Study results may help target anti–PD-1/PD-L1 agents to appropriate RCC patients

The study assessed factors associated with survival outcomes in patients with metastatic clear cell renal cell carcinoma receiving immune checkpoint inhibitors.

A recently published article in JAMA Network Open identified baseline factors associated with diminished response and subsequent lower overall survival (OS) and progression-free survival (PFS) with anti–PD-1/PD-L1 immunotherapies in patients with metastatic clear cell renal cell carcinoma (ccRCC).1

Specifically, the systematic review and meta-analysis found that among patients receiving anti–PD-1/PD-L1 immune checkpoint inhibitors (ICIs) for metastatic ccRCC, OS and PFS were lower in those who were older, had low PD-L1 expression, had a favorable or intermediate MSKCC risk score, and whose disease histology included the absence of sarcomatoid tumor differentiation.

“These findings can be supported by biological evidence related to age-related immunologic changes and tumor evasion of host immunity. Results from this investigation may help to target the delivery of ICIs among patients with metastatic ccRCC,” the authors wrote.

Overall, this systematic review and meta-analysis of the literature involved a search of the MEDLINE and Cochrane Register of Trials databases for studies involving patients with metastatic ccRCC that examined factors linked to varying response to PD-1/PD-L1 inhibitors. The period of time searched was 2006 to September 2019. Eventually, 7 trials were selected for inclusion in the study.

To determine subgroup survival differences, the researchers compared the ratio of subgroup-specific hazard ratios (HRs). The ratio of HR for OS for men aged ≥75 years to men aged <65 years was 1.51. Regarding PD-L1 expression, the ratios of HR for PFS were 2.21 and 1.36, respectively, for PD-L1 <1% to PD-L1 ≥10% and PD-L1 <1% to PD-L1 ≥ 1%.

The ratio of HR for PFS for patients with no sarcomatoid differentiation to patients with sarcomatoid differentiation was 1.54. Regarding MSKCC risk score, the ratios of HR for PFS were 1.62 and 1.53, respectively, for immediate risk to poor risk and favorable risk to poor risk. Further, the HR for PFS was 0.96 for favorable risk to intermediate risk.

Although the investigators suggested their findings may help identify characteristics of optimal ccRCC patients for ICIs, they noted that ICIs may still be a useful tool in the subgroups associated with diminished response. “It is important to recognize that such subgroups may still benefit from PD-1/PD-L1 inhibitors. Although the efficacy of these immunotherapies may be diminished, such therapies may still be more efficacious than the prior standard therapies within these subgroups,” the authors wrote.

Several ICIs are currently approved by the FDA for the treatment of patients with RCC. For example, the PD-1 inhibitor nivolumab (Opdivo) is approved as a single agent for second-line RCC and in combination regimens for frontline RCC. The PD-L1 inhibitor avelumab (Bavencio), and the PD-1 inhibitor pembrolizumab (Keytruda) are both approved for use in combination with axitinib (Inlyta) for frontline RCC.


1. Sati N; Boyne DJ; Cheung WY, et al. 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:systematic review and meta-analysis. JAMA Netw Open. 2021;4(1):e2034201. doi: 10.1001/jamanetworkopen.2020.34201

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