New First Line Treatment Options of Clear Cell Renal Cell Cancer Patients with PD-1 or PD-L1 Immune-Checkpoint Inhibitor-Based Combination Therapies

Abstract

In metastatic renal cell carcinoma (mRCC) the PD-1 immune-checkpoint inhibitor (ICI) Nivolumab became a standard second line treatment option in 2015 based on a significant improvement of overall survival compared to Everolimus. Current pivotal phase 3 studies showed that PD-1 ICI-based combinations were more efficacious than the VEGFR-TKI Sunitinib, a previous standard of care, leading to approval of three new regimens as guideline-recommended first-line treatment. Nivolumab plus Ipilimumab is characterized by a survival advantage, a high rate of complete response and durable remissions in intermediate and poor prognosis patients. Despite frequent immune-mediated side effects, fewer symptoms and a better quality of life were observed compared to Sunitinib. Pembrolizumab or Avelumab plus Axitinib were characterized by an improved progression-free-survival and a high response rate with a low rate of intrinsic resistance. In addition, Pembrolizumab plus Axitinib reached a significant survival benefit. The side effect profile is driven by the chronic toxicity of Axitinib, but there is additional risk of immune-mediated side effects of the PD-1/PD-L1 ICIs. The quality of life data published so far do not suggest any improvement regarding patient-reported outcomes compared to the previous standard Sunitinib. The PD-1/PD-L1 ICIs thus form the backbone of the first-line therapy of mRCC.

Outcomes based on age in patients with metastatic renal cell carcinoma treated with first line targeted therapy or checkpoint immunotherapy: Older patients more prone to toxicity

“…On investigating the effect of nivolumab and ipilimumab in patients with mRCC, neither discontinuation due to immune-related AEs nor the overall incidences of AEs negatively affected OS [31]. In fact, because a positive trend between AEs and OS was seen, these early AEs might reflect an immune activation, suggesting a potentially positive prognostic value of AEs to long-term survival with CPI [31,32]. To this point, recommendations concerning therapeutic intervention and management for older patients with mRCC resemble the one for younger.…”

A narrative review of individualized treatments of genitourinary tumors: is the future brighter with molecular evaluations?

“…The second is associated with a high frequency of TP53 alterations that leads to likely resistance to TKIs and favors the use of chemotherapy or immunotherapy in metastatic sarcomatoid cases (38). Immunotherapy with ICPI represents a major advance in the therapy of metastatic RCC with both clear-cell and non-clear-cell histology (39). The assessment of PD-L1 in RCC to predict response to ICPI is currently discouraged due to several limitations including the different antibodies and the different scoring systems (40).…”

Ubiquitin Modification Patterns of Clear Cell Renal Cell Carcinoma and the Ubiquitin Score to Aid Immunotherapy and Targeted Therapy

“…Renal cancer is a malignancy with a moderate mutation burden, but it dramatically responds to immune checkpoint blockade (ICB) therapy ( Braun et al, 2020 ). Results from several clinical trials have shown that anti-PD-1/CTLA-4 combination therapy has a superior clinical effect over VEGFR-targeted therapy, marking a new era of immunotherapy for renal cell carcinoma ( Grimm et al, 2020 ). Although there were abundant infiltrating T cells in clear cell renal cell carcinoma (ccRCC), the anti-tumor response was suppressed by Tregs and myeloid cells, resulting in inadequate durable benefit from ICB ( Díaz-Montero et al, 2020 ).…”