EUROPEAN UROLOGY OPEN SCIENCE 46 (2022) 39–42 available at www.sciencedirect.com journal homepage: www.eu-openscience.europeanurology.com Research Letter: Open Science Is Adjuvant Immunotherapy Worth for All Patients with From an oncological standpoint, patients with non- Clear-cell Renal Cell Carcinoma at High Risk of metastatic ccRCC who might be offered adjuvant Recurrence? immunotherapy may harbor heterogeneous disease entities that cannot be captured by the KEYNOTE-564 criteria [1]. Results from the KEYNOTE-564 trial were published 1 yr According to the Leibovich score [6] and the ECOG-ACRIN ago in the New England Journal of Medicine [1]. Patients with 2805 (ASSURE) prognostic model [7], the estimated 5-yr clear-cell renal cell carcinoma (ccRCC) who met the proto- DFS varies significantly in each KEYNOTE-564 risk group col-defined criteria for high risk of recurrence (stage T2 (Table 1). While these models are not devoid of limitations with nuclear grade 4 or sarcomatoid differentiation, stage [6,7], specific prognostic factors (eg, tumor size, World T3, regional lymph-node metastasis, or stage M1 with no Health Organization/International Society of Urological evidence of disease [NED]) were randomly assigned to Pathology grade, presence of necrosis, and vascular inva- receive either adjuvant pembrolizumab or placebo. The pri- sion, integrated into the above-mentioned scores) might mary endpoint was disease-free survival (DFS). Within this play a key role in modulating the risk of recurrence in pivotal randomized clinical trial, treatment with pem- individual patients. Overall, the estimated 5-yr DFS among brolizumab showed a disease-free survival (DFS) benefit eligible patients may range from 12% to 95% according to compared to placebo (DFS at 24 mo: 77.3% vs 68.1%) [1]. the Leibovich score [6] and from 8% to 79% according to Grade 3 adverse events occurred in 32.4% of the patients the ASSURE model [7]. Therefore, although DFS might not who received pembrolizumab and 17.7% of those who necessarily be a reliable surrogate metric for OS [8], we received placebo. In the updated analysis after 30 mo of fol- might argue that the higher the risk of recurrence, the bet- low-up, adjuvant pembrolizumab continued to show a ben- ter is the cost/benefit ratio for adjuvant pembrolizumab. efit in DFS compared with placebo (hazard ratio 0.63, 95% Interestingly, in our prospectively collected multicenter confidence interval 0.50–0.80) [2] both in the intention- data set (n = 681 consecutive patients with M0 ccRCC trea- to-treat population and across several prespecified and ted between 2015 and 2021 at Careggi Hospital, San Luigi exploratory subgroups. Subgroup analyses showed a benefit Hospital, and UZ Leuven), 26% of the patients could have irrespective of the presence of sarcomatoid features, nuclear met the KEYNOTE-564 eligibility criteria, most of whom tumor grade 4, or M1 with NED status at baseline, although (87%) had pT3a N0 stage. While these patients would have the numbers in some subgroups were small and should be been classified as at ‘‘intermediate-high’’ risk, their esti- interpreted with caution [2]. The safety profile of adjuvant mated 5-yr DFS could range significantly (Table 1), underly- pembrolizumab remained consistent with the primary find- ing the need to better stratify ‘‘eligible’’ patients using ings of the study [1]. However, overall survival (OS) data are available prognostic models [3,4]. still immature. A second issue concerns the potential value of lymph In this scenario, both the European Association of Urol- node dissection (LND) in the new era of adjuvant ogy and European Society of Medical Oncology changed immunotherapy. While patients with pN+ disease represent their guidelines, introducing a (weak) recommendation for ideal candidates for adjuvant pembrolizumab [9] (with an adjuvant pembrolizumab following surgery with curative estimated 5-yr DFS ranging from 8% to 56% according to intent in patients with ccRCC meeting the KEYNOTE-564 the ASSURE model [7]; Table 1), in our data set only 6% of eli- study criteria [3,4]. Accordingly, the European Medicines gible patients had pN+ disease (of whom almost all had pT3– Agency approved the use of pembrolizumab as monother- 4 ccRCC). This finding highlights the current controversies apy in the adjuvant setting [5]. regarding the anatomical templates and potential benefits Notably, several issues regarding patient selection and of LND for RCC [10]. In fact, current guidelines recommend the cost-effectiveness of adjuvant immunotherapy need to removal of ‘‘clinically enlarged lymph nodes for staging, be addressed. prognosis and follow-up implications’’, and not to offer First, while patient selection is key, achieving this goal in extended LND to patients with organ-confined disease [3]. clinical practice is still an unmet need. Namely, understand- However, in patients with cN0 locally advanced disease, ing how to pick the right patients from eligible candidates pN status might be key in stratifying those at higher risk of (for whom the risk of treatment-related harm may be worth relapse after surgery (Table 1) and could refine decision- the benefit) is complex and nuanced. making. https://doi.org/10.1016/j.euros.2022.10.002 0302-2838/Ó 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 40 EUROPEAN UROLOGY OPEN SCIENCE 46 (2022) XXX Table 1 – Estimated 5 - yr MFS (according to the Leibovich score [6]) and 5 - yr DFS (according to the ASSURE model [7] ) for all patients eligible for adjuvant immunotherapy according to the KEYNOTE - 564 study criteria [1], stratified by pT stage, pN stage , and W orld Health Organization /International Society of Urological Pathology grade. aPembro = adjuvant pembrolizumab; ccRCC = clear - cell renal cell carcinoma; DFS = disease - free survival; HiR = high risk; IR = intermediate risk; KN - 564 KEYNOTE - 564 study; LR = low risk; LS = Leibovich score; MFS = metastasis - free survival VI = va scular invasion . a Using the online calculator at https://cancernomograms.com/nomograms/492. EUROPEAN UROLOGY OPEN SCIENCE 46 (2022) XXX 41 Third, the differential impact of adjuvant immunother- [2] Powles T, Tomczak P, Park SH, et al. Pembrolizumab versus placebo apy on DFS and OS across patient populations (M0 vs M1 as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a NED) is still a matter of debate [4]. In the KEYNOTE-564 trial, multicentre, randomised, double-blind, placebo-controlled, phase M1 NED status was defined as complete resection of all 3 trial. Lancet Oncol 2022;23:1133–44. https://doi.org/10.1016/ metastases at the time of or within 1 yr after nephrectomy S1470-2045(22)00487-9. [1]. Notably, patients with oligometastatic RCC represent a [3] Bedke J, Albiges L, Capitanio U, et al. 2021 updated European Association of Urology guidelines on the use of adjuvant heterogeneous cohort that requires a multidisciplinary pembrolizumab for renal cell carcinoma. Eur Urol 2022;81:134–7. approach. In this context, the potential value of (cytoreduc- https://doi.org/10.1016/j.eururo.2021.11.022. tive) nephrectomy plus complete metastasectomy followed [4] Powles T, Albiges L, Bex A, et al. ESMO clinical practice guideline by adjuvant pembrolizumab versus upfront PD-1-based update on the use of immunotherapy in early stage and advanced combination therapy requires further investigation [3,4]. renal cell carcinoma. Ann Oncol 2021;32:1511–9. https://doi.org/ 10.1016/j.annonc.2021.09.014. Lastly, as a non-negligible proportion of patients with [5] European Medicines Agency. CHMP post-authorisation summary of ccRCC could meet the KEYNOTE-564 eligibility criteria, the positive opinion for Keytruda (II-108). https://www.ema.europa.eu/ cost-effectiveness and economic sustainability of adjuvant en/documents/variation-report/keytruda-h-c-003820-ii-0108- immunotherapy must be carefully assessed, especially in epar-assessment-report-variation_en.pdf. [6] Leibovich BC, Blute ML, Cheville JC, et al. Prediction of progression single-payer health care systems. after radical nephrectomy for patients with clear cell renal cell A recent study using a decision analytic Markov model carcinoma: a stratification tool for prospective clinical trials. Cancer found that adjuvant pembrolizumab was not cost-effective 2003;97:1663–71. https://doi.org/10.1002/cncr.11234. at a 5-yr time horizon. In fact, at current prices, pem- [7] Correa AF, Jegede OA, Haas NB, et al. Predicting disease recurrence, brolizumab was found to be cost-effective only for the sub- early progression, and overall survival following surgical resection for high-risk localized and locally advanced renal cell carcinoma. Eur set of ccRCC patients highest risk 5 yr after treatment Urol 2021;80:20–31. https://doi.org/10.1016/j.eururo.2021.02.025. (including patients with complete metastasectomy, regio- [8] Harshman LC, Xie W, Moreira RB, et al. Evaluation of disease-free nal lymph node involvement, or pT3 tumors >7 cm with sar- survival as an intermediate metric of overall survival in patients comatoid features) [11]. with localized renal cell carcinoma: a trial-level meta-analysis. Cancer 2018;124:925–33. https://doi.org/10.1002/cncr.31154. Given the increasing costs of managing cancer as new [9] Capitanio U, Larcher A, Montorsi F. Re: Toni K. Choueiri, Piotr agents become available [12] and the current lack of predic- Tomczak, Se Hoon Park, et al. Adjuvant pembrolizumab after tive biomarkers, further research is needed to refine patient nephrectomy in renal-cell carcinoma. N Engl J Med 2021;385:683– selection for adjuvant immunotherapy, taking into consid- 94: Adjuvant pembrolizumab after nephrectomy: a plea to eration a variety of factors including granular tumor fea- reconsider the need for lymph node dissection. Eur Urol 2022;81: e28. https://doi.org/10.1016/j.eururo.2021.09.034. tures (modulating the risk of recurrence; Table 1), the [10] Bhindi B, Wallis CJD, Boorjian SA, et al. The role of lymph node expected survival benefit, treatment-related toxicity, ands dissection in the management of renal cell carcinoma: a systematic patients’ life expectancy, quality of life, and preferences. review and meta-analysis. BJU Int 2018;121:684–98. https://doi. The applicability of the KEYNOTE-564 findings in real- org/10.1111/bju.14127. [11] Sharma V, Wymer KM, Joyce DD, et al. Cost effectiveness of life scenarios should also be investigated before recom- adjuvant pembrolizumab after nephrectomy for high risk renal cell mending adjuvant pembrolizumab for all-comers [13]. carcinoma: insights for patient selection from a Markov model. J In summary, despite the positive findings from the KEY- Urol. In press. https://doi.org/10.1097/JU.0000000000002953. NOTE-564 trial [1,2], several unmet clinical needs remain. [12] Martini A, Mottet N, Montorsi F, et al. A plea for economically Furthermore, results from other three adjuvant immune sustainable evidence-based guidelines. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2022.08.001. checkpoint inhibitor trials (IMmotion010 [14], PROSPER [13] Fallara G, Larcher A, Rosiello G, et al. How to optimize the use of [15], and CheckMate-914 [16]) have recently been reported. adjuvant pembrolizumab in renal cell carcinoma: which patients Unfortunately, none of these trials met their primary end- benefit the most? World J Urol. In press. https://doi.org/10.1007/ point (improvement in DFS in comparison to placebo or s00345-022-04153-6. [14] Pal SK, Uzzo R, Karam JA, et al. Adjuvant atezolizumab versus placebo observation), calling again into question the benefits of for patients with renal cell carcinoma at increased risk of recurrence adjuvant therapy in the field of RCC. Although the explana- following resection (IMmotion010): a multicentre, randomised, tion for such contradictory results is complex and is likely to double-blind, phase 3 trial. Lancet 2022;400:1103–16. https://doi. be multifactorial, further steps are needed to optimize org/10.1016/S0140-6736(22)01658-0. patient selection (using clinical and molecular biomarkers) [15] Allaf M, Kim SE, Harshman LC, et al. LBA67 – Phase III randomized study comparing perioperative nivolumab (nivo) versus and improve the value proposition of adjuvant pem- observation in patients (Pts) with renal cell carcinoma (RCC) brolizumab for ccRCC at high risk of recurrence. undergoing nephrectomy (PROSPER, ECOG-ACRIN EA8143), a While we await robust OS data from the KEYNOTE-564 National Clinical Trials Network trial. Ann Oncol 2022;33: trial, as well as results from the multiarm, multistage RAM- S1432–3. https://doi.org/10.1016/j.annonc.2022.08.072. [16] Motzer RJ, Russo P, Gruenwald V, et al. LBA4 – Adjuvant nivolumab PART trial [17] and the LITESPARK-022 trial [18], individual- plus ipilimumab (NIVO+IPI) vs placebo (PBO) for localized renal cell ized shared decision-making will be key to reducing the risk carcinoma (RCC) at high risk of relapse after nephrectomy: results of overtreatment by selecting those patients who are most from the randomized, phase III CheckMate 914 trial. Ann Oncol likely to benefit from adjuvant immunotherapy. 2022;33:S1430. https://doi.org/10.1016/j.annonc.2022.08.069. [17] Oza B, Frangou E, Smith B, et al. RAMPART: a phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with Conflicts of interest: The authors have nothing to disclose. resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse. Contemp Clin Trials 2021;108:106482. https://doi. References org/10.1016/j.cct.2021.106482. [18] Choueiri TK, Bedke J, Karam JA, et al. LITESPARK-022: a phase 3 [1] Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after study of pembrolizumab + belzutifan as adjuvant treatment of clear nephrectomy in renal-cell carcinoma. N Engl J Med 2021;385:683–94. cell renal cell carcinoma (ccRCC). J Clin Oncol 2022;40:TPS4602. https://doi.org/10.1056/NEJMoa2106391. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS4602. 42 EUROPEAN UROLOGY OPEN SCIENCE 46 (2022) XXX Michele Marchioni a,b,* g Department of Urology, University Hospital Henri Mondor, APHP, Créteil, Daniele Amparore a,c France Laura Marandino a,d h Department of Urology, Radboud University Medical Center, Nijmegen, The Riccardo Bertolo a,e Netherlands Selcuk Erdem a,f i Department of Urology, Kocaeli University School of Medicine, Kocaeli, Turkey Alexandre Ingels a,g j Urology Clinic, Department of Medical, Surgical and Health Science, Stijn Muselaers a,h University of Trieste, Trieste, Italy Onder Kara a,i k Department of Urology, University Hospitals Leuven, Leuven, Belgium Nicola Pavan a,j l Department of Emergency and Organ Transplantation, Urology, Andrology Eduard Roussel a,k and Kidney Transplantation Unit, University of Bari, Bari, Italy Umberto Carbonara a,l m Department of Urology, Pederzoli Hospital, Peschiera del Garda, Italy Angela Pecoraro a,m n Department of Urology, Fundació Puigvert, Autonoma University of Pietro Diana a,n Barcelona, Barcelona, Spain Alessio Pecoraro o,p o Unit of Urological Robotic Surgery and Renal Transplantation, University of Riccardo Campi a,o,p,*, on behalf of the European Association of Urology Florence, Careggi Hospital, Florence, Italy p Young Academic Urologists Renal Cancer Working Group Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy a European Association of Urology Young Academic Urologists Renal Cancer Working Group, Arnhem, The Netherlands *Corresponding authors. Department of Urology, SS Annunziata Hospital, b G. D’Annunzio University of Chieti, Chieti, Italy (M. Marchioni). Department of Urology, SS Annunziata Hospital, G. D’Annunzio University of Chieti, Chieti, Italy Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi c Division of Urology, Department of Oncology, School of Medicine, San Luigi di Firenze, Largo Brambilla 3, 50134 Firenze, Italy. Tel. +39 055 275 Hospital, University of Turin, Turin, Italy 8020; Fax: +39 055 275 8014 (R. Campi). d Division of Experimental Oncology, Urological Research Institute, IRCCS San E-mail addresses: mic.marchioni@gmail.com (M. Marchioni) Raffaele Scientific Institute, Milan, Italy riccardo.campi@gmail.com (R. Campi). e Department of Urology, San Carlo Di Nancy Hospital, Rome, Italy f Division of Urologic Oncology, Department of Urology, Faculty of Medicine, October 4, 2022 Istanbul University, Istanbul, Turkey Associate Editor: M. Carmen Mir