For over a decade, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors have been the standard first-line agents in the management of patients with advanced or metastatic clear cell renal cell carcinoma.1-3 Historically, phase III trials of first-line VEGF therapies included interferon-α as a comparator treatment, and phase III trials comparing established first-line agents did not have superiority in progression-free or overall survival as a primary endpoint.1-3 Treatment with the VEGF tyrosine kinase inhibitors sunitinib (Sutent) and pazopanib (Votrient) has resulted in improved progression-free survival (8.4–9.5 months) and objective responses (25%–31%) for patients with treatment-naive clear cell renal cell carcinoma.1 In the targeted therapy era, median overall survival for patients with advanced renal cell carcinoma has ranged from 28 to 29 months.1
Key Findings of CheckMate 214
As reported by Motzer and colleagues and reviewed in this issue of The ASCO Post, the phase III open-label CheckMate 214 trial compared nivolumab (Opdivo) combined with ipilimumab (Yervoy) vs sunitinib in patients with treatment-naive clear cell renal cell carcinoma.4 Sunitinib is the ideal comparator in this study, as it has been an established first-line agent in the management of renal cell carcinoma.1 The coprimary endpoints were objective responses rate, progression-free survival, and overall survival among intermediate- and poor-risk patients.
The study utilized the International Metastatic Database Consortium risk model to stratify patients into favorable-, intermediate-, and poor-risk groups.5 This is a contemporary model in patients initiated on targeted therapy that utilizes clinical parameters for risk stratification.5 In this model, patients with intermediate- and poor-risk renal cell carcinoma have a median overall survival of 27.0 and 8.8 months, respectively.5
The results of the CheckMate 214 trial will challenge the current front-line treatment paradigm for patients with metastatic renal cell carcinoma.— Rana R. McKay, MD
Tweet this quote
At a median follow-up of 25.2 months, nivolumab plus ipilimumab had a significant overall survival benefit over sunitinib among intermediate- and poor-risk patients: median overall survival was not reached with nivolumab plus ipilimumab vs 26.0 months with sunitinib (hazard ratio [HR] = 0.63, 99.8% confidence interval [CI] = 0.44–0.89, P < .001). This is the first study to demonstrate a statistically significant overall survival benefit over sunitinib, and thus nivolumab plus ipilimumab should be considered a new standard of care in this patient population. Based on these results, the U.S. Food and Drug Administration granted approval to nivolumab plus ipilimumab for the treatment of intermediate- and poor-risk treatment-naive patients with advanced renal cell carcinoma.
The median progression-free survival was 11.6 months and 8.4 months in the nivolumab plus ipilimumab group vs sunitinib group, which did not meet the prespecified threshold for statistical significance (HR = 0.82, 99.1% CI = 0.64–1.05, P = .03). Progression-free survival differed between arms by 6 months following randomization and demonstrated a similar pattern as was observed in CheckMate 25, a phase III open-label trial comparing nivolumab vs everolimus (Afinitor) in clear cell renal cell carcinoma following VEGF targeted therapy.6 This suggests that early disease progression in some patients receiving checkpoint blockade can evolve to disease stabilization or regression, highlighting that progression-free survival may underestimate the efficacy of immune checkpoint inhibitors.7,8
Subsequent Lines of Therapy
In light of the differing progression-free and overall survival outcomes, evaluation of subsequent lines of therapy is important. More patients in the sunitinib arm went on to receive subsequent therapy (54% of patients treated with sunitinib and 39% of patients treated with nivolumab plus ipilimumab), demonstrating the overall survival benefit observed in the nivolumab plus ipilimumab–treated patients was not due to the activity of subsequent therapies. Interestingly, only 27% of sunitinib-treated patients received subsequent nivolumab. Furthermore, no crossover was allowed on the study; thus patients receiving sunitinib did not have access to nivolumab plus ipilimumab. This raises the question as to whether subsequent nivolumab plus ipilimumab can improve survival for intermediate- and poor-risk patients following VEGF blockade.
Treatment with nivolumab plus ipilimumab demonstrated a superior objective responses rate compared with sunitinib (42% vs 27%, P < .001; complete response in 9% vs 1%). These response rates are unprecedented and higher than those observed with conventional VEGF targeted therapy, particularly in intermediate- and poor-risk patients.1 Additionally, the durability of response to nivolumab plus ipilimumab was impressive (> 1 year in 81% of responders, median duration not reached), highlighting the long-term activity of this combination.
Exploratory Analyses: Favorable-Risk Disease and PD-L1 Expression
An exploratory analysis evaluated the outcomes of patients with favorable-risk renal cell carcinoma. The objective response rate was higher in sunitinib-treated patients than in those receiving nivolumab plus ipilimumab—29% with nivolumab plus ipilimumab vs 52% with sunitinib (P < .001), although complete responses were observed in 11% vs 6% of patients, respectively. Additionally, progression-free survival favored sunitinib over nivolumab plus ipilimumab (25.1 months for sunitinib vs 15.2 months for nivolumab plus ipilimumab, P < .001). Although fewer patients in the favorable-risk group (12%) had programmed cell death ligand 1 (PD-L1) expression ≥ 1% compared with intermediate- and poor-risk patients (28%), risk stratification was dependent on clinical parameters and not on biomarkers that reflect underlying disease biology. This raises the question as to whether some intermediate-risk patients may benefit from VEGF-targeted therapy and whether a subset of favorable-risk patients—eg, represented by those who demonstrated a complete response to nivolumab plus ipilimumab—may preferentially benefit from nivolumab plus ipilimumab.
An exploratory analysis of outcomes by PD-L1 expression status demonstrated that although PD-L1 expression was prognostic of worse outcomes, it was not entirely predictive of improved survival or response to nivolumab plus ipilimumab. Similarly, PD-L1 status was not predictive of survival to nivolumab monotherapy in previously treated patients with renal cell carcinoma.6 In the IMmotion 151 phase III study of atezolizumab (Tecentriq) and bevacizumab (Avastin) compared with sunitinib, treatment with atezolizumab and bevacizumab resulted in improved progression-free survival in PD-L1–positive patients, achieving the study’s primary endpoint.9 These data highlight that the role of PD-L1 status as a predictive biomarker in renal cell carcinoma remains unclear. More refined predictive biomarkers to select patients for VEGF-targeted therapy alone, checkpoint blockade, or combination therapy are warranted to inform treatment decision making.
Toxicity
The toxicity profile of nivolumab plus ipilimumab differed from that seen with sunitinib. Grade 3 or 4 adverse events occurred in 46% of patients receiving nivolumab plus ipilimumab and 63% of sunitinib patients, with 22% and 12% of patients, respectively, requiring treatment discontinuation for treatment-related adverse events. Of patients receiving nivolumab plus ipilimumab, 35% required high-dose glucocorticoids to manage immune-mediated adverse events. Close surveillance and prompt aggressive treatment are warranted to manage toxic adverse events associated with combination immunotherapy. Management algorithms have been developed to help oncologists and multidisciplinary specialists manage specific immune-mediated adverse events associated with immune checkpoint inhibitor therapy.10
Closing Thoughts
The results of the CheckMate 214 trial will challenge the current front-line treatment paradigm for patients with metastatic renal cell carcinoma. Although the combination of nivolumab plus ipilimumab has clearly demonstrated significant clinical activity in metastatic renal cell carcinoma, questions remain regarding patient selection for treatment and the efficacy of current second-line treatments following treatment with nivolumab plus ipilimumab. ■
Dr. McKay is Assistant Professor of Medicine, UC San Diego School of Medicine, Moores Cancer Center, University of California San Diego.
DISCLOSURE: Dr. McKay is an advisor/consultant for Janssen and Novartis and has received institutional research funding from Pfizer and Bayer.
REFERENCES
1. Motzer RJ, Hutson TE, McCann L, et al: Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med 370:1769-1770, 2014.
2. Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115-124, 2007.
3. Sternberg CN, Davis ID, Mardiak J, et al: Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomized phase III trial. J Clin Oncol 28:1061-1068, 2010.
4. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378:1277-1290, 2018.
5. Heng DY, Xie W, Regan MM, et al: Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: Results from a large, multicenter study. J Clin Oncol 27:5794-5799, 2009.
6. Motzer RJ, Escudier B, McDermott DF, et al: Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803-1813, 2015.
7. Topalian SL, Sznol M, McDermott DF, et al: Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32:1020-1030, 2014.
8. Villaruz LC, Socinski MA: The clinical viewpoint: Definitions, limitations of RECIST, practical considerations of measurement. Clin Cancer Res 19:2629-2636, 2013.
9. Motzer RJ, Powles T, Atkins MB, et al: IMmotion151: A randomized phase III study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma. 2018 Genitourinary Cancers Symposium. Abstract 578. Presented February 10, 2018.
10. Brahmer JR, Lacchetti C, Schneider BJ, et al: Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. February 14, 2018 (early release online).
