Update on the treatment of metastatic clear cell and non-clear cell renal cell carcinoma - Beyond the Abstract

This commentary is an overview of the future and obstacles of nivolumab. The past year has been marked by a number of positive developments surrounding the treatment of advanced renal cell carcinoma. In the months that followed our March 2015 mini-review published in Biomarker Research (1), particularly exciting news has been occurring in the context of the CheckMate 025 study, a phase III randomized controlled trial comparing single-agent nivolumab (Opdivo) to everolimus (Affinitor) in 821 patients with advanced renal cell carcinoma previously treated with anti-angiogenic therapy (2).

Constituting the first time a PD-1 inhibitor has been found to confer a survival advantage in late-stage renal cell carcinoma (RCC) among patients participating in a phase III trial, nivolumab was found to improve overall survival in comparison to everolimus. The CheckMate 025 trial is now in an open-label extension phase with patients in the everolimus cohort permitted to cross over and receive nivolumab.

As an IgG4 monoclonal antibody, nivolumab inhibits the PD-1 receptor on T-cells, which are upregulated during inflammatory processes in order to prevent overstimulation of the immune response. The inhibition of PD-1 signaling by nivolumab thus culminates in heightened immune cell proliferation and cytokine production that has been found to have anti-tumor therapeutic promise in many cancers ranging from melanoma and non-small cell lung cancer to renal cell carcinoma (3).

While the oncology community awaits the publication of the complete results of the CheckMate 025 trial, the expected findings of the phase III trial are consistent with a past phase II study examining nivolumab’s therapeutic efficacy in RCC patients with previous anti-angiogenic treatment (4). The aforementioned phase II trial randomly assigned patients with clear-cell metastatic RCC to 0.3, 2, or 10 mg/kg doses of nivolumab with the aim of examining progression-free survival. While no dose-response relationship was found for progression-free survival, objective responses of long durations were observed with 54% of responders having objective responses exceeding 12-20+ months.

Even though the CheckMate 025 trial results hold considerable promise, numerous challenges remain in the road towards nivolumab becoming a standard of care for the treatment of advanced renal cell carcinoma. Given a general lack of predictive biomarkers to gauge nivolumab’s therapeutic efficacy in individual patients, future analyses is urgently needed to help clinicians select patients who may especially benefit from nivolumab, and further studies are needed to examine whether PD-1 ligand levels may predict patient responses to nivolumab (3). In addition, nivolumab has proven itself to be a very expensive medication with some estimating that its typical course of combined treatment may exceed $200,000 (5). Research is thus undoubtedly needed to assess the cost-effectiveness of such immunotherapies, and concerted efforts should be taken to make such drugs affordable for patients in need.

1. Xu KY, Wu S. Update on the treatment of metastatic clear cell and non-clear cell renal cell carcinoma. Biomark Res. 2015;3:5.
2. Bristol Myers Squibb. CheckMate-025, a Pivotal Phase III Opdivo (nivolumab) Renal Cell Cancer Trial, Stopped Early. 2015.
3. Bukowski RM, Figlin RA, Motzer RJ. Targeted Therapy for Metastatic Renal Cell Carcinoma: Introduction. In: Renal Cell Carcinoma. New York: Springer, 2015.
4. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015;33(13):1430-1437.
5. Immunotherapy drug combo could combat melanoma. NHS Choices 2015.

Written by:
Kevin Y. Xu 
Department of Medical Education, Icahn School of Medicine at Mount Sinai, New York, NY, USA;

Shenhong Wu
Division of Hematology/Oncology, Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY, USA,
Northport VA Medical Center, Northport, NY, USA.

AbstractUpdate on the treatment of metastatic clear cell and non-clear cell renal cell carcinoma