Current and Emerging Therapies for First-Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma - Beyond the Abstract

The treatment landscape for patients with advanced clear cell renal cell carcinoma (RCC) rapidly evolved more than a decade ago with the introduction of tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor (VEGF) pathway. Further understanding of tumor biology, including tumor immune evasion and mechanisms of resistance, has led to a new era of therapeutic advances highlighted by the approvals of nivolumab and cabozantinib in 2015 and 2016, respectively.

Nivolumab is a checkpoint inhibitor that targets programmed cell death protein 1 (PD-1), a receptor that suppresses the immune response and thereby allows tumor cells to evade immune surveillance. By targeting PD-1, nivolumab reactivates the suppressed immune response. Cabozantinib is an oral TKI that targets VEGF receptors, as well as the receptor tyrosine kinases MET and AXL which are implicated as mechanisms of tumor development, progression, and treatment resistance. Nivolumab and cabozantinib were initially approved for patients with advanced RCC who had received previous antiangiogenic therapy,1-3 with expansion to the first-line setting in 2018 based on outcomes from recent studies.4-6

In the phase 3 CheckMate 214 trial, nivolumab was paired with ipilimumab, a checkpoint inhibitor of cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), in previously untreated patients with advanced RCC. Compared with the TKI sunitinib (a standard of care), the nivolumab-ipilimumab combination demonstrated an overall survival (OS) benefit, which was particularly evident in the cohort of patients with intermediate- or poor-risk disease.4 Based on these outcomes, the nivolumab-ipilimumab combination was approved as a first-line treatment for patients with intermediate- or poor-risk disease.

Cabozantinib was initially approved as second-line therapy for RCC based on results from the phase 3 METEOR trial.2,3 A subsequent randomized, phase 2 trial (CABOSUN) in the first-line setting demonstrated a progression-free survival (PFS) benefit with cabozantinib compared with sunitinib in patients with intermediate- or poor-risk disease.5,6 These studies supported the expanded indication of single-agent cabozantinib to all patients with advanced RCC.

Despite these treatment advances, there remain unmet needs and knowledge gaps. The nivolumab-ipilimumab combination provided durable responses in CheckMate 214, but a significant proportion of patients did not respond to the combination. Further, the efficacy and safety of the nivolumab-ipilimumab combination and single-agent cabozantinib as first-line therapies for patients with favorable-risk RCC relative to sunitinib remain to be established. Preliminary analysis of CheckMate 214 showed fewer responses and a shorter PFS with the combination in the cohort of patients with favorable-risk disease, but the OS data were immature, and CABOSUN enrolled only patients with intermediate- or poor-risk disease.

More recent studies are exploring anti–PD-1 and anti-programmed cell death ligand 1 (PD-L1) monotherapies, combinations of checkpoint inhibitors with VEGF-targeted therapy, and predictive biomarkers. VEGF is an established target in RCC and is associated with suppression of the immune response. IMmotion 151 is a phase 3 study evaluating first-line therapy with the combination of atezolizumab (anti–PD-L1) and bevacizumab (anti-VEGF) versus single-agent sunitinib. Initial results demonstrated a PFS benefit with the combination in patients with a high PD-L1 expression on tumor-infiltrating immune cells.7  Similar results were seen in the intention-to-treat population, which included all patients regardless of PD-L1 expression. OS is a more reliable measure of immunotherapy efficacy, and these data are pending. The combination was well tolerated, with a safety profile that was significantly better than that of sunitinib and likely better than that of nivolumab-ipilimumab or cabozantinib, although we recognize the limitations of cross-study comparisons.

Studies are also evaluating checkpoint inhibitors in combination with TKIs, including cabozantinib, axitinib, and lenvatinib.8-10 These TKIs all target VEGF receptors, and some inhibit additional targets with immunomodulatory activity. Results from early-phase studies have demonstrated the feasibility of these combinations and significant antitumor activity, supporting the initiation of phase 3 trials with checkpoint inhibitor-TKI combinations.

A key component of these trials will be biomarker analyses. Although there are currently no validated predictive biomarkers in RCC, data from these studies may help to select the optimal treatment for the individual patient. There are a number of potential candidates, including PD-1/PD-L1 expression, tumor-infiltrating lymphocytes, and expression levels of TKI targets. A single biomarker may help to direct therapy for some patients, while composite biomarkers may be needed for others.

We are only at the beginning of a new therapeutic era in RCC. As we wait for these ongoing trials of checkpoint inhibitors used alone and in combination to read out, we are actively considering how these regimens might be incorporated into the ever-expanding treatment landscape.

Cancer Treat Rev. 2018;70:127-137

Authors: Michael B. Atkins1 and Nizar M. Tannir2
1. Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA
2. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Writing and editorial assistance was provided by Michael Raffin (Fishawack Communications Inc., Conshohocken, PA, USA) and supported by Exelixis, Inc. (Alameda, CA, USA).


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