ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma

Abstract

•This special article provides key recommendations on the immunotherapy treatments of renal cell carcinoma.•Recommendations are based on available scientific data and the authors' collective expert opinion.•Authorship includes a multidisciplinary group of renal carcinoma experts. This article focuses on the recent immunotherapy updates to the treatment of renal cell carcinoma (RCC) as given in the RCC: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.1Escudier B. Porta C. Schmidinger M. et al.Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2019; 30: 706-720Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar View the ESMO eUpdate here: [https://www.esmo.org/guidelines/genitourinary-cancers/renal-cell-carcinoma/eupdate-renal-cell-carcinoma-treatment-recommendations-4]. The KEYNOTE-564 phase III trial evaluated pembrolizumab (17 cycles of 200 mg 3-weekly therapy) versus placebo as adjuvant therapy for 994 patients with clear cell RCC (ccRCC) with intermediate (pT2, grade 4 or sarcomatoid, N0 M0; or pT3, any grade, N0 M0) or high risk (pT4, any grade, N0 M0; or any pT any grade, N+ M0); or M1 and no evidence of disease (NED; after primary tumour plus soft tissue metastases completely resected ≤1 year from nephrectomy).2Choueiri T.K. Tomczak P. Park S.H. et al.Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: randomized, double-blind, phase III KEYNOTE-564 study.J Clin Oncol. 2021; 39: LBA5Crossref Google Scholar The median follow-up, defined as time from randomisation to data cut-off, was 24.1 months. The primary endpoint of disease-free survival (DFS) per investigator assessment was met [hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.53-0.87, P = 0.001]. The estimated 24-month DFS rate was 77% versus 68% for pembrolizumab and placebo, respectively. Benefit occurred across broad subgroups of patients including those with M1/NED disease after metastasectomy. Investigator-assessed DFS was considered preferable to DFS by central review due to its clinical applicability. Overall survival (OS) showed a non-statistically significant trend towards a benefit in the pembrolizumab arm (HR 0.54, 95% CI 0.30-0.96, P = 0.0164). Follow-up was short and few OS events occurred [2-year OS rate of 97% (pembrolizumab) versus 94% (placebo)]. Grade 3-5 all-cause adverse events occurred in 32% versus 18% of patients for pembrolizumab and placebo, respectively. Adjuvant pembrolizumab should be considered optional for patients with intermediate- and high-risk (defined as per study) operable ccRCC after careful patient counselling regarding immature OS and potential long-term adverse events [I, C]. Treatment should start within 12 weeks of surgery and continue for up to 1 year. The significant DFS efficacy signal, the early but promising OS signal and the acceptable tolerability profile all contributed to this decision. This level [I, C] recommendation distinguishes adjuvant pembrolizumab from the adjuvant vascular endothelial growth factor receptor (VEGFR)-targeted trials, which gave inconsistent DFS signals and showed no trend towards OS benefit.3Harshman L.C. Xie W. Moreira R.B. et al.Evaluation of disease-free survival as an intermediate metric of overall survival in patients with localized renal cell carcinoma: a trial-level meta-analysis.Cancer. 2018; 124: 925-933Crossref PubMed Scopus (18) Google Scholar The authors of this article acknowledge that the correlation between DFS and OS is uncertain for operable ccRCC and unproven for adjuvant immunotherapy in renal cancer.4Sun M. Marconi L. Eisen T. et al.Adjuvant vascular endothelial growth factor-targeted therapy in renal cell carcinoma: a systematic review and pooled analysis.Eur Urol. 2018; 74: 611-620Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Therefore, a number of issues need to be addressed to underpin this recommendation for the future. Firstly, a significant and clinically meaningful OS signal will be needed. Secondly, disclosure of the impact of the different patient populations, including the M1/NED population, in the KEYNOTE-564 study on OS is required. Thirdly, it is apparent that a high proportion of patients, cured by surgery alone, are receiving unnecessary and potentially harmful treatment. This requires urgent attention with clinical and molecular biomarkers for outcome and predisposition to toxicity, as well as quality-of-life data. Finally, the results of other adjuvant trials with immune checkpoint inhibitors (ICIs) will be relevant, especially if more mature OS data are available from other studies. Meta-analysis studies should occur, although the authors acknowledge that different ICIs may have different efficacy in advanced ccRCC, and should be considered distinct from one another. The authors would ideally like ongoing, supportive efficacy data while waiting for the final and statistically robust OS analysis, which is unlikely to occur in the short term. •Adjuvant pembrolizumab should be considered optional for patients with intermediate- or high-risk operable ccRCC (as defined by the study) after careful patient counselling regarding immature OS and potential long-term adverse events [I, C]. Further data are required in the future including positive OS data. Treatment should start within 12 weeks of surgery and continue for up to 1 year.•Regarding the M1 NED population, systemic therapy with programmed cell death protein 1 (PD-1)-based combination therapy is the standard of care for patients who relapse within 1 year of nephrectomy [I, A].•Metastasectomy as an alternative to this systemic therapy in patients with synchronous or early oligometastatic disease is not usually recommended [I, D] and requires a multidisciplinary team decision.•Adjuvant pembrolizumab can be offered to these patients after complete resection of their oligometastatic disease [II, B].•Incomplete resection should not be offered to patients with oligometastatic disease [III, D]. The ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) table has been updated (Table 7). The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee. ESMO-MCBS v1.15Cherny N.I. Dafni U. Bogaerts J. et al.ESMO-Magnitude of Clinical Benefit Scale version 1.1.Ann Oncol. 2017; 28: 2340-2366Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar was used to calculate scores for new therapies/indications approved by the European Medicines Agency (EMA) since 1 January 2016 or the Food and Drug Administration (FDA) since 1 January 2020 (https://www.esmo.org/guidelines/esmo-mcbs).Table 7ESMO-MCBS table for new therapies/indications in RCCaEMA approvals since January 2016 and FDA approvals since 1 January 2020.TherapyCabozantinibDisease settingAdvanced RCC after prior VEGF-targeted therapyTrialA study of cabozantinib versus everolimus in subjects with metastatic RCC that has progressed after prior VEGFR TKI therapy (METEOR)18Powles T. Motzer R.J. 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: 663-669Crossref PubMed Scopus (47) Google Scholar,28Cella D. Escudier B. Tannir N.M. et al.Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial.J Clin Oncol. 2018; 36: 757-764Crossref PubMed Scopus (30) Google Scholar, 29Motzer R.J. Escudier B. Powles T. et al.Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma.Br J Cancer. 2018; 118: 1176-1178Crossref PubMed Scopus (37) Google Scholar, 30Choueiri T.K. Escudier B. Powles T. 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: 917-927Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar, 31Choueiri T.K. Escudier B. Powles T. et al.Cabozantinib versus everolimus in advanced renal-cell carcinoma.N Engl J Med. 2015; 373: 1814-1823Crossref PubMed Scopus (820) Google ScholarPhase IIINCT01865747ControlEverolimusMedian OS: 17.1 monthsAbsolute survival gainOS gain: 4.3 monthsHR (95% CI)OS HR: 0.70 (0.58-0.85)QoL/toxicityQoL was an exploratory endpoint; not eligible for ESMO-MCBS gradingESMO-MCBS scorebESMO-MCBS v1.15 The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee (https://www.esmo.org/guidelines/esmo-mcbs/scale-evaluation-forms-v1.0-v1.1/scale-evaluation-forms-v1.1).3 (Form 2a)TherapyCabozantinib plus nivolumabDisease settingFirst-line treatment of advanced RCC in combination with nivolumabTrialA study of nivolumab combined with cabozantinib versus sunitinib in participants with previously untreated advanced or metastatic RCC (CheckMate 9ER)7Choueiri T.K. Powles T. Burotto M. et al.Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med. 2021; 384: 829-841Crossref PubMed Scopus (362) Google ScholarPhase IIINCT03141177ControlSunitinibMedian PFS: 8.3 monthsOS at 1 year 75.6%Absolute survival gainPFS gain: 8.3 monthsOS gain: 10.1%HR (95% CI)PFS HR: 0.51 (0.41-0.64)OS HR: 0.60 (0.40-0.89)c98.89% CI.QoL/toxicityQoL was an exploratory endpoint; not eligible for ESMO-MCBS gradingESMO-MCBS scorebESMO-MCBS v1.15 The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee (https://www.esmo.org/guidelines/esmo-mcbs/scale-evaluation-forms-v1.0-v1.1/scale-evaluation-forms-v1.1).4d>30% of control arm patients never received subsequent immunotherapy, suboptimal post-progression treatment may exaggerate OS benefit.42,eForm 2a cannot be applied since median OS was NR in the control arm; consequently, the score was derived from Form 2b criteria with an upgrade for early stopping based on the OS advantage detected. (Form 2b)TherapyLenvatinib plus everolimusDisease settingAdvanced or metastatic RCC following one prior VEGF-targeted therapyTrialA study of lenvatinib alone, and in combination with everolimus, in subjects with unresectable advanced or metastatic RCC following one prior VEGF-targeted treatment32Motzer R.J. Hutson T.E. 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: 1473-1482Abstract Full Text Full Text PDF PubMed Scopus (608) Google ScholarPhase IINCT01136733ControlEverolimusMedian PFS: 5.5 monthsMedian OS: 15.4 monthsAbsolute survival gainPFS gain: 9.1 monthsOS gain: 10.1+ monthsHR (95% CI)PFS HR: 0.40 (0.24-0.68)OS HR: 0.51 (0.30-0.88)QoL/toxicityESMO-MCBS scorebESMO-MCBS v1.15 The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee (https://www.esmo.org/guidelines/esmo-mcbs/scale-evaluation-forms-v1.0-v1.1/scale-evaluation-forms-v1.1).4 (Form 2a)TherapyLenvatinib plus pembrolizumabDisease settingFirst-line treatment of advanced RCCTrialTrial to compare the efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab versus sunitinib alone in first-line treatment of subjects with advanced renal cell carcinoma (CLEAR)6Motzer R. Alekseev B. Rha S.Y. et al.Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.N Engl J Med. 2021; 384: 1289-1300Crossref PubMed Scopus (344) Google ScholarPhase IIINCT02811861ControlSunitinibMedian PFS: 9.2 monthsOS at 2 years 70.4%Absolute survival gainPFS gain: 14.7 monthsOS gain: 8.8%HR (95% CI)PFS HR: 0.39 (0.32-0.49)OS HR: 0.66 (0.49-0.88); P = 0.005 <0.016 for early stoppingQoL/toxicityESMO-MCBS scorebESMO-MCBS v1.15 The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee (https://www.esmo.org/guidelines/esmo-mcbs/scale-evaluation-forms-v1.0-v1.1/scale-evaluation-forms-v1.1).4eForm 2a cannot be applied since median OS was NR in the control arm; consequently, the score was derived from Form 2b criteria with an upgrade for early stopping based on the OS advantage detected.,fFDA approved; not EMA approved. (Form 2b)TherapyNivolumabDisease settingTreatment of advanced RCC after failure of one or two regimens of antiangiogenic therapyTrialStudy of nivolumab versus everolimus in subjects with advanced or metastatic clear cell RCC who have received prior antiangiogenic therapy (CheckMate 025)33Motzer R.J. Escudier B. McDermott D.F. et al.Nivolumab versus everolimus in advanced renal-cell carcinoma.N Engl J Med. 2015; 373: 1803-1813Crossref PubMed Scopus (3870) Google Scholar, 34Cella D. Grunwald V. Nathan P. et al.Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial.Lancet Oncol. 2016; 17: 994-1003Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 35Shah R. Botteman M. Solem C.T. et al.A Quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis of nivolumab versus everolimus in advanced renal cell carcinoma (aRCC).Clin Genitourin Cancer. 2019; 17: 356-365.e1Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 36Motzer R.J. Escudier B. George S. et al.Nivolumab versus everolimus in patients with advanced renal cell carcinoma: updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial.Cancer. 2020; 126: 4156-4167Crossref PubMed Scopus (96) Google ScholarPhase IIINCT01668784ControlEverolimusMedian OS: 19.6 monthsAbsolute survival gainOS gain: 5.4 monthsHR (95% CI)OS HR: 0.73 (0.57-0.93)QoL/toxicityReduced grade 3-4 AEs 19% versus 37%QoL was reported in an exploratory analysis; not eligible for ESMO-MCBS gradingESMO-MCBS scorebESMO-MCBS v1.15 The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee (https://www.esmo.org/guidelines/esmo-mcbs/scale-evaluation-forms-v1.0-v1.1/scale-evaluation-forms-v1.1).5 (Form 2a)TherapyNivolumab plus ipilimumabDisease settingFirst-line treatment of intermediate-/poor-risk advanced RCCTrialA study of nivolumab combined with ipilimumab versus sunitinib monotherapy in subjects with previously untreated, advanced or metastatic RCC (CheckMate 214)9Albiges L. Tannir N.M. Burotto M. et al.Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial.ESMO Open. 2020; 5: e001079Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar,37Cella D. Grünwald V. Escudier B. et al.Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial.Lancet Oncol. 2019; 20: 297-310Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 38Motzer R.J. Escudier B. McDermott D.F. et al.Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial.J Immunother Cancer. 2020; 8: e000891Crossref PubMed Scopus (102) Google Scholar, 39Motzer R.J. Rini B.I. McDermott D.F. 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: 1370-1385Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar, 40Motzer R.J. Tannir N.M. McDermott D.F. et al.Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.N Engl J Med. 2018; 378: 1277-1290Crossref PubMed Scopus (2211) Google ScholarPhase IIINCT02231749ControlSunitinibMedian OS: 26.6 monthsAbsolute survival gainOS gain: 21.5 monthsHR (95% CI)OS HR: 0.65 (0.54-0.78)QoL/toxicityQoL was reported in an exploratory analysis; not eligible for ESMO-MCBS gradingESMO-MCBS scorebESMO-MCBS v1.15 The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee (https://www.esmo.org/guidelines/esmo-mcbs/scale-evaluation-forms-v1.0-v1.1/scale-evaluation-forms-v1.1).4d>30% of control arm patients never received subsequent immunotherapy, suboptimal post-progression treatment may exaggerate OS benefit.42 (Form 2a)TherapyPembrolizumab plus axitinibDisease settingFirst-line treatment of advanced clear cell RCCTrialA study to evaluate efficacy and safety of pembrolizumab in combination with axitinib versus sunitinib monotherapy as a first-line treatment of locally advanced or metastatic RCC (KEYNOTE-426)8Powles T. Plimack E.R. Soulières D. et al.Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial.Lancet Oncol. 2020; 21: 1563-1573Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar,41Rini B.I. Plimack E.R. Stus V. et al.Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med. 2019; 380: 1116-1127Crossref PubMed Scopus (1450) Google ScholarPhase IIINCT02853331ControlSunitinibMedian PFS: 11.1 monthsMedian OS: 35.7 monthsAbsolute survival gainPFS gain: 4.3 monthsEstimated OS gain: 16.8 monthsgCalculated estimate of gain based on the PE HR 0.68.HR (95% CI)PFS HR: 0.71 (0.60-0.84)OS HR: 0.68 (0.55-0.85)QoL/toxicityESMO-MCBS scorebESMO-MCBS v1.15 The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee (https://www.esmo.org/guidelines/esmo-mcbs/scale-evaluation-forms-v1.0-v1.1/scale-evaluation-forms-v1.1).4d>30% of control arm patients never received subsequent immunotherapy, suboptimal post-progression treatment may exaggerate OS benefit.42 (Form 2a)TherapyTivozanibDisease settingTreatment as first targeted therapy in recurrent or metastatic RCC with a clear cell componentTrialA study to compare tivozanib with sorafenib in subjects with advanced RCC (TIVO-1)11Motzer R.J. 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: 3791-3799Crossref PubMed Scopus (291) Google ScholarPhase IIINCT01030783ControlSorafenibMedian PFS: 9.1 monthsMedian OS: 28.8 monthsAbsolute survival gainPFS gain: 2.8 monthsOS gain: 0.5 monthsHR (95% CI)PFS HR: 0.80 (0.64-0.99)OS HR: 1.245 (0.954-1.624) NSQoL/toxicityNo QoL benefitESMO-MCBS scorebESMO-MCBS v1.15 The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee (https://www.esmo.org/guidelines/esmo-mcbs/scale-evaluation-forms-v1.0-v1.1/scale-evaluation-forms-v1.1).1 (Form 2b)AE, adverse event; CI, confidence interval; EMA, European Medicines Agency; ESMO-MCBS, European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; FDA, Food and Drug Administration; HR, hazard ratio; HRQoL, health-related quality of life; NR, not reached; NS, not significant; OS, overall survival; PE, point estimate; PFS, progression-free survival; QoL, quality of life; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.a EMA approvals since January 2016 and FDA approvals since 1 January 2020.b ESMO-MCBS v1.15Cherny N.I. Dafni U. Bogaerts J. et al.ESMO-Magnitude of Clinical Benefit Scale version 1.1.Ann Oncol. 2017; 28: 2340-2366Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee (https://www.esmo.org/guidelines/esmo-mcbs/scale-evaluation-forms-v1.0-v1.1/scale-evaluation-forms-v1.1).c 98.89% CI.d >30% of control arm patients never received subsequent immunotherapy, suboptimal post-progression treatment may exaggerate OS benefit.42Gyawali B. de Vries E.G.E. Dafni U. et al.Biases in study design, implementation, and data analysis that distort the appraisal of clinical benefit and ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scoring.ESMO Open. 2021; 6: 100117Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholare Form 2a cannot be applied since median OS was NR in the control arm; consequently, the score was derived from Form 2b criteria with an upgrade for early stopping based on the OS advantage detected.f FDA approved; not EMA approved.g Calculated estimate of gain based on the PE HR 0.68. Open table in a new tab AE, adverse event; CI, confidence interval; EMA, European Medicines Agency; ESMO-MCBS, European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; FDA, Food and Drug Administration; HR, hazard ratio; HRQoL, health-related quality of life; NR, not reached; NS, not significant; OS, overall survival; PE, point estimate; PFS, progression-free survival; QoL, quality of life; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor. First-line PD-1 inhibitor therapy with either VEGFR-targeted therapy or cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibition has improved overall outcome for patients with advanced ccRCC.6Motzer R. Alekseev B. Rha S.Y. et al.Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.N Engl J Med. 2021; 384: 1289-1300Crossref PubMed Scopus (344) Google Scholar, 7Choueiri T.K. Powles T. Burotto M. et al.Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med. 2021; 384: 829-841Crossref PubMed Scopus (362) Google Scholar, 8Powles T. Plimack E.R. Soulières D. et al.Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial.Lancet Oncol. 2020; 21: 1563-1573Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 9Albiges L. Tannir N.M. Burotto M. et al.Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial.ESMO Open. 2020; 5: e001079Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar Recent data from the CLEAR trial show a significant OS advantage for lenvatinib–pembrolizumab (20 mg daily and 200 mg every 3 weeks, respectively, until progression) compared with sunitinib alone (HR 0.66, 95% CI 0.49-0.88, P = 0.005) [median OS not reached (NR)].6Motzer R. Alekseev B. Rha S.Y. et al.Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.N Engl J Med. 2021; 384: 1289-1300Crossref PubMed Scopus (344) Google Scholar Response rates (RRs) and progression-free survival (PFS) also favoured lenvatinib–pembrolizumab [RR 71% versus 36%; PFS HR 0.39, (95% CI 0.32-0.49), median PFS 23.9 months (20.8, 27.7) versus 9.2 months (95% CI 6.0-11.0 months), P < 0.001].6Motzer R. Alekseev B. Rha S.Y. et al.Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.N Engl J Med. 2021; 384: 1289-1300Crossref PubMed Scopus (344) Google Scholar Dose reductions for treatment-related toxicity were common in the combination arm (68.8% versus 50.3% for sunitinib).6Motzer R. Alekseev B. Rha S.Y. et al.Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.N Engl J Med. 2021; 384: 1289-1300Crossref PubMed Scopus (344) Google Scholar These results led to the FDA approval of lenvatinib–pembrolizumab (not EMA approved). Lenvatinib–pembrolizumab joins other VEGFR–PD-1 inhibitor-targeted combinations (axitinib–pembrolizumab or cabozantinib–nivolumab) to be recommended for first-line treatment of advanced ccRCC irrespective of International Metastatic RCC Database Consortium (IMDC) risk groups [I, A]. There is no preferred VEGFR tyrosine kinase inhibitor (TKI)–PD-1 inhibitor-targeted combination, and indirect comparisons across trials are not recommended [I, D].1Escudier B. Porta C. Schmidinger M. et al.Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2019; 30: 706-720Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar,6Motzer R. Alekseev B. Rha S.Y. et al.Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.N Engl J Med. 2021; 384: 1289-1300Crossref PubMed Scopus (344) Google Scholar,7Choueiri T.K. Powles T. Burotto M. et al.Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med. 2021; 384: 829-841Crossref PubMed Scopus (362) Google Scholar Ipilimumab–nivolumab also continues to be recommended for first-line treatment of IMDC intermediate- and poor-risk disease [I, A].9Albiges L. Tannir N.M. Burotto M. et al.Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial.ESMO Open. 2020; 5: e001079Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar Sunitinib [I, A], pazopanib [I, A] and tivozanib [II, B] are alternatives to PD-1 inhibitor-based first-line combinations when immunotherapy is contraindicated or not available.8Powles T. Plimack E.R. Soulières D. et al.Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial.Lancet Oncol. 2020; 21: 1563-1573Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 9Albiges L. Tannir N.M. Burotto M. et al.Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial.ESMO Open. 2020; 5: e001079Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 10Motzer R.J. Hutson T.E. Cella D. et al.Pazopanib versus sunitinib in metastatic renal-cell carcinoma.N Engl J Med. 2013; 369: 722-731Crossref PubMed Scopus (1335) Google Scholar, 11Motzer R.J. 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: 3791-3799Crossref PubMed Scopus (291) Google Scholar, 12Motzer R.J. Hutson T.E. Tomczak P. et al.Sunitinib versus Interferon alfa in metastatic renal-cell carcinoma.N Engl J Med. 2007; 356: 115-124Crossref PubMed Scopus (4970) Google Scholar Cabozantinib [II, A] is an alternative in IMDC intermediate- and poor-risk disease for those patients who cannot receive first-line PD-1 inhibitor-based therapy,13Choueiri T.K. Hessel C. Halabi S. et al.Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update.Eur J Cancer. 2018; 94: 115-125Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar while surveillance may be appropriate for selected patients with IMDC favourable-risk disease with low tumour burden [III, C].14Rini B.I. Dorff T.B. Elson P. et al.Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial.Lancet Oncol. 2016; 17: 1317-1324Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar The OS signals in the IMDC favourable-risk patients treated with VEGFR–PD-1 combinations are immature and not yet superior to sunitinib. Better response and PFS data, however, support the use of the combination in this exploratory and underpowered subset. Further follow-up data are awaited. The combination of lenvatinib–everolimus (18 mg daily and 5 mg daily, respectively, until progression) was also included as a third arm in the CLEAR trial and was compared with sunitinib alone.6Motzer R. Alekseev B. Rha S.Y. et al.Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.N Engl J Med. 2021; 384: 1289-1300Crossref PubMed Scopus (344) Google Scholar This combination achieved a significant PFS advantage compared with sunitinib [HR 0.65, 95% CI 0.53-0.80, P < 0.001, median PFS 14.7 months (95% CI 11.1-16.7 months) versus 9.2 months (95% CI 6.0-11.0 months)], but did not demonstrate an OS benefit (HR 1.15, 95% CI 0.88-1.50). Dose reductions for treatment-related toxicity with lenvatinib–everolimus were common (73.2% versus 50.3% for sunitinib), reflecting the adverse event profile. Thus, lenvatinib–everolimus should not be regarded as a standard first-line treatment of metastatic disease [I, D]. The PFS advantage over sunitinib underpins the activity for the combination, however, which can be recommended as a subsequent therapy after first-line treatment, along with other agents [III, B]. Robust prospective second-line data exclusively after first-line PD-1 inhibitor-based combination therapy are lacking. Prospective datasets exist for axitinib, pazopanib and sunitinib, but they include mixed patient populations and small numbers.15Powles T.B. Oudard S. Grünwald V. et al.718P A phase II study of patients with advanced or metastatic renal cell carcinoma (mRCC) receiving pazopanib after previous checkpoint inhibitor treatment.Ann Oncol. 2020; 31: S564Abstract Full Text Full Text PDF Google Scholar, 16Grande E. Alonso Gordoa T. Reig Torras O. et al.INMUNOSUN-SOGUG trial: a prospective phase II study to assess the efficacy and safety of sunitinib as second-line (2L) treatment in patients (pts) with metastatic renal cell cancer (RCC) who received immunotherapy-based combination upfront.J Clin Oncol. 2020; 38: 5060Crossref Google Scholar, 17Ornstein M.C. Pal S.K. Wood L.S. 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: 1386-1394Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar There are also retrospective, exploratory, subset analyses from studies with other endpoints (cabozantinib, tivozanib, lenvatinib–everolimus).18Powles T. Motzer R.J. 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: 663-669Crossref PubMed Scopus (47) Google Scholar, 19Rini B.I. Pal S.K. Escudier B.J. 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: 95-104Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 20Glen H. Puente J. Heng D.Y.C. et al.A phase 2 trial of lenvatinib 18 mg versus 14 mg once daily (QD) in combination with everolimus (5 mg QD) in renal cell carcinoma (RCC) after 1 prior VEGF-targeted treatment.J Clin Oncol. 2018; 36: TPS707Crossref Google Scholar Responses were seen (∼20%) in all of these studies and outcome was in line with the expectations for sequencing therapy. All of these agents have been given the same level of cautious recommendation, due to the imperfections of the datasets [III, B]. It is likely that all approved VEGFR-targeted therapy has some activity and should be considered the standard of care. The role of further ICIs after PD-1 inhibitor-based first-line combination therapy remains experimental and is not considered standard of care. Prospective data on further lines of therapy after first-line PD-1 inhibitor combination therapy and second-line VEGFR-based therapy are lacking. It is likely that sequencing different targeted therapies approved in advanced RCC is beneficial, as was the case in the pre-ICI era [IV, B]. Rechallenge with ICIs is unproven, and should not be regarded as a standard option. The treatment algorithms for systemic first-line and second-line treatment of ccRCC have been updated (Figures 1 and 2 in the original published guideline, respectively).1Escudier B. Porta C. Schmidinger M. et al.Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2019; 30: 706-720Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar These are now combined into one algorithm for this update (Figure 1). Until recently, guidelines for the treatment of advanced papillary renal cancer patients have been largely based on subset analysis from small, randomised trials that compared everolimus and sunitinib, and included all non-ccRCC patients.21Armstrong A.J. Halabi S. Eisen T. et al.Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial.Lancet Oncol. 2016; 17: 378-388Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar,22Tannir N.M. Jonasch E. Albiges L. et al.Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial.Eur Urol. 2016; 69: 866-874Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar The papillary subsets of patients in these trials were modest (ESPN n = 27 and ASPEN n = 70). ASPEN showed improved RR and PFS for sunitinib compared with everolimus [RR of 24% versus 5%; median PFS 8.1 months (80% CI 5.8-11.1 months) versus 5.5 months (80% CI 4.4-5.6 months), HR 1.6, (80% CI 1.1-2.3)], but not OS.21Armstrong A.J. Halabi S. Eisen T. et al.Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial.Lancet Oncol. 2016; 17: 378-388Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar Therefore, sunitinib became the preferred agent. Small, single-arm datasets for axitinib (n = 44) and pazopanib (n = 18) also reported modest responses in papillary renal cancer, but have not been widely adopted.23Negrier S. Rioux-Leclercq N. Ferlay C. et al.Axitinib in first-line for patients with metastatic papillary renal cell carcinoma: results of the multicentre, open-label, single-arm, phase II AXIPAP trial.Eur J Cancer. 2020; 129: 107-116Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar,24Buti S. Bersanelli M. Maines F. et al.First-line pazopanib in non-clear-cell renal carcinoma: the Italian Retrospective Multicenter PANORAMA study.Clin Genitourin Cancer. 2017; 15: e609-e614Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Early evidence suggested that mesenchymal-epithelial transition (MET) exon alterations occur in papillary RCC (type 1) and may be used to select patients for a precision medicine-based therapy.25Choueiri T.K. Heng D.Y.C. Lee J.L. et al.Efficacy of savolitinib vs sunitinib in patients with MET-driven papillary renal cell carcinoma: the SAVOIR phase 3 randomized clinical trial.JAMA Oncol. 2020; 6: 1247-1255Crossref PubMed Scopus (50) Google Scholar First-line treatment recommendations for papillary RCC have changed based on three recent datasets. The Southwest Oncology Group (SWOG) PAPMET trial, a randomised, phase II study, explored cabozantinib (n = 44) versus sunitinib (n = 46) versus savolitinib (n = 29) versus crizotinib (n = 28) in advanced papillary renal cancer.26Pal S.K. Tangen C. Thompson Jr., I.M. et al.A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial.Lancet. 2021; 397: 695-703Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar The last two arms of this study were discontinued due to futility. PFS was the primary endpoint. Results showed a PFS advantage for cabozantinib over sunitinib [9.0 months (95% CI 6-12 months) versus 5.6 months (95% CI 3-7 months), HR 0.60, (95% CI 0.37-0.97), P = 0.02]. Cabozantinib was also associated with higher RRs (23% versus 4% for sunitinib). OS (an underpowered secondary endpoint) was not significantly different between the arms. Median OS for cabozantinib and sunitinib was 20 months (95% CI 19.3 months-NR) versus 16 months (95% CI 13-22 months), respectively. Adverse event profiles were in line with previous reports for these agents. Pembrolizumab was explored in a single-arm trial which included a spectrum of non-ccRCC patients (Keynote 427).27McDermott D.F. Lee J.L. Ziobro M. et al.Open-label, single-arm, phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced non-clear cell renal cell carcinoma.J Clin Oncol. 2021; 39: 1029-1039Crossref PubMed Google Scholar Data on 118 papillary cancer patients were reported. RR was 29%, PFS was 5.5 months (95% CI 3.9-6.1 months) and OS was 31.5 months (95% CI 25.5 months-NR). Adverse event profiles were in line with pembrolizumab single-agent studies. The SAVOIR trial explored savolitinib (a MET inhibitor) as first-line treatment of MET-driven tumours [defined as chromosome 7 gain, MET amplification, MET kinase domain variations or hepatocyte growth factor (HGF) amplification by DNA alteration analysis (∼30% of screened patients were MET positive)].25Choueiri T.K. Heng D.Y.C. Lee J.L. et al.Efficacy of savolitinib vs sunitinib in patients with MET-driven papillary renal cell carcinoma: the SAVOIR phase 3 randomized clinical trial.JAMA Oncol. 2020; 6: 1247-1255Crossref PubMed Scopus (50) Google Scholar Savolitinib (n = 27) was compared with sunitinib (n = 33). The trial was stopped early, largely due to accrual issues. The efficacy data appeared to favour savolitinib [median PFS 7.0 months (95% CI 2.8 months-NR) versus 5.6 months (95% CI 4.1-6.9 months), PFS HR 0.71 (95% CI 0.37-1.36), OS HR 0.51 (94% CI 0.21-1.17), RR 27% versus 7%, for savolitinib and sunitinib, respectively]. The median OS for savolitinib was NR. Savolitinib was well tolerated compared with sunitinib, with 42% grade 3 or more adverse events (versus 81% with sunitinib). Robust data with a statistically significant OS signal remain elusive in this disease, mainly due to the challenges of conducting large, randomised trials in rare cancers. The guideline authors therefore focused on the randomised data available or those from larger phase II trials to support their recommendations. Clinical trials are required in this disease. Robust data are also lacking for second-line therapy for papillary renal cancer. Any targeted therapy or immunotherapy recommended in the first-line setting that has not previously been given is cautiously recommended [IV, B]. The evidence of an OS advantage for second-line therapy and the principal of sequencing therapy have not been proven in randomised trials. Best supportive care alone may be considered in selected individuals [IV, C]. A new treatment algorithm for systemic first-line and second-line treatment of papillary renal cancer has been added (Figure 5); this figure replaces part of Figure 4 in the original published guideline. •Lenvatinib–pembrolizumab [I, A; ESMO-MCBS v1.1 score: 4] is now FDA approved but not EMA approved and joins other VEGFR–PD-1 inhibitor-targeted combinations (axitinib–pembrolizumab [I, A; ESMO-MCBS v1.1 score: 4] or cabozantinib–nivolumab [I, A; ESMO-MCBS v1.1 score: 4]) to be recommended for first-line treatment of advanced ccRCC, irrespective of the IMDC risk groups. There is no preferred VEGFR TKI–PD-1 inhibitor combination and indirect comparisons across trials are not recommended [I, D].•Ipilimumab–nivolumab continues to be recommended as first-line treatment of IMDC intermediate- and poor-risk disease [I, A; ESMO-MCBS v1.1 score: 4].•ICI-based therapy is particularly active in sarcomatoid renal tumours and should be strongly recommended above single-agent VEGFR TKI [II, A].•Sunitinib [I, A], pazopanib [I, A] and tivozanib [II, B; ESMO-MCBS v1.1 score: 1] are alternatives to PD-1 inhibitor-based first-line combinations when immunotherapy is contraindicated or not available. Cabozantinib [II, A] is also an alternative in IMDC intermediate- and poor-risk disease for those patients who cannot receive first-line PD-1 inhibitor-based therapy.•Sunitinib or pazopanib are potential alternatives to PD-1 inhibitor-based combination therapy in IMDC favourable-risk disease due to a lack of clear superiority for PD-1-based combinations over sunitinib in this subgroup of patients, and the non-inferior effectiveness of sunitinib and pazopanib demonstrated by the COMPARZ trial [I, B].•Surveillance is an alternative approach in a small subset of patients. This requires careful consideration [III, C].•Only ICI-based combinations with a survival advantage are recommended in the first-line setting. Axitinib–avelumab and bevacizumab–atezolizumab are not yet associated with an OS advantage and are therefore not recommended [I, D].•Cessation of ICIs should be considered after 2 years of therapy [IV, C].•Lenvatinib–everolimus should not be regarded as a standard first-line treatment of metastatic disease [I, D] but can be recommended as a subsequent therapy after first-line treatment, along with other agents [III, B]. •Sequencing VEGFR TKI therapy after PD-1 inhibitor-based first-line therapy is associated with modest RRs and should be considered the standard of care [III, B]. These data are derived from suboptimal studies. The chosen agent should be a VEFGR-targeted agent that they have not previously received [III, B].•Randomised data to support continued ICIs after progression on first-line ICI-based therapy is lacking and this therapy is not recommended [IV, D]. •Cabozantinib is the preferred first-line agent for advanced papillary RCC without additional molecular testing [II, B].•Alternative options include sunitinib [II, B], pembrolizumab [III, B] without additional molecular testing and savolitinib (where available) in MET-driven tumours [III, C].•Second-line therapy should focus on those first-line agents that have not been used previously [IV, C]. Best supportive care can be considered in selected patients due to the lack of data for systemic therapy [IV, C]. The ESMO Guidelines Committee acknowledges and thanks the following people who have acted as reviewers for this article: Ignacio Duran Martinez, Ravindran Kanesvaran and Bernadett Szabados, ESMO Faculty (genitourinary tumours, non-prostate). Manuscript editing support was provided by Louise Green, Catherine Evans and Jennifer Lamarre (ESMO Guidelines staff). Nathan Cherny, Chair of the ESMO-MCBS Working Group, Urani Dafni ESMO-MCBS Working Group Member/Frontier Science Foundation Hellas and Giota Zygoura of Frontier Science Foundation Hellas provided review and validation of the ESMO-MCBS scores. Nicola Latino (ESMO Scientific Affairs staff) and Angela Corstorphine of Kstorfin Medical Communications Ltd provided coordination and support of the ESMO-MCBS scores and preparation of the ESMO-MCBS table.