eUpdate – Renal Cell Carcinoma Treatment Recommendations

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.

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Acknowledgements

Text update

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. 

Text update 

Systemic treatment for clear cell renal cell carcinoma

First-line treatment

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 [1]. 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.  

Recommendations:

• 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].

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References

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