Factors Modifying the Associations of Single or Combination Programmed Cell Death 1 and Programmed Cell Death Ligand 1 Inhibitor Therapies With Survival Outcomes in Patients With Metastatic Clear Cell Renal Cell Carcinoma: A Systematic Review and Meta-analysis.

Importance: Programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors are immune checkpoint inhibitors widely used in the treatment of metastatic clear cell renal cell carcinoma (ccRCC) and other cancers. There is a lack of understanding regarding which factors are associated with therapeutic response. Objectives: To conduct a systematic literature review of trials reporting on factors associated with differential response to PD-1/PD-L1 inhibitors among patients diagnosed with metastatic ccRCC and quantitatively synthesize the magnitude to which each factor modified the response to PD-1/PD-L1 inhibitors. Data Sources: The MEDLINE and Cochrane Register of Trials databases were searched for studies published in English from 2006 onward. Searches were last run on September 3, 2019. Study Selection: This systematic review and meta-analysis assessed 662 phase 2/3 randomized clinical trials that provided subgroup analyses of any baseline characteristics regarding the treatment response to PD-1/PD-L1 inhibitors, alone or as part of a combination therapy, with respect to overall survival (OS) or progression-free survival (PFS) among patients with metastatic ccRCC. Data Extraction and Synthesis: A novel quantitative approach was used 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. Main Outcomes and Measures: Main outcomes were OS and PFS. Results: From an initial 662 reports, 7 trials were considered eligible for inclusion. Meta-analyses suggested the treatment response to PD-1/PD-L1 inhibitors in patients with metastatic ccRCC was significantly associated with age (OS: ratio of HR for age ≥75 years to HR for age <65 years, 1.51; 95% CI, 1.01-2.26), PD-L1 expression (PFS: ratio of HR for PD-L1 < 1% to HR for PD-L1 ≥ 10%, 2.21; 95% CI, 1.14-4.27; ratio of HR for PD-L1 < 1% to HR for PD-L1 ≥ 1%, 1.36; 95% CI, 1.10-1.68), Memorial Sloan Kettering Cancer Center risk score (PFS: ratio of HR for immediate risk score to HR for poor risk score, 1.62; 95% CI, 1.14-2.29; ratio of HR for favorable risk score to HR for poor risk score, 1.53; 95% CI, 1.00-2.34; ratio of HR for favorable risk score to HR for intermediate risk score, 0.96; 95% CI, 0.70-1.30), and sarcomatoid tumor presence (PFS: ratio of HR for no sarcomatoid differentiation to HR for sarcomatoid differentiation, 1.54; 95% CI, 1.07-2.21). Conclusions and Relevance: This analysis suggests that older age, low levels of PD-L1 expression, and the absence of sarcomatoid tumor differentiation are associated with a diminished response to anti-PD-1/PD-L1 immunotherapies with respect to survival outcomes among patients with metastatic ccRCC.