Robert J. Motzer, M.D.. Memorial Sloan ... Haider MT, Hunter KD, Robinson SP, et al. ... Koller MT, Raatz H, Steyerberg EW, Wolbers M. Competing risks and the ...
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Treatment of Advanced Renal-Cell Carcinoma To the Editor: In their article on the CheckMate 025 trial, Motzer and colleagues (Nov. 5 issue)1 report that nivolumab, as compared with everolimus, prolonged survival among patients with previously treated advanced renal-cell carcinoma. This trial opens the era of checkpoint inhibitors in renal-cell carcinoma and could help determine the most effective treatment sequence. Sunitinib and pazopanib are multitargeted tyrosine kinase inhibitors and first-line options that have similar efficacy.2 However, with nivolumab as second-line treatment, they may not be equivalent. Indeed, the mechanism of efficacy of tyrosine kinase inhibitors in renal-cell carcinoma is still largely unknown and may not rely only on the action on endothelial cells through the inhibition of vascular endothelial growth factor receptor. Sunitinib was shown to have direct antitumor effects and to exacerbate intratumoral heterogeneity in renalcell carcinoma,3 results that may be interesting since immunotherapies may work best in tumors with a high mutational burden.4 Furthermore, sunitinib has an immune effect that could have a positive or negative influence on the efficacy of this week’s letters
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nivolumab.5 Those effects could change the guidelines for the choice of first-line treatment. We wonder whether the authors would discuss the efficacy of nivolumab as a second-line treatment after the failure of sunitinib or pazopanib. Olivier Huillard, M.D. Jerome Alexandre, M.D., Ph.D. François Goldwasser, M.D., Ph.D. Hôpital Cochin Paris, France olivier.huillard@aphp.fr No potential conflict of interest relevant to this letter was reported. 1. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab ver-
sus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803-13. 2. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369: 722-31. 3. Stewart GD, O’Mahony FC, Laird A, et al. Sunitinib treatment exacerbates intratumoral heterogeneity in metastatic renal cancer. Clin Cancer Res 2015;21:4212-23. 4. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509-20. 5. Guislain A, Gadiot J, Kaiser A, et al. Sunitinib pretreatment improves tumor-infiltrating lymphocyte expansion by reduction in intratumoral content of myeloid-derived suppressor cells in human renal cell carcinoma. Cancer Immunol Immunother 2015; 64:1241-50. DOI: 10.1056/NEJMc1515613
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Treatment of Advanced Renal-Cell Carcinoma
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Soluble Urokinase Receptor and Chronic Kidney Disease
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Polymer-free Drug-Coated Coronary Stents
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Progesterone in Women with Recurrent Miscarriages
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Functional Dyspepsia
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Tumor Regression and Allograft Rejection after Administration of Anti–PD-1
To the Editor: Clinical and preclinical evidence has suggested that cabozantinib targets the bone microenvironment and shows dramatic effects on bone metastases in castration-resistant prostate cancer.1,2 Consequently, we believe that it would be quite useful to have data with respect to the efficacy of cabozantinib on multiple skeletal disease–specific clinical end points (e.g., time to skeletal-related events, bone radiologic progression-free survival, and bone pain) in the subgroup of patients with bone metastases, including those with advanced renal-cell carcinoma.
n engl j med 374;9 nejm.org March 3, 2016
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Correspondence
In our laboratory, we have explored the potential direct role of cabozantinib in bone using a totally human model of primary osteoclasts and osteoblasts. In brief, we found that noncytotoxic doses of cabozantinib had a significant inhibitory effect on osteoclast activity; moreover, cabozantinib induced in mature osteoblasts a significant decrease in the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) and a concomitant up-regulation of osteoprotegerin levels. Data regarding skeletalspecific end points in the study by Motzer et al. could provide further evidence of a double antiresorptive and antitumoral effect of cabozantinib against the vicious cycle of bone metastases that occur in almost 35% of patients with advanced renal-cell carcinoma.3 Daniele Santini, M.D., Ph.D. Giuseppe Tonini, M.D., Ph.D. Campus Bio-Medico University of Rome Rome, Italy d.santini@unicampus.it No potential conflict of interest relevant to this letter was reported. 1. Dai J, Zhang H, Karatsinides A, et al. Cabozantinib inhibits prostate cancer growth and prevents tumor-induced bone lesions. Clin Cancer Res 2014;20:617-30. 2. Smith MR, Sweeney CJ, Corn PG, et al. Cabozantinib in chemotherapy-pretreated metastatic castration-resistant prostate cancer: results of a phase II nonrandomized expansion study. J Clin Oncol 2014;32:3391-9. 3. Woodward E, Jagdev S, McParland L, et al. Skeletal complications and survival in renal cancer patients with bone metastases. Bone 2011;48:160-66. DOI: 10.1056/NEJMc1515613
at 12 months, the percentages were 76% (95% CI, 70 to 80) and 75% (95% CI, 67 to 82), respectively. Among these patients, the median overall survival after previously receiving sunitinib was 23.6 months (95% CI, 20.4 to 28.1); the median had not been reached for pazopanib (95% CI, 19.7 to not estimable). Our results showed similar outcomes in the rates of objective response and overall survival among patients in the nivolumab group who had previously received either sunitinib or pazopanib. In response to Santini and Tonini: the effects of cabozantinib on the bone microenvironment have been well documented.3 In patients with advanced renal-cell carcinoma, bone metastases contribute to substantial complications, including bone pain, skeletal-related events (e.g., bone fracture, bone irradiation or surgery, and spinalcord compression), and symptoms of hypercalcemia.4 Bone metastases are associated with reduced rates of progression-free survival and overall survival among such patients.2 In the Metastatic RCC Phase 3 Study Evaluating Cabozantinib versus Everolimus (METEOR) trial,5 bone metastases were present in 23% of the patients in the cabozantinib group and 20% of those in the everolimus group. In a prespecified analysis in this subgroup, marked prolongation of progression-free survival was observed with cabozantinib, with a median duration of 7.4 months in the cabozantinib group and 2.7 months in the everolimus group (hazard ratio, 0.33; 95% CI, 0.21 to 0.51). In addition, skeletal-related events in patients who had previous events were reported in 15 of 91 patients (16%) in the cabozantinib group and in 31 of 90 patients (34%) in the everolimus group. These results suggest that the efficacy benefit of cabozantinib is maintained among patients with renal-cell carcinoma who have bone metastases (a patient population with a poor clinical outcome) and warrants further investigation into the underlying mechanism of activity.
The authors reply: Nivolumab was approved for use in patients with advanced renal-cell carcinoma who have received previous antiangiogenic therapy on the basis of survival results in the CheckMate 025 trial.1,2 Huillard et al. ask whether nivolumab has differential efficacy after firstline treatment with sunitinib versus pazopanib. In our trial, 63% of the patients had received previous sunitinib treatment, and 32% had received pazopanib. At a minimum follow-up of 14 months, Robert J. Motzer, M.D. patients in the nivolumab group who had previ- Memorial Sloan Kettering Cancer Center ously been treated with sunitinib or pazopanib New York, NY had an objective response rate of 23% (95% con- motzerr@mskcc.org fidence interval [CI], 18 to 28) and 28% (95% CI, Bernard Escudier, M.D. 20 to 37), respectively. Among patients receiving Institut Gustave Roussy nivolumab, the overall survival rate at 18 months Villejuif, France was 61% (95% CI, 54 to 67) among patients who Toni K. Choueiri, M.D. had received sunitinib and 63% (95% CI, 54 to Dana–Farber Cancer Institute 71) among those who had received pazopanib; Boston, MA n engl j med 374;9 nejm.org March 3, 2016
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Since publication of their article, the authors report no further potential conflict of interest. 1. Motzer RJ, Sharma P, McDermott DF, et al. CheckMate 025 phase III trial: outcomes by key baseline factors and prior therapy for nivolumab (NIVO) vs everolimus (EVE) in advanced renal cell carcinoma (RCC). Presented at the 2016 Genitourinary Cancers Symposium, San Francisco, January 7–9, 2016. abstract. 2. Opdivo (nivolumab) injection (prescribing information). Princeton, NJ:Bristol-Myers Squibb, November 2015 (http:// packageinserts.bms.com/pi/pi_opdivo.pdf).
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3. Haider MT, Hunter KD, Robinson SP, et al. Rapid modifica-
tion of the bone microenvironment following short-term treatment with cabozantinib in vivo. Bone 2015;81:581-92. 4. McKay RR, Lin X, Perkins JJ, Heng DY, Simantov R, Choueiri TK. Prognostic significance of bone metastases and bisphosphonate therapy in patients with renal cell carcinoma. Eur Urol 2014;66:502-9. 5. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1814-23. DOI: 10.1056/NEJMc1515613
Soluble Urokinase Receptor and Chronic Kidney Disease To the Editor: Hayek et al. (Nov. 12 issue)1 found that plasma levels of soluble urokinasetype plasminogen activator receptor (suPAR) predicted incident chronic kidney disease and renalfunction decline in patients with vasculopathy and a relatively low prevalence of proteinuria. This finding prompted us to perform a subanalysis involving patients with biopsy-proven glomerulonephritis and early (stage I or II) chronic kidney disease and without proteinuria from our cohort 2: indeed, these 63 patients had higher mean (±SD) suPAR levels than healthy controls (3188±2078 vs. 1908±1685 pg per milliliter, P
