treatment effect of PD-1/PD-L1 inhibitors in mRCC patients was modified by age (overall survival: ratio of HR_{age > 75} vs. HR_{age < 65}=1.51; 95% CI:1.01-2.26; I²=0%), PD-L1 expression (progression-free survival: ratio of HR _{PD-L1 > 10%} vs. HR _{PD-L1 < 1%}=2.21; 95% CI:1.14-4.27; I²=2.26%), and sarcomatoid tumor presence (progression-free survival: HR_{no sarcomatoid differentiation} vs. HR_{sarcomatoid differentiation}=1.54; 95% CI:1.07-2.21; I²=0%).

CONCLUSIONS

Evidence suggests that older age, lower levels of PD-L1 expression, and no sarcomatoid tumour differentiation diminish the clinical efficacy of anti-PD-1/PD-L1 immunotherapies among mRCC patients.