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Therapeutic Strategies for Hereditary Kidney Cancer: Beyond the Abstract

The understanding of the mechanism and biology of hereditary kidney cancer has improved tremendously over the last few decades which helped in the development of various new drugs. Over the last decade, seven drugs targeting the Hypoxia-inducible factor(HIF) pathway have been approved by Food and Drugs Administration, which have provided safer and efficacious treatment options for patients with both hereditary and sporadic metastatic clear cell renal cell cancer. More recently, there has been an uptake in interest in immune checkpoint inhibitors for sporadic metastatic RCC. 

Nivolumab, an anti-PD-1 antibody, and Ipilimumab, a monoclonal anti-CTLA4 antibody, have been tried either in a combination or monotherapy for metastatic renal carcinomas. (1) In a phase II study, five of forty patients treated with Ipilimumab had partial responses, but since the toxicity was extensive, it led to decreased interest for further development of anti-CTLA-4 in RCC. (2) In an open-label, phase 3 study of 821 patients, nivolumab, was compared to everolimus in patients with advanced renal cell carcinoma who have failed prior antiangiogenic therapy. The median overall survival was 25 months with nivolumab vs. 19.6 months with everolimus leading to its approval as second-line therapy in renal cell cancer. Checkmate214 (NCT02231749) is a Phase III trial comparing Nivolumab combined with Ipilimumab versus sunitinib in previously untreated patients. (3) In metastatic RCC, a Phase IA study of Atezolizumab, an anti-PD-L1 antibody, exhibited a good response rate with no major adverse events. (4) These studies are promising and prove that immune checkpoint inhibitors either alone or in combination with the Tyrosine Kinase inhibitors (TKI) have efficacy in patients with RCC.

Though the immune therapies are promising in sporadic RCC, the data on their effectiveness in hereditary renal cell cancers is lacking. Future clinical trials using immune checkpoint inhibitors in hereditary renal cancers are needed to evaluate their efficacy in hereditary renal cancers and provide another agent in the armamentarium against these cancers.

Written by: Amit L Jain, MD1, Abhinav Sidana, MD1.

1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA


References:

1. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. The New England journal of medicine. 2015;373:1803-13.

2. Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, et al. Ipilimumab (Anti-CTLA4 Antibody) Causes Regression of Metastatic Renal Cell Cancer Associated With Enteritis and Hypophysitis. Journal of immunotherapy (Hagerstown, Md : 1997). 2007;30:825-30.

3. Rexer H. [Therapy of untreated local advanced or metastatic renal cell carcinoma. Phase III, randomized, open-label study of nivolumab combined with ipilimumab versus sunitinib monotherapy in subjects with previously untreated, local advanced or metastatic renal cell carcinoma (CheckMate 214 - AN 36/15 of the AUO)]. Der Urologe Ausg A. 2015;54:1443-5.

4. McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, et al. Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016;34:833-42