Search

Background: Natural killer (NK) cells are important contributors to antitumor immunity in clear-cell renal cell carcinoma (ccRCC). However, their phenotype, function, and association with clinical outcomes in ccRCC remain poorly understood., Materials and Methods: We analyzed single-cell RNA sequencing data from 13 primary tumors, 1 localized tumor extension, and 1 metastasis from ccRCC patients at different clinical stages. For each primary tumor specimen, paired normal kidneys were also analyzed. Differential gene expression analysis was carried out to investigate NK cell phenotypes and to derive a gene expression signature. Gene signatures from NK cell subclusters of interest were used to interrogate bulk transcriptomic datasets and expression with clinical outcomes. Finally, tumor-infiltrating NK cell function (cytokine production and cytotoxicity) was assessed by isolation of live NK cells from ccRCC tissue, co-culture with K562 target cells, and measurement of cytokine production (interferon-γ) and cytotoxicity (CD107a) markers by flow cytometry., Results: Single-cell transcriptomic data were analyzed from 13 patients with ccRCC (tumor/normal kidney), resulting in 21 139 NK cells. Clustering analysis revealed six NK cell subsets. Bright-like NK cells were significantly enriched in advanced ccRCC compared with localized ccRCC and normal kidney, expressed markers of tissue residency (ZNF683/Hobit, ITGA1/CD49a, CD9, ITGAE/CD103), and had decreased expression of cytotoxicity genes (GZMB/Granzyme-B, PRF1/perforin). In independent cohorts (The Cancer Genome Atlas ccRCC cohort, CheckMate 025), a gene expression score representing this dysfunctional NK cell phenotype was enriched in advanced ccRCC and was associated with worse overall survival. Functional interrogation of tumor-infiltrating NK cells from ccRCC confirmed that tumor-resident CD49a+CD9+ NK cells had impaired cytotoxicity compared with CD49a-CD9- NK cells., Conclusions: A dysfunctional, tumor-resident NK cell phenotype was enriched among patients with metastatic disease and associated with worse survival in patients with advanced ccRCC across multiple patient cohorts. Restoration of NK cell function (via cytokine stimulation or NK cell engineering) could provide a novel avenue for therapeutic intervention against ccRCC., (Copyright © 2025. Published by Elsevier Ltd.)

Aim: Network meta-analyses (NMAs) increasingly feature time-varying hazards to account for non-proportional hazards between different drug classes. This paper outlines an algorithm for selecting clinically plausible fractional polynomial NMA models. Methods: The NMA of four immune checkpoint inhibitors (ICIs) + tyrosine kinase inhibitors (TKIs) and one TKI therapy for renal cell carcinoma (RCC) served as case study. Overall survival (OS) and progression free survival (PFS) data were reconstructed from the literature, 46 models were fitted. The algorithm entailed a-priori face validity criteria for survival and hazards, based on clinical expert input, and predictive accuracy against trial data. Selected models were compared with statistically best-fitting models. Results: Three valid PFS and two OS models were identified. All models overestimated PFS, the OS model featured crossing ICI + TKI versus TKI curves as per expert opinion. Conventionally selected models showed implausible survival. Conclusion: The selection algorithm considering face validity, predictive accuracy, and expert opinion improved the clinical plausibility of first-line RCC survival models.

Background: The comparative efficacy and health-related quality of life (HRQoL) outcomes of nivolumab plus cabozantinib versus pembrolizumab plus axitinib as first-line treatments for advanced renal cell carcinoma (aRCC) have not been assessed in head-to-head trials., Objective: To assess the efficacy and HRQoL outcomes of nivolumab plus cabozantinib versus pembrolizumab plus axitinib., Design, Setting, and Participants: Patient-level data for nivolumab plus cabozantinib from the CheckMate 9ER trial and published data for pembrolizumab plus axitinib from the KEYNOTE-426 trial were used. CheckMate 9ER data were reweighted to match the key baseline characteristics as reported in KEYNOTE-426., Intervention: Nivolumab (240 mg every 2 wk) plus cabozantinib (40 mg once daily) and pembrolizumab (200 mg every 3 wk) plus axitinib (5 mg twice daily, initially)., Outcome Measurements and Statistical Analysis: Hazard ratios (HRs) for progression-free survival (PFS), duration of response, overall survival (OS), and deterioration in HRQoL were assessed using weighted Cox proportional-hazard models, with sunitinib as a common anchor. Objective response rates (ORRs) and changes in HRQoL scores from baseline were assessed as difference-in-differences for the two treatments relative to sunitinib., Results and Limitations: After balancing patient characteristics between the trials, nivolumab plus cabozantinib was associated with significantly improved PFS (HR [95% confidence interval {CI}] 0.70 [0.53-0.93]; p = 0.01) and a significantly decreased risk of confirmed deterioration in HRQoL (Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-related Symptoms: HR [95% CI] 0.48 [0.34-0.69]) versus pembrolizumab plus axitinib. OS was similar between treatments (HR [95% CI] 0.99 [0.67-1.44]; p = 0.94). Nivolumab plus cabozantinib was associated with numerically greater ORRs (difference-in-difference [95% CI] 8.4% [-1.7 to 18.4]; p = 0.10) and longer duration of response (HR [95% CI] 0.79 [0.47-1.31]; p = 0.36) than pembrolizumab plus axitinib. Comparative studies using data with a longer duration of follow-up are warranted., Conclusions: Nivolumab plus cabozantinib significantly improved PFS and HRQoL compared with pembrolizumab plus axitinib as first-line treatment for aRCC., Patient Summary: This study was conducted to indirectly compare the results of two immunotherapy-based combinations-nivolumab plus cabozantinib versus pembrolizumab plus axitinib-for patients who have not received any treatment for advanced renal cell carcinoma. Patients who received nivolumab plus cabozantinib had a significant improvement in the length of time without worsening of their disease and in their perceived physical and mental health compared with pembrolizumab plus axitinib; patients remained alive for a similar length of time from the start of either treatment. This analysis further adds to our current knowledge of the relative benefits of these two treatment regimens and will help with physician and patient treatment decisions., (Copyright © 2023. Published by Elsevier B.V.)

Background: In the primary analysis of the CLEAR study, lenvatinib plus pembrolizumab significantly improved progression-free survival and overall survival versus sunitinib in patients with advanced renal cell carcinoma (data cutoff Aug 28, 2020). We aimed to assess overall survival based on 7 months of additional follow-up., Methods: This is a protocol-prespecified updated overall survival analysis (data cutoff March 31, 2021) of the open-label, phase 3, randomised CLEAR trial. Patients with clear-cell advanced renal cell carcinoma who had not received any systemic anticancer therapy for renal cell carcinoma, including anti-vascular endothelial growth factor therapy, or any systemic investigational anticancer drug, were eligible for inclusion from 200 sites (hospitals and cancer centres) across 20 countries. Patients were randomly assigned (1:1:1) to receive lenvatinib (20 mg per day orally in 21-day cycles) plus pembrolizumab (200 mg intravenously every 21 days; lenvatinib plus pembrolizumab group), lenvatinib (18 mg per day orally) plus everolimus (5 mg per day orally; lenvatinib plus everolimus group [not reported in this updated analysis]) in 21-day cycles, or sunitinib (50 mg per day orally, 4 weeks on and 2 weeks off; sunitinib group). Eligible patients were at least 18 years old with a Karnofsky performance status of 70 or higher. A computer-generated randomisation scheme was used, and stratification factors were geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint was progression-free survival assessed by independent imaging review according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). In this Article, extended follow-up analyses for progression-free survival and protocol-specified updated overall survival data are reported for the intention-to-treat population. No safety analyses were done at this follow-up. This study is closed to new participants and is registered with ClinicalTrials.gov, NCT02811861., Findings: Between Oct 13, 2016, and July 24, 2019, 1417 patients were screened for inclusion in the CLEAR trial, of whom 1069 (75%; 273 [26%] female, 796 [74%] male; median age 62 years [IQR 55-69]) were randomly assigned: 355 (33%) patients (255 [72%] male and 100 [28%] female) to the lenvatinib plus pembrolizumab group, 357 (33%) patients (275 [77%] male and 82 [23%] female) to the sunitinib group, and 357 (33%) patients to the lenvatinib plus everolimus group (not reported in this updated analysis). Median follow-up for progression-free survival was 27·8 months (IQR 20·3-33·8) in the lenvatinib plus pembrolizumab group and 19·4 months (5·5-32·5) in the sunitinib group. Median progression-free survival was 23·3 months (95% CI 20·8-27·7) in the lenvatinib plus pembrolizumab group and 9·2 months (6·0-11·0) in the sunitinib group (stratified hazard ratio [HR] 0·42 [95% CI 0·34-0·52]). Median overall survival follow-up was 33·7 months (IQR 27·4-36·9) in the lenvatinib plus pembrolizumab group and 33·4 months (26·7-36·8) in the sunitinib group. Overall survival was improved with lenvatinib plus pembrolizumab (median not reached [95% CI 41·5-not estimable]) versus sunitinib (median not reached [38·4-not estimable]; HR 0·72 [95% CI 0·55-0·93])., Interpretation: Efficacy benefits of lenvatinib plus pembrolizumab over sunitinib were durable and clinically meaningful with extended follow-up. These results support the use of lenvatinib plus pembrolizumab as a first-line therapy for patients with advanced renal cell carcinoma., Funding: Eisai and Merck Sharp & Dohme., Competing Interests: Declaration of interests TKC reports research funding, paid to their institution, from AstraZeneca, Aveo, Bayer, Bristol-Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, and Takeda; 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, Up-To-Date, and CME events; payment or honoraria for lectures, presentations, manuscript writing, or educational events from AstraZeneca, Aravive, Aveo, Bayer, Bristol-Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infiniti, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, Takeda, Tempest, Up-To-Date, and CME events; support for attending meetings or travel from Eisai, Merck, Exelixis, and Pfizer; patents planned, issued, or pending related to ctDNA and biomarkers of response to immune checkpoint inhibitors (no royalties as of April 12, 2022); participated on a data safety monitoring board or advisory board for Aravive; a leadership or fiduciary role in other board, society, committee, or advocacy group, for KidneyCan (unpaid), committees for American Society of Clinical Oncology, European Society for Medical Oncology, National Comprehensive Cancer Network®, and Genitourinary Steering Committee of the National Cancer Institute; stock or stock options from Pionyr, Tempest, Precede Bio, and Osel; and salary and research support from Dana-Farber and Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School, and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute. ME reports research funding from Kissei, Sanofi, Astellas, ONO, Takeda, and Bayer; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from MSD, ONO, Chugai, Novartis, Pfizer, Bristol Myers Squibb, Takeda, Janssen, and Merck. RM reports research funding, paid to their institution from Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, Merck, Pfizer, and Aveo Pharmaceuticals and consulting fees from AstraZeneca, Aveo Pharmaceuticals, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly, Merck, Novartis, Pfizer, and Takeda. UDG reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis oncology, Eisai, Janssen, MSD, Pfizer, Ipsen, and Roche and support for attending meetings or travel from Janssen, Bristol-Myers Squibb, and Ipsen. TB reports research support, paid to their institution from AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Merck, and Novartis; consulting fees from Bristol Myers Squibb, Astellas, Janssen, and Sanofi/Aventis; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Bristol-Myers Squibb, Servier, and Pfizer; and receipt of equipment, materials, drugs, medical writing, gifts, or other services, paid to their institution from Bristol-Myers Squibb, AstraZeneca, Roche, and Servier. NSB reports consulting fees from Bristol-Myers Squibb, Ipsen, Eisai, Janssen, Pfizer, Roche, Merck, EMD Serono, AstraZeneca, and Bayer; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events (personal) from Bristol-Myers Squibb, Ipsen, and Merck; and support for attending meetings or travel from Eisai and Janssen. MJM-V reports consulting fees from Astellas Pharma, Bristol-Myers Squibb, EUSA Pharma, Ipsen, Eisai, Janssen-Cilag, Novartis, Pfizer, Roche, and Sanofi; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Astellas Pharma, Bristol-Myers Squibb, Ipsen, EUSA Pharma, Janssen-Cilag, Pfizer, and Roche; and support for attending meetings or travel from Astellas Pharma, Bristol-Myers Squibb, Ipsen, Janssen-Cilag, Pfizer, and Roche. BM reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Roche, Pfizer, Bristol-Myers Squibb, Astellas, Novartis, Bayer, MSD, Merck Serono, Sanofi, Servier, AstraZeneca, Amgen, Janssen, Eisai, E Lilly, and Pierre Farbre; support for attending meetings or travel from Bristol-Myers Squibb and Merck Serono; and participation on a data safety monitoring board or advisory board for Roche, Pfizer, Bristol-Myers Squibb, Astellas, Novartis, Bayer, MSD, Merck Serono, Sanofi, Servier, AstraZeneca, Amgen, Janssen, Eisai, E Lilly, and Pierre Farbre. TH reports grants or contracts, paid to their institution, from Bristol-Myers Squibb, Eisai, Exelixis, Johnson & Johnson, and Pfizer; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Astellas Pharma, Bristol-Myers Squibb, Eisai, Exelixis, Johnson & Johnson, and Pfizer; and participation on a data safety monitoring board or advisory board for Astellas Pharma, Bayer/Onyx, Bristol Myers Squibb, Exelixis, Johnson & Johnson, Novartis, and Pfizer. BMcG reports grants or contracts, paid to their institution from Exelixis, SeaGen, Pfizer, Bristol Myers Squibb and consulting fees from Astellas, Bristol-Myers Squibb, Calithera, Eisai, Exelixis, Pfizer, and SeaGen. TP reports research funding from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; consulting fees from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; support for attending meetings or travel Astra Zeneca, Ipsen, MSD, Pfizer, and Roche. VG reports grants or contracts, paid to their institution, from AstraZeneca, Bristol-Myers Squibb, MSD, Pfizer, Ipsen; consulting fees from Bristol-Myers Squibb, Pfizer, Roche, MSD, Oncorena, PCI Biotech, Nanobiotix, Merck Serono, EUSA Pharm, Debiopharm, Eisai, and Apogepha; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Eisai, Ipsen, Janssen-Cilag, Merck Serono, MSD, Novartis, Pfizer, Roche, AstraZeneca, and Astellas; support for attending meetings or travel from Pfizer and Merck; participation on a data safety monitoring board or advisory board for Bristol-Myers Squibb, Ipsen, Eisai, PharmaMar, and PharmaMar; leadership or fiduciary role in other board, society, committee, or advocacy group from National Working Group AIO (Working Group on Internal Oncology in the German Cancer Society), German Cancer Society; and stock or stock options in AstraZeneca, Bristol-Myers Squibb, MSD, and SeaGen. BA reports grants or contracts from Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche; consulting fees from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events: Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, Roche; payment for expert testimony from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche; and support for attending meetings or travel from Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche. SYR reports grants or contracts from Amgen, Merck, Bristol-Myers Squibb, MSD, Lilly, Daiichi Sankyo, Beigene, Eisai, and AstraZeneca; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Amgen, Lilly, Bristol-Myers Squibb, MSD, and Eisai; and participation on a data safety monitoring board or advisory board from Amgen, MSD, Bristol-Myers Squibb, Merck, Indivumed, Beigene, Eisai, and Daiichi Sankyo. AK reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Merck, Bristol-Myers Squibb, Ipsen, Eisai, Janssen, AbbVie; leadership or fiduciary role in for Kidney Cancer Canada; and stock in Verity Pharma. TAG reports grants or contracts from Pfizer, Roche, and Ipsen; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Lilly, Pfizer, Roche, Bristol-Myers Squibb, MSD, Eisai, Bayer, Janssen, Sanofi, and Astellas. JCG reports consulting fees for an advisory board meeting from Merck Sharp & Dohme (Australia), Bristol-Myers Squibb, and GlaxoSmithKline; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Janssen–Cilag, Ipsen, Merck Sharp and Dohme (Australia), and AstraZeneca (Australia); and support for attending meetings or travel AstraZeneca (Australia), GlaxoSmithKline, and MSD. MS reports grants or contracts from Pfizer, GlaxoSmithKline, AVEO, Bristol Myers Squibb, Novartis, Bayer, Roche/Genentech, Immatics, Wilex, Ipsen, Exelixis, and Eisai; consulting fees from Pfizer, GlaxoSmithKline, Novartis, Bayer, Roche, Aveo, EUSA Pharm, Astellas, Ipsen, Exelixis, Pelloton, Eisai, Bristol-Myers Squibb, MSD, Apogepha, and Oncorena; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Pfizer, GlaxoSmithKline, AVEO, Novartis, Bayer, EUSA Pharma, Astellas, Ipsen, Exelixis, Pelloton, Eisai, Bristol-Myers Squibb, MSD, and Apogepha; and support for attending meetings or travel from Pfizer, EUSAPharm, Ipsen, Eisai, Bristol-Myers Squibb, MSD, and Apogepha. JRM reports grants or contracts, paid to their institution from Corvus Pharmaceuticals, Eisai, Genentech/Roche, Lilly, Merck, Novartis, Peloton Therapeutics, Pfizer, Replimune, Seattle Genetics/Astellas, Sillajen, Tizona Therapeutics, Tocagen, and Vyriad, and consulting fees from Exelixis. RX, KM, and JMcK are employees of Eisai. RFP is an employee of and holds stock in Merck, Rahway, NJ, USA. CGP reports consulting fees from Angelini Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Ipsen, and MSD; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Angelini Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, General Electric, Ipsen, and MSD; and participation on a data safety monitoring board or advisory board for Bristol-Myers Squibb, Eisai, MSD, the European Society of Medical Oncology, and the Italian Association for Medical Oncology. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: In patients with renal cell carcinoma (RCC) on cabozantinib, venous thromboembolism (VTE) management remains challenging due to limited safety data regarding direct oral anticoagulants (DOACs) use in conjunction with cabozantinib. We investigated the safety of cabozantinib with different anticoagulants in patients with RCC., Methods: In this retrospective multicenter study (9 sites), patients with advanced RCC were allocated into 4 groups: (1) cabozantinib without anticoagulation, cabozantinib with concomitant use of (2) DOACs, (3) low molecular weight heparin (LMWH), or (4) warfarin. The primary safety endpoint was the proportion of major bleeding events (defined per International Society on Thrombosis and Hemostasis criteria). The primary efficacy endpoint was the proportion of new/recurrent VTE while anticoagulated., Results: Between 2016 and 2020, 298 patients with RCC received cabozantinib (no anticoagulant = 178, LMWH = 41, DOAC = 64, and warfarin = 15). Most patients had clear cell histology (78.5%) and IMDC intermediate/poor disease (78.2%). Cabozantinib was first, second, or ≥ third line in 21.8%, 31.9%, 43.3% of patients, respectively. Overall, there was no difference in major bleeding events between the no anticoagulant, LMWH, and DOAC groups (P = .088). Rate of new/recurrent VTE was similar among anticoagulant groups. Patients with a VTE had a statistically significantly worse survival than without a VTE (HR 1.48 [CI 95% 1.05-2.08, P = .02])., Conclusion: This real-world cohort provides first data on bleeding and thrombosis complications in patients with RCC treated with cabozantinib with or without concurrent anticoagulation. DOACs appear safe for VTE treatment for patients with RCC on cabozantinib, but optimized anticoagulation management, including individualized risk-benefit discussion, remains important in clinical practice., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Sarcomatoid differentiation in patients diagnosed with renal cell carcinoma (sRCC) imply aggressive behavior and often metastatic disease at the time of diagnosis. We aim to examine the overall survival (OS) in patients with sRCC using the National Cancer Database (NCDB)., Materials and Methods: We identified patients diagnosed with sRCC between 2010-2015. We employed Kaplan-Meier curves and multivariable Cox proportional hazards regression models to examine the impact of several potential risk factors on OS in patients diagnosed with sRCC., Results: In total, 8582 patients with renal cancer were found to have sarcomatoid differentiation, with 4105 patients (47.8%) being diagnosed with AJCC stage IV disease. The median OS was 17.2 months (IQR 5.4, 68.7 months). Compared to patients who did not undergo surgery, OS was significantly longer in patients undergoing partial or total nephrectomy across all stages. This result remained consistent on multivariable Cox proportional hazards regression adjusting for patient and tumor characteristics (Surgery: Hazard ratio 0.54, 95%Confidence interval 0.43 - 0.68, P < .001)., Conclusion: In our cohort sRCC was found to have an unfavorable median OS, which was mainly caused by the high number of cases diagnosed with late-stage disease. Additionally, surgery was associated with favorable OS across all stages. This study supports the notion that surgical therapy, even in the setting of cytoreductive surgery, provides a survival benefit in patients with sRCC., (Copyright © 2022. Published by Elsevier Inc.)

Background: Despite 4 approved combination regimens in the first-line setting for advanced renal cell carcinoma (aRCC), adverse event (AE) costs data are lacking., Materials and Methods: A descriptive analysis on 2 AE cost comparisons was conducted using patient-level data for the nivolumab-based therapies and published data for the pembrolizumab-based therapies. First, grade 3/4 AE costs were compared between nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + axitinib using data from the CheckMate 214 (median follow-up [mFU]: 13.1 months), CheckMate 9ER (mFU: 12.8 months), and KEYNOTE-426 (mFU: 12.8 months) trials, respectively. Second, grade 3/4 AE costs were compared between nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + lenvatinib using data from the CheckMate 214 (mFU: 26.7 months), CheckMate 9ER (mFU: 23.5 months), and KEYNOTE-581 (mFU: 26.6 months) trials, respectively. Per-patient costs for all-cause and treatment-related grade 3/4 AEs with corresponding any-grade AE rates ≥ 20% were calculated based on the Healthcare Cost and Utilization Project database and inflated to 2020 US dollars., Results: Per-patient all-cause grade 3/4 AE costs for nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + axitinib were $2703 vs. $4508 vs. $5772, and treatment-related grade 3/4 AE costs were $741 vs. $2722 vs. $4440 over ~12.8 months of FU. For nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + lenvatinib, per-patient all-cause grade 3/4 AE costs were $3120 vs. $5800 vs. $9285, while treatment-related grade 3/4 AE costs were $863 vs. $3162 vs. $5030 over ~26.6 months of FU., Conclusion: Patients with aRCC treated with first-line nivolumab-based therapies had lower grade 3/4 all-cause and treatment-related AE costs than pembrolizumab-based therapies, suggesting a more favorable cost-benefit profile., (© The Author(s) 2022. Published by Oxford University Press.)

Importance: Dysregulated metabolism is a hallmark of renal cell carcinoma (RCC). Glutaminase is a key enzyme that fuels tumor growth by converting glutamine to glutamate. Telaglenastat is an investigational, first-in-class, selective, oral glutaminase inhibitor that blocks glutamine utilization and downstream pathways. Preclinically, telaglenastat synergized with cabozantinib, a VEGFR2/MET/AXL inhibitor, in RCC models., Objective: To compare the efficacy and safety of telaglenastat plus cabozantinib (Tela + Cabo) vs placebo plus cabozantinib (Pbo + Cabo)., Design, Setting, and Participants: CANTATA was a randomized, placebo-controlled, double-blind, pivotal trial conducted at sites in the US, Europe, Australia, and New Zealand. Eligible patients had metastatic clear-cell RCC following progression on 1 to 2 prior lines of therapy, including 1 or more antiangiogenic therapies or nivolumab plus ipilimumab. The data cutoff date was August 31, 2020. Data analysis was performed from December 2020 to February 2021., Interventions: Patients were randomized 1:1 to receive oral cabozantinib (60 mg daily) with either telaglenastat (800 mg twice daily) or placebo until disease progression or unacceptable toxicity., Main Outcomes and Measures: The primary end point was progression-free survival (Response Evaluation Criteria in Solid Tumors version 1.1) assessed by blinded independent radiology review., Results: A total of 444 patients were randomized: 221 to Tela + Cabo (median [range] age, 61 [21-81] years; 47 [21%] women and 174 [79%] men) and 223 to Pbo + Cabo (median [range] age, 62 [29-83] years; 68 [30%] women and 155 [70%] men). A total of 276 (62%) patients had received prior immune checkpoint inhibitors, including 128 with prior nivolumab plus ipilimumab, 93 of whom had not received prior antiangiogenic therapy. Median progression-free survival was 9.2 months for Tela + Cabo vs 9.3 months for Pbo + Cabo (HR, 0.94; 95% CI, 0.74-1.21; P = .65). Overall response rates were 31% (69 of 221) with Tela + Cabo vs 28% (62 of 223) with Pbo + Cabo. Treatment-emergent adverse event (TEAE) rates were similar between arms. Grade 3 to 4 TEAEs occurred in 160 patients (71%) with Tela + Cabo and 172 patients (79%) with Pbo + Cabo and included hypertension (38 patients [17%] vs 40 patients [18%]) and diarrhea (34 patients [15%] vs 29 patients [13%]). Cabozantinib was discontinued due to AEs in 23 patients (10%) receiving Tela + Cabo and 33 patients (15%) receiving Pbo + Cabo., Conclusions and Relevance: In this randomized clinical trial, telaglenastat did not improve the efficacy of cabozantinib in metastatic RCC. Tela + Cabo was well tolerated with AEs consistent with the known risks of both agents., Trial Registration: ClinicalTrials.gov Identifier: NCT03428217.

Background and Objectives: Novel immunotherapy-based combination treatments have drastically improved clinical outcomes for previously untreated patients with advanced/metastatic renal cell carcinoma (aRCC). This study aimed to assess the temporal trends in grade 3/4 adverse event (AE) rates and associated costs of nivolumab plus cabozantinib combination therapy versus sunitinib monotherapy in previously untreated patients with aRCC., Methods: Individual patient data from the CheckMate 9ER trial (nivolumab plus cabozantinib: N = 320; sunitinib: N = 320) were used to calculate the proportion of patients experiencing grade 3/4 AEs. AE unit costs were obtained from the United States (US) 2017 Healthcare Cost and Utilization Project (HCUP) and inflated to 2020 US dollars. Per-patient-per-month (PPPM) all-cause and treatment-related grade 3/4 AE costs over 18-months, temporal trends, and top drivers of AE costs were evaluated in both treatment arms., Results: Overall, the proportion of patients experiencing grade 3/4 AEs decreased over time, with the highest rates observed in the first 3 months for the nivolumab plus cabozantinib and sunitinib arms. Compared with sunitinib, nivolumab plus cabozantinib was associated with consistently lower average all-cause AE costs PPPM [month 3: $2021 vs. $3097 (p < 0.05); month 6: $1653 vs. $2418 (p < 0.05); month 12: $1450 vs. $1935 (p > 0.05); month 18: $1337 vs. $1755 (p > 0.05)]. Over 18 months, metabolism and nutrition disorders ($244), laboratory abnormalities ($182), and general disorders and administration site conditions ($122) were the costliest all-cause PPPM AE categories in the nivolumab plus cabozantinib arm, and laboratory abnormalities ($443), blood and lymphatic system disorders ($254), and metabolism and nutrition disorders ($177) were the costliest in the sunitinib arm. Trends of treatment-related AE costs were consistent with all-cause AE costs., Conclusions: Nivolumab plus cabozantinib was associated with lower costs of grade 3/4 AE management PPPM than sunitinib, which accumulated over the 18-month study period., (© 2022. The Author(s).)

Tyrosine kinase inhibitors have been successfully developed in combination with immune checkpoint inhibitors to treat advanced renal cell carcinoma (RCC), further advancing treatment. While safety profiles are generally manageable with combination regimens, overlapping adverse events (AEs) and immune-related AEs can make treatment more complex. The CheckMate 9ER study evaluated the tyrosine kinase inhibitor cabozantinib in combination with the anti-programmed cell death protein-1 antibody nivolumab in patients with previously untreated advanced RCC. Cabozantinib + nivolumab demonstrated superiority over sunitinib for progression-free survival, overall survival, and objective response rate. These outcomes supported the approval of cabozantinib + nivolumab as a first-line therapy for advanced RCC. The safety profile was manageable with prophylaxis, supportive care, dose holds and reductions for cabozantinib, and dose holds and immunosuppressive therapy for nivolumab. This review discusses the safety results of CheckMate 9ER and provides guidance on managing some of the more clinically relevant AEs with a focus on overlapping AEs, including diarrhea, elevated amylase/lipase, hepatotoxicity, dermatologic reactions, fatigue, endocrine disorders, and nephrotoxicity. We discuss AE management strategies (prophylaxis, supportive care, dose modification, and immunosuppressive therapy), and provide recommendations for identifying the causative agent of overlapping AEs and for consulting specialists about organ-specific immune-related AEs. Optimizing AE management can maintain tolerability and should be a priority with cabozantinib + nivolumab treatment., (Copyright © 2021. Published by Elsevier Ltd.)

Purpose: COSMIC-021 is evaluating cabozantinib plus atezolizumab in patients with solid tumors. We report results from patients with advanced clear cell (cc) and non-clear cell (ncc) renal cell carcinoma (RCC)., Methods: This phase Ib study (NCT03170960) enrolled patients age ≥ 18 years with advanced RCC. A dose-escalation stage was followed by expansion cohorts. For cohort expansion, prior systemic therapy was not permitted for ccRCC but allowed for nccRCC. Patients received oral cabozantinib 40 mg once a day (ccRCC and nccRCC) or 60 mg once a day (ccRCC only) plus atezolizumab (1,200 mg intravenously, once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1; the secondary end point was safety., Results: A total of 102 patients were enrolled. Median follow-up was 25.8, 15.3, and 13.3 months for the 40-mg ccRCC, 60-mg ccRCC, and nccRCC groups, respectively. ORR was 53% (80% CI, 41 to 65) in the 40-mg ccRCC group (n = 34) and 58% (80% CI, 46 to 70) in the 60-mg ccRCC group (n = 36), 3% and 11%, respectively, with complete response; median progression-free survival (exploratory end point) was 19.5 and 15.1 months, respectively. In nccRCC (n = 32), ORR was 31% (80% CI, 20 to 44), all partial responses; median progression-free survival was 9.5 months. Grade 3 or 4 treatment-related adverse events (TRAEs) were reported by 71% of patients in the 40-mg ccRCC group, 67% in the 60-mg ccRCC group, and 38% in the nccRCC group; TRAEs leading to discontinuation of both agents occurred in 15%, 6%, and 3% of patients, respectively. There were no grade 5 TRAEs., Conclusion: The novel combination of cabozantinib plus atezolizumab demonstrated encouraging clinical activity and acceptable tolerability in patients with advanced ccRCC and nccRCC. Disease control was observed across dose levels and histologic subtypes., Competing Interests: Sumanta K. PalConsulting or Advisory Role: F. Hoffmann LaRocheResearch Funding: Eisai, Genentech, Roche, Exelixis, PfizerTravel, Accommodations, Expenses: Genentech, Seattle Genetics Bradley McGregorConsulting or Advisory Role: Bayer, Seattle Genetics/Astellas, Exelixis, AstraZeneca, Astellas Pharma, Genentech/Roche, Nextar, Janssen Oncology, Pfizer, EMD Serono, Eisai, Dendreon, Bristol Myers SquibbResearch Funding: Bristol Myers Squibb, Exelixis, Calithera Biosciences, Seattle Genetics/Astellas Cristina SuárezConsulting or Advisory Role: Bristol Myers Squibb, Ipsen, Sanofi, Pfizer, EUSA Pharma, Astellas Pharma, Novartis, Merck Sharp & Dohme, EisaiSpeakers' Bureau: Bristol Myers Squibb, Ipsen, Pfizer, Roche/Genentech, AstraZeneca, Merck Sharp & DohmeResearch Funding: Astellas Pharma, Roche/Genentech, Exelixis, AstraZeneca, Bristol Myers Squibb, Pfizer, Novartis, Janssen Oncology, Calithera Biosciences, AB Science, Arog, AVEO, Bayer, SFJ Pharmaceuticals Group, Blueprint Medicines, Clovis Oncology, Boehringer Ingelheim, Cougar Biotechnology, Deciphera, GlaxoSmithKline, Incyte, Karyopharm Therapeutics, MedImmune, Nanobiotix, Millennium, Puma Biotechnology, TevaTravel, Accommodations, Expenses: Bristol Myers Squibb, Roche, Ipsen Che-Kai TsaoConsulting or Advisory Role: Eisai, Clovis Oncology, MerckResearch Funding: Exelixis William KellyHonoraria: Janssen Oncology, BayerConsulting or Advisory Role: Merck Sharp & DohmeResearch Funding: Sanofi, Novartis, Janssen Oncology, Bayer, Exelixis, Seattle Genetics, Endocyte, Amgen, BioClin Therapeutics, Sarah Cannon Research Institute, RocheTravel, Accommodations, Expenses: Janssen Oncology, Merck Sharp & Dohme Ulka VaishampayanConsulting or Advisory Role: Pfizer, Exelixis, Bayer, Bristol Myers Squibb/Medarex, Merck Serono, Advanced Accelerator Applications, Alkermes, Helsinn TherapeuticsSpeakers' Bureau: Pfizer, Bayer, ExelixisResearch Funding: Astellas Pharma, Exelixis, Bristol Myers Squibb, Merck KGaA Lance PagliaroResearch Funding: Pfizer, Genentech/Roche, Exelixis, Merck Sharp & DohmeTravel, Accommodations, Expenses: Merck Benjamin L. MaughanConsulting or Advisory Role: Janssen Oncology, Exelixis, Tempus, Bristol Myers Squibb, Astellas Medivation, Bayer, AVEO, Clovis Oncology, Merck, Peloton TherapeuticsResearch Funding: Clovis Oncology, Bristol Myers Squibb, Bavarian Nordic, ExelixisTravel, Accommodations, Expenses: Exelixis Yohann LoriotHonoraria: Sanofi, PfizerConsulting or Advisory Role: Janssen, Astellas Pharma, Roche, AstraZeneca, MSD Oncology, Seattle Genetics, Bristol Myers Squibb, Immunomedics, Taiho PharmaceuticalResearch Funding: Sanofi, Janssen Oncology, MSD Oncology, AstraZeneca, Clovis Oncology, Exelixis, Boehringer Ingelheim, Incyte, Pfizer, Oncogenex, Medivation, CureVac, NektarTravel, Accommodations, Expenses: Astellas Pharma, Janssen Oncology, Roche, MSD Oncology, AstraZeneca, Seattle Genetics Daniel CastellanoConsulting or Advisory Role: Janssen Oncology, Roche/Genentech, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Ipsen, Bristol Myers Squibb, MSD Oncology, Bayer, Lilly, Sanofi, Pierre Fabre, Boehringer IngelheimResearch Funding: Janssen OncologyTravel, Accommodations, Expenses: Pfizer, Roche, Bristol Myers Squibb, AstraZeneca Spain Sandy SrinivasConsulting or Advisory Role: Eisai, Bayer, Bristol Myers Squibb, Merck, Exelixis, AstraZeneca, Seattle GeneticsResearch Funding: Bristol Myers Squibb, Genentech, Merck, Exelixis, Eisai, Bayer, AstraZeneca, Seattle Genetics/AstellasOther Relationship: Pfizer Rana R. McKayConsulting or Advisory Role: Janssen, Novartis, Tempus, Exelixis, Pfizer, Bristol Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion Therapeutics, Calithera Biosciences, AstraZenecaResearch Funding: Pfizer, Bayer, Tempus Robert DreicerConsulting or Advisory Role: Astellas Pharma, Pfizer, Eisai, Merck, EMD Serono, Propella Therapeutics, Myovant Sciences, Bayer, Tavanta Therapeutics, Veru, Infinity Pharmaceuticals, Pfizer/AstellasResearch Funding: Seattle Genetics, Bristol Myers Squibb, Exelixis, Novartis Thomas HutsonEmployment: Texas OncologyHonoraria: Pfizer, Astellas Pharma, Bristol Myers Squibb, Exelixis, Eisai, Novartis, Johnson & Johnson, Bayer/OnyxConsulting or Advisory Role: Bayer/Onyx, Pfizer, Novartis, Astellas Pharma, Johnson & Johnson, Bristol Myers Squibb, Eisai, ExelixisSpeakers' Bureau: Pfizer, Johnson & Johnson, Eisai, Exelixis, Astellas Pharma, Bristol Myers SquibbResearch Funding: Pfizer, Johnson & Johnson, Exelixis, Eisai, Bristol Myers Squibb Sarita DubeyEmployment: Genentech/RocheStock and Other Ownership Interests: Genentech/Roche Scott WernekeEmployment: ExelixisStock and Other Ownership Interests: Exelixis Ashok PanneerselvamEmployment: ExelixisStock and Other Ownership Interests: Exelixis Dominic CurranEmployment: Exelixis, Syneos Health (I)Stock and Other Ownership Interests: ExelixisTravel, Accommodations, Expenses: Exelixis Christian ScheffoldEmployment: ExelixisStock and Other Ownership Interests: ExelixisPatents, Royalties, Other Intellectual Property: Patent Toni K. ChoueiriEmployment: Dana Farber Cancer HospitalLeadership: Dana Farber Cancer Hospital, NCCN, KidneyCan, ASCOStock and Other Ownership Interests: Pionyr, Tempest TherapeuticsHonoraria: NCCN, UpToDate, Michael J. Hennessy Associates, ASCO, Harborside Press, Analysis Group, AstraZeneca, Alexion Pharmaceuticals, Sanofi/Aventis, Bayer, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Peloton Therapeutics, Pfizer, Corvus Pharmaceuticals, Ipsen, Foundation Medicine, Eisai, PlatformQ Health, Clinical Care Options, Navinata Health, Kidney Cancer Association, Exelixis, Prometheus, Lpath, The New England Journal of Medicine, Lancet Oncology, Cerulean Pharma, Alligent, EMD Serono, HERON, Lilly, Janssen Oncology, IQvia, Aveo, NCI GU Steering CommitteeConsulting or Advisory Role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, Alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Navinata Health, Harborside Press, ASCO, The New England Journal of Medicine, Lancet Oncology, EMD Serono, HERON, Lilly, ESMO, NiKang Therapeutics, Kanaph Therapeutics, Infinity Pharmaceuticals, AraviveResearch Funding: Pfizer, Novartis, Merck, Exelixis, TRACON Pharma, GlaxoSmithKline, Bristol Myers Squibb, AstraZeneca, Peloton Therapeutics, Roche/Genentech, Celldex, Agensys, Eisai, Takeda, Prometheus, Ipsen, Corvus Pharmaceuticals, Cerulean Pharma, Seattle Genetics/Astellas, Bayer, Foundation Medicine, Roche, Calithera Biosciences, Analysis Group, NCI, Gateway for Cancer Research, Congressionally Directed Medical Research Programs (DOD)Patents, Royalties, Other Intellectual Property: International Patent Application No. PCT/US2018/058430, titled Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, International Patent Application No. PCT/US2018/12209, titled PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint ResponseTravel, Accommodations, Expenses: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, Alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, UpToDate, Peloton Therapeutics, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Harborside Press, Navinata Health, The New England Journal of Medicine, Lancet Oncology, EMD Serono, HERON, Lilly, ESMOOther Relationship: Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, Parexel Neeraj AgarwalConsulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Gilead SciencesResearch Funding: Bayer, Bristol Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, CRISPR Therapeutics, ArvinasNo other potential conflicts of interest were reported.

Background: In patients with genitourinary cancers, the effect of immune checkpoint inhibitors (ICIs) on kidney function is unknown., Patients and Methods: This is a retrospective cohort study of patients with renal cell carcinoma (RCC) and urothelial carcinoma who received ICIs at two major cancer centers between 2012 and 2018. Cumulative incidence and Fine and Gray subdistribution hazard models were performed to determine predictors of the co-primary outcomes, (1) acute kidney injury (AKI) and (2) sustained estimated glomerular filtration rate (eGFR) loss, defined as a >20% decline in eGFR sustained ≥90 days. We also determined the association between immune-related adverse events (irAE) and adverse kidney outcomes among patients surviving ≥1 year., Results: 637 patients were included; 320 (50%) patients had RCC and 317 (50%) patients had urothelial carcinoma. Half of the cohort had eGFR<60 mL/min/1.73 m 2  at baseline. irAEs, AKI, and sustained eGFR loss were common, occurring in 33%, 25% and 16%, respectively. Compared to patients with urothelial carcinoma, patients with RCC were more likely to develop irAEs (aHR 1.61, 95% CI 1.20-2.18) and sustained eGFR loss (aHR 1.97, 95% CI 1.24-3.12), but not AKI (aHR 1.53, 95% CI 0.97-2.41). Among patients surviving ≥1 years, experiencing a non-renal irAE was associated with a significantly higher risk of sustained eGFR loss (aHR 1.71, 95% CI 1.14-2.57)., Conclusion: AKI and sustained eGFR loss are common in patients with genitourinary cancers receiving ICIs. irAEs may be a novel risk factor for kidney function decline among patients receiving ICIs., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: HS, SS, IA, ML, SZ, NR, DC, DEL, KR, CS, MDK, MES have nothing to declare. OR: Research support from Merck. Speaker for activities supported by educational grants from BMS and Merck. Consultant for Merck, Celgene, Five Prime, GSK, Bayer, Roche/Genentech, Puretech, Imvax, Sobi. In addition, Dr. Rahma has a patent “Methods of using pembrolizumab and trebananib” pending. BM: discloses payment for consulting with Bayer, Astellas, Astra Zeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, BMS, Calithera, Dendreon and EMD Serono. He received research support to Dana Farber Cancer Institute (DFCI) from Bristol Myers Squibb, Calithera, Exelixis, Seattle Genetics. GS: Advisory Board: BMS, Genentech, EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Immunomedics; Research Support to Institution: Sanofi, Astrazeneca, Immunomedics; Travel costs: BMS, Astrazeneca; Speaking fees: Physicians Education Resource (PER), Onclive, Research to Practice, Medscape; Writing fees: Uptodate, Editor of Elsevier Practice Update Bladder Cancer Center of Excellence; Steering committee of trials/studies: BMS, Bavarian Nordic, Seattle Genetics, QED (all unpaid), and Astrazeneca, EMD Serono, Debiopharm (paid). SM: Salaried position as a Deputy Editor at UpToDate (Wolters Kluwer). SG: scientific coordinator for the ASCEND trial. XG: Honorarium from Exelixis. XW: Research support to Institution: BMS. MDM - MD Advisory Board for Pfizer, Exelixis, Eisai and Merck. TKC - AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb, Eisai, Exelixis, GlaxoSmithKline, Ipsen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi/Aventis, Takeda (institutional and personal) related to research, consultancy and advisory boards. TKC is supported in part by the Dana Farber/Harvard Cancer Center Kidney SPORE Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Therapies for genitourinary malignancies have evolved considerably in the past five years. Combination treatment targeting biologically relevant immune and angiogenic pathways is improving patient survival in metastatic renal cell carcinoma (RCC), whereas immune checkpoint blockade (ICB), novel targeted therapy, and antibody drug conjugates have changed the landscape of urothelial cancer (UC) treatment. A daily challenge for clinicians is identifying patients who derive a preferential benefit from the available therapeutic options. The completion of large-scale genomics projects has yielded comprehensive descriptions of the molecular heterogeneity present in RCC and UC, although clinical applications of these data continue to evolve. Major molecular subtypes of RCC align well with histology subtype, and although some molecular characteristics appear to carry prognostic information, biomarkers predicting benefit from tyrosine kinase inhibitor (TKI) or immunotherapy are generally lacking. Unexpectedly, similar work has demonstrated that UC can be grouped into "molecular subtypes" that share properties with those found in breast cancer and other solid tumors. Furthermore, this molecular subtype classification is prognostic and potentially predictive of differential benefit from conventional and targeted therapies. This article provides an update on the current state of molecular biomarker development and potential clinical utility in RCC and UC.

The current standard of care for treatment of metastatic renal cell carcinoma (mRCC) patients is PD-1/PD-L1 inhibitors until progression or toxicity. Here, we characterize the clinical outcomes for 19 mRCC patients who experienced an initial clinical response (any degree of tumor shrinkage), but after immune-related adverse events (irAE) discontinued all systemic therapy. Clinical baseline characteristics, outcomes, and survival data were collected. The primary endpoint was time to progression from the date of treatment cessation (TTP). Most patients had clear cell histology and received anti-PD-1/PD-L1 therapy as second-line or later treatment. Median time on PD-1/PD-L1 therapy was 5.5 months (range, 0.7-46.5) and median TTP was 18.4 months (95% CI, 4.7-54.3) per Kaplan-Meier estimation. The irAEs included arthropathies, ophthalmopathies, myositis, pneumonitis, and diarrhea. We demonstrate that 68.4% of patients ( n = 13) experienced durable clinical benefit off treatment (TTP of at least 6 months), with 36% ( n = 7) of patients remaining off subsequent treatment for over a year after their last dose of anti-PD-1/PD-L1. Three patients with tumor growth found in a follow-up visit, underwent subsequent surgical intervention, and remain off systemic treatment. Nine patients (47.4%) have ongoing irAEs. Our results show that patients who benefitted clinically from anti-PD-1/PD-L1 therapy can experience sustained beneficial responses, not needing further therapies after the initial discontinuation of treatment due to irAEs. Investigation of biomarkers indicating sustained benefit to checkpoint blockers are needed. Cancer Immunol Res; 6(4); 402-8. ©2018 AACR ., (©2018 American Association for Cancer Research.)