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Introduction: Rare genitourinary tumors are lacking of randomized and observational data. We aimed to describe the clinical characteristics and outcomes of patients with collecting duct carcinoma (CDC) through the Meet-URO 23/I-RARE database., Materials and Methods: We performed a multicentric retrospective-prospective study within the Meet-URO network, enrolling patients from March 2021 (retrospectively up from 2011) until March 2023. The primary objective was to describe the clinical characteristics of patients with CDC, the secondary objectives were to assess the oncological outcomes in terms of relapse-free survival (RFS), progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) to treatment., Results: 37 patients with CDC were enrolled. Four patients underwent only surgery, 33 received first-line systemic therapy. Median OS was 22.1 months (95% CI, 8.9-31.9). Median RFS for patients with localized disease at onset (n = 30) was 3.7 months (95% CI, 1.9-12.8), median PFS for first-line treatment was 3.3 months (95% CI, 2.7-9.9), with an ORR of 27%. Female sex and good performance status (PS) were associated with longer PFS (P = .072 and P < .01, respectively) and OS (P = .030 and P = .141, respectively)., Conclusions: Patients with CDC had dismal prognosis, with scarce benefit from the available treatments. Female sex and good PS seemed to be associated with better prognosis., Competing Interests: Disclosure The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although nivolumab prolongs overall survival (OS) in pretreated patients with metastatic renal cell carcinoma (mRCC), underlining clinical and biological features of long-term responses are still to be determined. This study aims to investigate clinical and pathological characteristics of mRCC patients who achieved long-term responses during nivolumab treatment., Materials and Methods: A retrospective analysis was performed on mRCC patients receiving nivolumab as second or further therapy line between May 2016 and January 2019 in 34 Italian Oncology Centres. Outcome assessments and logistic regression were performed to evaluate factors influencing long-term responses., Results: A total of 571 patients with a median age of 61 years (range 17-85) were included in the analysis. With a median follow-up of 22.1 (1.0-89.0) months, 23.1% of patients were 2-year progression-free on treatment with nivolumab, hence they were categorized as long-term responders. Baseline characteristics, including age, gender, and histology, were similar between long- and short-term responders. Karnofsky Performance Status ≥ 80% was significantly associated with long-term response (p = 0.02), while bone metastases (p = 0.03), International mRCC Database Consortium intermediate-poor risk (p < 0.01) and Neutrophil-to-Lymphocyte Ratio ≥ 3.2 (p = 0.02) were associate with short-term responses. Long-term responders exhibited a median progression-free survival of 55.0 months versus 4.0 months of the short-term responders. The median OS was not reached in long-term responders while it was 17.0 months for short*term responders., Conclusion: This retrospective analysis sheds light on factors associated with long-term response to nivolumab in mRCC. Understanding these clinical features will be essential for selecting patients who may mostly benefit from immunotherapy., (© 2024. The Author(s).)

Background: Nowadays, different therapeutic options are available for the first-line treatment of metastatic renal cell carcinoma (mRCC). Immuno-combinations are the standard first-line therapy in all mRCC patients regardless of the International Metastatic RCC Database Consortium (IMDC) risk category, even though TKI monotherapy is still a therapeutic option in selected patients. However, comparisons between the different first-line treatment strategies are lacking and few real-world data are available in this setting. For this reason, the regimen choice represents an important issue in clinical practice and the optimal treatment sequence remains unclear., Methods: The REGAL study is a multicentric prospective observational study enrolling mRCC patients treated with first-line systemic therapy according to clinical practice in a real-world setting. A retrospective cohort of mRCC patients who received first-line systemic therapy from the 1st of January 2021 will also be included. The primary objective is to identify potential prognostic and predictive factors that could help guide the treatment choice; secondary objectives included the assessment of the prognostic performance of the novel prognostic Meet-URO score (IMDC score + neutrophil-to-lymphocyte ratio + bone metastases) compared with the IMDC score and the comparison between treatment strategies according to response and survival outcomes and toxicity profile., Discussion: Considering the high number of therapeutic first-line strategies available for mRCC, the identification of clinical prognostic and predictive factors to candidate patients to a preferable systemic therapy is still an unmet clinical need. The Meet-URO 33 study aims to provide a large-scale real-world database on mRCC patients, to identify the clinical predictive and prognostic factors and the different performances between the ICI-based combinations according to response, survival and toxicity., Trial Registration: CESC IOV 2023-78., (© 2024. The Author(s).)

Background: Peritoneal metastases (PM) have been reported in approximately 1% of patients with metastatic Renal Cell Carcinoma (mRCC). Outcome data are limited due to the rarity of this metastatic site. Therefore, the aim of our study is to describe renal cell carcinoma (RCC) patients with PM treated as per clinical practice., Materials and Methods: Baseline characteristics and outcome data of patients with PM from RCC were retrospectively collected from 18 Italian oncological referral centers adhering to the Meet-Uro group, from January 2016 to January 2023., Results: We collect 81 RCC patients with PM. 78/81 received systemic treatment, 3/81 only best supportive care. First line treatment included tyrosine-kinase inhibitors (TKI) (46/78), ImmuneOncology (IO)-TKI (26/78) and IO-IO (6/78), with different Objective Response Rate (ORR) (43.4% in TKI monotherapy group vs 50% in IO-TKI group, respectively) and Disease Control Rate (DCR) (60.8% in TKI treated patients vs. 76.9% in IO-TKI treated patients). Median PFS was 6.4 months (95%CI 4.18-14.8) in patients treated with TKI monotherapy vs 23.7 months (95%CI 11.1-NR) in patients treated with IO-TKI (p < 0.015). The median OS (mOS) was 22.7 months (95%CI 13.32 - 64.7) in the TKI monotherapy group vs 34.5 mo (95%CI NR-NR) in the IO-TKI group with 53.8% of patients alive at 1 years in the latter group, (p < 0.16). Primary refractory patients were 36.9% for TKI and 15.3% for IO-TKI. According to International Metastatic renal cell carcinoma Database Consortium (IMDC) score, mPFS and mOS were consistent among risk categories. Median PFS was 36.6 months (95%CI 10.9-NR) for good risk patients compared to 10 months (95%CI 7.5-29.8) for intermediate risk and 2.96 months (95%CI 2.43-11.28) for poor risk population (p < 0.0005) whereas mOS was NR (95%CI 28.65-NR) for good risk patients compared to 35.3 months (95%CI 24.6-NA) and 12.4 months (95%CI 3.52-NR) for intermediate and poor risk population, respectively, (p < 0.0002). Only 34/78 (43.5%) received a second line treatment that was TKI (ORR 8.3% and DCR 41.6%) or IO (ORR 18.1% and DCR 40.9%)., Conclusion: We report one of the largest case series regarding PM from RCC. Characteristics of patients suggest a more aggressive behavior of PM from mRCC. Outcome data suggest that TKI-IO as first line treatment, and TKI as second line, confirm their activity for these patients with dismal prognosis., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The purpose of this European Society for Radiotherapy and Oncology (ESTRO) project, endorsed by the European Association of Urology, is to explore expert opinion on the management of patients with oligometastatic and oligoprogressive renal cell carcinoma by means of stereotactic ablative radiotherapy (SABR) on extracranial metastases, with the aim of developing consensus recommendations for patient selection, treatment doses, and concurrent systemic therapy. A questionnaire on SABR in oligometastatic renal cell carcinoma was prepared by a core group and reviewed by a panel of ten prominent experts in the field. The Delphi consensus methodology was applied, sending three rounds of questionnaires to clinicians identified as key opinion leaders in the field. At the end of the third round, participants were able to find consensus on eight of the 37 questions. Specifically, panellists agreed to apply no restrictions regarding age (25 [100%) of 25) and primary renal cell carcinoma histology (23 [92%] of 25) for SABR candidates, on the upper threshold of three lesions to offer ablative treatment in patients with oligoprogression, and on the concomitant administration of immune checkpoint inhibitor. SABR was indicated as the treatment modality of choice for renal cell carcinoma bone oligometatasis (20 [80%] of 25) and for adrenal oligometastases 22 (88%). No consensus or major agreement was reached regarding the appropriate schedule, but the majority of the poll (54%-58%) retained the every-other-day schedule as the optimal choice for all the investigated sites. The current ESTRO Delphi consensus might provide useful direction for the application of SABR in oligometastatic renal cell carcinoma and highlight the key areas of ongoing debate, perhaps directing future research efforts to close knowledge gaps., Competing Interests: Declaration of interests The Division of Radiation Oncology of European Institute of Oncology (IEO) has received research funding from Associazione Italiana per la Ricerca sul Cancro (AIRC) and Fondazione IEO-CCM (Istituto Europeo di Oncologia-Centro Cardiologico Monzino) all outside the current project. BAJ-F has received speaker fees from Roche, Bayer, Janssen, Carl Zeiss, Ipsen, Accuray, Astellas, Elekta, and IBA AstraZeneca (all outside the current project). AVL has received speaker fees from AstraZeneca (outside the current project). SGi (in the last 3 years) reports personal honoraria for participation on advisory boards from Amgen and MSD; invited speaker fees for the European Society of Medical Oncology (ESMO), and the Swiss group for Clinical Cancer Research (SAKK), the German-speaking European School of Oncology, and the Swiss Academy of Multidisciplinary Oncology; a travel grant from AstraZeneca and Bayer; institutional honoraria for participation on advisory boards or independent data monitoring–steering committees from AAA International, Amgen, AstraZeneca, Astellas Pharma, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, DAIICHI Sankyo, Innomedica, Ipsen, Meister-ConCept, Modra Pharmaceuticals, MSD, Myriad Genetic, Novartis, Orion, Pfizer, Roche, and Telixpharma; was an invited speaker for SAKK, American Society of Clinical Oncology Genitourinary, ESMO, PeerVoice, Silvio Grasso Consulting, and WebMD-Medscape; and has a patent for a research method for biomarker WO2009138392. The remaining authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We present the final prespecified overall survival (OS) analysis of the open-label, phase III CLEAR study in treatment-naïve patients with advanced renal cell carcinoma (aRCC). With an additional follow-up of 23 months from the primary analysis, we report results from the lenvatinib plus pembrolizumab versus sunitinib comparison of CLEAR. Treatment-naïve patients with aRCC were randomly assigned to receive lenvatinib (20 mg orally once daily in 21-day cycles) plus pembrolizumab (200 mg intravenously once every 3 weeks) or sunitinib (50 mg orally once daily [4 weeks on/2 weeks off]). At this data cutoff date (July 31, 2022), the OS hazard ratio (HR) was 0.79 (95% CI, 0.63 to 0.99). The median OS (95% CI) was 53.7 months (95% CI, 48.7 to not estimable [NE]) with lenvatinib plus pembrolizumab versus 54.3 months (95% CI, 40.9 to NE) with sunitinib; 36-month OS rates (95% CI) were 66.4% (95% CI, 61.1 to 71.2) and 60.2% (95% CI, 54.6 to 65.2), respectively. The median progression-free survival (95% CI) was 23.9 months (95% CI, 20.8 to 27.7) with lenvatinib plus pembrolizumab and 9.2 months (95% CI, 6.0 to 11.0) with sunitinib (HR, 0.47 [95% CI, 0.38 to 0.57]). Objective response rate also favored the combination over sunitinib (71.3% v 36.7%; relative risk 1.94 [95% CI, 1.67 to 2.26]). Treatment-emergent adverse events occurred in >90% of patients who received either treatment. In conclusion, lenvatinib plus pembrolizumab achieved consistent, durable benefit with a manageable safety profile in treatment-naïve patients with aRCC.

Background: The addition of neutrophil to lymphocyte ratio (NLR) and bone metastases to the IMDC classification provided by the Meet-URO score, resulted in higher prognostic accuracy in metastatic renal cell carcinoma (mRCC) patients receiving ≥2nd line nivolumab or cabozantinib in 2 retrospective analyses and 1st line nivolumab-ipilimumab in an expanded access programme. Prognostic estimates for older mRCC patients might be key for clinical decision-making., Methods: The outcome of real-world older (≥70 years) mRCC patients treated with any line cabozantinib within the multicenter observational prospective ZEBRA (Meet-URO 9) study was analyzed according to the baseline Meet-URO score. The primary endpoint was overall survival (OS). The discriminative ability by Harrell's c-index and calibration were assessed to compare the Meet-URO and IMDC scores., Results: A total of 104 mRCC patients received cabozantinib as 1st (38%), 2nd (20%), or ≥3rd (41%) line. With a median follow-up of 11.2 months, the median OS (mOS) was of 18.4 months. According to the IMDC score, favorable (15%), intermediate (65%) and poor-risk (19%) patients had a mOS not reached, of 15.6 and 5.7 months respectively (p = .011). According to the Meet-URO score groups, mOS was not reached in both group 1 (10%) and group 2 (25%), while in group 3 (33%), group 4 (25%) and group 5 (8%) mOS was of 13.6, 12.5, and 3.7 months, respectively (p < .001). The discriminative ability of the Meet-URO score was maintained by merging groups 1 to 2 vs. 3 to 4 vs. 5 (p < .001). The Meet-URO score (with either the original 5-group stratification or the modified 3-group one) showed higher accuracy than the IMDC score (c-index of 0.686 and 0.676 vs. 0.622)., Conclusion: This analysis confirmed the prognostic accuracy of the Meet-URO score in older mRCC patients treated with cabozantinib and its role as a convenient tool for informing the patient and clinical decisions., Competing Interests: Disclosure SR received honoraria as a speaker at scientific events and travel accommodation from Amgen, GSK, BMS, and MSD. SB received honoraria as speaker at scientific events and advisory role by BMS, Pfizer, MSD, Ipsen, Roche, Eli Lilly, AstraZeneca, Pierre-Fabre, Novartis. GF services advisory boards for Astellas, Janssen, Pfizer, Bayer, MSD, Merck and received travel accomodation from Astellas, Janssen, Bayer. GP services advisory boards/consulting for Astellas, AstraZeneca, BMS, Janssen, IPSEN, Merk, MSD, Novartis, Pfizer. MS services advisory boards/consulting for Janssen, received research funding from Janssen and received travel accomodation from Ipsen, BMS, Janssen, Pfizer, Astellas Pharma. PR services advisory boards for MSD, AstraZeneca and Janssen. GLB reports personal fees from AstraZeneca and Astellas and non-financial support from Janssen. DS received honoraria for the advisory board from Amgen, Jansen, MSD, BMS, Bayer, Astra Zeneca, Ipsen, Novartis, and Merck. CN received honoraria as a speaker at scientific events from Astellas and BMS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Although in metastatic renal cell carcinoma (mRCC) patients with intermediate and poor risk the benefit of combination strategies versus tyrosine kinase inhibitor (TKI) has been ascertained, in those with favorable risk data are ambiguous. Herein, we investigated the impact of number and type of metastatic site in patients with favorable risk to contribute to the best therapeutic choice., Material and Methods: Multicenter data regarding patients with favorable risk mRCC carcinoma receiving first-line TKIs, sunitinib or pazopanib, were retrospectively collected. We divided our population into 2 groups based on the number of metastatic sites and analyzed its impact on tumor response and efficacy outcome. The Kaplan-Meier method was used to estimate efficacy outcomes and the log-rank test to examine differences between subgroups., Results: A total of 107 patients with a median age of 69 years were included in the final analysis. Patients with 1 metastatic site, compared with patients with > 1 site, had a significantly longer overall survival (OS) (not reached vs. 66 months) and a trend, although not statistically significant, of better progression-free survival (PFS) (31 vs. 17 months). In patients with 1 metastatic site, liver involvement was correlated with worse PFS and OS at the univariate analysis (P = .01) and was confirmed as independent poor prognostic factor for PFS at multivariate analysis., Conclusion: In conclusion, we reported a longer OS in favorable risk mRCC patients receiving TKI with only 1 metastatic site. Nevertheless, in patients with a single metastatic site, hepatic involvement correlated with worse PFS compared to other metastatic sites., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Renal c carcinoma (RCC) is one of the most common urinary cancers worldwide, with a predicted increase in incidence in the coming years. Immunotherapy, as a single agent, in doublets, or in combination with anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), has rapidly become a cornerstone of the RCC therapeutic scenario, but no head-to-head comparisons have been made. In this setting, real-world evidence emerges as a cornerstone to guide clinical decisions., Objective: The objective of this retrospective study was to assess the outcome of patients treated with first-line immune combinations or immune oncology (IO)-TKIs for advanced RCC., Design, Setting, and Participants: Data from 930 patients, 654 intermediate risk and 276 poor risk, were collected retrospectively from 58 centers in 20 countries. Special data such as sarcomatoid differentiation, body mass index, prior nephrectomy, and metastatic localization, in addition to biochemical data such as hemoglobin, platelets, calcium, lactate dehydrogenase, neutrophils, and radiological response by investigator's criteria, were collected., Outcome Measurements and Statistical Analysis: Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. The median follow-up was calculated by the inverse Kaplan-Meier method., Results and Limitations: The median follow-up time was 18.7 mo. In the 654 intermediate-risk patients, the median OS and PFS were significantly longer in patients with the intermediate than in those with the poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria (38.9 vs 17.3 mo, 95% confidence interval [CI] p < 0.001, and 17.3 vs 11.6 mo, 95% CI p < 0.001, respectively). In the intermediate-risk subgroup, the OS was 55.7 mo (95% CI 31.4-55.7) and 40.2 mo (95% CI 29.6-51.6) in patients treated with IO + TKI and IO + IO combinations, respectively (p = 0.047). PFS was 30.7 mo (95% CI 16.5-55.7) and 13.2 mo (95% CI 29.6-51.6) in intermediate-risk patients treated with IO + TKI and IO + IO combinations, respectively (p < 0.001). In the poor-risk subgroup, the median OS and PFS did not show a statistically significant difference between IO + IO and IO + TKI. Our study presents several limitations, mainly due to its retrospective nature., Conclusions: Our results showed differences between the IO + TKI and IO + IO combinations in intermediate-risk patients. A clear association with longer PFS and OS in favor of patients who received the IO + TKI combinations compared with the IO-IO combination was observed. Instead, in the poor-risk group, we observed no significant difference in PFS or OS between patients who received different combinations., Patient Summary: Renal cancer is one of the most frequent genitourinary tumors. Treatment is currently based on immunotherapy combinations or immunotherapy with tyrosine kinase inhibitors, but there are no comparisons between these.In this study, we have analyzed the clinical course of 930 patients from 58 centers in 20 countries around the world. We aimed to analyze the differences between the two main treatment strategies, combination of two immunotherapies versus immunotherapy + antiangiogenic therapy, and found in real-life data that intermediate-risk patients (approximately 60% of patients with metastatic renal cancer) seem to benefit more from the combination of immunotherapy + antiangiogenic therapy than from double immunotherapy. No such differences were found in poor-risk patients. This may have important implications in daily practice decision-making for these patients., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Real-world cabozantinib use has increased since its approval to treat patients with advanced renal cell carcinoma (RCC) in 2016. We reviewed cabozantinib use in real-world clinical practice and compared outcomes with pivotal cabozantinib randomized control trials (RCTs). This PRISMA-standard systematic literature review evaluated real-world effectiveness and tolerability of cabozantinib in patients with RCC (PROSPERO registration: CRD42021245854). Systematic MEDLINE, Embase, and Cochrane database searches were conducted on November 2, 2022. Eligible publications included ≥ 20 patients with RCC receiving cabozantinib. After double-screening for eligibility, standardized data were abstracted, qualitatively summarized, and assessed for risk of bias using the Newcastle-Ottawa Scale. Of 353 screened publications, 41 were included, representing approximately 11,000 real-world patients. Most publications reported cabozantinib monotherapy cohort studies (40/41) of retrospective (39/41) and multicenter (32/41) design; most included patients from North America and/or Europe (30/41). Baseline characteristics were demographically similar between real-world and pivotal RCT populations, but real-world populations showed greater variation in prevalence of prior nephrectomy, multiple-site/brain metastasis, and nonclear-cell RCC histology. Cabozantinib activity was reported across real-world treatment lines and tumor types. Overall survival, progression-free survival, and objective response rate values from pivotal RCTs were within the ranges reported for equivalent outcomes across real-world studies. Common real-world grade ≥ 3 adverse events were consistent with those in pivotal RCTs (fatigue, palmar-plantar erythrodysesthesia syndrome, diarrhea, hypertension), but less frequent. No new tolerability concerns were identified. Real-world RCC survival outcomes for cabozantinib monotherapy were broadly consistent with pivotal RCTs, despite greater heterogeneity in real-world populations., Competing Interests: Disclosure MG-G: Consultancy or advisory role: Amgen, Astellas Medivation, AstraZeneca, Bayer/Onyx, Bristol Myers Squibb, Eisai, Ipsen, Janssen-Cilag, MSD Oncology, Pfizer, Roche, and Sanofi; Research funding (to institution): AstraZeneca, Ipsen, Janssen-Cilag, Merck, MSD Oncology, Pfizer, and Roche; Travel, accommodations, and expenses: Astellas Pharma, AstraZeneca, Ipsen, Janssen-Cilag, Pfizer, and Roche. LB: Consultancy or advisory role: AstraZeneca, Ipsen, MSD, Novartis, Pfizer, and Roche. MTC: Consultancy or advisory role: Astellas, AstraZeneca, AXDev, Eisai, EMD Serono, Exelixis, Genentech, Pfizer, and SeaGen; Research funding: ApricityHealth, Aravive, AstraZeneca, Exelixis, Janssen, and Pfizer/EMD Serono; Nonbranded educational programs: Bristol Myers Squibb, Merck, Pfizer/EMD Serono, and Roche. AM: Consultancy or advisory role: Bristol Myers Squibb, Clovis Oncology, Eisai, GSK, Ipsen, Pfizer, and Tesaro. BV: Consultancy or advisory role: Bristol Myers Squibb, EUSA Pharma, and Merck Sharp & Dohme; travel/accommodation/expenses: Bristol Myers Squibb, EUSA Pharma, and Ipsen; Research funding (institution): Bristol Myers Squibb, Exelixis, Ipsen, Merck Sharp & Dohme, and Pfizer; Honoraria (self): Bristol Myers Squibb, Ipsen, and Pfizer; Speaker bureau/expert testimony: Bristol Myers Squibb, Eisai, EUSA Pharma, Merck Serono, Merck Sharp & Dohme, and Pfizer. JZ: Research funding: Ipsen. PD: Employment: Ipsen; Stock and other ownership interests: Biogen and Ipsen. GP: Consulting or advisory role: Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Janssen, Ipsen, Lilly, Merck, MSD, Novartis, Pfizer, and Roche. LA: Consulting or advisory role: Astellas Pharma, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche; Travel, accommodation, expenses: Bristol Myers Squibb, Ipsen, and MSD., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: We conducted a systematic literature review to identify evidence for use of vascular endothelial growth factor (VEGF)-targeted (anti-VEGF) treatment in patients with renal cell carcinoma (RCC) following prior checkpoint inhibitor (CPI)-based therapy., Methods: This was a PRISMA-standard systematic literature review; registered with PROSPERO (CRD42021255568). Literature searches were conducted in MEDLINE®, Embase, and the Cochrane Library (January 28, 2021; updated September 13, 2022) to identify publications reporting efficacy/effectiveness and safety/tolerability evidence for anti-VEGF treatment in patients with RCC who had received prior CPI therapy., Results: Of 2,639 publications screened, 48 were eligible and featured 2,759 patients treated in trials and 2,209 in real-world studies (RWS). Most patients with available data were treated with anti-VEGF tyrosine kinase inhibitor-based regimens (trials: 93 %; RWS: 100 %), most commonly cabozantinib, which accounted for 46 % of trial and 62 % of RWS patients in publications with available data. Collectively, there was consistent evidence of anti-VEGF treatment activity after prior CPI therapy. Activity was reported for all anti-VEGF regimens and regardless of prior CPI-based regimen. No new safety signals were detected for subsequent anti-VEGF therapy; no studies suggested increased immune-related adverse events associated with prior CPI therapy. The results were limited by data quality; study heterogeneity prohibited meta-analyses., Conclusion: Based on the available data (most commonly for cabozantinib), anti-VEGF therapy appears to be a rational treatment choice in patients with RCC who have progressed despite prior CPI-based therapy. Results from ongoing trials of combination anti-VEGF plus CPI regimen post prior CPI therapy trials will contribute more definitive evidence., Plain Language Summary: Anticancer treatments that work by reducing levels of a substance in the body called Vascular Endothelial Growth Factor are known as anti-VEGF drugs. Reducing VEGF levels helps to reduce blood supply to tumors, which can slow the speed at which the cancer grows. Some other types of anticancer drugs that help the immune system to fight cancer cells are called checkpoint inhibitors. Here, we looked at published studies that investigated how anti-VEGF drugs work, and what side effects they cause, in people who have already been treated with checkpoint inhibitors for a type of kidney cancer called renal cell carcinoma. We aimed to summarize the available evidence to help doctors decide how best to use anti-VEGF drugs in these patients. We found 48 studies that included almost 5,000 patients. The results of the studies showed that anti-VEGF drugs have anticancer effects in people with renal cell carcinoma who had already been treated with checkpoint inhibitors. All of the VEGF-targeting drugs had anticancer effects, irrespective of what checkpoint inhibitor treatment people had received before. There were different amounts of evidence available for the different anti-VEGF drugs. The anti-VEGF cabozantinib had the largest amount of evidence. Importantly, previous checkpoint inhibitor treatment did not seem to affect the number or type of side-effects associated with anti-VEGF drugs. Results from ongoing, well-designed studies will be helpful to confirm these results. Our findings may be useful for doctors considering using anti-VEGF drugs in patients with renal cell carcinoma who have received checkpoint inhibitor treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: Low sodium levels have been associated with negative outcomes among patients with metastatic renal cell carcinoma (mRCC) receiving therapies other than immune checkpoint inhibitors (ICIs)., Objective: To investigate the role of natremia in patients with mRCC receiving nivolumab as a second-line or subsequent therapy., Design, Setting, and Participants: In this retrospective cohort study, the clinical and biochemical data of patients with mRCC receiving nivolumab were collected from October 2015 to November 2019 as part of a multicenter Italian study. Data analysis was performed from February to March 2023., Exposure: Nivolumab was administered intravenously at a dose of 3 mg/kg every 2 weeks and, since May 2018, at a fixed dose of 240 mg every 2 weeks or 480 mg every 4 weeks. Patients were divided into 2 groups according to their median serum sodium value (<140 or ≥140 mEq/L)., Main Outcomes and Measures: The primary outcomes were the associations of pre-ICI and post-ICI sodium levels with overall survival (OS), progression-free survival (PFS), objective response rate, and disease control rate (DCR). The Kaplan-Meier method was used to estimate PFS and OS, and differences between groups were compared using the log-rank test., Results: A total of 401 patients with mRCC receiving nivolumab as second-line therapy were evaluated, and 355 eligible patients (median [range] age, 76 [44-84] years; 258 male patients [72.7%]) were included in the final cohort. Among patients with pre-ICI sodium greater than or equal to 140 mEq/L compared with those with sodium less than 140 mEq/L, the median PFS was 9.3 months (95% CI, 6.5-11.5 months) vs 7.4 months (95% CI, 4.6-10.1 months; P = .90), and the median OS was 29.2 months (95% CI, 21.8-35.9 months) vs 20.0 months (95% CI, 14.1-26.8 months; P = .03). Patients with post-ICI sodium values greater than or equal to 140 mEq/L had longer PFS (11.1 months [95% CI, 8.5-1.5 months] vs 5.1 months [95% CI, 4.1-7.5 months]; P = .01) and OS (32.9 months [95% CI, 25.1-42.6 months] vs 17.1 months [95% CI, 12.6-24.5 months]; P = .006) compared with patients with sodium values less than 140 mEq/L. Patients with both pre-ICI and post-ICI sodium values greater than or equal to 140 mEq/L exhibited a significant improvement in clinical outcomes compared with those with a value less than 140 mEq/L (PFS, 11.5 months [95% CI, 8.8-16.4 months] vs 5.8 months [95% CI, 4.4-8.3 months]; P = .008); OS, 37.6 months [95% CI, 29.0-49.9 months] vs 19.4 months [95% CI, 14.1-24.5 months]; P = .01). Moreover, sodium levels greater than or equal to 140 mEq/L were associated with significantly better DCR than lower sodium levels., Conclusions and Relevance: In this retrospective cohort study of patients with mRCC receiving nivolumab, sodium values greater than or equal to 140 mEq/L, both before and/or after ICI, were associated with better OS and PFS, as well as a higher DCR, compared with levels less than 140 mEq/L. These findings suggest that sodium levels may be associated with survival outcomes in patients with mRCC and may have potential use as variables to consider in patients' risk scores.

Background: Obesity has been associated with improved response to immunotherapy in cancer patients. We investigated the role of body mass index (BMI) in patients from the ARON-1 study (NCT05287464) treated by dual immuno-oncology agents (IO+IO) or a combination of immuno-oncology drug and a tyrosine kinase inhibitors (TKI) as first-line therapy for metastatic renal cell carcinoma (mRCC)., Patients and Methods: Medical records of patients with documented mRCC treated by immuno-oncology combinations were reviewed at 47 institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (OS), and overall clinical benefit (OCB), defined as the sum of the rate of partial/complete responses and stable disease. Univariate and multivariate analyses were used to explore the association of variables of interest with survival., Results: A total of 675 patients were included; BMI was >25 kg/m 2 in 345 patients (51%) and was associated with improved OS (55.7 vs. 28.4 months, P < .001). The OCB of patients with BMI >25 kg/m 2 versus those with BMI ≤25 kg/m 2 was significantly higher only in patients with nonclear cell histology (81% vs. 65%, P = .011), and patients with liver metastases (76% vs. 58%, P = .007), Neutrophil to lymphocyte ratio >4 (77% vs 62%, P = .022) or treated by nivolumab plus ipilimumab (77% vs. 64%, P = .044). In the BMI ≤25 kg/m 2 subgroup, significant differences were found between patients with NLR >4 versus ≤4 (62% vs. 82%, P = .002) and patients treated by IO+IO versus IO+TKIs combinations (64% vs. 83%, P = .002)., Conclusion: Our study suggests that the prognostic significance and the association of BMI with treatment outcome varies across clinico-pathological mRCC subgroups., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Over the past decade, the management of metastatic renal cell carcinoma (RCC) has undergone rapid evolution, culminating in a significant improvement in prognosis with frontline immunotherapy. RCC is a highly immunogenic and pro-angiogenic cancer, and mounting evidence has established the immunosuppressive effects of pro-angiogenic factors on the host's immune system. Anti-angiogenic agents such as tyrosine kinase inhibitors (TKIs) and bevacizumab, which obstruct the vascular endothelial growth factor pathway, have demonstrated the potential to enhance antitumor activity and improve the efficacy of immune checkpoint inhibitors (ICIs). Consequently, various combinations of TKIs and ICIs have been assessed and are currently considered the preferred regimens for all metastatic RCC patients, regardless of their prognostic risk score. Nevertheless, some inquiries have arisen within the medical community, as metastatic RCC patients with favorable risk scores who received ICIs and TKIs in combination showed no statistically significant advantage in overall survival compared to those treated with sunitinib alone. Considering these concerns, this review aims to elucidate the rationale behind TKI and ICI combination therapies, provide a summary of current first-line metastatic RCC combinations approved for use, with a focus on favorable-risk patients, and outline present challenges and future perspectives in this context., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The extent of tumor shrinkage has been deemed a predictor of survival for advanced/metastatic renal cell carcinoma (RCC), a disease with historically poor survival., Objective: To perform an exploratory analysis of overall survival (OS) by tumor response by 6 mo, and to assess the efficacy and survival outcomes in specific subgroups., Design, Setting, and Participants: CLEAR was an open-label, multicenter, randomized, phase 3 trial of first-line treatment of advanced clear cell RCC., Intervention: Patients were randomized 1:1:1 to lenvatinib 20 mg orally daily with pembrolizumab 200 mg intravenously once every 3 wk, lenvatinib plus everolimus (not included in this analysis), or sunitinib 50 mg orally daily for 4 wk on treatment/2 wk of no treatment., Outcome Measurements and Statistical Analysis: Landmark analyses were conducted to assess the association of OS with tumor shrinkage and progressive disease status by 6 mo. Progression-free survival, duration of response, and objective response rate (ORR) were analyzed by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk subgroup and by the presence of target kidney lesions. Efficacy was assessed by an independent review committee as per Response Evaluation Criteria in Solid Tumors version 1.1., Results and Limitations: Landmark analyses by tumor shrinkage showed that patients enrolled to lenvatinib plus pembrolizumab arm with a confirmed complete response or >75% target-lesion reduction by 6 mo had a 24-mo OS probability of ≥91.7%. A landmark analysis by disease progression showed that patients with no progression by 6 mo had lower probabilities of death in both arms. Patients with an IMDC risk classification of intermediate/poor had longer median progression-free survival (22.1 vs 5.9 mo) and a higher ORR (72.4% vs 28.8%) with lenvatinib plus pembrolizumab versus sunitinib. Similarly, results favored lenvatinib plus pembrolizumab in IMDC-favorable patients and those with/without target kidney lesions. Limitations of the study are that results were exploratory and not powered/stratified., Conclusions: Lenvatinib plus pembrolizumab showed improved efficacy versus sunitinib for patients with advanced RCC; landmark analyses showed that tumor response by 6 mo correlated with longer OS., Patient Summary: In this report of the CLEAR trial, we explored the survival of patients with advanced renal cell carcinoma by assessing how well they initially responded to treatment. We also explored how certain groups of patients responded to treatment overall. Patients were assigned to cycles of either lenvatinib 20 mg daily plus pembrolizumab 200 mg every 3 wk or sunitinib 50 mg daily for 4 wk (followed by a 2-wk break). Patients who either had a "complete response" or had their tumors shrunk by >75% within 6 mo after starting treatment with lenvatinib plus pembrolizumab had better survival than those with less tumor reduction by 6 mo. Additionally, patients who had more severe disease (as per the International Metastatic Renal Cell Carcinoma Database Consortium) at the start of study treatment survived for longer without disease progression with lenvatinib plus pembrolizumab than with sunitinib., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The upfront treatment of metastatic renal cell carcinoma (mRCC) has been revolutionized by the introduction of immune-based combinations. The role of cytoreductive nephrectomy (CN) in these patients is still debated. The ARON-1 study (NCT05287464) was designed to globally analyze real-world data of mRCC patients receiving first-line immuno-oncology combinations. This sub-analysis is focused on the role of upfront or delayed partial or radical CN in three geographical areas (Western Europe, Eastern Europe, America/Asia)., Methods: We conducted a multicenter retrospective observational study in mRCC patients treated with first-line immune combinations from 55 centers in 19 countries. From 1152 patients in the ARON-1 dataset, we selected 651 patients with de novo mRCC. 255 patients (39%) had undergone CN, partial in 14% and radical in 86% of cases; 396 patients (61%) received first-line immune-combinations without previous nephrectomy., Results: Median overall survival (OS) from the diagnosis of de novo mRCC was 41.6 months and not reached (NR) in the CN subgroup and 24.0 months in the no CN subgroup, respectively (P<0.001). Median OS from the start of first-line therapy was NR in patients who underwent CN and 22.4 months in the no CN subgroup (P<0.001). Patients who underwent CN reported longer OS compared to no CN in all the three geographical areas., Conclusions: No significant differences in terms of patients' outcome seem to clearly emerge, even if the rate CN and the choice of the type of first-line immune-based combination varies across the different Cancer Centers participating in the ARON-1 project.

Background: The BONSAI phase II trial recently demonstrated the activity of cabozantinib in metastatic collecting duct patients. The outcomes of patients in this setting treated with immunotherapy as second-line is unknown. The aim of the present report was to describe outcomes of patients enrolled in the BONSAI trial that received nivolumab as second-line treatment., Material and Methods: We describe the oncological outcomes in terms of overall response rate, progression-free survival, overall survival and safety. We excluded patients that did not receive any second-line treatment or were treated with agents other than nivolumab., Results: We identified five patients of whom one was excluded due to lack of data. Three patients obtained clinical benefit (one partial response, two stable disease); the second-line progression-free survival (nivolumab) ranged from 2.8 to 19.9 months to and second-line overall survival ranged from 5.1 to 26.5 months. No new safety signals were observed., Conclusions: Nivolumab may be considered as second-line therapy option after cabozantinib failure in selected metastatic collecting duct carcinoma patients.

Background: Immune checkpoint inhibitors are the standard of care for first-line treatment of patients with metastatic renal cell carcinoma, yet optimised treatment of patients whose disease progresses after these therapies is unknown. The aim of this study was to determine whether adding atezolizumab to cabozantinib delayed disease progression and prolonged survival in patients with disease progression on or after previous immune checkpoint inhibitor treatment., Methods: CONTACT-03 was a multicentre, randomised, open-label, phase 3 trial, done in 135 study sites in 15 countries in Asia, Europe, North America, and South America. Patients aged 18 years or older with locally advanced or metastatic renal cell carcinoma whose disease had progressed with immune checkpoint inhibitors were randomly assigned (1:1) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus cabozantinib (60 mg orally once daily) or cabozantinib alone. Randomisation was done through an interactive voice-response or web-response system in permuted blocks (block size four) and stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk group, line of previous immune checkpoint inhibitor therapy, and renal cell carcinoma histology. The two primary endpoints were progression-free survival per blinded independent central review and overall survival. The primary endpoints were assessed in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT04338269, and is closed to further accrual., Findings: From July 28, 2020, to Dec 27, 2021, 692 patients were screened for eligibility, 522 of whom were assigned to receive atezolizumab-cabozantinib (263 patients) or cabozantinib (259 patients). 401 (77%) patients were male and 121 (23%) patients were female. At data cutoff (Jan 3, 2023), median follow-up was 15·2 months (IQR 10·7-19·3). 171 (65%) patients receiving atezolizumab-cabozantinib and 166 (64%) patients receiving cabozantinib had disease progression per central review or died. Median progression-free survival was 10·6 months (95% CI 9·8-12·3) with atezolizumab-cabozantinib and 10·8 months (10·0-12·5) with cabozantinib (hazard ratio [HR] for disease progression or death 1·03 [95% CI 0·83-1·28]; p=0·78). 89 (34%) patients in the atezolizumab-cabozantinib group and 87 (34%) in the cabozantinib group died. Median overall survival was 25·7 months (95% CI 21·5-not evaluable) with atezolizumab-cabozantinib and was not evaluable (21·1-not evaluable) with cabozantinib (HR for death 0·94 [95% CI 0·70-1·27]; p=0·69). Serious adverse events occurred in 126 (48%) of 262 patients treated with atezolizumab-cabozantinib and 84 (33%) of 256 patients treated with cabozantinib; adverse events leading to death occurred in 17 (6%) patients in the atezolizumab-cabozantinib group and nine (4%) in the cabozantinib group., Interpretation: The addition of atezolizumab to cabozantinib did not improve clinical outcomes and led to increased toxicity. These results should discourage sequential use of immune checkpoint inhibitors in patients with renal cell carcinoma outside of clinical trials., Funding: F Hoffmann-La Roche and Exelixis., Competing Interests: Declaration of interests SKP reports their institution received grants from or has contracts with Exelixis, Xencor, Pfizer, Allogene Therapeutics, AstraZeneca, Genentech, and CRISPR Therapeutics; reports payment or honoraria for lectures, presentations, or speakers' bureaus from EMD Serono and Pfizer; and reports meeting or travel support from CRISPR Therapeutics and Roche. LA reports their institution received consulting fees from Astellas, Ipsen, BMS, Janssen, Merck, MSD, Pfizer, Eisai, and Roche; and reports travel support from BMS, MSD, and Ipsen. CSu reports grants from or contracts with AB Science, Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca AB, Bayer, Blueprint Medicines, Boehringer Ingelheim España, BMS, Clovis Oncology, Exelixis, Genentech, GlaxoSmithKline, F Hoffmann-La Roche, Novartis, Pfizer, and Sanofi-Aventis; speakers' bureau fees from Astellas Pharma, BMS, F Hoffmann-La Roche, Ipsen, and Pfizer; participation on a data safety monitoring board or advisory board for Astellas Pharma, Bayer, BMS, Eusa Pharma, F Hoffmann-La Roche, Ipsen, MSD, Novartis, Pfizer, and Sanofi-Aventis. MHV reports grants from or contracts with Pfizer; consulting fees from Aveo, Calithera, Eisai, Exelixis, Pfizer, Genentech, Oncorena, MICURx, and Merck; and participation on a data safety monitoring board or advisory board with AstraZeneca, Affimed, Genentech, and Merck. GdV reports consulting fees from Pfizer, MSD, BMS, Roche, Merck, Bayer, Astellas, AstraZeneca, and Ipsen; reports payment or honoraria for lectures, presentations, or speakers' bureaus from Pfizer, MSD, BMS, Roche, Merck, Astellas, and Ipsen; and reports travel support from MSD, Pfizer, and Roche. JC reports grants from or contracts with Pfizer; and participation on a data safety monitoring board or advisory board with Aveo, Exelixis, and Pfizer; and is a board member with VHL Alliance. GP reports consulting fees from Astellas, Roche, and Pfizer; and reports payment or honoraria for lectures, presentations, or speakers' bureaus from AstraZeneca, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, MSD, Novartis, and Gilead Sciences. FZ reports consulting fees from Apogepha Pharma, Astellas Pharma, AstraZeneca Germany, Bayer Vital, Bristol Myers Squibb, Ipsen, Janssen-Cilag, Merck, Pfizer, and Roche; reports payment or honoraria for lectures, presentations, or speakers' bureaus from Astellas, Bayer Vital, Ipsen, Janssen-Cilag, Merck, Pfizer, and Sanofi-Aventis; and reports travel support from Astellas, Ipsen, Janssen-Cilag, and Pfizer. SG, BL, and MH are employees of Genentech. OK is an employee of F Hoffmann-La Roche. GB and MK are employees of F Hoffmann-La Roche and report stock ownership. CSc is an employee of Exelixis. TP reports grants from or contracts with AstraZeneca, BMS, Exelixis, Ipsen, MSD, Novartis, Pfizer, Seagen, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche; reports payment or honoraria for lectures, presentations, or speakers' bureaus from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, MSD, Novartis, Pfizer, Seagen, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, and Mash Up; and reports travel support from Roche, Pfizer, MSD, AstraZeneca, and Ipsen. TKC reports support for the present manuscript from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infiniti, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Nuscan, Pfizer, Roche, Sanofi-Aventis, Surface Oncology, Takeda, Tempest, UpToDate, Peerview, Physicians' Education Resource, MJH Life Sciences, Research to Practice, France Foundation, Springer, WebMed, ASiM Ce, and Caribou Publishing; reports their institution received grants from or has contracts with AstraZeneca, Aveo, Arcus, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi-Aventis, and Takeda; reports consulting fees from AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infiniti, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Nuscan, Pfizer, Roche, Sanofi-Aventis, Surface Oncology, Takeda, Tempest, UpToDate, Peerview, Physicians' Education Resource, MJH Life Sciences, Research to Practice, France Foundation, Springer, WebMed, ASiM Ce, and Caribou Publishing; reports participation on a data safety monitoring board or advisory board with Aravive; reports leadership or role with KidneyCan, American Society of Clinical Oncology, European Society for Medical Oncology, National Comprehensive Cancer Network, and National Cancer Institute; has stock or stock options in Pionyr, Tempest, Precede Bio, Osel, and Curesponse; and declares other financial or non-financial interests in Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School, the Trust family, Michael Brigham, Pan-Mass Challenge, Hinda L and Arthur Marcus Foundation, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Immuno-oncology combinations have achieved survival benefits in patients with metastatic renal cell carcinoma (mRCC)., Objective: The ARON-1 study (NCT05287464) was designed to globally collect real-world data on the use of immuno-combinations as first-line therapy for mRCC patients., Patients and Methods: Patients aged ≥ 18 years with a cytologically and/or histologically confirmed diagnosis of mRCC treated with first-line immuno-combination therapies were retrospectively included from 47 International Institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit (OCB)., Results: A total of 729 patients were included; tumor histology was clear-cell RCC in 86% of cases; 313 patients received dual immuno-oncology (IO + IO) therapy while 416 were treated with IO-tyrosine kinase inhibitor (IO + TKI) combinations. In the overall study population, the median OS and PFS were 36.5 and 15.0 months, respectively. The median OS was longer with IO+TKI compared with IO+IO therapy in the 616 patients with intermediate/poor International mRCC Database Consortium (IMDC) risk criteria (55.7 vs 29.7 months; p = 0.045). OCB was 84% for IO+TKI and 72% for IO + IO combination (p < 0.001)., Conclusions: Our study may suggest that immuno-oncology combinations are effective as first-line therapy in the mRCC real-world context, showing outcome differences between IO + IO and IO + TKI combinations in mRCC subpopulations., Clinical Trial Registration: NCT05287464., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose of Review: In this review, we analyze the current state of research in development of new biomarkers that may be useful in managing metastatic renal cell carcinoma (mRCC) setting., Recent Findings: Combining tumor-based biomarkers (gene expression profile) and blood-based biomarkers (ctDNA, cytokines) would be helpful in acquiring information regarding RCC and might be significant in the decision-making process. Renal cell carcinoma (RCC) is the sixth most frequently diagnosed neoplasm in men and tithe in women, making it responsible for 5% and 3% of all diagnosed cancers respectively. Metastatic stage represents a non-negligible percentage at diagnosis and is characterized by poor prognosis. Despite clinical features and prognostic score could guide clinicians in therapeutic approach of this disease, biomarkers predictive of response to treatment remain an unmet need., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: First-line therapies based on immune-checkpoint inhibitors (ICIs) significantly improved survival of metastatic renal cell carcinoma (mRCC) patients. Cabozantinib was shown to target kinases involved in immune-escape and to prolong survival in patients pre-treated with tyrosine-kinase-inhibitors (TKIs). The impact of ICIs combinations in first line on subsequent therapies is still unclear., Methods: This is an open label, multicenter, single arm, phase II study designed to assess activity, safety and efficacy of cabozantinib in mRCC patients progressed after an adjuvant or first line anti-Programmed Death (PD)-1/PD-Ligand (PD-L) 1-based therapy. Primary endpoint was progression free survival (PFS), secondary endpoints were overall survival (OS), objective response rate (ORR) and safety., Results: 31 patients were included in the analysis. After a median (m) follow-up of 11.9 months, mPFS was 8.3 months (90%CI 3.9-17.4) and mOS was 13.8 months (95%CI 7.7-29.0). ORR was 37.9% with an additional 13 patients achieving disease stability. Grade 3-4 adverse events occurred in 47% of patients, including more frequently creatine phosphokinase (CPK) serum level elevation, neutropenia, hyponatremia, diarrhea, hand-food syndrome, oral mucositis and hypertension., Conclusions: The BREAKPOINT trial met its primary endpoint showing that cabozantinib as second line therapy after ICIs was active in mRCC. Safety profile was manageable., Trial Registration Number: NCT03463681 - A Study of CaBozantinib in Patients With Advanced or Unresectable Renal cEll cArcinoma (BREAKPOINT) - https://clinicaltrials.gov/ct2/show/NCT03463681.

Non-clear cell renal cell carcinoma (nccRCC) represents a heterogeneous histological group which is 20-25% of those with renal cell carcinoma (RCC). Patients with nccRCC have limited therapeutic options due to their exclusion from phase III randomized trials. The aim of the present study was to investigate the effectiveness and tolerability of pembrolizumabaxitinib combination in chromophobe and papillary metastatic RCC (mRCC) patients enrolled in the I-RARE (Italian Registry on rAre genitor-uRinary nEoplasms) observational ongoing study (Meet-URO 23). Baseline characteristics, objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) and toxicities were retrospectively and prospectively collected from nccRCC patients treated in 14 Italian referral centers adhering to the Meet-Uro group, from December 2020 to April 2022. Only patients with chromophobe and papillary histology were considered eligible for the present pre-specified analysis. There were 32 eligible patients who received pembrolizumab-axitinib as first-line treatment, of whom 13 (40%) had chromophobe histology and 19 (60%) were classified as papillary RCC. The DCR was 78.1% whereas ORR was 43.7% (11 patients achieved stable disease and 14 patients obtained partial response: 9/19 papillary, 5/13 chromophobe). Six patients (18.7%) were primary refractory. Median PFS was 10.8 months (95%CI 1.7-11.5). Eleven patients (34.3%) interrupted the full treatment due to immune-related adverse events (irAEs): G3 hepatitis (n = 5), G3 hypophisitis (n = 1), G3 diarrhea (n = 1), G3 pancreatitis (n = 1), G3 asthenia (n = 1). Twelve patients (37.5%) temporarily interrupted axitinib only due to persistent G2 hand-foot syndrome or G2 hypertension. Pembrolizumab-axitinib combination could be an active and feasible first-line treatment option for patients with papillary or chromophobe mRCC.

A concomitant drug-based score was developed by our group and externally validated for prognostic and predictive purposes in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). The model considers the use of three classes of drugs within a month before initiating ICI, assigning score 1 for each between proton pump inhibitor and antibiotic administration until a month before immunotherapy initiation and score 2 in case of corticosteroid intake. In the present analysis, the drug score was validated in a prospective population of 305 patients with metastatic renal cell carcinoma treated with ipilimumab plus nivolumab in the first-line setting. The value of the model in predicting overall survival and progression-free survival was statistically significant and clinically meaningful, with an overall survival rate at 12 months of 73% vs. 44% (P<0.0001), and median progression-free survival of 11.6 (95% CI: 9.1-14.1) months versus 4.8 (95% CI: 2.7-7.0) months (P=0.002), respectively, for patients belonging to the favorable group (score 0-1) versus the unfavorable (score 2-4). Further development will be represented by the gut microbiome analysis according to the drug-based model classification and to the outcome of patients to ICI therapy to demonstrate the link between drug exposure and immune sensitivity., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The role and sequencing of combination immuno-oncology (IO) therapy following progression on or after first-line IO therapy has not been well-established. The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology (FRACTION) program is an open-label, phase 2 platform trial designed to evaluate multiple IO combinations in patients with advanced renal cell carcinoma (aRCC) who progressed during or after prior IO therapy. Here, we describe the results for patients treated with nivolumab plus ipilimumab. For enrollment in track 2 (reported here), patients with histologically confirmed clear cell aRCC, Karnofsky performance status ≥70%, and life expectancy ≥3 months who had previously progressed after IO (anti-programmed death 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4)) therapy were eligible. Previous treatment with anti-CTLA-4 therapy plus anti-PD-1/PD-L1 therapy precluded eligibility for enrollment in the nivolumab plus ipilimumab arm. Patients were treated with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 480 mg every 4 weeks for up to 2 years or until progression, toxicity, or protocol-specified discontinuation. The primary outcome measures were objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS) rate at 24 weeks. Secondary outcomes were safety and tolerability up to 2 years. Overall survival (OS) was a tertiary/exploratory endpoint. Overall, 46 patients were included with a median follow-up of 33.8 months. The ORR was 17.4% (95% CI, 7.8 to 31.4) with eight (17.4%) patients achieving partial response. Stable disease was achieved in 19 (41.3%) patients, while 14 (30.4%) had progressive disease. Median DOR (range) was 16.4 (2.1+ to 27.0+) months. The PFS rate at 24 weeks was 43.2%, and median OS was 23.8 (95% CI, 13.2 to not reached) months. Grade 3-4 immune-mediated adverse events were reported in seven (15.2%) patients. No treatment-related deaths were reported. Patients with aRCC treated with nivolumab plus ipilimumab may derive durable clinical benefit after progression on previous IO therapies, including heavily pretreated patients, with a manageable safety profile that was consistent with previously published safety outcomes. These outcomes contribute to the knowledge of optimal sequencing of IO therapies for patients with aRCC with high unmet needs., Trial Registration Number: NCT02996110., Competing Interests: Competing interests: TKC reports consulting or advisory board fees, honoraria, and research grants from AstraZeneca, Aravive, AVEO Pharmaceuticals, Bayer, Bristol Myers Squibb (BMS), Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVIA, Infinity, Ipsen, Janssen, Kanaph, Lilly, Merck, NiKang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH and others), outside the submitted work. Institutional patents filed on molecular mutations and immunotherapy response/toxicity, and circulating tumor DNA. Equity holdings: Tempest, Pionyr, Osel, and Precede Bio. Committees: NCCN, GU Steering Committee, ASCO/ESMO, ACCRU, and KidneyCan. Medical writing and editorial assistance support may have been funded by communications companies in part. Mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/foreign components. The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. Dr Choueiri is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan-Mass Challenge, and Loker Pinard Funds for Kidney Cancer Research at DFCI. CV provided upon request for scope of clinical practice and research. HK reports institutional research grant funding from Apexigen, BMS, and Merck; personal fees from Array Biopharma, BMS, Calithera Biosciences, Celldex, ChemoCentryx, Clinigen, Elevate Bio, GI reviewers, GigaGen, Immunocore, Instil Bio, Iovance, Merck, Shionogi, and Signatera. SG reports consulting or advisory role from BMS, Bayer, Pfizer, Exelixis, Corvus Pharmaceuticals, Sanofi/Genzyme, EMD Serono, Seattle Genetics/Astellas, Eisai, Merck, AVEO Pharmaceuticals, and QED Therapeutics; and research funding (institutional) from Pfizer, Merck, Agensys, Novartis, BMS, Bayer, Eisai, Seattle Genetics/Astellas, Calithera Biosciences, Immunomedics, Corvus Pharmaceuticals, and Surface Oncology. SST reports consulting or advisory board fees from Merck, Intellisphere LLC, Natera, BMS, and Exelixis; patent pending (Fred Hutchinson Cancer Center); and research funding (institutional) from Genentech, BMS, Merck Sharp & Dohme, Calithera Biosciences, Pfizer, Jounce Therapeutics, Nektar, Exelixis, and Clinigen Group. TMK has nothing to disclose. RP reports consulting fees from Karyopharm Therapeutics and BiolineRx. SN has nothing to disclose. GP reports advisory board fees from AstraZeneca, BMS, Ipsen, Janssen, Merck Sharp & Dohme, Novartis, and Pfizer. MAC reports consulting or advisory fees from Astellas Pharma, AbbVie, Roche/Genentech, Pfizer, and Foundation Medicine; and research funding (institutional) from BMS, AstraZeneca, Pfizer, and Gilead Science. VC reports consulting or speakers’ bureau fees from Ipsen, Eisai, Merck, AstraZeneca, Pfizer, Novartis, BMS, Astellas and Janssen. EF has nothing to disclose. C-HL reports research funding (institutional) from BMS, Calithera Biosciences, Eisai, Eli Lilly, Exelixis, Merck, and Pfizer; consulting fees from Amgen, BMS, Exelixis, Eisai, Merck, Pfizer, and EMD Serono; and honoraria from AiCME, Intellisphere, and Research to Practice. SJH reports compensation for advisory boards and speakers’ bureaus from Astellas, AstraZeneca, Bayer, BMS, Eisai, Exelixis, Janssen, Ipsen, Merck, Roche, Sanofi, Seagen, and SignalChem; institutional research or grant funding from Astellas, AstraZeneca, Ayala, Bayer, BMS, Eisai, Exelixis, Janssen, Ipsen, Merck, Roche, Sanofi, Seagen, and SignalChem. WHM reports consulting or advisory board fees from BMS, Merck, Roche, Novartis, GlaxoSmithKline, and Amgen; honoraria from BMS, Roche, Novartis, and GlaxoSmithKline; and research funding (institutional) from Merck, BMS, Novartis, GlaxoSmithKline, Roche, AstraZeneca, MethylGene, and MedIm. SSS, C-WL, HD, and PB are employed by and has stock ownership in BMS. RJM reports advisory board fees from AstraZeneca, AVEO Pharmaceuticals, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer; and research funding (institutional) from BMS, Eisai, Exelixis, Genentech/Roche, Merck, and Pfizer. BE reports research funding (institutional) from BMS; consulting fees from Pfizer, BMS, Ipsen, AVEO Pharmaceuticals, Oncorena, and Eisai; honoraria from Pfizer, BMS, Ipsen, Oncorena, and Eisai; and travel accommodations and expenses from BMS, Ipsen, and Merck Sharp & Dohme., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The standard of care for locoregional renal cell carcinoma is surgery, but many patients experience recurrence. The objective of the current study was to determine if adjuvant atezolizumab (vs placebo) delayed recurrence in patients with an increased risk of recurrence after resection., Methods: IMmotion010 is a randomised, double-blind, multicentre, phase 3 trial conducted in 215 centres in 28 countries. Eligible patients were patients aged 18 years or older with renal cell carcinoma with a clear cell or sarcomatoid component and increased risk of recurrence. After nephrectomy with or without metastasectomy, patients were randomly assigned (1:1) to receive atezolizumab (1200 mg) or placebo (both intravenous) once every 3 weeks for 16 cycles or 1 year. Randomisation was done with an interactive voice-web response system. Stratification factors were disease stage (T2 or T3a vs T3b-c or T4 or N+ vs M1 no evidence of disease), geographical region (north America [excluding Mexico] vs rest of the world), and PD-L1 status on tumour-infiltrating immune cells (<1% vs ≥1% expression). The primary endpoint was investigator-assessed disease-free survival in the intention-to-treat population, defined as all patients who were randomised, regardless of whether study treatment was received. The safety-evaluable population included all patients randomly assigned to treatment who received any amount of study drug (ie, atezolizumab or placebo), regardless of whether a full or partial dose was received. This trial is registered with ClinicalTrials.gov, NCT03024996, and is closed to further accrual., Findings: Between Jan 3, 2017, and Feb 15, 2019, 778 patients were enrolled; 390 (50%) were assigned to the atezolizumab group and 388 (50%) to the placebo group. At data cutoff (May 3, 2022), the median follow-up duration was 44·7 months (IQR 39·1-51·0). Median investigator-assessed disease-free survival was 57·2 months (95% CI 44·6 to not evaluable) with atezolizumab and 49·5 months (47·4 to not evaluable) with placebo (hazard ratio 0·93, 95% CI 0·75-1·15, p=0·50). The most common grade 3-4 adverse events were hypertension (seven [2%] patients who received atezolizumab vs 15 [4%] patients who received placebo), hyperglycaemia (ten [3%] vs six [2%]), and diarrhoea (two [1%] vs seven [2%]). 69 (18%) patients who received atezolizumab and 46 (12%) patients who received placebo had a serious adverse event. There were no treatment-related deaths., Interpretation: Atezolizumab as adjuvant therapy after resection for patients with renal cell carcinoma with increased risk of recurrence showed no evidence of improved clinical outcomes versus placebo. These study results do not support adjuvant atezolizumab for treatment of renal cell carcinoma., Funding: F Hoffmann-La Roche and Genentech, a member of the Roche group., Competing Interests: Declaration of interests SKP reports advisory or consulting fees from Pfizer, Novartis, Aveo, Myriad Pharmaceuticals, Genentech, Exelixis, Bristol Myers Squibb, Astellas Pharma, Ipsen, and Eisai; and travel support from CRISPR Therapeutics and Roche. RU reports receiving advisory or consulting fees from Pfizer, Merck, and Haymarket Media. JAK reports research grants or funding paid to their institution from Roche/Genentech, Mirati, Merck, and Elypta; consulting fees from Pfizer, Merck, Roche or Genentech, and Johnson & Johnson; participation on a data safety monitoring board or advisory board for Pfizer; and stock ownership or stock options in MedTek and ROM Technologies. VAM reports advisory or consulting fees from Pfizer, Merck, Bristol Myers Squibb, and Ethicon; and participation on a data safety monitoring board or advisory board for Pfizer, Merk, Bristol Myers Squibb, and Ethicon. CS reports grants from Roche; advisory or consulting fees from Bristol Myers Squibb, Ipsen, Astella, Sanofi, Bayer, Merck Sharp, Dohme, and Pfizer; and support for travel from Bristol Myers Squibb, Roche, and Pfizer. LA reports research grants or funding paid to their institution from Bristol Myers Squibb; consulting fees paid to their institution from Astellas, AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, Merck, Merck Sharpe & Dohme, Novartis, Pfizer, and EISAI; and payment or honoraria paid to their institution from Astella, Bristol Myers Squibb, Ipsen, and Merck Sharpe & Dohme. BR reports payment of grants or contracts to their institution from Pfizer, Roche, Incyte, AstraZeneca, Seattle Genetics, Arrowhead Pharmaceuticals, Immunomedics, Bristol Myers Squibb, Mirati Therapeutics, Merck, Surface Oncology, Aravive, Exelixis, Janssen, Pionyr, and Genentech/Roche; advisory or consulting fees from Bristol Myers Squibb, Pfizer, Genentech/Roche, Aveo, Synthorx, Merck, Corvus, Surface Oncology, Aravive, Alkermes, Arrowhead, Shionogi, Eisai, Nikang Therapeutics, EUSA, Athenex, Allogene Therapeutics, and Debiopharm; travel support from Merck and Bristol Myers Squibb; and stock ownership or stock options in PTC Therapeutics. YT reports research funding from Astellas Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Pfizer, and Takeda; and payment or honoraria from Astella, Bristol Myers Squibb, Chugai Pharmaceuticals, Novartis, and Ono Pharmaceutical. AGK reports advisory or consulting fees from Janssen, Zodiac, and Pfizer; and travel support from Janssen, Ipsen, and AstraZeneca. GP reports payment or honoraria from AstraZeneca, Bayer, BMS, Eisai, Janssen, Ipsen, Merck, Merck Sharpe & Dohme, Novartis, Pfizer, and Roche; and travel support from Ipsen and Janssen. MZ reports grants from Bristol Myers Squibb and Exelixis; and advisory or consulting fees from Pfizer, EMD Serono, Exelixis, Janssen, and Blue Earth. MH, BC, WL, and SD are employees of Genentech, and report stock ownership or stock options. DB is an employee of F Hoffmann-La Roche. OK is an employee of F Hoffmann-La Roche, and reports stock ownership or stock options. AB reports a restricted research grant payment to their institution from Pfizer; payment to their institution for attending steering committee meetings from Roche/Genentech; and payment to their institution for participation on the data safety monitoring board of Merck Sharpe & Dohme. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Immune checkpoint inhibitor (ICI)-based combinations have become the first-line standard of care in metastatic renal cell carcinoma (mRCC), but their activity on the primary tumor is still one of the most debated issues., Patients and Methods: The aim of our analysis was to evaluate the primary tumor's response to first-line therapy with cabozantinib or nivolumab+ipilimumab, and its correlation with metastatic response and with patient outcomes., Results: Sixty-seven mRCC patients met the criteria for inclusion in the final analysis (30 treated with cabozantinib and 37 with nivolumab+ipilimumab). In the overall population, the primary tumor control rate (PTCR) was 90.9%; no complete responses (CR) were achieved. A significant correlation was found between the baseline size of the primary tumor's longest diameter and its response according to RECIST v1.1 criteria at the time of the second radiological assessment (rs = -0.351; P = .049). Moreover, a significant correlation between the type of primary tumor response and the response of the metastases was observed in the overall population (rs = 0.50; two-sided P < 0.001). There was also a significant correlation between primary tumor response and 1-year survival rate (P = .002), even when adjusted for the IMDC prognostic group and type of therapy (HR = 8.70; 95%CI, 2.52-30.05; P = .001)., Conclusion: Extension of the primary tumor did not affect patient survival, while its response was significantly related to the response on metastatic disease and survival. No significant differences in terms of primary tumor shrinkage were identified between treatment with nivolumab+ipilimumab or cabozantinib in this cohort., Competing Interests: Disclosure The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. RI served as consultant for Astellas, BMS, Ipsen; Janssen, Merk, MSD, Novartis; Pfizer; Sanofi and received research grant from Pfizer. SS served as consultant for Astellas, BMS, Ipsen, Janssen, MSD, Novartis, Pfizer, Sanofi-Genzyme. EV served as consultant for Ipsen, Janssen, Merck, MSD, Pfizer. Astellas, Novartis. CC served as consultant for Pfizer, BMS, MSD, Janssen. SB served as consultant for Pfizer, BMS, MSD, Roche, Astellas, Janssen, Ipsen, Bayer, Sanofi-Genzyme, Merck, AstraZeneca. Travel accommodation from Pfizer, BMS, Roche, Astellas, Janssen, Ipsen, AstraZeneca. UDG served as consultant for Astellas, Bayer, BMS, Ipsen, Janssen, Merck, Pfizer and Sanofi; has received travel support from BMS, Ipsen, Janssen and Pfizer; and has received research funding from AstraZeneca, Roche and Sanofi (Inst). UB served as consultant for Advisory board BMS, MSD, Janssen. He received speaker's fees BMS, Ipsen, Janssen, Astellas. GT served as consultant for BMS and MSD. GP served as consultant for Astellas, Astra-Zeneca, Bayer, BMS, Ipsen, Janssen, Merck, MSD, Pfizer, Novartis, Sanofi. CC, MM. AF, LG, FM, AC, MGM, DB, FMD, MD, FP, FR declared not conflict of interests., (Copyright © 2022. Published by Elsevier Inc.)

Background: Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era., Methods: We investigated the Meet-URO-15 study dataset of 571 pretreated mRCC patients receiving nivolumab as second or further lines about the prognostic role of the previous nephrectomy (received in either the localized or metastatic setting) in the overall population and according to the Meet-URO score groups., Results: Patients who underwent nephrectomy showed a significantly reduced risk of death (HR 0.44, 95% CI 0.32-0.60, p < 0.001) with a longer median overall survival (OS) (35.9 months vs 12.1 months), 1-year OS of 71.6% vs 50.5% and 2-years OS of 56.5% vs 22.0% compared to those who did not. No significant interaction between nephrectomy and the overall five Meet-URO score risk groups was observed (p = 0.17). It was statistically significant when merging group 1 with 2 and 3 and group 4 with 5 (p = 0.038) and associated with a longer OS for the first three prognostic groups (p < 0.001), but not for groups 4 and 5 (p = 0.54)., Conclusions: Our study suggests an overall positive impact of the previous nephrectomy on the outcome of pretreated mRCC patients receiving immunotherapy. The clinical relevance of cytoreductive nephrectomy, optimal timing and patient selection deserves further investigation, especially for patients with Meet-URO scores of 1 to 3, who are the once deriving benefit in our analyses. However, that benefit is not evident for IMDC poor-risk patients (including the Meet-URO score groups 4 and 5) and a subgroup of IMDC intermediate-risk patients defined as group 4 by the Meet-URO score., (© 2022. The Author(s).)

Background: Despite the increasing number of treatment options, reliable prognostic/predictive biomarkers are still missing for patients affected by metastatic clear cell renal cell carcinoma (mccRCC)., Methods: Patients with mccRCC undergoing standard first line treatment were enrolled. Blood (12 ml) was drawn at treatment baseline and circulating free DNA (cfDNA) was extracted from plasma. Next-generation sequencing (NGS) was performed on cfDNA using the Oncomine Pan-Cancer Cell-Free Assay and clinical outcomes were correlated with liquid biopsy findings., Results: A total of 48 patients were enrolled, 12 received immunotherapy and 36 received a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). A cfDNA cut-off of 0.883 ng/μl stratified patients based on progression-free survival (PFS) and overall survival (OS) (p = 0.001 and p = 0.008, respectively). cfDNA amount was also correlated with best response (p = 0.006). Additional cfDNA cut-points divided patients into short, intermediate and long responders, with PFS of 4.87 vs 9.13 vs 23.1 months, respectively (p < 0.001). PFS resulted to be significantly shorter in carriers of mutant TP53 compared to not carriers (p = 0.04). Patients with high cfDNA levels and mutant TP53 have the worst PFS, while patients with low cfDNA amounts and no mutations in TP53 displayed the longest PFS (p = 0.004)., Conclusions: The present study demonstrates that cfDNA and TP53 are potential predictive biomarkers of response in mccRCC to be further explored in larger and/or prospective studies., (© 2022. The Author(s).)

Background: Nivolumab and cabozantinib are currently approved agents in metastatic renal cell carcinoma (mRCC) but there are no data available for patients progressing to both treatments. The aim of this study was to compare active therapeutic options and best supportive care (BSC) after progression to nivolumab and cabozantinib in mRCC., Methods: In this retrospective study, we selected 50 patients from eight Italian centers. The primary endpoint of the study was the overall survival (OS) of patients on active treatment versus BSC. Secondary endpoints were the progression-free survival (PFS) and objective response rate (ORR). The efficacy of active therapy was also investigated., Results: After progression to both nivolumab and cabozantinib, 57.1% of patients were given active treatment (mainly everolimus and sorafenib) while 42.9% received BSC. The median OS was 13 months (95% CI: 4-NR) in actively treated patients and 3 months (95% CI: 2-4) in BSC patients (p = 0.001). Patients treated with sorafenib had better disease control than those treated with everolimus (stable disease: 71.4% vs. 16.7%, progression disease: 14.3% vs. 58.3%; p = 0.03), with no significant differences in PFS (5 and 3 months, 95% CI: 1-6 vs. 2-5; p = 0.6) and OS (12 and 4 months, 95% CI: 3-NR vs. 2-NR; p = 0.2)., Conclusion: After treatment with both nivolumab and cabozantinib, the choice of a safe active systemic therapy offered better outcomes than BSC., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Importance: Metastatic collecting duct carcinoma (mCDC) is a rare type of non-clear cell renal cell carcinoma (ncRCC) with poor prognosis and no standard treatments. Despite retrospective series that have documented the benefit of cabozantinib in ncRCC, no prospective trials have evaluated this treatment in mCDC., Objective: To determine whether cabozantinib is an active treatment in patients with mCDC., Design, Setting, and Participants: The caBozantinib in cOllectiNg ductS Renal Cell cArcInoma (BONSAI) trial was an open-label, single-arm, phase 2 clinical trial carried out between January 2018 and November 2020 at a single academic center with data cut off in September 2021 on behalf of the the Italian Network for Research in Urologic-Oncology (Meet-URO 2). Eligible patients had histologic diagnosis of centrally confirmed mCDC with measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). In total, 25 patients were screened., Interventions: Patients received cabozantinib, 60 mg orally once daily, until disease progression, unacceptable toxic effects, or withdrawal of consent., Main Outcomes and Measures: The primary end point was objective response rate (ORR) per RECIST, version 1.1., Results: At data cut off, of 25 patients enrolled, 23 started treatment because 2 were excluded after failing the screening process at pathologic review. The median follow-up cannot be estimated using the reverse Kaplan-Meier estimator. The median time to censoring was 11 months (95% CI, 0-22 months). Median (range) age was 66 (53-74) years. As best overall response, 3 patients presented stable disease, 1 patient achieved a complete response, and 7 a partial response. The ORR was 35% (95% CI, 16%-57%). The median progression-free survival was 4 months (95% CI, 3-13 months). The median OS was 7 months (95% CI, 3-31 months). All patients reported at least 1 grade (G) 1 to 2 adverse event (AE). The most common G1 to G2 AEs were fatigue (14 [60%]), anorexia (9 [39%]), hand-foot syndrome (7 [30%]), hypothyroidism (7 [30%]), mucositis (7 [30%]), diarrhea (5 [22%]), and hypertension (3 [13%]). Six G3 AEs were reported: 2 arterial hyperthension, 1 pulmonary thromboembolism, 1 bleeding, and 2 fatigue. There were no permanent discontinuations from the study owing to AEs. Four patients (17%) required dose reduction to 40 mg, and 4 (17%) required a transitory interruption to manage toxic effects., Conclusions and Relevance: The study met the ORR primary end point, showing encouraging efficacy of cabozantinib in untreated patients with mCDC. Further investigations to advance the molecular understanding of this tumor are ongoing., Trial Registration: ClinicalTrials.gov Identifier: NCT03354884.

The recent approval of immune checkpoint inhibitor (ICI)-based combinations has redefined the first-line standard of care of metastatic renal cell carcinoma (mRCC) patients. Although the undisputed advantage of these combinations, most patients progressed, requiring subsequent therapies. The change of first-line therapy inevitably led to modification of the all mRCC treatment algorithm; to date, the most appropriate second-line options remain still unclear. The aim of our review was to provide a useful summary of the available evidence in order to overcome the doubts about treatment sequences. Retrospectively, the efficacy of second-line VEGFR-TKIs seems to be greater after failure of a dual ICIs combination rather than after ICIs plus VEGFR-TKIs, nevertheless prospective data of second-line TKIs are limited. Moreover, ICI re-challenge could be an option but, again, most data derived from retrospective series emphasizing the identification of predictive factors of response to select mRCC patients that could benefit from this strategy. Novel molecules and different ICI-based combinations are under evaluation with the aim of implementing the second-line setting. In particular, belzutifan, ciforadenant (CPI-444), and talazoparib achieved encouraging objective response rates (ORR) in phase I/II trials. Phase III trials comparing these new molecules with the standard of care are currently ongoing. The first-line regimen, and the type and duration of response emerged as crucial factors that could influence the efficacy of second-line therapy. Prognostic models that integrate clinical features and molecular biomarkers with a predictive value are warranted to guide clinicians in the decision-making process with the ultimate goal of offering to the patients the most effective therapy in a personalized, precision medicine-based, therapeutic strategy., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Nivolumab showed an overall survival (OS) benefit in pretreated metastatic renal cell carcinoma (mRCC). The role of stereotactic body radiotherapy (SBRT) in mRCC remains to be defined., Objective: Our aim was to evaluate the efficacy and safety of SBRT in combination with nivolumab in second- and third-line mRCC patients., Design, Setting, and Participants: The NIVES study was a phase II, single-arm, multicenter trial in patients with mRCC with measurable metastatic sites who progressed after antiangiogenic therapy, of whom at least one was suitable for SBRT., Intervention: The patients received SBRT to a lesion at a dose of 10 Gy in three fractions for 7 d from the first infusion of nivolumab. Nivolumab was given at an initial dose of 240 mg every 14 d for 6 mo and then 480 mg q4-weekly in responding patients., Outcome Measurements and Statistical Analysis: We hypothesized that nivolumab plus SBRT improves the objective response rate (ORR) compared with nivolumab alone from 25% (derived from historical controls) to 40%. Secondary endpoints were progression-free survival (PFS), OS, disease control rate (DCR) of irradiated and nonirradiated metastases, and safety., Results and Limitations: Sixty-nine patients were enrolled from July 2017 to March 2019. The ORR was 17% and the DCR was 55%. The median PFS was 5.6 mo (95% confidence interval [CI], 2.9-7.1) and median OS 20 mo (95% CI, 17-not reached). After 1.5 yr of follow-up, 23 patients died. The median time to treatment response was 2.8 mo and median duration of response was 14 mo. No new safety concerns arose., Conclusions: We did not find sufficient evidence to suggest that nivolumab in combination with SBRT provides an added benefit in pretreated mRCC patients; it should however be evaluated in patients with oligometastatic or oligoprogressive disease., Patient Summary: Nivolumab in combination with stereotactic body radiotherapy does not provide evidence of increased outcomes in metastatic renal cell carcinoma patients. However this approach was safe and showed a good response of the irradiated lesions., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Cabozantinib improves survival in metastatic renal cell carcinoma (mRCC) after prior antiangiogenics. The best treatment at disease progression (PD) is unknown. Being also a AXL/MET inhibitor, involved in acquired resistance, we hypothesized a prolonged tumor growth control in patients continuing cabozantinib despite PD., Research Design and Methods: This retrospective multicenter study enrolled patients receiving cabozantinib after the first line between 2014 and 2020. We compared patients maintaining cabozantinib after first PD due to clinical benefit and good tolerability with those who changed therapy. The postprogression survival (PPS) of both was our primary endpoint., Results: We analyzed 89 patients: 45 received cabozantinib beyond PD and 44 switched therapy. 40.4%, 31.5%, and 28.1% of patients received 1, 2, or >2 prior treatment, respectively. 84.3% were intermediate-poor International Metastatic Renal Cell Carcinoma Database risk. Patients continuing cabozantinib showed a higher response rate to cabozantinib before PD (46.7% vs 25%, p = 0.03) and were more heavily pretreated. Continuing cabozantinib showed a significantly longer PPS compared with switching therapy (median PPS 16.9 vs 13.2 months, HR 0.66, 95%CI 0.48-0.92, p = 0.011)., Conclusions: We observed longer PPS in patients continuing cabozantinib beyond PD, suggesting that this could be an effective option.

Background: Cabozantinib strongly inhibits osteoclast differentiation and bone resorption in vitro. We aimed to evaluate its effect on bone turnover markers (BTMs) in metastatic renal cell carcinoma., Methods: This is a monocentric prospective study on patients with mRCC treated with cabozantinib between October 2016 and July 2018. We collected blood samples at baseline and after 3 and 6 months of treatment. We compared sets of data obtained from plasma samples in the whole population with unpaired 2-tailed Student t tests and data for a subset of patients for which all timepoints were available with paired 2-tailed Student t tests. We used the Kaplan-Meier method for survival analyses and the log-rank test to compare the curves., Results: Our analysis included 39 patients. At month 3, the mean C-terminal cross-linked telopeptides of type I collagen (CTx) and the mean N-terminal propeptide of type 1 collagen (PINP) levels were significantly decreased in the whole population ( p = 0.013 and p < 0.0001, respectively), as well as at paired analysis ( p = 0.015 and p = 0.045, respectively). No differences were observed between baseline and 6 months ( p = 0.053 and p = 0.087, respectively). After 3 months, the mean parathyroid hormone (PTH) levels significantly increased in the whole population ( p = 0.004), as well as at paired analysis; the mean PTH levels increased significantly at 3 and 6 months, respectively ( p = 0.019 and p = 0.041, respectively). Changes in BTM levels were not associated with outcome., Conclusions: Cabozantinib significantly reduced bone resorption as demonstrated by the decrease of CTx and showed a transient secondary increase of PTH.

Background: Renal cell carcinoma with sarcomatoid differentiation is a highly aggressive form of kidney cancer., Objective: We aimed to analyze the outcomes of patients treated with cabozantinib for metastatic renal cell carcinoma with sarcomatoid features., Methods: We retrospectively collected data from 16 worldwide centers. Overall survival and progression-free survival were analyzed using Kaplan-Meier curves. Cox proportional models were used for univariate and multivariate analyses., Results: We collected data from 66 patients with metastatic sarcomatoid renal cell carcinoma receiving cabozantinib as second-line (51%) or third-line (49%) therapy. The median progression-free survival from the start of cabozantinib was 7.59 months (95% confidence interval [CI] 5.75-17.49) and was longer in male patients (8.81 vs 5.95 months, p = 0.042) and in patients without bone metastases (7.59 vs 5.11 months, p = 0.010); the median overall survival was 9.11 months (95% CI 7.13-23.80). At the multivariate analysis, female sex (hazard ratio = 1.81; 95% CI 1.02-3.37, p = 0.046), bone metastases (hazard ratio = 2.62; 95% CI 1.34-5.10, p = 0.005), and International Metastatic Renal Cell Carcinoma Database Consortium criteria (hazard ratio = 3.04; 95% CI 1.54-5.99, p = 0.001) were significant predictors of worse overall survival., Conclusions: Our data show that cabozantinib is active in pretreated patients with sarcomatoid renal cell carcinoma. Biomarkers are needed in this field to select patients for multi-kinase inhibitors or other options., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Severe immune-related Adverse Events (irAEs) develop in 10-27% of patients treated with Immune-Oncology (IO) [Powles (Lancet 391:748-757, 2018); Galsky (Lancet 395:1547-1557, 2020); Haanen (Ann Oncol 28:119-142, 2017)]. The aim of our study was to evaluate efficacy and clinical outcome of metastatic renal cell carcinoma (mRCC) patients who stopped Immune Checkpoint Inhibitors (ICIs) due to early Grade (G) 3-G4 irAEs., Methods: We retrospectively collected data from 204 mRCC patients treated with ICIs in 6 Italian referral centers adhering to the Meet-Uro group, between February 2017 and January 2020. To properly weight the results, patients who did not report early G3-G4 toxicities have been included as control group. Primary endpoint was to evaluate 6 months Progression Free Survival (PFS) after early treatment interruption for Grade (G) 3-4 toxicities compared to the control group. Secondary endpoints were to evaluate Time to treatment failure (TTF) and overall survival (OS) in both groups. All statistical analyses were performed using SPSS software (version 19.00, SPSS, Chicago)., Results: 18/204 (8.8%) patients had early treatment interruption for serious (G3-G4) irAEs. Early was defined as interruption of IO after only one or two administrations. Immune related nephritis and pancreatitis were the most common irAE that lead to treatment interruption. 6/18 patients received IO-IO combination whereas 12/18 patients antiPD1. In the study group, 12/18 (66.6%) were free from progression at 6 months since IO interruption, TTF was 1.6 months (95% CI 1.6-2.1), mPFS was 7.4 months (95% CI 3.16-11.6) and mOS was 15.5 months (5.1-25.8). In the control group 111/184 (60.3%) patients were free from progression at 6 months, TTF was 4.6 months (95% CI 3.5-5.6), mPFS was 4.6 months (95% CI 3.5-5.6) and mOS was 19.6 months (95% CI 15.1-24.0). In the overall population, mPFS was 5.0 months (95% CI 4.0-5.9) and mOS was 19.6 months (95% CI 15.1-24.0)., Conclusions: ICIs seem to maintain efficacy even after early interruption due to severe irAE., (© 2021. The Author(s).)

Objective: To assess the efficacy and tolerability of rechallenge with sunitinib and other targeted therapies (TTs) in patitents with relapsed recurrent renal cell carcinoma (RCC) in the advanced setting., Methods: In this multi-institutional retrospective study, patients with relapsed RCC were rechallenged with sunitinib or other systemic TTs as a first-line therapeutic approach after failed adjuvant sunitinib treatment. Patient characteristics, treatments and clinical outcomes were recorded. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR) and overall survival (OS)., Results: A total of 34 patients with relapses were recorded, and 25 of these (73.5%) were men. Twenty-five patients were treated with systemic TT: 65% of patients received TT against the vascular endothelial growth factor pathway (including sunitinib), 21.7% received mammalian target of rapamycin inhibitors and 13% received immunotherapy. The median (interquartile range) time to relapse was 20.3 (5.2-20.4) months from diagnosis, and 7.5 months (1.0-8.5) from the end of adjuvant suntinib treatment. At a median follow-up of 23.5 months, 24 of the 25 patients had progressed on first-line systemic therapy. The median PFS was 12.0 months (95% confidence interval [CI] 5.78-18.2). There were no statistical differences in PFS between different treatments or sunitinib rechallenge. PFS was not statistically different in patients relapsing on or after adjuvant suntinib treatment (≤ 6 or >6 months after adjuvant suntinib ending). The ORR was 20.5%. The median OS was 29.1 months (95% CI 16.4-41.8)., Conclusions: Rechallenge with sunitinib or other systemic therapies is still a feasible therapeutic option that provides patients with advanced or metastastic RCC with additional clinical benefits with regard to PFS and OS after failed response to adjuvant sunitinib., (© 2021 The Authors BJU International © 2021 BJU International Published by John Wiley & Sons Ltd.)

Background: The combination of immune checkpoint blockade (ICB) with standard therapies is becoming a common approach for overcoming resistance to cancer immunotherapy in most human malignancies including metastatic renal cell carcinoma (mRCC). In this regard, insights into the immunomodulatory properties of antiangiogenic agents may help designing multidrug schedules based on specific immune synergisms., Methods: We used orthogonal transcriptomic and phenotyping platforms combined with functional analytic pipelines to elucidate the immunomodulatory effect of the antiangiogenic agent pazopanib in mRCC patients. Nine patients were studied longitudinally over a period of 6 months. We also analyzed transcriptional data from The Cancer Genome Atlas (TCGA) RCC cohort (N = 571) to assess the prognostic implications of our findings. The effect of pazopanib was assessed in vitro on NK cells and T cells. Additionally, myeloid-derived suppressor (MDSC)-like cells were generated from CD14 + monocytes transfected with mimics of miRNAs associated with MDSC function in the presence or absence of pazopanib., Results: Pazopanib administration caused a rapid and dramatic reshaping in terms of frequency and transcriptional activity of multiple blood immune cell subsets, with a downsizing of MDSC and regulatory T cells in favor of a strong enhancement in PD-1 expressing cytotoxic T and Natural Killer effectors. These changes were paired with an increase of the expression of transcripts reflecting activation of immune-effector functions. This immunomodulation was marked but transient, peaking at the third month of treatment. Moreover, the intratumoral expression level of a MDSC signature (MDSC INT) was strongly associated with poor prognosis in RCC patients. In vitro experiments indicate that the observed immunomodulation might be due to an inhibitory effect on MDSC-mediated suppression, rather than a direct effect on NK and T cells., Conclusions: The marked but transient nature of this immunomodulation, peaking at the third month of treatment, provides the rationale for the use of antiangiogenics as a preconditioning strategy to improve the efficacy of ICB., (© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear., Methods: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated., Results: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels., Conclusions: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: From 10% to 26% of patients with metastatic renal cell carcinoma (mRCC) experience rapidly progressive disease (PD) on treatment with sunitinib., Objective: To investigate the benefit of subsequent treatment with another tyrosine kinase inhibitor (TKI) or a mammalian target of rapamycin (mTOR) inhibitor in such primary refractory patients., Design, Setting, and Participants: A total of 150 mRCC patients with rapidly PD on first-line sunitinib (within two cycles, n=93, or four cycles, n=57) were identified: median age 59yr; nephrectomy 86%; histological subtypes: clear cell (77.8%), papillary (14%), and sarcomatoid features (18%); according to the Memorial Sloan-Kettering Cancer Center and French classifications: good risk (11% and 7%, respectively), intermediate (68% and 63%, respectively), and poor (21% and 29%, respectively)., Outcome Measurements and Statistical Analysis: Data were retrospectively collected by a questionnaire from 19 European oncology centers between March 2005 and March 2011. Progression-free survival (PFS) and overall survival (OS) were calculated (Kaplan-Meier method)., Results and Limitations: Median OS from the start of first-line treatment was 7.4mo. Second-line treatment was administered to 86 (57%) patients (44 mTOR inhibitors: 23 everolimus and 21 temsirolimus; 39 TKIs alone or in combination; three chemotherapy). Second-line PFS was not significantly different between TKIs and mTOR inhibitors (2.0 vs 0.9mo; p=0.536). Median OS from the start of second-line treatment was 5.0mo for mTOR inhibitors and 6.6mo for TKIs (p=0.15)., Conclusions: Treatment with further TKIs or mTOR inhibitors for mRCC patients primarily refractory to first-line sunitinib in the observed time period achieved very minimal benefit, suggesting avoiding TKI rechallenge and possibly preferring alternative strategies, such as immune checkpoint inhibitors, after PD to a treatment line including a TKI in this setting., Patient Summary: The present work collected data about 150 patients affected by metastatic renal cell carcinoma, who received one of the current standard of care as first-line treatment, namely, the antiangiogenic drug sunitinib, and experienced rapid worsening of the disease. We investigated and described the subsequent outcome of such patients treated with two different types of drug, administered as second-line therapy, to better understand the best strategy to adopt for patients who got no benefit from sunitinib and to describe the current therapeutic approach in such cases., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: Despite the current immunotherapy era, VEGFR inhibitors maintain effectiveness in metastatic renal cell cancer. Real-world data concerning pazopanib are limited. The aim of this study is to add information about efficacy and safety of pazopanib as first-line treatment in metastatic renal cell cancer patients not enrolled into clinical trials., Methods: Retrospective analysis (the PAMERIT study) of first-line pazopanib in real-world metastatic renal cell cancer patients among 39 Centers in Italy. Outcomes were progression-free survival, overall survival, objective response rate and treatment-related adverse events. Kaplan-Meier curves, log-rank test and multivariable Cox's models were used and adjusted for age, histology, previous renal surgery, International Metastatic RCC Database Consortium score and pazopanib initial dose., Results: Among 474 patients, 87.3% had clear cell metastatic renal cell cancer histology. Most of them (84.6%) had upfront renal surgery. Median progression-free survival and overall survival were 15.8 and 34.4 months, respectively, significantly correlating with International Metastatic RCC Database Consortium's good prognosis (P < 0.001), ECOG PS 0 (P < 0.001), age (<75 years, P = 0.005), surgery (P < 0.001) and response to pazopanib (P < 0.001). After 3 months of pazopanib, overall disease control rate have been observed in 76.6% patients. Among International Metastatic RCC Database Consortium's favorable group patients, 57/121 (47%) showed complete/partial response. No unexpected AEs emerged., Conclusions: In this real-world study, metastatic renal cell cancer patients treated with first-line pazopanib reached greater progression-free survival and overall survival than in pivotal studies and had high response rates when belonging to International Metastatic RCC Database Consortium's favorable group, without new toxicities. Pazopanib has been confirmed a valid first-line option for International Metastatic RCC Database Consortium's good prognosis metastatic renal cell cancer patients who cannot be submitted to immunotherapy., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objectives: The aim of our study was to collect data about of the outcome of metastatic renal cell carcinoma patients who progressed after immune checkpoint inhibitors in order to enhance data about efficacy and safety of treatment beyond immune-oncology (IO)., Materials and Methods: A total of 162 eligible patients, progressing to IO, were enrolled from 16 Italian referral centers adhering to the Meet-Uro association. Baseline characteristics, outcome data and toxicities were retrospectively collected. Descriptive analysis was made using median values and ranges. Kaplan-Meier method and Mantel-Haenszel log-rank test were performed to compare differences between groups., Results: A total of 111 patients (68.5%) were treated after IO progression. In all, 51 patients (31.5%) did not receive further treatment for clinical deterioration. Median IO progression free survival (PFS) was 4 months (95% confidence interval [CI]: 3.1-4.8). IO-PFS tends to be longer in patients reporting adverse events (AE) of any grade (5.03 [95% CI: 3.8-6.1] vs. 2.99 [95% CI: 2.4-3.5] months P=0.004). Subsequent therapies included cabozantinib (n=79, 48%), everolimus (n=11, 6.7%), and others (n=21, 12.9%).Median PFS post-IO was 6.5 months (95% CI: 5.1-7.8). Cabozantinib showed longer PFS compared with everolimus (7.6 mo [95% CI: 5.2-10.1] vs. 3.2 mo [95% CI: 1.8-4.5]) (hazard ratio: 0.2; 95% CI: 0.1026-0.7968) and other drugs (4.3 mo [95% CI: 1.3-7.4]) (hazard ratio: 0.6; 95% CI: 0.35-1.23). All grade AE were reported in 83 patients (74%) and G3 to G4 AE in 39 patients (35%). Target therapies post-IO showed median overall survival of 14.7 months (95% CI: 0.3-21.4)., Conclusions: In our real world experience after progression to IO, vascular endotelial groth factor-tyrosine kinase inhibitors, given to patients, proved to be active and safe choices. Cabozantinib was associated with a better outcome in terms of median PFS., Competing Interests: E.V. reports personal fees from BMS, outside the submitted work. G.P. reports personal fees from Bayer, BMS, Ipsen, Merck, MSD, Novartis, Pfizer, outside the submitted work. The remaining authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, and VEGFR-3, recently approved in Europe for the first-line treatment of metastatic renal cell carcinoma (mRCC)., Methods: Retrospective analysis of safety and activity of tivozanib administered at 1.34 mg daily (3 weeks on, 1 week off) within a compassionate-use program to patients with mRCC with no prior systemic treatment in Italy., Results: From August 2018 to April 2019, 64 patients have started tivozanib in 9 oncology units. The median age was 67.5 years (range 40-85), 62.5% males. According to International Metastatic Renal Cell Carcinoma Database Consortium criteria, 27.1% of patients were good prognosis, 57.6% intermediate, and 15.3% poor. Primary tumor had been removed in 71.9% of patients. Histology was clear cell 89%, papillary 4.7%, and unclassified 6.3%. The response rate was 34.4%, stable disease 40.6%, and progression 15.6%. Grade 3-4 toxicities were 7.8% hypertension, 4.7% anemia, 3.1% mucositis, 3.1% asthenia, 1.6% diarrhea, 1.6% anorexia, 1.6% worsening of renal function, and 3.1% cardiac events. Dose reduction to 0.89 mg was applied to 17.2% of patients, and the discontinuation rate due to toxicity was 5.8%. Median progression-free survival was 12.4 months, with 68.7% of patients alive at 12 months. The developing of hypertension predicted increased progression-free survival at multivariate analysis (HR, 0.128; 95% CI, 0.03-0.59; p = 0.008)., Conclusions: Tivozanib showed good activity and favorable safety profile in a real-world cohort of unselected patients with mRCC. Predictive biomarkers of response to antiangiogenic therapy are urgently needed in order to identify RCC patients who could still receive a monotherapy with VEGFR inhibitors in the first line., (© 2021 S. Karger AG, Basel.)

Background: CheckMate 025 has shown superior efficacy for nivolumab over everolimus in patients with advanced renal cell carcinoma (aRCC) along with improved safety and tolerability. This analysis assesses the long-term clinical benefits of nivolumab versus everolimus., Methods: The randomized, open-label, phase 3 CheckMate 025 trial (NCT01668784) included patients with clear cell aRCC previously treated with 1 or 2 antiangiogenic regimens. Patients were randomized to nivolumab (3 mg/kg every 2 weeks) or everolimus (10 mg once a day) until progression or unacceptable toxicity. The primary endpoint was overall survival (OS). The secondary endpoints were the confirmed objective response rate (ORR), progression-free survival (PFS), safety, and health-related quality of life (HRQOL)., Results: Eight hundred twenty-one patients were randomized to nivolumab (n = 410) or everolimus (n = 411); 803 patients were treated (406 with nivolumab and 397 with everolimus). With a minimum follow-up of 64 months (median, 72 months), nivolumab maintained an OS benefit in comparison with everolimus (median, 25.8 months [95% CI, 22.2-29.8 months] vs 19.7 months [95% CI, 17.6-22.1 months]; hazard ratio [HR], 0.73; 95% CI, 0.62-0.85) with 5-year OS probabilities of 26% and 18%, respectively. ORR was higher with nivolumab (94 of 410 [23%] vs 17 of 411 [4%]; P < .001). PFS also favored nivolumab (HR, 0.84; 95% CI, 0.72-0.99; P = .0331). The most common treatment-related adverse events of any grade were fatigue (34.7%) and pruritus (15.5%) with nivolumab and fatigue (34.5%) and stomatitis (29.5%) with everolimus. HRQOL improved from baseline with nivolumab but remained the same or deteriorated with everolimus., Conclusions: The superior efficacy of nivolumab over everolimus is maintained after extended follow-up with no new safety signals, and this supports the long-term benefits of nivolumab monotherapy in patients with previously treated aRCC., Lay Summary: CheckMate 025 compared the effects of nivolumab (a novel immunotherapy) with those of everolimus (an older standard-of-care therapy) for the treatment of advanced kidney cancer in patients who had progressed on antiangiogenic therapy. After 5 years of study, nivolumab continues to be better than everolimus in extending the lives of patients, providing a long-lasting response to treatment, and improving quality of life with a manageable safety profile. The results demonstrate that the clinical benefits of nivolumab versus everolimus in previously treated patients with advanced kidney cancer continue in the long term., (© 2020 American Cancer Society.)

Background: Sarcomatoid renal cell carcinoma (sRCC) represents a rare form of renal cell carcinoma marked by an aggressive biology, poor prognosis and little benefit from anti-angiogenic targeted therapy. More promising results come from the recent therapeutic strategy based on immune checkpoint inhibitor (ICI) combinations., Materials and Methods: For this meta-analysis, we searched MEDLINE/PubMed, the Cochrane Library and American Society of Medical Oncology (ASCO) Meeting abstracts for phase II or III randomised clinical trials. Data extraction was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. The hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) with the relative 95% confidence intervals were extracted from studies. Summary HRs were calculated using random- or fixed-effects models, depending on the heterogeneity of the included studies., Results: Four studies were selected for final analysis, including 467 patients (226 treated in with ICI combinations and 241 received sunitinib in the control arms). ICI-based combinations were associated with an improved PFS and OS compared with sunitinib, with a reduction of more than 40% of progression (HR = 0.56; p < 0.0001) and mortality (HR = 0.56; p = 0.001) risk. Moreover, ICI-based combinations are associated with a objective response rate (ORR) of more than 50% (versus 20% with sunitinib), corresponding to a doubled risk of achieving an ORR compared with controls (relative risk [RR] = 2.15; p < 0.00001). Finally, immunotherapy significantly increased the possibility to obtain complete responses (RR = 8.15, p = 0.0002) with an incidence of 11%., Conclusion: Our data support the efficacy of ICI-based combinations for sRCC therapy, redefining the first-line treatment., Competing Interests: Conflict of interest statement R.I. reports serving as a consultant or playing an advisory role for Pfizer, Janssen, Sanofi, IPSEN, MSD and Novartis and receiving travel accommodations from Pfizer, Janssen and Ipsen. C.C. reports serving as a consultant of IPSEN and Merk. E.B. reports receiving funds from the Italian Association for Cancer Research AIRC-IG20583, the International Association for Lung Cancer (IASLC), the LILT (Lega Italiana per la Lotta contro i Tumori) and Fondazione Cariverona; receiving fee for speak’ and travel’ from MSD, AstraZeneca, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis and Roche; receiving consultant fee from Roche and Pfizer and receiving institutional research grants from Astra-Zeneca and Roche. S.B. reports serving as a consultant or playing an advisory role for Pfizer, BMS, MSD, Roche, Astellas, Janssen, Ipsen, Bayer, Merck and AstraZeneca and reports receiving travel accommodations from Pfizer, BMS, Roche, Astellas, Janssen, Ipsen, AstraZeneca and Exelixis. G.P. reports serving as a consultant or playing an advisory role for AstraZeneca, Bayer, BMS, Ipsen, MSD, Novartis and Pfizer. C.P. reports serving a consultant and speaker for EUSA, Bristol-Myers Squibb, MSD, Pfizer, Ipsen, Eisai, AstraZeneca, Janssen, Novartis and General Electrics and reports receiving honoraria from Roche. G.T. reports serving a consultant or playing an advisory role for BMS and Novartis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: Despite the initial clinical benefit, resistance to antiangiogenic therapies develops through the activation of alternative pathways. We measured plasma levels of circulating angiogenic factors to explore their predictive role in metastatic renal cell carcinoma (mRCC) patients treated with pazopanib., Materials and Methods: mRCC patients receiving first-line pazopanib were prospectively enrolled. The levels of circulating interleuchine (IL)-6, IL-8, stromal derived factor-1, vascular endothelial growth factor-A, hepatocyte growth factor (HGF), osteopontin, and E-selectin were quantified at baseline and every 4 weeks until disease progression (PD). Patients were dichotomized into "low" and "high" subgroups by a cutoff point defined by the respective median circulating angiogenic factor (CAF) value at baseline. Then, association with the objective response was determined. Changes in CAF levels between baseline and PD were also compared., Results: Among 25 patients included in the final data set, 6 patients were still on treatment. As best response, 12 patients presented a partial response (48%), 9 showed stable disease, and 4 showed PD. The median follow-up was 31.9 months. The median progression-free survival was 14.8 months. Low baseline levels of IL-6, IL-8, HGF, and osteopontin were found to be significantly associated with objective response. In addition, patients with low baseline levels of HGF showed longer progression-free survival and overall survival, whereas patients with low baseline levels of IL-8 showed longer overall survival. Among patients experiencing PD, the median plasma levels of stromal derived factor-1 and vascular endothelial growth factor-A were significantly higher compared with the baseline (P=0.01; P=0.011). Conversely, the median levels of E-selectin were significantly lower compared with the baseline (P=0.017)., Conclusion: Changes in levels of selected CAFs were associated with response/resistance to pazopanib in mRCC patients.

Background: Angiogenesis has been recognized as the most important factor for tumor invasion, proliferation, and progression in metastatic renal cell carcinoma (mRCC). However, few clinical data are available regarding the efficacy of cabozantinib following immunotherapy., Objective: To describe the outcome of cabozantinib in patients previously treated with immunotherapy., Patients and Methods: Patients with mRCC who received cabozantinib immediately after nivolumab were included. The primary endpoint was to assess the outcome in terms of efficacy and activity., Results: Eighty-four mRCC patients met the criteria to be included in the final analysis. After a median follow-up of 9.4 months, median overall survival was 17.3 months. According to the IMDC criteria, the rates of patients alive at 12 months in the good, intermediate, and poor prognostic groups were 100%, 74%, and 33%, respectively (p < 0.001). The median progression-free survival (PFS) was 11.5 months (95% CI 8.3-14.7); no difference was found based on duration of previous first-line therapy or nivolumab PFS. The overall response rate was 52%, stable disease was found as the best response in 25.3% and progressive disease in 22.7% of patients. Among the 35 patients with progressive disease on nivolumab, 26 (74.3%) patients showed complete/partial response or stable disease with cabozantinib as best response after nivolumab. The major limitations of this study are the retrospective nature and the short follow-up., Conclusions: Cabozantinib was shown to be effective and active in patients previously receiving immune checkpoint inhibitors. Therefore, cabozantinib can be considered a valid therapeutic option for previously treated mRCC patients, irrespective of the type and duration of prior therapies.

Circulating tumor cells (CTCs) are promising biomarkers for prognosis, therapeutic response prediction, and treatment monitoring in cancer patients. Despite its epithelial origin, renal cell carcinoma (RCC) shows low expression of epithelial markers hindering CTC-enrichment approaches exploiting epithelial cell surface proteins. In 21 blood samples serially collected from 10 patients with metastatic RCC entering the TARIBO trial, we overcame this limitation using the marker-independent Parsortix™ approach for CTC-enrichment coupled with positive and negative selection with the DEPArray™ with single cell recovery and analysis for copy number alterations (CNA) by next generation sequencing NGS. Two CTC subpopulations were identified: epithelial CTC (eCTC) and non-conventional CTC (ncCTC) lacking epithelial and leukocyte markers. With a threshold ≥1CTC/10 mL of blood, the positivity rates were 28% for eCTC, 62% for ncCTCs, and 71% considering both CTC types. In two patients with detectable eCTCs at baseline, progression free survival was less than 5 months. In an index case, hierarchical structure by translational oncology (TRONCO) identified three clones among 14 CTCs collected at progression and at baseline, each containing cells with a 9p21.3loss, a well-known metastasis driving subclonal alteration. CTCs detection in RCC can be increased by marker-independent approaches, and CTC molecular characterization can allow detection of subclonal events possibly related to tumor progression.

Objectives: stereotactic body radiation therapy (SBRT) use has increased overtime for the management of metastatic renal cell carcinoma (mRCC) patients, with a likely good control of irradiated lesions. We planned a retrospective multicenter Italian study, with the aim of investigating the outcome of treatment with SBRT for non-brain secondary lesions in mRCC patients., Methods: all consecutive metastatic non-brain lesions from mRCC that underwent SBRT at nine Italian institutions from January 2015 to June 2017 were considered. The primary endpoint of the study was the lesion-PFS, calculated from SBRT initiation to the local progression of the irradiated lesion., Results: 57 extracranial metastatic lesions from 48 patients with primary mRCC were treated with SBRT. At the median follow-up of 26.4 months, the median lesion-PFS was not reached (43 censored); 72.4% of lesions were progression-free at 40 months, with significantly better lesion-PFS for small metastatic lesions (<14 mm). SBRT was safe and the 1-year local disease control was 87.7%. After SBRT, 18 patients (37.5%) permanently interrupted systemic therapy., Conclusions: consistently with the previous literature, our findings support the use of SBRT in selected mRCC patients., Competing Interests: Declaration of Competing Interest M. Bersanelli received research funding from Seqirus, Pfizer, Bristol-Myers Squibb (BMS) and Novartis and honoraria for advisory role and as speaker at scientific events from BMS, Novartis, Pierre-Fabre and Pfizer. S. Buti received research funding from Novartis and honoraria for advisory role and as speaker at scientific events from Pfizer, BMS, IPSEN, Pierre-Fabre, Merck Sharp & Dohme (MSD), AstraZeneca. G. Procopio received honoraria for advisory role from Bayer, BMS, Ipsen, MSD, Novartis, Pfizer. All other authors declared no conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)