eUpdate – Renal Cell Carcinoma Treatment Recommendations
Published: 07 February 2020. Authors: ESMO Guidelines Committee
Clinical Practice Guidelines
This update refers to the Renal Cell Carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Escudier B, Porta C, Schmidinger M et al. Ann Oncol 2019; 30(5): 706–720.
The ESMO Guidelines Committee would like to thank the following expert group who drafted and reviewed the eUpdate before it was approved by the ESMO Guidelines Committee: Thomas Powles, Laurence Albiges, Axel Bex, Giuseppe Procopio, Camillo Porta, Manuela Schmidinger, Cristina Suarez, Guillermo de Velasco.
This article outlines updates based on recent published data.
Systemic treatment for clear cell renal cell carcinoma
The combination of pembrolizumab and axitinib (PA) is recommended as front-line/treatment-naïve therapy for advanced disease [I, A]. This is based on data from KEYNOTE-426, where PA was compared with sunitinib in this treatment-naive population . Results showed a significant overall survival (OS) advantage for PA at interim analysis (12.8-month median follow-up) [hazard ratio (HR) 0.53; 95% confidence interval (CI) 0.38–0.74; P<0.0001]. Reponses rates and progression-free survival (PFS) (HR 0.69; 95% CI 0.57–0.84; P<0.001) also significantly favoured the combination. These benefits appeared to be irrespective of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic subgroups and programmed death-ligand 1 (PD-L1) biomarker status. More mature follow-up and patient-reported outcome data are awaited. Preliminary data, submitted to the European Medicines Agency (EMA), does not suggest that PA has favourable patient-reported outcomes compared with sunitinib. Peer review data are awaited.
Updated data on the combination of ipilimumab and nivolumab (IN) in front-line disease (32-month median follow-up) demonstrated benefits that seemed confined to the IMDC intermediate- and poor-risk population, reflecting the EMA approval [I, A] [2, 3]. The study showed that the OS advantage for the immune combinations was maintained over sunitinib (OS HR 0.66; 95% CI 0.45–0.80). A significant proportion of the population benefited from long-term remission. In an exploratory analysis, the PD-L1 biomarker-positive population shows some enrichment for survival (OS HR 0.45; 95% CI 0.29–0.41), but this has not been widely adopted and does not feature in the guidelines. IN had better patient-reported outcomes than sunitinib.
Randomised trials of axitinib/avelumab and bevacizumab/atezolizumab have also been reported in the front-line/treatment-naïve setting [4, 5]. Both combinations were tested against sunitinib. Both achieved their pre-defined PFS co-primary endpoint, but neither have achieved the significant OS advantage over sunitinib. For this reason, neither combination features in the guidelines despite axitinib and avelumab having EMA approval. Final OS data are awaited.
Vascular endothelial growth factor (VEGF)-targeted therapy is recommended in those patients where pembrolizumab/axitinib or ipilimumab/nivolumab are not available or are contraindicated [I, A–II, B]. These recommendations are based on randomised phase III studies carried out before the introduction of immune checkpoint inhibitors [6–8]. Surveillance can be considered for IMDC good-risk disease, although this population is not well-defined and requires experienced clinical input [V].
There are limited data for treatment after progression or intolerance on PA or IN. VEGF tyrosine kinase inhibitors (TKIs) are the recommended treatment for these patients. Prospective data exist but are limited to axitinib, while cabozantinib and tivozanib have been investigated in immune-refractory disease, usually after single-agent nivolumab [III, B] [9–12]. There is no preferential VEGF-targeted therapy currently available in this setting [V]. If a patient has been exposed to a specific VEGF-targeted therapy, an alternative should be used subsequently. Randomised data are required. There is no evidence that sequencing immune checkpoint inhibitors after progression with IN or PA is of clinical benefit.
- The combination of PA should be considered as a front-line therapeutic option for patients with advanced disease, irrespective of IMDC prognostic subgroups and PD-L1 biomarker status [I, A], while the combination of IN should be considered as a first-line option in patients with IMDC intermediate- and poor-risk disease [I, A].
- VEGF-targeted therapy is recommended in those patients where pembrolizumab/axitinib or ipilimumab/nivolumab are not available or are contraindicated [I, A–II, B].
- There is limited data for treatment after progression or intolerance on PA or IN. VEGF TKIs are the recommended treatment for these patients [III, B].
- Rini BI, Plimack ER, Stus V et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019; 380(12): 1116–1127.
- Motzer RJ, Tannir NM, McDermott DF et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018; 378(14): 1277–1290.
- Motzer RJ, Rini BI, McDermott DF et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol 2019; 20(10): 1370–1385.
- Motzer RJ, Penkov K, Haanen J et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019; 380(12):1103–1115.
- Rini BI, Powles T, Atkins MB et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet 2019; 393(10189): 2404–2415.
- Motzer RJ, Hutson TE, Cella D et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013; 369(8): 722–731.
- Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356(2): 115–124.
- Motzer RJ, Nosov D, Eisen T et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol 2013; 31(30): 3791–3799.
- Rini BI, Pal SK, Escudier BJ et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol 2020; 21(1): 95–104.
- Powles T, Motzer RJ, Escudier B et al. Outcomes based on prior therapy in the phase 3 METEOR trial of cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer 2018; 119(6): 663–669.
- Ornstein MC, Pal SK, Wood LS et al. Individualised axitinib regimen for patients with metastatic renal cell carcinoma after treatment with checkpoint inhibitors: a multicentre, single-arm, phase 2 study. Lancet Oncol 2019; 20(10): 1386–1394.
- Auvray M, Auclin E, Barthelemy P et al. Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma. Eur J Cancer 2019; 108: 33–40.