Anti–PD-L1 Combination vs Sunitinib in Metastatic Renal Cell Carcinoma

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In a meta-analysis reported in a research letter in JAMA Network Open, Maiorano et al found that first-line anti–PD-L1 treatment combinations did not significantly improve overall survival vs sunitinib in patients with metastatic renal cell carcinoma. A progression-free survival benefit was observed, but no significant benefit in objective response rate was seen. 

As stated by the investigators, “In the past 10 years, immune checkpoint inhibitors have been used to manage metastatic renal cell carcinoma. Different combinations of immune checkpoint inhibitors and tyrosine kinase inhibitors or double immune checkpoint inhibitors have been approved by regulatory agencies for first-line treatment of metastatic renal cell carcinoma after demonstrating prolonged survival vs sunitinib in randomized clinical trials…. [C]ombinations based on anti–PD-1 vs anti–PD-L1 agents currently dominate first-line treatments of metastatic renal cell carcinoma. We aimed to assess the association of anti–PD-L1 treatment combinations with survival and response rate among patients with metastatic renal cell carcinoma.”

Study Details

The analysis included comparisons with sunitinib (n =1,107) in three trials: atezolizumab plus bevacizumab in IMmotion150 and IMmotion151, and avelumab plus axitinib in JAVELIN Renal 101 (n = 1,100) in the anti–PD-L1 treatment combination groups.

Key Findings

Anti–PD-L1 treatment combinations were not associated with significantly improved overall survival vs sunitinib (hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.75–1.03, P = .11). However, anti–PD-L1 treatment combinations were associated with significantly improved progression-free survival vs sunitinib (HR = 0.78, 95% CI = 0.69–0.88, P < .001).

Objective response rates in the trials ranged from 43% to 51% with anti–PD-L1 treatment combinations and from 26% to 33% with sunitinib. Overall, the benefit with anti–PD-L1 treatment combinations was not statistically significant (odds ratio [OR] = 1.63, 95% CI = 0.79–3.35, P = .19).

Among 1,032 patients with PD-L1–positive disease, those receiving anti–PD-L1 treatment combinations did not have significantly improved overall survival vs sunitinib (HR = 0.84, 95% CI = 0.67–1.05, P = .12) but had improved progression-free survival (HR = 0.66, 95% CI = 0.56–0.79, P < .001) and objective response (OR = 2.28, 95% CI = 1.17–4.46, P = .02).

The investigators discussed potential mechanisms for the apparent poorer performance of anti–PD-L1 vs anti–PD-1 agents in this setting: “Because PD-1 is expressed on the T-cell membrane surface, anti–PD-1 agents are more effective than anti–PD-L1 agents in activating T cells even with lower or no PD-L1 expression, which partially explains why immune checkpoint inhibitors were active in cases with lower or absent PD-L1 expression. In contrast, PD-L1 is expressed by tumor cells; therefore, anti–PD-L1 agents dysregulate tumor cell signaling rather than simply acting on T cells. In other tumor subtypes, such as non–small cell lung cancer, evidence suggests that anti–PD-1 agents could be more effective than anti–PD-L1 agents, as anti–PD-1 agents simultaneously block PD-1 binding with both PD-L1 and PD-L2…. However, anti–PD-L1 agents did not influence the PD-1/PD-L2 interaction, which may inhibit T-cell activation. Therefore, in the setting of anti–PD-L1 agent use, the PD-1 or PD-L2 could be used by the tumor to escape the antitumor immune response.”

Brigida Anna Maiorano, MD, PhD, of the Oncology Unit, IRCCS Foundation Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, is the corresponding author for the JAMA Network Open article.

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