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Interannual correlation between satellite-derived sea surface temperature (SST) and surface chlorophyll a (Chl a) are examined in the coastal upwelling zone off Punta Eugenia on the west coast of the Baja California Peninsula, area identified as intense biological productivity and oceanographic transition between mid-latitude and tropical ocean conditions. We used empirical orthogonal functions (EOF) analysis separately and jointly on the two fields from 1997 through 2007, a time period dominated by different remote forcing; ENSO conditions (weak, moderate and strong) and the largest intrusion of subarctic water reported in the last 50 yr. Coastal Upwelling Index anomalies (CUI) and the Multivariate ENSO Index (MEI) were used to identify the influence of local (wind stress) and remote (ENSO) forcing over the interannual variability of both variables. The individual EOF1 analysis showed the greater variability of SST and Chl a offshore, their corresponding amplitude time series presented the highest peaks during the intrusion of subartic water (2002?2004) and were significantly correlated with the MEI (RSST ≈ 0.68, RChl a ≈ -0.30, P < 0.001) and moderately correlated with the CUI (RSST ≈ -0.4, RChl a ≈ 0.25, P < 0.001), showing similar trends. The joint EOF1 and the SST-Chl a correlations pattern show the area where both variables covary tightly; a band near to the coast with the largest correlations (R > 0.4) mainly regulated by ENSO cycles. This was revealed when we calculate the homogeneous correlations for the periods El Niño-La Niña and the intrusion of subartic water. Both, SST and Chl a showed higher coupling and two distinct physical-biological responses; on average ENSO influence were clearly along the coast mostly in SST while the subarctic water influence, were observed offshore mostly in Chl a. We found a coastal chlorophyll bloom correlated strongly with high wind stress anomalies that reach the coast off Punta Eugenia during spring and summer 2002 and continued its presence during 2003 which showed an enrichment pattern similar to that observed at high latitudes (∼ 40° N). This observation may provide an explanation of why Punta Eugenia is one of the most important biological action centers. [ABSTRACT FROM AUTHOR]

An interdisciplinary study of the ‘El Bajo de Espiritu Santo’ (EBES) seamount in the Gulf of California leads to a number of conclusions on the interaction between the dynamics and the biology on a shallow seamount. The EBES seamount is a mid-latitude, shallow seamount where the frequency of the tidal forcing (K1+M2) is superinertial. It is a place of high concentration of zooplankton, fish larvae and pelagic fish. A number of processes identified here are capable of locally enhancing productivity at very different time scales. Entrainment induced by vertical shear of the currents generates mixing on its summit. Three-dimensional tidal advection is important during spring tides. Surface hydrographic fields change quickly due to common, short-lived wind bursts, which force current jets out of the neighboring Bay of La Paz. Impinging large-scale flows perturb the vertical structure along the flanks of the seamount. Low frequency (1–3 weeks) cool and warm events, consequence of the large-scale dynamics in the Gulf of California, also reach the seamount. Recent consecutive El Nin˜o y La Nin˜a events produced large (2–3°C) interannual temperature differences. Not only biomass but diversity is also high, 104 different species of fish larvae have been identified here. This is thought to be due to the specific geographical location of the seamount. Outflows from the Bay of La Paz (and the variability observed in near-surface temperature record suggests that there are other phenomena) promote higher diversity of species by carrying larvae and zooplankton from regions biologically different to the EBES seamount. [Copyright &y& Elsevier]

Background: Belzutifan, a hypoxia-inducible factor 2a inhibitor, showed clinical activity in clear-cell renal-cell carcinoma in early-phase studies. Methods: In a phase 3, multicenter, open-label, active-controlled trial, we enrolled participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies and randomly assigned them, in a 1:1 ratio, to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable toxic effects occurred. The dual primary end points were progression-free survival and overall survival. The key secondary end point was the occurrence of an objective response (a confirmed complete or partial response). Results: A total of 374 participants were assigned to belzutifan, and 372 to everolimus. At the first interim analysis (median follow-up, 18.4 months), the median progression-free survival was 5.6 months in both groups; at 18 months, 24.0% of the participants in the belzutifan group and 8.3% in the everolimus group were alive and free of progression (two-sided P = 0.002, which met the prespecified significance criterion). A confirmed objective response occurred in 21.9% of the participants (95% confidence interval [CI], 17.8 to 26.5) in the belzutifan group and in 3.5% (95% CI, 1.9 to 5.9) in the everolimus group (P<0.001, which met the prespecified significance criterion). At the second interim analysis (median follow-up, 25.7 months), the median overall survival was 21.4 months in the belzutifan group and 18.1 months in the everolimus group; at 18 months, 55.2% and 50.6% of the participants, respectively, were alive (hazard ratio for death, 0.88; 95% CI, 0.73 to 1.07; two-sided P = 0.20, which did not meet the prespecified significance criterion). Grade 3 or higher adverse events of any cause occurred in 61.8% of the participants in the belzutifan group (grade 5 in 3.5%) and in 62.5% in the everolimus group (grade 5 in 5.3%). Adverse events led to discontinuation of treatment in 5.9% and 14.7% of the participants, respectively. Conclusions: Belzutifan showed a significant benefit over everolimus with respect to progression-free survival and objective response in participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies. Belzutifan was associated with no new safety signals. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; LITESPARK-005 ClinicalTrials.gov number, NCT04195750.). [ABSTRACT FROM AUTHOR]

Background: microRNAs (miRNAs) are small noncoding RNA molecules that post-transcriptionally regulate gene expression. In the present study, we describe miRNA expression in early node-positive BC and identify a 8-miRNA score that could contribute to prognosis assessment. Methods: First, microarray analysis was performed using RNA samples extracted from primary breast cancer. The expression of miRNAs was analyzed by RT-qPCR using the TaqMan Arrays from Applied Biosystems. After a suitable normalization of the 677 miRNAs analyzed, 123 presented a good correlation between their levels of expression in frozen tissue and paraffin tissue. A supervised analysis was done in order to identify MIR that could predict relapse. Results: 172 patients with node-positive chemotherapy-treated early BC were included in the present study. The median age at diagnosis was (53.7) years, 128 cases (74.4%) had positive estrogen receptor, and 163 patients (94,7%) received adjuvant chemotherapy. After a median follow up of 8,1 years, 71 p (41.2%) relapsed. Supervised analyses identified 8 microRNAs (has miR-30e, miR-30a, miR-21, miR-210, miR-93, miR-150, miR-99b, miR-572) associated with higher risk of relapse (5 year PFS 50% vs 90%, HR 3.75, 95% CI 2.27 -6.19) and with estimated overall survival (median not reached, HR 4.51, 95% CI 2.36-8.61). Interestingly, miRNAs defined 2 prognostic groups (high and low risk) regardless of type of adjuvant chemotherapy (with or without anthracyclines) and histological subtype (luminal A, B or triple negative). Conclusions: This study suggests that miRNA expression could contribute to assess molecular prognosis of breast cancer and identifies clusters of miRNAs that could improve outcome prediction. A validation study in node-negative and triple negative disease is planned. [ABSTRACT FROM AUTHOR]

Background and Purpose: Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading to the question of whether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions., Patients and Methods: We evaluated the association between AR expression, assessed through NanoString ® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis., Results: Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC., Conclusions: AR-overexpression and its association with other genes could favor a transcriptomic signature set to aid in identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Renal cell carcinoma (RCC) is a heterogenous disease which the incidence is increasing worldwide. The identification and understanding of the role of the Von Hipple Lindau (VHP) in regulating the hypoxia-inducible factor signaling pathway has revolutionized the treatment of this disease. Belzutifan is an oral hypoxia-inducible factor (HIF)-2α inhibitor, which has demonstrated efficacy in treating von Hippel-Lindau (VHL) disease and for the treatment of adults with RCC who experienced disease progression after PD-1/PD-L1- and VEGFR-targeted therapies. One of the most common adverse effect of this drug is anemia; however, it is treatment is not well known. This review summarizes role of the VHL-HIF pathway in ccRCC aroused the interest of targeting HIF activity, the history of belzutifan development and their relationship to anemia as well as propose a management algorithm., 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 © 2024 Elsevier Ltd. All rights reserved.)

Background and Objective: Adjuvant pembrolizumab significantly improved overall survival (OS) in renal cell carcinoma (RCC), but real-world data on sequential treatment are scarce. We sought to evaluate the clinical outcomes of first-line (1L) systemic therapy following adjuvant immune oncology (IO)-based regimens., Methods: A retrospective study including patients with recurrent RCC following adjuvant IO across 29 international institutions was conducted. The primary endpoint was progression-free survival (PFS) on 1L systemic therapy estimated using the Kaplan-Meier method. Preplanned subanalyses of clinical outcomes by type of 1L systemic therapy, recurrence timing, and International Metastatic RCC Database Consortium (IMDC) risk groups were performed. Treatment-related adverse events leading to treatment discontinuation, dose reduction, or corticosteroid use were assessed., Key Findings and Limitations: A total of 94 patients were included. Most received adjuvant pembrolizumab (n = 37, 39%), atezolizumab (n = 28, 30%), or nivolumab + ipilimumab (n = 15, 16%). The cohort included 49 (52%) patients who had recurrence within 3 mo of the last adjuvant IO dose, whereas 45 (48%) recurred beyond 3 mo. Bone metastases were significantly higher in tumors recurring at <3 mo (10/49, 20%) than those recurring at >3 mo (1/45, 2.2%; p = 0.008). Most patients received 1L vascular endothelial growth factor-targeted therapy (VEGF-TT; n = 37, 39%), IO + VEGF-TT (n = 26, 28%), or IO + IO (n = 12, 13%). The remaining underwent local therapy. The median follow-up for the 1L systemic therapy cohort was 15 mo. The 18-mo PFS and OS rates were 45% (95% confidence interval [CI]: 34-60) and 85% (95% CI: 75-95), respectively. Treatment-related adverse events occurred in 32 (42%) patients and included skin toxicity (n = 7, 9.2%), fatigue (n = 6, 7.9%), and diarrhea/colitis (n = 4, 5.3%). Limitations included selecting patients from large academic centers and the short follow-up period., Conclusions and Clinical Implications: A subset of patients with recurrent RCC following adjuvant IO respond to systemic therapies, including VEGF-TT and IO-based regimens. Notably, patients with favorable-risk disease may derive more benefit from VEGF-TT than from IO therapies in this setting. Future approaches utilizing radiographic tools and biomarker-based liquid biopsies are warranted to detect occult metastatic disease and identify candidate patients for adjuvant IO therapy., Patient Summary: Adjuvant pembrolizumab significantly improved overall survival in renal cell carcinoma (RCC). There are limited data on clinical outcomes after the recurrence of RCC tumors following adjuvant immunotherapy. In this study, we find that patients respond to subsequent systemic therapies across different treatment options., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Radium-223 is an active therapy option for bone metastatic castration-resistant prostate cancer (mCRPC). The lack of adequate biomarkers for patient selection and response assessment are major drawbacks for its use., Objective: To assess the prognostic value of bone metabolism biomarkers (BMBs) in ra-223-treated mCRPC patients., Design, Setting, and Participants: A prospective cohort study of mCRPC patients treated with Ra-223 (PRORADIUM study: NCT02925702) was conducted., Outcome Measurements and Statistical Analysis: The main objective of the study was to evaluate the association between high (≥median) baseline values in at least three bone formation (bone alkaline phosphatase [BAP] and C-terminal type-I collagen propeptide) and bone resorption (N-terminal telopeptide and pyridinoline) biomarkers, and survival. The independent prognostic value of each BMB was also assessed. The association with time to radiographic, clinical, and prostate-specific antigen (PSA) progression; time to skeletal-related events; and PSA response were secondary objectives. Multivariable (MV) Cox-regression models were evaluated., Results and Limitations: A total of 169 patients were included. Of the patients, 70.4% received Ra-223 in second/third line; 144 (85.2%) were Eastern Cooperative Oncology Group 0-1, 126 (74.6%) were in pain, and 80 (47.5%) had more than ten bone metastases. Sixty-seven (39.6%) patients had elevation in at least three BMBs. The median overall survival was 12.1 mo (95% confidence interval [CI]: 10-14.7). No association was observed with other treatment-related secondary outcome parameters. Patients with high values in three or more BMBs had significantly worse survival (9.9 vs 15.2 mo; hazard ratio [HR]: 1.8 [95% CI: 1.3-2.5]; p < 0.001) in the univariate analysis, but not independent in the MV analysis (HR: 1.33; 95% CI: 0.89-2; p = 0.181). High baseline BAP was the only biomarker associated with survival in the MV model (HR: 1.89; 95% CI: 1.28-2.79; p = 0.001). Addition of BAP to the MV clinical model increased the area under the receiver operating characteristic curve 2-yr value from 0.667 to 0.755 (p = 0.003)., Conclusions: Biomarkers of bone formation, especially BAP, have prognostic value in mCRPC patients treated with radium-223. Its predictive value remains to be assessed, ideally in prospective, adequately powered, randomised clinical trials., Patient Summary: In this study, we evaluate the role of bone metabolism biomarkers to help improve the use of radium-223 as therapy for advanced prostate cancer. We found that bone alkaline phosphatase may be a suitable tool., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Cancer is a risk factor for developing severe COVID19. Additionally, SARS-CoV2 has a special tropism for renal cells and complications like thrombosis or cytokine storm could be enhanced by standard treatments in kidney cancer (i.e., antiangiogenics or immunotherapy). Thus, understanding the impact of COVID19 in patients with this tumor is key for their correct management., Methods: We designed a retrospective case-control study comparing the outcome of three groups of advanced kidney cancer patients on systemic treatment: cohort A (developed COVID19 while on antiangiogenics), cohort B (developed COVID19 while on immunotherapy) and cohort C (non-infected). Matching factors were age, gender, and treatment., Results: 95 patients were recruited in 16 centers in Spain from September 2020 to May 2021. Finally, 85 were deemed as eligible (23 cohort A, 21 cohort B, 41 cohort C). Patients with COVID required more dose interruptions (25 vs. six) and hospitalizations (10 vs. none) than those without COVID (both p = 0.001). No difference between cohorts A and B was observed regarding hospitalization or length of stay. No ICU admission was registered and one patient in cohort B died due to COVID19. Regarding cancer evolution, three patients in cohort A presented progressive disease after COVID19 compared to two in cohort B. One case in cohort B, initially deemed as stable disease, achieved a partial response after COVID19., Conclusions: Kidney cancer patients who developed COVID19 while on systemic therapy required more treatment interruptions and hospitalizations than those non-infected. However, no significant impact on cancer outcome was observed. Also, no difference was seen between cases on antiangiogenics or immunotherapy., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Immune checkpoint inhibitors (ICI)-based combinations have become the standard first-line treatment for advanced clear cell renal cell carcinoma (ccRCC). Despite significant improvements in survival and the achievement of sustained long-term responses, a subset of patients remains refractory to ICI, and most will eventually develop resistance. Thus, identifying predictive biomarkers for ICI efficacy and resistance is essential for optimizing therapeutic strategies. Up to now, tissue-based biomarkers have not been successful as predictive biomarkers in RCC. Circulating blood-based biomarkers offer a promising alternative. These biomarkers, including circulating immune cells, soluble factors, tumor-derived markers, and those based on metabolomics, are less invasive, offer reproducibility over time, and provide a comprehensive assessment of tumor biology and patient immune status, as well as allow dynamic monitoring during treatment. This review aims to evaluate the current evidence on the different candidate circulating biomarkers being investigated for their potential to predict ICI efficacy in RCC patients., Competing Interests: RF: Honoraria: Bayer, Astellas, Janssen, BMS, MSD, Ipsen, Pfizer, Merck, Astra Zeneca. NC has provided expertise through participation in scientific advisory boards to AstraZeneca and to Servier and received a research grant from Cytune Pharma, Roche, and Sanofi, although these grants were not on the matter of this manuscript. GdV: grants and personal fees from Pfizer, Roche, and Ipsen; and personal fees from Bristol-Myers Squibb, Astellas, Janssen, Bayer, Merck, and MSD. LA: Consulting or Advisory Role: Astellas Pharma (Inst), Bristol:Myers Squibb (Inst), Eisai (Inst), Ipsen (Inst), Janssen (Inst), MSD (Inst), Pfizer (Inst), Roche (Inst). Travel, Accommodations, Expenses: BMS, Ipsen, MSD. LCA: Travel/accomodation: Pfizer, Ipsen, BMS. Honoraria: Ipsen, Janssen. The rest of authors declare no competing interests., (© The Author(s) 2024.)

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.)

Background: Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors., Methods: This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons., Results: Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node-only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher., Conclusions: Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Nivolumab plus ipilimumab is approved as first-line regimen for intermediate-risk or poor-risk metastatic renal cell carcinoma, and nivolumab monotherapy as second-line therapy for all risk groups. We aimed to examine the efficacy and safety of nivolumab monotherapy and nivolumab plus ipilimumab combination as an immunotherapeutic boost after no response to nivolumab monotherapy in patients with intermediate-risk and poor-risk clear-cell metastatic renal cell carcinoma., Methods: TITAN-RCC is a multicentre, single-arm, phase 2 trial, done at 28 hospitals and cancer centres across Europe (Austria, Belgium, Czech Republic, France, Germany, Italy, Spain, and the UK). Adults (aged ≥18 years) with histologically confirmed intermediate-risk or poor-risk clear-cell metastatic renal cell carcinoma who were formerly untreated (first-line population) or pretreated with one previous systemic therapy (anti-angiogenic or temsirolimus; second-line population) were eligible. Patients had to have a Karnofsky Performance Status score of at least 70 and measurable disease per Response Evaluation Criteria in Solid Tumours (version 1.1). Patients started with intravenous nivolumab 240 mg once every 2 weeks. On early progressive disease (week 8) or non-response at week 16, patients received two or four doses of intravenous nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) boosts (once every 3 weeks), whereas responders continued with intravenous nivolumab (240 mg, once every 2 weeks), but could receive two to four boost doses of nivolumab plus ipilimumab for subsequent progressive disease. The primary endpoint was confirmed investigator-assessed objective response rate in the full analysis set, which included all patients who received at least one dose of study medication; safety was also assessed in this population. An objective response rate of more than 25% was required to reject the null hypothesis and show improvement, on the basis of results from the pivotal phase 3 CheckMate-025 trial. This study is registered with ClinicalTrials.gov, NCT02917772, and is complete., Findings: Between Oct 28, 2016, and Nov 30, 2018, 207 patients were enrolled and all received nivolumab induction (109 patients in the first-line group; 98 patients in the second-line group). 60 (29%) of 207 patients were female and 147 (71%) were male. 147 (71%) of 207 patients had intermediate-risk metastatic renal cell carcinoma and 51 (25%) had poor-risk disease. After median follow-up of 27·6 months (IQR 10·5-34·8), 39 (36%, 90% CI 28-44; p=0·0080) of 109 patients in the first-line group and 31 (32%, 24-40; p=0·083) of 98 patients in the second-line group had a confirmed objective response for nivolumab with and without nivolumab plus ipilimumab. Confirmed response to nivolumab at week 8 or 16 was observed in 31 (28%) of 109 patients in the first-line group and 18 (18%) of 98 patients in the second-line group. The most frequent grade 3-4 treatment-related adverse events (reported in ≥5% of patients) were increased lipase (15 [7%] of 207 patients), colitis (13 [6%]), and diarrhoea (13 [6%]). Three deaths were reported that were deemed to be treatment-related: one due to possible ischaemic stroke, one due to respiratory failure, and one due to pneumonia., Interpretation: In treatment-naive patients, nivolumab induction with or without nivolumab plus ipilimumab boosts significantly improved the objective response rate compared with that reported for nivolumab monotherapy in the CheckMate-025 trial. However, overall efficacy seemed inferior when compared with approved upfront nivolumab plus ipilimumab. For second-line treatment, nivolumab plus ipilimumab could be a rescue strategy on progression with approved nivolumab monotherapy., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests MOG reports institutional research grants from Bristol Myers Squibb, Intuitive Surgical, and Bayer Vital; personal consulting fees from AstraZeneca, Bristol Myers Squibb, Ipsen, MSD, Pfizer, Astellas Pharma, EUSA Pharma, Merck Serono, Roche Pharma, Eisai, Bayer Vital, Janssen, Gilead, and Novartis; personal honoria from AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, Ipsen, Merck Serono, EUSA Pharma, Janssen, Astellas Pharma, and Takeda; and travel expenses from Merck Serono, Bristol Myers Squibb, Bayer, Pfizer, and AstraZeneca. PB reports grants from Bristol Myers Squibb, Ipsen, MSD, Pfizer, Merck, AstraZeneca, Janssen, and Gilead; consulting fees from Bristol Myers Squibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas Pharma, AAA Pharma, Novartis, Gilead, and Bayer; payment or honoria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bristol Myers Suibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas Pharma, Bayer, AAA Pharma, and Novartis; and travel expenses Bristol Myers Squibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, and Astellas Pharma. ManS reports personal consulting fees for advisory boards from Bristol Myers Squibb, MSD, Eisai, Ipsen, and Exelixis; personal honoria for lectures from Bristol Myers Squibb, MSD, Merck, Eisai, Ipsen, Exelixis, EUSA Pharma, and AstraZeneca; and personal participation on advisory boards for Bristol Myers Squibb, MSD, Merck, Eisai, Ipsen, Exelixis, EUSA Pharma, and AstraZeneca. JB reports an educational grant from Astellas Pharma; consulting fees from Bristol Myers Squibb, MSD, Merck, Ipsen, and Pfizer; payment or honoria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ipsen and Merck; travel expenses from Ipsen and Merck; and participation on a data safety monitoring board or advisory board for MSD, Pfizer, and Ipsen. BPV reports consulting fees from Bristol Myers Squibb, MSD Oncology, Astellas Pharma, AstraZeneca, Novartis, Bayer, and Advanced Accelerator Applications-Novartis; payment or honoria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Ipsen, Roche, EUSA Pharma, Pfizer, Merck, Astellas Pharma, AstraZeneca, and Bayer; and travel expenses from Merck, Pfizer, Advanced Accelerator Applications-Novartis, and Roche. KL payment for medical writing (to their institution) for manuscript writing from Bristol Myers Squibb and Intuitive Surgical; and travel expenses from Ipsen. ID reports institutional research grants from Roche and AstraZeneca; honoria for lectures, presentations, or educational events from Bristol Myers Squibb, MSD, Ipsen, Roche Genentech, Janssen, Astellas Pharma, EUSA Pharma, Bayer, Novartis, Gilead, and Bayer; travel expenses from Merck-Pfizer, Ipsen, Janssen, Bayer, and AstraZeneca; participation on an advisory board for Bristol Myers Sqibb, MSD, Ipsen, Roche Genentech, Astellas Pharma, EUSA Pharma, Bayer, Novartis, Eisai, Debio Pharma, Pharmacyclics, and Gilead; is the cofounder of GO NORTE (GU cooperative group, unpaid); is Vice President of Germ Cell Spanish Group (unpaid); is an executive board member of the GUARD consortium (GU cooperative group, unpaid); has received institutional medical writing support from Roche Genentech; and has procured substances for preclinical research purposes from Jansen (institutional research group). GdV reports consulting fees from Bristol Myers Squibb, Astellas Pharma, MSD, Merck, and Eisai; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, Bristol Myers Squibb, Roche, Novartis, Ipse, Pfizer, Astellas Pharma, Pierre Fabre, MSD, Merck, and Janssen; travel expenses from Roche and MSD; and participation on a data safety monitoring board or advisory board for AstraZeneca. FP reports participation on a data safety monitoring board or advisory board for Daiichi and Novartis. PM reports payment or honoria for lectures, presentation, speaker bureaus, manuscript writing or educational events from Bayer; payments for expert testimony from Amgen; travel expenses from Bayer; and reports participation on a data safety monitoring board or advisory board for Pfizer, Novartis, and Astellas Pharma. LA reports consulting fees, paid to their institution, from Bristol Myers Squibb, Ipsen, Roche, Novartis, Pfizer, Astellas Pharma, Merck, MSD, AstraZeneca, Janssen, and Eisai; and travel expenses from Bristol Myers Squibb, MSD, Ipsen, and Pfizer. EE, NC, MarS, US, SF, and GB declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: While surgical management of renal cell carcinoma (RCC) is curative for many patients, others may relapse and could benefit from adjuvant treatments. Immune checkpoint inhibitors (ICI) have been proposed as a potential adjuvant therapy for improving survival in these patients, but the benefit/risk ratio of ICI in the perioperative setting remains unclear., Methods: A systematic review and a meta-analysis of phase III trials of perioperative ICI (anti PD1/PD-L1 alone or in combination with anti-CTLA4 agents) in RCC was conducted., Results: The analysis included results from 4 phase III trials, comprising 3,407 patients. ICI did not show a significant increase in disease-free survival (Hazard Ratio [HR] 0.85; 95% confidence interval [CI] 0.69-1.04; p: 0.11) or overall survival [OS] (HR 0.73; 95% CI 0.40-1.34; p: 0.31). High-grade adverse events were more frequent in the immunotherapy arm (OR 2.65; 95% CI 1.53-4.59; p: <0.001), and high-grade treatment-related adverse events were 8 times more frequent in the experimental arm (OR: 8.07; 95% CI: 3.14-20.75; p: <0.001). Subgroup analyses showed statistically significant differences favoring the experimental arm in females (HR: 0.71; 95 CI 0.55-0.92; p: 0.009), in sarcomatoid differentiation (HR: 0.60 95% CI 0.41-0.89; p: 0.01), and PD-L1 positive tumors (HR HR: 0.74; 95% CI 0.61-0.90; p: 0.003). No significant effect was found in patients according to age, type of nephrectomy (radical vs. partial), and stage (M1 without evidence of disease vs. M0 patients)., Conclusion: Our comprehensive meta-analysis generally suggests that immunotherapy does not confer a survival advantage in the perioperative setting for RCC, with the exception of one positive study. While the overall results are not statistically significant, individual patient factors and other variables may play a role in determining who benefits from immunotherapy. Therefore, despite the mixed findings, immunotherapy may still be a viable treatment option for certain patients, and further studies are needed to determine which patient subgroups would be most likely to benefit., Competing Interests: Declaration of Competing Interest This research did not receive additional support from an organization beyond the authors’ academic institutions. Guillermo de Velasco: GDV is supported by ISCIII-AES-2021 PI21/01922 Consulting and advisory services from Pfizer, Novartis, Bayer, Roche, Ipsen, Astellas Pharma, Bristol-Myers Squibb, MSD and Merck; research funding from Ipsen; and Honoraria, travel and accommodation expenses from Pfizer, Ipsen, Bristol-Myers-Squibb, Astellas Pharma and Roche; Daniel Castellano: Consulting or Advisory Role—Astellas Pharma; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Ipsen; Janssen Oncology; Lilly; MSD Oncology; Novartis; Pfizer; Pierre Fabre; Roche/Genentech; Sanofi; Roberto Iacovelli: Advisory Board member—Astellas, BMS, EISAI, IPSEN, Janssen, MSD, Novartis, Pfizer, Sanofi. Consultant for Astellas, EISAI, MSD, Pfizer; Laurence Albiges: Consulting/advisory role—BMS, Pfizer, Novartis, Sanofi, Amgen, Bristol-Myers Squibb, Bayer, and Cerulean; research funding—Pfizer and Novartis. Rest of authors including corresponding author confirm no other conflict of interest to disclose. The authors declare there are no patents to disclose. The authors declare there are not addition relationships or activities to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.)

Introduction: The long-term clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) and a complete response (CR) to the tyrosine kinase inhibitor (TKI) sunitinib are poorly known. The characteristics of these patients could reveal previously undetected associations with clinical variables., Patients and Methods: This observational, retrospective study (ATILA) used data from a registry of patients with mRCC who had received first-line sunitinib and had achieved CR from 2007 to 2018 in Spain., Results: Sixty-two patients with CR were included; 48 patients (77.4%) received sunitinib in monotherapy and 14 (22.6%) combined with or followed by local treatment. Median age was 58.5 years (range, 32-81). Most patients (79.0%) had clear cell histology and had undergone previous nephrectomy (90.3%). The majority (70.2%) had an intermediate IMDC prognosis, 23% favorable and 7.0% poor. The median time on treatment with sunitinib was 28.2 months (IQR, 16.7-41.0) and the median time to CR was 10.9 months (IQR, 7.2-19.3). After a median follow-up of 8 years (range, 3-13 years), the median PFS was not reached. The overall median duration of complete response was 64.1 months (IQR, 32.2-99.4). The tolerance and safety profile of sunitinib was consistent with previous reports., Conclusion: Durable CR to sunitinib was observed in patients regardless the prognosis group, metastasis site or histology type, with 75% of patients remaining in CR after 10 years., Clinicaltrials: gov: NCT03916458., Competing Interests: Disclosures G.d.V. received research grants from Pfizer, Roche, and Ipsen; consulting or honoraria fees from Ipsen, Pfizer, Roche, Bayer, Astellas, BMS, MSD and Merck. T.A.G. received research grants from Pfizer, Roche, and Ipsen; consulting fees from Ipsen, Pfizer, Roche, Sanofi, Bayer, Astellas, Janssen-Cilag, BMS, and EISAI; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Pfizer, Eisai, and Merck; and support for attending meetings and/or travel from Pfizer, Sanofi, BMS, and IPSEN. A.R.-V. served in advisory boards for MSD, Pfizer, BMS, Astellas, Janssen, Bayer, Clovis and Roche; received honoraria or travel expenses from Pfizer, MSD, Astellas, BMS, Janssen, Astra Zeneca, Roche, Bayer, and Sanofi Aventis; and research funding from Takeda, Pfizer, and Merck. G.A.P. served in speaker bureaus for Ipsen, BMS, Roche, and Janssen. M.C. served in advisory or consultancy roles for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, EUSA Pharma, Lilly, Roche; received honoraria for lectures for Abbot, Bristol-Myers Squibb, EUSA Pharma, Ipsen, Novartis, Pfizer, Pierre Fabre, Roche; holds institutional financial interests in Astra Zeneca, Merck, Pfizer, Roche, and received travel expenses from Ipsen, Lilly, Merck, Pfizer, and Pierre Fabre. A.P. received research grants from Pfizer and BMS; advisory boards/speaker fees from Pfizer, BMS, Ipsen, Roche, Merck, MSD, Janssen, Astellas, Bayer, Sanofi; and travel expenses from Pfizer, BMS, Janssen and Roche. E.G. received grant support from Astellas, Janssen, Sanofi, Bayer, Ipsen, Ferrer, Pfizer, Roche, GSK and BMS; consulting fees from Sanofi, Janssen, Astellas, Bayer, Ipsen, Pfizer, Roche, Novartis, Eisai, EUSA Pharma, BMS, AstraZeneca, Merck, Rovi, Daiichi Sankyo and Techdow; payment or honoraria for lectures, presentations, speakers’ bureaus, man-uscript writing, or educational events from Astellas, Janssen, Sanofi, Bayer, Ipsen, Pfizer, Roche, BMS, Rovi, Daiichi Sankyo, Leo Pharma, Menarini, Eisai, MSD, Boehringer Ingelheim, Merck, EUSA Pharma and Novartis; support for attending meetings and/or travel from As-tellas, Janssen, Sanofi, BMS, Bayer, Ipsen, Roche, Novartis, Pierre Fabre, Pfizer and Eisai. N.F.N. received support from Roche, BMS, Boehringuer, Sanofi, Bayer, Astra Zeneca, Janssen, MSD, Lilly, Pfizer and IPSEN. I.C.-G. participated in advisory boards of Pfizer, EISAI and BMS. O.R. had consulting or advisory roles with BMS, EISAI, Ipsen; received travel and accommodations support from Ipsen and Pfizer. M.J.M. received honoraria and /or travel support from Janssen-Cilag, Bayer healthcare, Sanofi Aventis, Astellas Medivation, Roche, Ipsen, EISAI, Novartis and Pfizer; advisory boards and speaking for: Pfizer, Astellas, Roche, Ipsen, BMS, Eusa Pharma, Sanofi, Novartis, Janssen andPierre Fabre. N.V.C. received consultant fees from Janssen; speaking fees from Sanofi, Astra Zeneca, Astellas, Janssen, Roche, MSD, Ipsen; and travel support from Pfizer, Pierre Fabre, BMS. A.L.M. received support for attending meetings from Roche and MSD. C.G.d.E. has held consultant or advisory roles with Janssen, Sanofi, Bayer, Astellas; speaking roles from Janssen, Sanofi, Bayer, Astellas, Roche, Ipsen, Pfizer; and other support from Janssen, Sanofi and Roche. M.A.C. has held consulting or advisory role with BMS, MSD, Bayer, EUNSA, Pfizer, Roche, Janssen, Pierre Fabre, Ipsen; received travel expenses from Janssen, Astellas, Roche, Ipsen, and MSD. A.R.S. held consulting or advisory roles for Roche, Bristol, Sanofi, Merck, Ipsen and Eisai. I.C.G. has served as consultant or advisory board to Pzifer, Bristol-Myers Squibb, Ipsen, Roche and EusaPharma; has served as speaker to Pfizer, Bristol-Myers Squibb and Ipsen; and received travel and/or accommodation grants from Pfizer. R.A. has participated in advisory boards for Pfizer, Roche, Sanofi and Servier. X.G.d.M. has participated in advisory boards or as invited speaker for Astellas, BMS, Ipsen, Roche, Eusa Pharma, Eisai, Pfizer and Pharmamar. J.C. reports support from Janssen, Roche, AstraZéneca, Astellas, BMS, Pfizer, Sanofi, and Novartis. J.A. received advisory boards/speaker fees from Novartis, Pfizer, Merck, Roche, BMS; and travel and accommodations from AstraZeneca, BMS, Pfizer, Astellas and Sanofi. S.H.P. participated in advisory boards and as speaker for GSK, Clovis, Astra-Zeneca/MSD and Pfizer. Ú.A. is an employee of Pfizer. All other authors report no conflicts of interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest Filipa Carneiroreports receiving consulting fees from BMS, Roche, MSD, Astellas, Ipsen; support for attending meetings from Janssen, Ipsen and BMS. Guillermo de Velasco reports receiving a grant from BMS, Roche; consulting fees from Astellas, BMS, MSD, Merck, Roche, Janssen, Pierre-Fabre, Bayer, and Ipsen; honoraria from Astellas, BMS, MSD, Merck, Roche, Janssen, Pierre-Fabre, Bayer, Ipsen, Pfizer, and Novartis; support for attending meetings from Roche, Pfizer, Ipsen; and participation on a board for AstraZeneca.

Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) are key antiangiogenic drugs for renal cancer treatment. While Von Hippel-Lindau dysfunction constitutes the base for VEGFR-TKIs sensitivity, the role for individual and concurrent mutations in the genes encoding for the chromatin remodelers Polybromo-1 ( PBRM1 ) and Lysine Demethylase 5C ( KDM5C ) is poorly understood. Here, we analyzed the tumor mutational and expression profiles of 155 unselected clear cell RCC (ccRCC) cases treated with first-line VEGFR-TKIs and the ccRCC cases of IMmotion151 trial were used for validation. We found that concurrent PBRM1 and KDM5C ( PBRM1 & KDM5C ) mutations occurred in 4-9% of cases and were enriched in Memorial Sloan Kettering Cancer Center favorable-risk patients. In our cohort, tumors only mutated in PBRM1 or concurrently mutated in PBRM1 and KDM5C had increased angiogenesis (P=0.0068 and 0.039; respectively), and tumors only mutated in KDM5C showed a similar trend. Best response to VEGFR-TKIs corresponded to PBRM1 & KDM5C mutated cases, followed by those mutated only in KDM5C or only in PBRM1 (P=0.050, 0.040 and 0.027 versus non-mutated cases, respectively), with a trend for longer progression free survival (PFS) in the group with only PBRM1 mutated (HR=0.64; P=0.059). Validation in the IMmotion151 trial revealed a similar correlation with increased angiogenesis and the PFS of patients in the VEGFR-TKI-arm was the longest in PBRM1 & KDM5C mutated cases, intermediate for only PBRM1 or only KDM5C mutated patients and the shortest in non-mutated cases (P=0.009 and 0.025, for PBRM1 & KDM5C and PBRM1 versus non-mutated cases). In conclusion, somatic PBRM1 and KDM5C mutations are common in patients with metastatic ccRCC and likely cooperate increasing tumor angiogenesis and VEGFR-TKI-based antiangiogenic therapy benefit., Competing Interests: None., (AJCR Copyright © 2023.)