Page 67 - Read Online

Page 2 of 19 Serzan et al. J Cancer Metastasis Treat 2021;7:39 https://dx.doi.org/10.20517/2394-4722.2021.76

INTRODUCTION
Kidney cancer is increasing in incidence worldwide with 403,000 new cases and 175,000 deaths annually
[1]
based on the most recent GLOBOCAN statistics from 2018 . Renal cell carcinoma (RCC) is the most
common form of kidney cancer, and is further classified by histologic subtypes with clear cell (cc) RCC
[2]
being the most common (75%) followed by papillary (10%) and chromophobe (5%) . Localized RCC is
typically managed with partial or radical nephrectomy associated with 5-year survival rates ranging from
70% to 90% depending on stage; however, up to 20% of such patients experience metastatic recurrence .
[3]
Approximately 20% of patients are diagnosed with metastatic disease at initial presentation. Metastatic clear
cell renal cell carcinoma (ccRCC) historically carried a 5-year survival rate of 13% . Advances in
[4]
understanding the pathophysiology of RCC have elucidated the roles for targeted therapy against vascular
endothelial growth factor receptors (VEGFR) with multi-kinase inhibitors, immune checkpoint inhibitors
(ICI), and combination anti-VEGF and ICI regimens that have markedly improved outcomes.

ccRCC is near ubiquitously characterized by loss of heterozygosity of the von Hippel Lindau (VHL) gene
[5-7]
(90%) on chromosome 3p8 due to VHL gene mutation (82%) or epigenetic hypermethylation (8%) .
Functional inactivation of the VHL tumor suppressor gene leads to accumulation of the transcription factor
Hypoxia Inducible Factor-2α in the absence of hypoxia. This accumulation serves as an oncoprotein driving
[8,9]
several downstream pathways including VEGFA production leading to highly vascularized tumors . Anti-
angiogenic tyrosine kinase inhibitors (TKI) of the VEGF pathway including sunitinib, pazopanib, and
cabozantinib have improved outcomes in randomized clinical trials and are FDA approved therapies in the
first line setting for metastatic RCC [10-13] . The Cancer Genome Atlas comprehensive genetic analyses have
identified a subset of ccRCC patients with alterations in genes including MTOR (6%), PTEN (4.3%), and
PIK3CA (2.9%), leading to activation of the mechanistic target of rapamycin (mTOR) pathway . Activation
[6]
of this intracellular pathway leads to increased cell growth and division, thereby presenting biologic
[14]
rationale for mTOR inhibition with everolimus and temsirolimus .
Immunotherapy with checkpoint inhibitors (ICI) to the programmed cell death (PD-1) and cytotoxic T
lymphocyte-associated antigen 4 (CTLA-4) pathways have also been investigated in patients with ccRCC.
Nivolumab (anti-PD1) was approved in the second line for patients whose disease had progressed on anti-
angiogenic therapy based on the phase 3 Checkmate 025 study demonstrating overall survival (OS) and
overall response rate (ORR) benefits compared to the mTOR inhibitor, everolimus . The Checkmate 214
[15]
trial compared combination nivolumab and ipilimumab (anti-CLTA-4) to sunitinib for patients with
treatment naïve advanced RCC. This study demonstrated significant improvement in OS and ORR favoring
combination ICI therapy in the intermediate/poor risk (see below) populations, leading to FDA approval in
[16]
April 2018 .
In this review, we discuss the recent and emerging first-line treatment options in ccRCC, with a focus on
axitinib/pembrolizumab, axitinib/avelumab, cabozantinib/nivolumab, and lenvatinib/pembrolizumab and
compare their efficacy to nivolumab/ipilimumab as well as VEGFR TKI and CPI monotherapy. We review
safety and efficacy data and provide treatment recommendations based on clinical evidence and desired
goals of therapy. In addition, we consider treatment sequencing and the need for biomarkers; we look to the
future as novel combinations with immunotherapy backbones come to the forefront of the treatment
paradigm.

Clinical prognostic biomarkers
The selection of first line treatment for patients with advanced ccRCC has been guided by risk stratification
models developed by the Memorial Sloan Kettering Cancer Center (MSKCC) and the International