In the October 25 issue of The ASCO Post, we presented two important studies in previously treated advanced renal cell carcinoma, including the paper by Motzer et al “Nivolumab versus everolimus in advanced renal-cell carcinoma” (CheckMate 025), published in The New England Journal of Medicine, September 25, 2015 (early release online), and that by Choueiri et al on “Cabozantinib versus everolimus in advanced renal-cell carcinoma” (METEOR trial), also in The New England Journal of Medicine, September 25, 2015 (early release online). Here, Brian I. Rini, MD, FACP, of the Cleveland Clinic Taussig Cancer Institute shares his personal perspective on the impact of these important studies on clinical care.
The landscape of treatment for metastatic renal cell carcinoma has again shifted. Built upon a foundation of therapy targeting the vascular endothelial growth factor (VEGF) pathway with a small subset of patients benefitting from immunotherapy (high-dose interleukin-2 [Proleukin]), recent data have expanded the therapeutic armamentarium while simultaneously raising new questions. The most impressive new data have come from the CheckMate 025 trial—reported by Motzer and colleagues and summarized in this issue of The ASCO Post—in which the anti–programmed cell death protein 1 (PD-1) antibody nivolumab (Opdivo) was compared to everolimus (Afinitor), an oral mammalian target of rapamycin (mTOR) inhibitor, in patients with refractory metastatic renal cell carcinoma.1 An overall survival advantage was demonstrated with a very tolerable safety profile.
Emerging Questions
Assuming U.S. Food and Drug Administration approval, these data make nivolumab likely the predominant standard of care in refractory renal cell carcinoma. One perspective is to ask the question of which refractory renal cell carcinoma patients should not get nivolumab? Aside from those with contraindications such as autoimmune disease, the answer to this question is not clear.
Disappointingly, tumor expression of the ligand for PD-1 (PD-L1), while prognostic, did not predict for or against response to nivolumab and thus is not presently of clinical utility. Whether this will hold true for other drugs in this class in renal cell carcinoma or whether using alternative antibodies or staining other cell populations (eg, infiltrating immune cells) will permit prediction of response awaits further investigation.
Of note, in CheckMate 025, there was no progression-free survival difference between the arms, and a substantial percentage of patients in the nivolumab arm (35%) had a best response of progressive disease. Although this subset likely includes patients with disease worsening before subsequent improvement, there are likely patients (eg, those with bulky, symptomatic disease) in whom subsequent VEGF-targeted therapy may be a better choice for initial disease control.
Several other questions also emerge. The complete response rate was identical (1%) in both arms of CheckMate 025, as was the duration of response (12 months), and thus, the potential of immunotherapy to induce durable and deep remissions is not yet realized—at least at this point in patient follow-up. Further, whether continuous therapy (as was employed in this study) is needed in patients with durable disease control will require additional investigation but has important cost and toxicity implications.
Role of Cabozantinib
Additional data in this setting have been presented on cabozantinib (Cometriq). This agent inhibits not only the VEGF receptor but other potentially biologically relevant receptors such as c-met and AXL, which have been shown in preclinical models to be associated with VEGF resistance. In the METEOR trial, reported by Choueiri and colleagues and summarized in this issue of The ASCO Post, cabozantinib demonstrated a progression-free survival and objective response rate advantage over everolimus in refractory renal cell carcinoma.2
Whether this benefit simply reflects an advantage of VEGF targeting over mTOR targeting in this setting or is a result of targeting of additional receptors is unclear. A smaller randomized trial of cabozantinib vs sunitinib in front-line renal cell carcinoma is awaited to provide further insight. This efficacy benefit came at a cost of toxicity, however, with 68% of cabozantinib-treated patients experiencing a grade 3 or higher adverse event and 60% requiring dose reductions.
As the dosing of cabozantinib has varied considerably among trials in different cancers, the optimal dosing strategy for this compound in renal cell carcinoma requires further study. Nonetheless, the progression-free survival observed with cabozantinib in this setting is impressive and provides a new option for this group of patients.
Closing Thoughts
Thus, just when the existing targeted therapies had likely been maximized in terms of patient benefit, these new treatment options emerge. Ongoing studies are moving checkpoint inhibitors into the front-line setting, and additionally combining immunotherapeutics and VEGF-targeted agents. While several questions remain as to how to optimally incorporate and sequence new and existing agents, the prognosis for metastatic renal cell carcinoma patients continues to improve. ■
Disclosure: Dr. Rini is a consultant for and has received research funding from Bristol-Myers Squibb and Exelexis.
References
1. Motzer RJ, Escudier B, McDermott DF, et al: Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803-1813, 2015.
2. Choueiri TK, Escudier B, Powles T, et al: Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1814-1823 2015.
Dr. Rini is Professor of Medicine, Lerner College of Medicine, Leader, GU Program, Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute.
