eUpdate – Renal Cell Carcinoma Treatment Recommendations

Published: 10 April 2017. 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 2016 (Suppl 5): v58–v68.


Systemic treatment – Second-line treatment

Text update

Second-line treatment has recently been dramatically modified by the report of two large phase III trials showing improvement in OS with nivolumab [an anti-programmed death 1 (PD-1) inhibitor] and cabozantinib [38–40] over everolimus. Both trials showed very significant improvement in OS and response rate, while PFS was improved only in the cabozantinib trial. In both trials, patients could be treated after either one or two TKIs.

  • Obviously, availability of these two drugs is still very limited, and several situations should be differentiated:
    • Only nivolumab is available: It should be recommended [Level of evidence (LOE) I; ESMO-Magnitude of Clinical Benefit Scale (MCBS) v1.0 score: 5].
    • Nivolumab and cabozantinib are both available: either drug is recommended. The ESMO-MCBS score associated with nivolumab is 5, while that of cabozantinib is 3.
    • Neither of these drugs is available: either everolimus [II, B] or axitinib [II, B] can be used.

The combination of lenvatinib and everolimus has recently been approved by the US Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) based on a small, phase II, randomised study of 150 patients, showing PFS and OS benefit over everolimus [LOE II; ESMO-MCBS v1.0 score: 4] [41]. It is the opinion of the ESMO Guidelines Committee that the encouraging positive findings of the phase II study require verification in an adequately powered phase III study.


Magnitude of Clinical Benefit Scale (MCBS) table for new therapies/indications in renal cell carcinoma*

Therapy Disease setting Trial Control Absolute survival gain HR (95% CI) QoL/toxicity MCBS score**
Nivolumab, a PD-1 checkpoint inhibitor Advanced clear-cell renal cell carcinoma previously treated with one or two regimens of antiangiogenic therapy Study of Nivolumab vs. Everolimus in Pre-Treated Advanced or Metastatic Clear-Cell Renal Cell Carcinoma (CheckMate 025) [1]
Phase III
Median OS: 19.6 months
OS gain:
5.4 months
OS HR: 0.73 (0.57-0.93) Improved toxicity profile and QoL 5 (Form 2a)
Cabozantinib Advanced renal cell carcinoma (RCC) in adults following prior vascular endothelial growth factor receptor (VEGFR)-tyrosine-kinase inhibitors A Study of Cabozantinib (XL184) vs Everolimus in Subjects with Metastatic Renal Cell Carcinoma (METEOR) [2]
Phase III
Median OS: 16.5 months
OS gain:
4.9 months
OS HR: 0.66 (0·53–0·83)  __ 3 (Form 2a)
Lenvatinib in combination with everolimus Advanced or metastatic renal cell carcinoma (RCC) following one prior vascular endothelial growth factor (VEGF)-targeted therapy

Lenvatinib, Everolimus, and the Combination in Patients with Metastatic Renal Cell Carcinoma: A Randomised, Phase 2,

Open-Label, Multicentre Trial [3]
Phase II

Median OS: 15.4 months
OS gain:
10.1 months
OS HR: 0.51 (0·30–0·88)   __ 4 (Form 2a; secondary endpoint of OS in a small phase II randomised study)

*EMA approvals from January 2016 to end January 2017.
** ESMO-MCBS version 1.0 [4]

CI, confidence interval; EMA, European Medicines Agency; HR, hazard ratio; OS, overall survival; PD-1, programmed death 1; QoL, quality of life


  1. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373: 1803–1813.
  2. Choueiri TK et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016; 17: 917-927.
  3. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 2015; 16:1473-1482.
  4. Cherny NI, Sullivan R, Dafni U, et al. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol 2015; 26: 1547–1573.