Use of immunotherapy with programmed cell death 1 vs programmed cell death ligand 1 in renal cell carcinoma: Lessons from CheckMate 9ER and IMmotion 151

Abstract

Immunotherapy has certainly revolutionized the treatment paradigm of cancer in general, and of renal cell carcinoma (RCC) in particular. For many years, cytokine-based therapies were the only available treatments for advanced RCC, providing weak results. However, with the progressive understanding of tumor immunology, immune checkpoint inhibitors (ICI) have come forward. Whether alone or in combination to other targeting agents, immunotherapy with programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are progressively integrating the therapeutic armatarium of advanced RCC. The PD-L1/PD-1 pathway has been shown to play an important role in tumorigenesis by participating to the immune escape mechanism. The binding of PD-1 ligand to the PD-1 receptor leads to the inactivation of the cytotoxic T cells in the tumor microenvironment. Thus, the blockage of either the receptor or its ligand should allow for an inhibition of the pathway and lead to an activation of these T cells with an anti-tumor immune response. However, with the multiplicity of immunotherapy studies across several cancer types, a performance disparity has started to show between anti–PD-1 and anti–PD-L1 regimens. This issue has been highlighted by numerous indirect comparison studies, the most recent being the meta-analysis performed by Duan et al. In these reviews, anti–PD-1 drugs exhibited superior efficacy compared with anti– PD-L1 for different solid tumors. Due the lack of headto-head comparisons between PD-1 and PD-L1, these results have often been considered of weak relevance. In advanced RCC, immunotherapy trials certainly add more evidence to the issue. In their metaanalysis, Duan et al. compared the results of the KEYNOTE-426 (comparing axitinib plus pembrolizumab, a PD-1 inhibitor, against sunitinib) and JAVELIN Renal 101 (comparing axitinib plus avelumab, a PD-L1 inhibitor, against sunitinib) trials. In summary, PD-1 based regimens appear to have superior outcomes in RCC when compared to PD-L1 inhibitors in advanced RCC. The KEYNOTE-426 trial randomized 861 patients to either a combination of axitinib and pembrolizumab versus sunitinib and reached its primary endpoints with significantly improved overall survival (OS) at 1 year (90% vs 78%), and at 2 years (74% vs 66%). Avelumab, however, failed to demonstrate similar OS superiority over sunitinib in the same clinical setting. The JAVELIN Renal 101 trial randomized 886 patients to receive either a combination of avelumab and axitinib or sutinib. At 32months, OS results were not significant between both arms (HR 0.8). Two additional trials published this year share similar results. The CheckMate 9ER trial randomized 651 patients to either a combination of cabozantinib and nivolumab (a PD1 inhibitor) or sutinib. Preliminary results presented at the European Society for Medical Oncology (ESMO) 2020 congress showed that overall survival was significantly improved at 1 year (87% vs 78%, HR 0.60). While, the IMmotion 151 phase III trial explored the association of atezolizumab (a PD-L1 inhibitor) with bevacizumab (VEGF) versus sunitinib. At a median follow up of 15months, OS data was reported not to be mature, but no significant difference was found between both groups. Several theories could explain this discrepancy. First, the blockage of the PD-1 receptor could be more efficient than the blockage of the ligand, if another ligand has the ability to activate that same receptor