BACKGROUND:Papillary renal cell cancer (pRCC) represents the largest subgroup within non-clear cell (ncc) RCC. Compared with clear cell RCC (ccRCC), pRCC is considered less sensitive to currently available systemic therapies. Here, we report exploratory results from the pRCC subgroup of the SUNNIFORECAST trial comparing ipilimumab/nivolumab with standard of care (SOC) based on central pathological review. METHODS AND PATIENTS:SUNNIFORECAST was a prospective, investigator-initiated, phase II trial evaluating ipilimumab/nivolumab versus SOC in patients with untreated, advanced nccRCC. The primary endpoint was the 12-month overall survival (OS) rate. Secondary endpoints included OS, progression-free survival (PFS), and overall response rate (ORR). PD-L1 expression was assessed exploratory. RESULTS:Of 309 randomized patients, 127 had confirmed papillary histology, in 56/173 cases the local diagnosis of pRCC required revision. Among the 127 patients with pRCC, 64 received ipilimumab/nivolumab and 63 SOC, predominantly TKI monotherapy. In the pRCC subgroup, the 12-month OS rate was 74.77% in the ipilimumab/nivolumab arm and 63.44% in the SOC arm (p = 0.085). Median OS was 24.89 months with ipilimumab/nivolumab versus 18.88 months with SOC. PD-L1 expression was evaluable in 116 of 127 patients. A CPS > 1 was more frequently observed with increasing IMDC risk category. Among patients with CPS < 1, the 12-month OS rate was 75.00% with ipilimumab/nivolumab and 68.36% with SOC (p = 0.963). In patients with CPS > 1, the 12-month OS rate was 82.38% in the ipilimumab/nivolumab arm and 63.33% in the SOC arm. DISCUSSION:This exploratory analysis has several limitations; however, it suggests that patients with pRCC treated with ipilimumab/nivolumab may derive a benefit in terms of 12-month OS rate, median OS, and ORR compared with SOC, particularly among those with CPS > 1. (Funded by Bristol Myers Squibb grant CA209-499; ClinicalTrials.gov, EUDRACT Number: 2016-000706-12; NCT03075423.).

BACKGROUND:Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare, molecularly defined subgroup of non-clear cell RCC (nccRCC) lacking an approved standard treatment. We report the exploratory analysis of this entity within the SUNNIFORECAST trial. METHODS:SUNNIFORECAST evaluated ipilimumab/nivolumab versus standard of care (SOC) in previously untreated, advanced nccRCC. The primary endpoint was the 12-months overall survival (OS) rate. Secondary endpoints included median OS, progression free survival (PFS) and overall response rate (ORR). PD-L1 expression was assessed exploratorily. RESULTS:Of 309 randomized patients, 30 had centrally confirmed FH-deficient RCC (ipilimumab/nivolumab, n=14; SOC, n= 16). The 12-months OS rate was 85.7% (95% confidence interval [CI] 53.9-96.2%) versus 73.3% (95% CI 43.6-89.1%), median OS was 35.7 months (95% CI 16.8 months-NE) versus 24.7 months (95% CI 10.6-37.7 months, hazard ratio [HR] 0.46 [0.17-1.20]), and ORR 42.9% versus 33.3%, favoring ipilimumab/nivolumab. Twenty-four patients were evaluable for PD-L1 expression; 21 had a combined positive score (CPS) ≥1. In this subgroup, the 12-months OS rate was 80.0% (95% CI 40.9-94.6%) versus 72.7% (95% CI 37.1-90.3%), median OS 38.3 months (95% CI 8.8 months-NE) versus 24.7 months (95% CI 8.8 months-NE, HR 0.43 [0.14-1.34]) and ORR 40.0% versus 36.4% for ipilimumab/nivolumab versus SOC, respectively. INTERPRETATION / DISCUSSION:Exploratory analyses suggest trends toward improved 12-months OS-rate, median OS and ORR with ipilimumab/nivolumab versus SOC in FH-deficient RCC. The majority of tumors demonstrated PD-L1-expression (e.g. CPS ≥ 1), warranting further investigation in prospective studies.

4522 Background: Non-clear cell renal cancers (nccRCC) are a rare and heterogeneous group of >20 histological and molecular defined entities. Due to the rarity of these entities, the clinical data are limited and large randomized trials are missing resulting in uncertainties for optimal treatment recommendations. So far, TKI therapy with or without immune checkpoint inhibitors (ICI) are considered standard of care (SOC) options in these diseases. Here we report the results of the academic prospective randomised European trial in therapy-naïve patients with advanced nccRCC entities, which compared ipilimumab/nivolumab (Ipi/Nivo) vs SOC. Methods: We randomly assigned patients (pts) with nccRCC in a 1:1 ratio to receive either nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses followed by a flat dose of 240 mg IV every 2 weeks or 480 mg every 4 weeks versus SOC by investigators choice until disease progression or intolerance occurred. Pts were stratified in papillary vs. non-papillary nccRCC and according to IMDC risk score. Central pathology was mandatory to confirm the correct diagnosis of the nccRCC subtype according to the WHO classification 2022.The primary endpoint was the overall survival (OS) rate at 12 months (mos), secondary endpoints were the OS rate at 6 mos and 18 mos, OS, progression-free survival (PFS) and response rate (RR). Results: 309 pts ( 70.9% male, 29.1% female) out of 316 pts were randomized to receive either Ipi/Nivo or SOC. 173 (56.0%) pts were of papillary subtype (pRCC) and 143 (44.0%) pts of non-papillary subtypes, whereas 59 pts had chromophobe (ccRCC), 20 sarcomatoid/rhabdoid, 10 collecting duct, 11 TFE3-rearranged or TFEB-altered RCC and 37 other histological features. According to the IMDC score, 23.9% were of favorable, 51.8% of intermediate and 24.3% of poor risk. The 12 mos OS rate for Ipi/Nivo of 78.3% (95%-CI 70.9%-83.9%) vs 68.3% (95%-CI 60.0%-75.3%) in the SOC arm was statistically significant (p=0.026). Median OS was 33.2 mos for the Ipi/Nivo arm and 25.2 mos for the SOC arm. The ORR of 32.8% vs. 19.4% and the median PFS of 5.4 mos vs 5.7 mos was not statistically significant different between both arms. The explorative endpoint CPS score differed between the various subentities and was associated with an advantage in OS. Pts with a CPS≥1 had an OS-rate at 12 months of 79.3% in the Ipi/Nivo arm vs. 58.3% and a median OS of 38.6 mos vs. 18.8 mos (p=0.007). Furthermore, pts who did not underwent a tumor nephrectomy (possibly due to high risk) had a survival benefit with 26.3 mos in the Ipi/Nivo arm vs 16.5 mos in the SOC arm (p=0.065) in contrast to nephrectomized pts with 38.9 mos vs 34.0 mos. Conclusions: The OS-Rate at 12 mos was significantly superior for Ipi/Nivo in comparison to SOC and the primary endpoint was met. Additionally, pts in the Ipi/Nivo arm had a longer median OS, especially those with a CPS≥1. Clinical trial information: NCT03075423 .

Non-clear cell renal cell carcinomas (nccRCC) account for approximately 20-25% of renal cell carcinomas. Approximately 20 different histologically and/or molecularly defined entities are subsumed under nccRCC. Many entities only have a share of 1% or less. Due to the rarity of the subpopulations, there are currently no larger randomized studies and there is a some uncertainty regarding the optimal treatment recommendations. The previous treatment recommendations for localized and advanced nccRCC are presented. Data from the various systemic therapies are presented. For nccRCC, there are no different entity-related therapy guidelines due to a lack of data and especially randomized studies. The tumors should be treated in the same way as clear cell renal cell carcinomas. Monotherapies with a tyrosine kinase inhibitor (TKI; in chromophobe RCC also with an mTOR inhibitor) or with combination therapy ICI/ICI or TKI/ICI (ICI: immune checkpoint inhibitor) can be used, depending on the risk factors and individual decision. Randomized trials are urgently needed.

Die nicht-klarzelligen Nierenzellkarzinome (nccRCC) haben einen Anteil von ca. 20–25

BACKGROUND:Non-clear cell renal cell cancers (nccRCCs) are a heterogeneous group of more than 20 different entities, but are rarely included in large, randomized trials. Tyrosine kinase inhibitors with or without immune checkpoint inhibition are considered as a standard of care (SOC), but optimal treatment is not yet defined. We designed the first prospective randomized trial comparing ipilimumab/nivolumab to SOC. PATIENTS AND METHODS:We randomized adult patients with previously untreated advanced or metastatic nccRCC 1:1 to nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses followed by fixed dose nivolumab of 240 mg every 2 weeks or 480 mg every 4 weeks or to SOC. Patients were stratified by histology and by IMDC risk score. Central pathology review was mandatory. The primary endpoint was the overall survival (OS) rate at 12 months, secondary endpoints included median OS, response rate, progression-free survival (PFS), safety and quality of life. RESULTS:In total, 157 patients were assigned to receive ipilimumab/nivolumab, and 152 to SOC. The 12-month survival rate was 78% with ipilimumab/nivolumab [95% confidence interval (CI) 71-84%] compared to 68% with SOC (95% CI 60-75%, P = 0.026). Median OS was 33.2 months versus 25.2 months, P = 0.163 [HR 0.81 (0.61-1.099)]. PFS was similar in both arms [HR 0.99 (0.77-1.28)]. The ORR was 32.8% versus 19.3%. No major differences between papillary and non-papillary RCC subtypes were observed for any endpoint. Exploratory analysis showed a significant OS advantage [HR 0.56 (95% CI 0.37-0.86)] associated with a PD-L1 CPS score ≥1. Treatment discontinuation due to toxicity occurred in 27 patients (17%) with ipilimumab/nivolumab and 13 patients (9%) with SOC. CONCLUSIONS:Ipilimumab/nivolumab demonstrated a significantly longer OS at the 12-month milestone and an acceptable toxicity profile. Our results therefore underline a relevant clinical benefit of ipilimumab/nivolumab in previously untreated nccRCC entities compared to current SOC.

INTRODUCTION:We evaluated the effectiveness and safety profile of the tyrosine kinase inhibitor sunitinib in patients with advanced or metastatic renal cell carcinoma (a/mRCC) in a real-world setting.METHODS:We analyzed data of adult a/mRCC patients treated with sunitinib. Data were derived from the German non-interventional post-approval multicenter STAR-TOR registry (NCT00700258). Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated using descriptive statistics and survival analyses for the entire cohort and patient subgroups.RESULTS:A total of 116 study sites recruited 702 patients treated with sunitinib (73.1% male; median age 68.0 years; median Karnofsky index 90%) between November 2010 and May 2020. The most frequent histological subtype was clear cell RCC (81.6%). Sunitinib was administered as first-line treatment in 83.5%, as second line in 11.7%, and as third line or beyond in 4.8% of the patients. Drug-related AEs and serious AEs were reported in 66.3% and 13.9% of the patients, respectively (most common AE: gastrointestinal disorders; 39.7% of all patients).CONCLUSIONS:This study adds further real-world evidence of the persisting relevance of sunitinib for patients with a/mRCC who cannot receive or tolerate immune checkpoint inhibitors. The study population includes a high proportion of patients with unfavorable MSKCC poor-risk score, but shows still good PFS and OS results, while the drug demonstrates a favorable safety profile. The STAR-TOR registry is also registered in the database of US library of medicine (NCT00700258).

Background: The role of immune checkpoint inhibitor (ICI) maintenance therapy in metastatic renal cell carcinoma (mRCC) is undefined.Objective: To determine whether switch maintenance therapy with nivolumab improves clinical outcomes in patients with mRCC with tyrosine kinase inhibitor (TKI) sensitivity. Design, setting, and participants: This open-label phase 2 trial randomized patients with a partial response or stable disease after 10-12-wk TKI induction therapy to either TKI or nivolumab maintenance. Key inclusion criteria were measurable disease, clear cell histology, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, and adequate organ function.Intervention: Intravenous nivolumab 8 x 240 mg every 2 wk, followed by 480 mg every 4 wk or sunitinib 50 mg (4-2 regimen) or pazopanib 800 mg once daily orally.Outcome measurements and statistical analyses: The primary endpoint was overall sur-vival (OS). Secondary endpoints were the objective response rate (ORR; Response Evaluation Criteria in Solid Tumors v1.1), progression-free survival (PFS), safety (Common Terminology Criteria for Adverse Events v4.03), and patient-reported out-comes (Functional Assessment of Cancer Therapy Kidney Symptom Index). The Kaplan-Meier method, two-sided log-rank tests, and Cox regression models were used for statistical analysis.Results and limitations: Maintenance therapy was nivolumab for 25 patients (51.0%) and TKI for 24 (48.9%). The median age was 65 yr (range 35-79). Nine patients (18.4%) were female, 31 (63.3%) had ECOG PS of 0, and 15 (30.6%) had favorable risk. OS data are immature (17 deaths, 34.7%). The ORR was 20.0% (n = 5) for nivolumab and 52.2% (n = 12) for TKI. PFS was worse with nivolumab (hazard ratio 2.57, 95% confidence inter-val 1.36-4.89; p = 0.003). Grade >= 3 adverse events occurred in 14 patients (56.0%) with nivolumab and 17 (70.8%) with TKI. A major limitation is early termination of our study.Conclusions: TKI treatment achieved superior ORR and PFS in comparison to nivolumab maintenance therapy. Our data do not indicate a role for nivolumab switch maintenance in mRCC.Patient summary: Patients with metastatic kidney cancer who experienced a tumor response or disease stabilization after a short period of targeted treatment with a tyro-sine kinase inhibitor did not benefit from a switch to the immunotherapy drug nivolu-mab. Patients who continued their original treatment achieved better responses and a longer time without disease progression. This trial is registered on EudraCT as 2016-002170-13 and on ClinicalTrials.gov as NCT02959554.(c) 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Objective: To evaluate the effectiveness and safety profile of the tyrosine kinase inhibitor Axitinib for patients with advanced or metastatic renal cell carcinoma (a/mRCC) in a real-world setting. Methods: Adult patients from the German non-interventional post-approval multicenter STAR-TOR registry with a/mRCC (NCT00700258) were included if treated with Axitinib in second line or beyond. Overall survival (OS), progression-free survival (PFS) and adverse events were evaluated across subgroups using descriptive statistics and survival analyses. Results: Between November 2012 and December 2020, 75 study sites recruited 210 patients treated with Axitinib (69,6% male; median age 69 years; median Karnofsky Index 80%). Clear cell RCC was the most frequent histological subtype (81.0%). Axitinib was administered as second-line in 51.4%, third-line in 24.8%, and fourth-line treatment and beyond in 23.8% of the patients, respectively. MSKCC score was 15.0% favorable, 33.6% intermediate, and 51.3% poor risk. Median PFS was 5.6 months, and median OS 18.3 months. Patients with lactate dehydrogenase (LDH) levels > 300U/l had a nominally significantly shorter OS than patients with LDH≤300U/l (8.2 vs. 19.0 months, p = 0.008). Drug related adverse and serious adverse events were reported in 56.7% and 17.6% of the patients, respectively (most common adverse event: gastrointestinal disorders; 37.6%). Conclusions: This real-world study confirms the clinical relevance of Axitinib in the second-line and beyond setting for a/mRCC with OS and PFS reported in concordance with pivotal trials, while demonstrating a favorable safety profile. A high LDH serum level could be a negative predictive marker for Axitinib effectiveness, which can aid in clinical decision making.

ZusammenfassungIn den letzten zwei Jahren sind Anti-VEGFR-Tyrosinkinase-Inhibitoren (TKI) in der Erstlinientherapie des fortgeschrittenen Nierenzellkarzinom nahezu komplett durch Immuntherapie-Kombinationen mit Checkpoint-Inhibitoren ersetzt worden. Die Prognose der Patienten konnte damit nochmals deutlich verbessert werden. In den entsprechenden Zulassungsstudien wurden mediane Überlebenszeiten von drei bis vier Jahren erreicht. Die TKI-Monotherapie hat bei günstigem Progressionsrisiko, bei Kontraindikationen gegen eine Immuntherapie und im Kontext der SARS-CoV-2-Pandemie aber weiterhin einen Stellenwert.Die Frage, welche Therapie für welche Patient/-innen geeignet ist, stellt sich vor dem Hintergrund von zwei CPI-TKI-Kombinationen und einer reinen CPI-Kombination als neuem Erstlinien-Standard auf einer neuen Basis. Temsirolimus und die Kombination Bevacizumab + Interferon-alpha spielen nahezu keine Rolle mehr. In der Zweitlinientherapie wurde für Nivolumab und Cabozantinib nach TKI-Vortherapie ein signifikanter Überlebensvorteil gegenüber Everolimus gezeigt. Die Kombination Lenvatinib + Everolimus sowie Axitinib sind weitere zugelassene Substanzen. Auch für TKI liegen Daten vor, allerdings mit begrenzter Aussagekraft. Everolimus als Monotherapie ist durch die neuen Optionen in der Zweitlinie abgelöst worden. Insgesamt fehlt es an Biomarkern, die bei der Therapiewahl unterstützen könnten. Die kürzlich erfolgte Aktualisierung der S3-Leitlinie war daher ein wichtiger Schritt, um evidenzbasiert in der klinischen Praxis Orientierung zu geben.Bei potenziell komplexeren Therapiealgorithmen und gleichzeitig nur wenig Evidenz muss auch die Frage nach der optimalen Sequenztherapie neu diskutiert werden. Die meisten Zweitlinien-Optionen wurden nach Versagen einer gegen VEGF-gerichteten TKI-Therapie geprüft, die nur noch für eine Minderheit der Patient/-innen infrage kommt.Im Rahmen eines interdisziplinären Expertengesprächs wurden im November 2020 die aktuelle Datenlage einschließlich neuerer Studienergebnisse sowie relevante Kriterien für die individuelle Therapieentscheidung diskutiert. Auch die SARS-CoV-2-Pandemie fand dabei Berücksichtigung. Ziel war es, gemeinsame Empfehlungen auf Basis der aktuell publizierten Daten und der eigenen klinischen Erfahrung für den Praxisalltag abzuleiten. Die Ergebnisse werden in dieser Publikation vorgestellt.

In the 2022 WHO classification more than 20 entities of renal cell carcinomas (RCC) were defined. Several molecularly defined RCC were separated. There is urgent need for studies investigating well defined patients with these specific entities. One prerequisite is an exact classification of non-clear cell RCC (nccRCC) including histopathological and molecular diagnostics. The SUNNIFORECAST study (NCT03075423) is a phase 2 randomised investigator-initiated trial of nivolumab with ipilimumab vs. standard of care in patients with previously untreated and advanced nccRCC. For study inclusion a reference pathology to confirm diagnosis of nccRCC was mandatory. 350 cases were submitted for reference pathology as paraffin blocks or unstained slides. Diagnoses was done by HE staining, immunohistochemistry and molecular testing. Reference pathology confirmed the diagnoses of nccRCC in 334 of 350 cases. Only few cases were diagnosed in reevaluation as ccRCC, liposarcoma or epithelioid angiomyolipoma. Histopathological diagnoses included papillary RCC (n=138-41%), chromophobe RCC (n=58-17%), RCC, NOS, mostly with sarcomatoid pattern (n=46-14%) TFE3 or TFEB altered RCC (n=25 and n=1,8%), FH-deficient RCC (n=33-10%), SDHB-deficient RCC (n=4-1%), SMARCB1-deficient renal medullary carcinoma (n=9-3%), collecting duct carcinoma (n=14-4%) and tubulocystic RCC (n=1). Interestingly no tumors out of the group of other oncocytic tumous or clear cell papillary renal cell tumors were detected. Compared to primary pathology diagnosis changed in 116/350 cases. There was no correct primary diagnosis in 28/33 cases of FH-deficient RCC, 3/4 cases of SDHB deficient RCC and 17/26 cases of translocation RCC. All chromophobe RCC showed sarcomatoid dedifferentiation or coagulative tumor necrosis. In papillary renal cell carcinoma, micropapillary and microcystic architecture was very frequently detected in G1/G2 tumors. Reference pathology is a prerequisite for clinical studies investigating ncc RCC. The diagnosis of molecular defined RCC is still problematic in daily diagnosis. The study was supported by a grant of BMS (BMS).

Introduction: Inhibition of neo-angiogenesis is a cornerstone of medical treatment in metastatic renal cell carcinoma (mRCC). While 1st line therapies were previously dominated by inhibitors of the vascular endothelial growth factor axis, 2nd line options were less clearly defined. We investigated the role of everolimus (EVE) or a tyrosine kinase inhibitor (TKI) in 2nd line treatment of mRCC patients. Methods: Key inclusion criteria were measurable mRCC, ECOG 0–1, IMDC risk: good or intermediate and adequate organ function. Patients who progressed on or were intolerant to bevacizumab + interferon were subject for randomization between TKI and EVE treatment. Cross-over occurred at time of progression during 2nd line treatment. Improvement of 2nd line progression-free survival (PFS) rate (PFR) at 6 months from 50% to 65% was the primary endpoint. Secondary endpoints were PFS, total PFS, objective response rate (ORR), overall survival (OS), safety, and patient reported outcomes. Results: In 2012–2015, a total of 22 patients were included. The study was stopped for poor accrual. Ten patients (46%) were randomized to receive 2nd line treatment with EVE (n = 5) or axitinib (n = 4)/sunitinib (n = 1). ECOG 0 was recorded in 20% (EVE) and 60% (TKI). Severe adverse events occurred in approx. 60% in each arm. ORR was 1/5 (20%) for TKI and 0/5 (0%) for EVE. PFR at 6 months was 20% in each arm. Median PFS was 3.7 months (EVE) and 2.2 months (TKI) (hazard ratio [HR] 1.0 [95% confidence interval [CI]: 0.26–3.85]). The OS was comparable between arms HR 1.12 (95% CI: 0.27–4.61). Conclusion: The rapid change of the treatment landscape, the limited use of bevacizumab and interferon in 1st line and the duration of 1st line treatment jeopardized BERAT trial recruitment. The small number of patients is a major limitation of our trial. Our observation indicated the poor prognosis in progressive patients and the limited efficacy of TKI or mTOR inhibitors in 2nd line treatment.

The treatment landscape in metastatic renal cell carcinoma (mRCC) has evolved dramatically in recent years. Within the German guideline committee for RCC we evaluated current medical treatments and gave recommendations. A systematic review of published evidence for medical treatment of mRCC was performed (July 2016–August 2019) to cover the duration from last guideline update in 2016. Evidence was graded according to SIGN ( http://www.sign.ac.uk/pdf/sign50.pdf ). Recommendations were made on the basis of a nominal group work with consensus approach and included patient advocates and shareholder of the German RCC treatment landscape. Each recommendation was graded according to its strength as strong recommendation (A) or recommendation (B). Expert statements were given, where appropriate. Strong first-line recommendations (IA) exist for axitinib + pembrolizumab (all risk categories) and ipilimumab + nivolumab (intermediate or poor risk only). Axitinib + avelumab is a recommended first-line treatment across patients with any risk category (IB). In patients who are not candidates for immune check point inhibitor (ICI) combinations, targeted agents should be offered as an alternative treatment. Subsequent treatment after ICI-based combinations remain ill-defined and no standard of care can be formulated. ICI-based combinations are the first-line standard of care and should be considered accordingly. There is an unmet medical need for pivotal studies that define novel standards in patients with failure of ICI-based combinations.

In mRCC patients (pts) combinations of tyrosine kinase inhibitors (TKI) and checkpoint inhibitors (CPI) are considered standards of care. Our study investigated whether a 1st line switch-maintenance approach (CPI after TKI) improved outcome in mRCC. 49 mRCC pts. with partial remission (PR) or stable disease (SD) after 12 weeks TKI induction therapy were 1:1 randomized to receive either TKI continuation (24 pts.) or nivolumab (NIVO; 25 pts.; 240 or 480 mg IV q2-4wk). Objective response rate (ORR) (according to RECIST 1.1), progression free survival (PFS) and adverse events (AE, according to CTCAE v4.03) were assessed from time of randomization. KM plots/log-Rank analyses were used for time to event analyses. PRO were assessed by the FACT Kidney Symptom Index (FKSI-15). Time to deterioration (TTD) was defined as time between randomization to PRO decrease ≥3 points. Data base was closed on December 2020. Median age was 65 years, 82% were male and 4% had ECOG 2. Main metastatic sites were lung (47%), lymph nodes (27%) and liver (24%). MSKCC risk was favorable in 31%, intermediate in 65% and poor in 4%. Response to TKI induction therapy was PR in 59% and SD in 41% of pts. ORR from randomization favored TKI continuation (16 vs. 48%; P=0.03). After a median follow-up of 26.3 mo (1.3-45.6), 40 PFS events and 17 deaths occurred. PFS was 3.0 vs. 11.9 mo. (HR = 2.57 [95% CI: 1.36 – 4.89]) in favor for TKI continuation. Median OS was not reached. 2-year OS was 64% for NIVO and 66% for TKI treatment (HR = 1.12 [95% CI: 0.43 – 2.89]; P=0.82). AEs for NIVO vs. TKI occurred in 96% vs. 100%, grade 3-5: 56% vs. 71% and serious AE (SAE): 48% and 50%, respectively. Median FKSI15 score at therapy initiation to end of therapy showed no significant difference, 46 and 47 for NIVO as well as for TKI with 42 and 43. Median TTD favoured NIVO (NR) vs. TKI (6.9 mo), but difference remained insignificant (P=0.16). Our data does not support the use of a switch-maintenance approach in mRCC. Although a lower degree of grade ≥3 AEs for NIVO was observed, a PRO benefit was not detected. A major limitation is the small sample size and the selection of TKI-sensitive pts.