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Ragheed Saoud,1 Thomas H Sanford,2 Stephen M Hewitt,3 Andrea B Apolo,3 Piyush K Agarwal1 1Section of Urology, Department of Surgery, The University of Chicago Medicine, Chicago, IL, USA; 2Department of Urology, Upstate University Hospital, Syracuse, NY, USA; 3Center for Cancer Research, National Cancer Institute, Bethesda, MD, USACorrespondence: Ragheed SaoudSection of Urology, Department of Surgery, The University of Chicago Medicine, 5841 S. Maryland Ave., Rm. J-663, Chicago, IL, 60637, USATel +1 773 702 9757Fax +1 773 926 0732Email Ragheed.saoud@uchospitals.eduAbstract: We present a case of a 69-year-old male patient diagnosed with high grade (T1 HG) urothelial carcinoma of the bladder who progressed rapidly towards muscle invasive disease and eventually death despite neoadjuvant chemotherapy and radical cystectomy. We postulate that this may be due to a deleterious underlying somatic gene mutation. Molecular pathologic data obtained on the initial, non-muscle invasive tumor and the final cystectomy specimen, revealed the same TP53 mutation (p.Arg110Pro) in both specimens with a variant allele frequency of 44%. The tumor was tested for 50 common gene mutations in urothelial carcinoma and no other identifiable DNA repair mutations were found, suggesting that this specific TP53 aberration, one that has never been reported in the bladder cancer literature, could be particularly deleterious. Knowing that bladder cancer cell lines that lack TP53 are more resistant to cisplatin and because the tumor lacked any other DNA mutation, this patient may have been a candidate for upfront surgery without neoadjuvant chemotherapy. In addition to histological analysis of the tumor, early molecular and cytogenetic characterization of resected tissue is essential in predicting progression and eventual prognosis of the disease based on identifiable gene mutations. Further comparative prospective studies are required to clarify the importance of molecular heterogeneity and subtyping in bladder cancer.Keywords: invasive, missense mutation, mismatch repair gene

Despite surgical resection, many patients with muscle invasive urothelial carcinoma (MIUC) experience recurrence. Adjuvant immune checkpoint inhibition (ICI) following radical resection in patients with MIUC demonstrates disparate outcomes among phase III randomized controlled trials (RCTs). Our objective was to synthesize available data regarding the disease-free survival (DFS) benefit of adjuvant ICIs for patients with MIUC and evaluate the overall safety profile of ICIs in this setting. The protocol was registered with PROSPERO, CRD42022352587. We searched MEDLINE, Embase, CENTRAL, and relevant conference proceedings from inception up to January 29, 2024. Only phase III RCTs comparing adjuvant ICI versus placebo/observation were selected. Study screening and selection, along with data extraction was performed in duplicate according to a predefined registered protocol. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was used. Quality assessment was performed using the Cochrane risk-of-bias (RoB 2) tool for randomized trials. The primary and secondary endpoints were DFS and serious adverse events, respectively. All outcomes were analyzed using random-effects meta-analysis owing to inter-study heterogeneity. Sensitivity and subgroup analyses were performed to identify potential sources of heterogeneity. A priori defined subgroups of interest included positive program death-ligand 1 (PD-L1) expression, previous use of neoadjuvant chemotherapy (NAC), primary tumor origin, pathologic lymph node status, and baseline Eastern Cooperative Oncology Group performance status. Pooled results across the 3 RCTs (2,220 patients) demonstrated significantly improved DFS for patients treated with ICI in the intention-to-treat cohorts (HR 0.76, 95% CI 0.65-0.90). There was considerable clinical and statistical heterogeneity (I 2  = 44%) due to differences in inclusion criteria and interventions. Overall, there was a low risk of bias among the RCTs. Regarding subgroup analyses, there was significant benefit among patients with negative PD-L1 expression (HR 0.76, 95% CI 0.64-0.90), those who received prior NAC (HR 0.69, 95% CI 0.52-0.91), and patients with lower tract (HR 0.71, 95% CI 0.55-0.92) but not upper tract disease (HR 1.21, 95% CI 0.87-1.68). This pooled analysis of DFS and safety provides support for ICI utilization in the setting of high-risk resected MIUC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: 1. Oscar-Thompson, Riveros, Apolo: None. 2. Sonpavde: a. Advisory Board: BMS, Genentech, EMD Serono, Merck, Astrazeneca, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, Infinity Pharmaceuticals, Lucence Health, IMV, Vial, Syapse, Tempus, Ellipses Pharma, PrecisCa, Primum b. Consultant/Scientific Advisory Board (SAB): Suba Therapeutics, Syapse, Servier, Merck, Syncorp c. Research Support to institution: Sanofi, Astrazeneca, Gilead, Helsinn, Lucence, BMS, EMD Serono, Jazz Therapeutics d. Speaker: BIO – INFORMAÇÃO BRASILEIRA DE ONCOLOGIA Ltda, OLE Forum (Mexico), Seagen, Gilead, Natera, Exelixis, Janssen, Bayer, Aveo e. Data safety monitoring committee honorarium: Mereo f. Employment: Spouse employed by Myriad. 3. Lalani: a. Honoraria - Astellas Pharma; Bayer; Bristol-Myers Squibb; Eisai; Ipsen; Merck; Novartis; Pfizer; Roche/Genentech b. Consulting or Advisory Role - Abbvie; Astellas Pharma; Bayer; Bristol-Myers Squibb; Eisai; Ipsen; Janssen; Merck; Pfizer; Roche/Genentech c. Research Funding - BioCanRx (Inst); Bristol-Myers Squibb (Inst); EMD Serono (Inst); Ipsen (Inst); Novartis (Inst); Roche (Inst). 4. Wallis a. Consulting Fees: Janssen Oncology, Nanostics Inc, Precision Point Specialty LLC, SESEN Bio b. Honoraria/Travel: AbbVie, Astellas, Astra Zeneca, Bayer, EMD Serono, Haymarket Media, c. Healing and Cancer Foundation, Knight Therapeutics, Merck, Science & Medicine Canada, d. TerSera Canada, Tolmar Pharmaceuticals Canada e. Research Funding: Knight Therapeutics, Tolmar Pharmaceuticals, Bayer 5. Satkunasivam a. Research Funding or Support to Institution: Pfizer, BMS, Anchiano Therapeutics, QED Therapeutics, Merck, CoImmune, UroGen, enGene, Photocure, Janssen b. Consulting: Pfizer (2022-2023), Intuitive Surgical (Proctor, 2019; 2023), GNE/Roche (2017) c. Stock: None d. Honoraria/Travel: None. If there are other authors, they 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 Inc. All rights reserved.)

Background: Muscle-invasive urothelial carcinoma is an aggressive disease with high rates of relapse. Whether pembrolizumab as adjuvant therapy would be effective in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery is unknown., Methods: In this phase 3 trial, we randomly assigned patients, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks for 1 year or to undergo observation. Randomization was stratified according to pathological stage, centrally tested programmed death ligand 1 (PD-L1) status, and previous neoadjuvant chemotherapy. The coprimary end points were disease-free survival and overall survival in the intention-to-treat population. We considered the trial to be successful if either disease-free survival or overall survival was significantly longer with pembrolizumab than with observation., Results: A total of 702 patients underwent randomization; 354 were assigned to receive pembrolizumab, and 348 were assigned to observation. As of July 5, 2024, the median duration of follow-up for disease-free survival was 44.8 months. The median disease-free survival was 29.6 months (95% confidence interval [CI], 20.0 to 40.7) with pembrolizumab and 14.2 months (95% CI, 11.0 to 20.2) with observation (hazard ratio for disease progression or death, 0.73; 95% CI, 0.59 to 0.90; two-sided P = 0.003). Grade 3 or higher adverse events (regardless of attribution) occurred in 50.7% of the patients in the pembrolizumab group and in 31.6% of the patients in the observation group., Conclusions: Among patients with high-risk muscle-invasive urothelial carcinoma after radical surgery, disease-free survival was significantly longer with adjuvant pembrolizumab than with observation. (Funded by the National Cancer Institute of the National Institutes of Health and others; Alliance A031501 AMBASSADOR ClinicalTrials.gov number, NCT03244384.)., (Copyright © 2024 Massachusetts Medical Society.)

Purpose: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts., Methods: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208)., Results: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients., Conclusion: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.

Objectives: Patient preferences have the potential to influence the development of new treatments for locally advanced/metastatic urothelial carcinoma (la/mUC), and therefore we explored how patients with la/mUC value different attributes of first-line treatments., Methods: An online preference survey and multidimensional thresholding (MDT) exercise were developed following a targeted literature review and qualitative interviews with physicians, patients with la/mUC, and their caregivers. Treatment attributes included two benefits (overall response rate [ORR], pain related to bladder cancer [scored 0-100; 100 being the worst pain possible]) and four treatment-related risks (peripheral neuropathy, severe side effects, mild to moderate nausea, mild to moderate skin reactions). A Dirichlet regression was used to estimate average preference weights. Marginal utility and the reduction in ORR that patients would accept in exchange for a 10-point decrease or a 10% decrease in other attributes were calculated., Results: A total of 100 patients were recruited and self-completed the survey and MDT. Mean patient age was 64.9 years (standard deviation, 7.6), 54% were female, and 38% identified as white. All included treatment attributes had a statistically significant impact on preferences. Changes in ORR had the largest impact, followed by cancer-related pain and treatment-related risks. Patients were willing to accept an 8.4% decrease in ORR to reduce their pain level by 10 points or a 7.8% decrease in ORR to reduce the risk of peripheral neuropathy by 10%. For a 10% decrease in severe side effects, mild to moderate nausea, or skin reaction, patients would accept decreases in ORR of 5.5%, 3.7%, or 3.4%, respectively., Conclusions: Of the attributes tested, changes in ORR were most important to patients. Patients made tradeoffs between treatment attributes indicating that a lower ORR may be acceptable for an improvement in other attributes such as reduced cancer-related pain or the risk of treatment-related adverse events., (© 2024. The Author(s).)

Purpose of Review: The most common definitive treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy. However, removing the bladder and surrounding organs poses risks of morbidity that can reduce quality of life, and raises the risk of death. Treatment strategies that preserve the organs can manage the local tumor and mitigate the risk of distant metastasis. Recent data have demonstrated promising outcomes in several bladder-preservation strategies., Recent Findings: Bladder preservation with trimodality therapy (TMT), combining maximal transurethral resection of the bladder tumor, chemotherapy, and radiotherapy (RT), was often reserved for nonsurgical candidates for radical cystectomy. Recent meta-analyses show that outcomes of TMT and radical cystectomy are similar. More recent bladder-preservation approaches include combining targeted RT (MRI) and immune checkpoint inhibitors (ICIs), ICIs and chemotherapy, and selecting patients based on genomic biomarkers and clinical response to systemic therapies. These are all promising strategies that may circumvent the need for radical cystectomy., Summary: MIBC is an aggressive disease with a high rate of systemic progression. Current management includes neoadjuvant cisplatin-based chemotherapy and radical cystectomy with lymph node dissection. Novel alternative strategies, including TMT approaches, combinations with RT, chemotherapy, and/or ICIs, and genomic biomarkers, are in development to further advance bladder-preservation options for patients with MIBC., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Nivolumab plus cabozantinib (NIVO + CABO) was approved for first-line treatment of advanced renal cell carcinoma (aRCC) based on superiority versus sunitinib (SUN) in the phase III CheckMate 9ER trial (18.1 months median survival follow-up per database lock date); efficacy benefit was maintained with an extended 32.9 months of median survival follow-up. We report updated efficacy and safety after 44.0 months of median survival follow-up in intent-to-treat (ITT) patients and additional subgroup analyses, including outcomes by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk score., Patients and Methods: Patients with treatment-naïve aRCC received NIVO 240 mg every 2 weeks plus CABO 40 mg once daily or SUN 50 mg for 4 weeks (6-week cycles), until disease progression/unacceptable toxicity (maximum NIVO treatment, 2 years). Primary endpoint was progression-free survival (PFS) per blinded independent central review (BICR). Secondary endpoints were overall survival (OS), objective response rate (ORR) per BICR, and safety and tolerability., Results: Overall, 323 patients were randomised to NIVO + CABO and 328 to SUN. Median PFS was improved with NIVO + CABO versus SUN [16.6 versus 8.4 months; hazard ratio (HR) 0.59; 95% confidence interval (CI) 0.49-0.71]; median OS favoured NIVO + CABO versus SUN (49.5 versus 35.5 months; HR 0.70; 95% CI 0.56-0.87). ORR (95% CI) was higher with NIVO + CABO versus SUN [56% (50% to 62%) versus 28% (23% to 33%)]; 13% versus 5% of patients achieved complete response, and median duration of response was 22.1 months versus 16.1 months, respectively. PFS and OS favoured NIVO + CABO over SUN across intermediate, poor and intermediate/poor IMDC risk subgroups; higher ORR and complete response rates were seen with NIVO + CABO versus SUN regardless of IMDC risk subgroup. Any-grade (grade ≥3) treatment-related adverse events occurred in 97% (67%) versus 93% (55%) of patients treated with NIVO + CABO versus SUN., Conclusions: After extended follow-up, NIVO + CABO maintained survival and response benefits; safety remained consistent with previous follow-ups. These results continue to support NIVO + CABO as a first-line treatment for aRCC., Trial Registration: ClinicalTrials.gov, NCT03141177., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Scott Delacroix, Jared Foster, Francesca Khani, Joseph Liao, Abdul Tawab-Amiri Pamela West, Alex Wyatt: No conflicts. David McConkey: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Grants and contracts – Department of Defense, Mark Foundation, Commonwealth Foundation. Brian Baumann: Consulting fees – Boston Scientific, Varian, Novartis, Blue Earth; leadership or fiduciary role – Board of Directors, National Association for Proton Therapy. Stephanie Cooper Greenberg: Patient advocate, Johns Hopkins Greenberg Bladder Cancer Institute and NCI’s Bladder Cancer Task Force. David DeGraff: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review Grants and contracts – Bristol Myers Squibb, Department of Defense; receipt of material – Astra-Zeneca. Jason Efstathiou: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review Consulting fees – Blue Earth Diagnostics, Boston Scientific, AstraZeneca, Genentech, Astellas/Pfizer, Lantheus; payment or honoraria – IBA, Elekta, UpToDate; advisory boards – Merck, Roivant Pharma, Myovant Sciences, Janssen, Bayer Healthcare, Progenics Pharmaceuticals, Pfizer, Astellas, Gilead, Lantheus, Blue Earth Diagnostics, Angiodynamics; committee leadership – Vice-Chair, GU Committee, NRG; Board member (unpaid) – Massachusetts Prostate Cancer Coalition (MPCC) American College of Radiation Oncology (ACRO), Radiation Oncology Institute (ROI). Susan Groshen: Financial support from NCI/GUSC for attending a 2-day workshop that led to the CTPM. Edward Kadel: Patent, “PD-L1 PROMOTER METHYLATION IN CANCER”; stock or stock options, 89bio, Apple, Amazon, Alphabet, Eli Lilly & Co, Inspire Medical Systems, Merck & Co, Roche, SPDR S&P Biotech ETF, Teladoc; employee of Genentech/Roche. William Kim: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Grants or contracts – NIH R01-CA241810, Merck; consulting fees – Focal Medical (spouse); advisory board – OncoRev; stock or stock options – Abbvie, Amgen, Apellis, BeiGene, BMS, Lilly, ImmunityBio, Moderna, Natera, NovoNordisk, Revolution Medicines, Tango Therapeutics, Zentalis; other financial or non-financial interests – Focal Medical, ownership interest (spouse). Seth Lerner: Co-Editor-in-Chief of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Advisory board – FerGene, Pfizer. BMS, Incyte; consultant – Vaxiion, Verity, Protara, C2i Genomics, Ferring, Aura Bioscience, Surge Therapeutics; clinical trials – Genentech (SWOG), Vaxiion, Endo, FKD, JBL (SWOG), Merck (Alliance), Aura Bioscience, Surge Therapeutics, QED Therapeutics; honoraria – UroToday, co-editor bladder cancer section UpToDate, Grand Rounds Urology; compensated editorial responsibilities – IOS Press. Trevor Levin: Grants or contracts – NCI SBIR 5R44CA200174-05; patents issued or pending – WO/2017/056451, WO/2020/023630, WO/2020/243587, WO/2022/216865A1; leadership or fiduciary role – Convergent Genomics (Executive and Board roles); stock or stock options – Convergent Genomics. Matthew Milowski: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Consulting: Loxo/Lilly; payments or honoraria, Medscape, Research to Practice; other financial or non-financial interests: Co-Editor in Chief, Clinical Genitourinary Cancer, Elsevier. Joshua Meeks: grants or contracts, VA, NIH, Department of Defense; consulting fees, Merck, AstraZeneca, Incyte, Janssen, BMS, UroGen, Prokarium, Imvax, Pfizer, Seagen/Astellas, Ferring; payments, Olympus, AUA, UroToday, OncLive; advisory boards, Astra-Zeneca, Medscape. David Miyamoto: grant support from NIH and the Radiation Oncology Institute. Kent Mouw: consulting fees, EMD Serono, Pfizer, UroGen, Riva Therapeutics. Eugene Pietzak: participation in a Data Safety Monitoring Committee or Advisory Board, QED Pharmaceuticals, Merck, Janssen, Urogen; society leadership, Chair of the Program Committtee, 2024 BCAN Think Tank. David Solit: consulting fees from Pfizer, Fog Pharma, PaigeAI, BridgeBio, Scorpion Therapeutics, FORE Therapeutics, Function Oncology, Pyramid, and Elsie Biotechnologies, Inc.; participation on a Data Safety Monitoring Board for Rain Therapeutics; stock or stock options from Scorpion Therapeutics, FORE Therapeutics, Function Oncology, Pyramid, Elsie Biotechnologies, Inc. Debashish Sundi: grants or contracts from Janssen, consulting fees from Janssen. Sara Wobker: royalties – Wolters Kluwer; honoraria – College of American Pathologists, American Society of Clinical Pathology, USCAP; travel reimbursement – Kidney Cancer Society. Andrea Apolo: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Peter Black: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Consulting fees – AbbVie, AstraZeneca, Astellas, Bayer, BMS, Combat, EMD-Serono, Ferring, Janssen, Merck, Nonagen, Nanobot, NanOlogy, Pfizer, Photocure, Prokarium, Sumitomo, TerSera, Tolmar, Verity; payments – Janssen, TerSera, Bayer, Pfizer; patents issued or pending – Veracyte.

SMARCB1 loss has long been observed in many solid tumors. However, there is a need to elucidate targetable pathways driving growth and metastasis in SMARCB1-deficient tumors. Here, we demonstrate that SMARCB1 deficiency, defined as genomic SMARCB1 copy number loss associated with reduced mRNA, drives disease progression in patients with bladder cancer by engaging STAT3. SMARCB1 loss increases the chromatin accessibility of the STAT3 locus in vitro. Orthotopically implanted SMARCB1 knockout (KO) cell lines exhibit increased tumor growth and metastasis. SMARCB1-deficient tumors show an increased IL6/JAK/STAT3 signaling axis in in vivo models and patients. Furthermore, a pSTAT3 selective inhibitor, TTI-101, reduces tumor growth in SMARCB1 KO orthotopic cell line-derived xenografts and a SMARCB1-deficient patient derived xenograft model. We have identified a gene signature generated from SMARCB1 KO tumors that predicts SMARCB1 deficiency in patients. Overall, these findings support the clinical evaluation of STAT3 inhibitors for the treatment of SMARCB1-deficient bladder cancer., (© 2024. The Author(s).)

Background: Mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) occur in a subset of cancers and have been shown to confer sensitivity to immune checkpoint inhibition (ICI); however, there is a lack of prospective data in urothelial carcinoma (UC)., Methods and Analysis: We performed a systematic review to estimate the prevalence of dMMR and MSI-H in UC, including survival and clinical outcomes. We searched for studies published up to 26 October 2022 in major scientific databases. We screened 1745 studies and included 110. Meta-analyses were performed if the extracted data were suitable., Results: The pooled weighted prevalences of dMMR in bladder cancer (BC) and upper tract UC (UTUC) were 2.30% (95% CI 1.12% to 4.65%) and 8.95% (95% CI 6.81% to 11.67%), respectively. The pooled weighted prevalences of MSI-H in BC and UTUC were 2.11% (95% CI 0.82% to 5.31%) and 8.36% (95% CI 5.50% to 12.53%), respectively. Comparing localised versus metastatic disease, the pooled weighted prevalences for MSI-H in BC were 5.26% (95% CI 0.86% to 26.12%) and 0.86% (95% CI 0.59% to 1.25%), respectively; and in UTUC, they were 18.04% (95% CI 13.36% to 23.91%) and 4.96% (95% CI 2.72% to 8.86%), respectively. Cumulatively, the response rate in dMMR/MSI-H metastatic UC treated with an ICI was 22/34 (64.7%) compared with 1/9 (11.1%) with chemotherapy., Conclusion: Both dMMR and MSI-H occur more frequently in UTUC than in BC. In UC, MSI-H occurs more frequently in localised disease than in metastatic disease. These biomarkers may predict sensitivity to ICI in metastatic UC and resistance to cisplatin-based chemotherapy., Competing Interests: Competing interests None declared.

Purpose: There is a significant unmet need for new and efficacious therapies in urothelial cancer (UC). To provide recommendations on appropriate clinical trial designs across disease settings in UC, the Society for Immunotherapy of Cancer (SITC) and the International Bladder Cancer Group (IBCG) convened a multidisciplinary, international consensus panel., Methods: Through open communication and scientific debate in small- and whole-group settings, surveying, and responses to clinical questionnaires, the consensus panel developed recommendations on optimal definitions of the disease state, end points, trial design, evaluations, sample size calculations, and pathology considerations for definitive studies in low- and intermediate-risk nonmuscle-invasive bladder cancer (NMIBC), high-risk NMIBC, muscle-invasive bladder cancer in the neoadjuvant and adjuvant settings, and metastatic UC. The expert panel also solicited input on the recommendations through presentations and public discussion during an open session at the 2021 Bladder Cancer Advocacy Network (BCAN) Think Tank (held virtually)., Results: The consensus panel developed a set of stage-specific bladder cancer clinical trial design recommendations, which are summarized in the table that accompanies this text., Conclusion: These recommendations developed by the SITC-IBCG Bladder Cancer Clinical Trial Design consensus panel will encourage uniformity among studies and facilitate drug development in this disease.

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: Primary urinary neuroendocrine neoplasms (U-NENs) are extremely rare thus optimal treatment is unknown. Grading and treatment are typically extrapolated from other primary sites. Since 2010, the clinical landscape for NENs has changed substantially. We performed a retrospective review of U-NENs to assess treatment patterns and oncologic outcomes of patients treated in the recent era of NEN therapy., Patients and Methods: A multicenter retrospective review of patients diagnosed after 2005 and alive after 2010. Time to treatment failure (TTF) was used to evaluate progression and toxicity for systemic therapy. Tumors were categorized as having either well-differentiated neuroendocrine tumor (WDNET) or poorly differentiated neuroendocrine carcinoma (PDNEC) histology., Results: A total of 134 patients from 6 centers were included in our analysis, including 94 (70%) bladder, 32 (24%) kidney, 2 (1.5%) urethra and 4 other urinary primaries (3.0%). Poorly-differentiated neuroendocrine carcinoma was more common in bladder (92%) than non-bladder tumors (8%). Median Ki-67 available in bladder primary was 90% (n = 24), kidney 10% (n = 23), ureter 95% (n = 1), urethra 54% (n = 2), and others 90% (n = 3). Patients received a median of 2 therapies (range 0-10). Median time to death was not reached in locoregional WDNETs versus 8.2 years (95% CI, 3.5-noncalculable) in metastatic WDNETs (predominantly renal primary). Median time to death was 3.6 years (95% CI, 2.2-9.2) in locoregional PDNECs versus 1 year (95% CI, 0.8-1.3) in metastatic PDNECs (predominantly bladder primary)., Conclusion: This is the most extensive series examining treatment patterns in patients with U-NENs in the recent era of NEN therapy. The apparent inferior survival for bladder NENs is likely due to the preponderance of PDNECs in this group. As predicted, treatments for U-NENs mirrored that of other more common NENs. In our retrospective cohort, we observed that patients with WD-UNETs treated with peptide receptor radionuclide therapy (PRRT) and everolimus suggested potential activity for disease control in WD-UNETs. Prospective studies are needed to assess the activity of new oncology drugs in UNENs., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability., Methods: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability., Results: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001)., Conclusion: NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.

Background: Precision oncology is gradually advancing into mainstream clinical practice, demonstrating significant survival benefits. However, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers., Methods: We present ENLIGHT, a transcriptomics-based computational approach that identifies clinically relevant genetic interactions and uses them to predict a patient's response to a variety of therapies in multiple cancer types without training on previous treatment response data. We study ENLIGHT in two translationally oriented scenarios: personalized oncology (PO), aimed at prioritizing treatments for a single patient, and clinical trial design (CTD), selecting the most likely responders in a patient cohort., Findings: Evaluating ENLIGHT's performance on 21 blinded clinical trial datasets in the PO setting, we show that it can effectively predict a patient's treatment response across multiple therapies and cancer types. Its prediction accuracy is better than previously published transcriptomics-based signatures and is comparable with that of supervised predictors developed for specific indications and drugs. In combination with the interferon-γ signature, ENLIGHT achieves an odds ratio larger than 4 in predicting response to immune checkpoint therapy. In the CTD scenario, ENLIGHT can potentially enhance clinical trial success for immunotherapies and other monoclonal antibodies by excluding non-responders while overall achieving more than 90% of the response rate attainable under an optimal exclusion strategy., Conclusions: ENLIGHT demonstrably enhances the ability to predict therapeutic response across multiple cancer types from the bulk tumor transcriptome., Funding: This research was supported in part by the Intramural Research Program, NIH and by the Israeli Innovation Authority., Competing Interests: Declaration of interests G.D., E.D.S., E. Elis, D.S.B.-Z., O.T., E.M., E. Elalouf, B.T., P.V., T.B., and R.A. are employees of Pangea Biomed. I.M. is a paid consultant of Pangea Biomed. E.S. is the Chairman of the Board of Pangea Biomed. E.R. is a co-founder of MedAware, Metabomed, and Pangea Biomed (divested) and an unpaid member of Pangea Biomed’s scientific advisory board. Z.R. is a co-founder of Pangea Biomed and an unpaid member of its scientific advisory board. R.B. is a member of Pangea Biomed’s scientific advisory board., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Bladder cancer is an aggressive and lethal disease. Even when presenting as localized muscle-invasive disease, the 5-year survival rate is about 70%, and the recurrence rate after radical cystectomy is approximately 50%. Neoadjuvant chemotherapy (NAC) has the potential to downstage the primary tumor and treat micrometastases, leading to a decrease in recurrence rates and an increase in cure rates. There is level 1 evidence in favor of neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy. However, data from clinical trials evaluating NAC for patients undergoing bladder-sparing treatments are less robust, so this strategy remains controversial. The response to NAC is prognostic and patients with favorable pathological response have better overall survival. Strategies to select patients based on molecular biomarkers have the potential to guide treatment decisions and even de-intensify treatment, avoiding local treatment for those with complete responses to systemic therapy. This review outlines the current literature on the use of NAC in the context of bladder preservation for muscle-invasive bladder cancer, highlights neoadjuvant studies in patients ineligible for cisplatin-based NAC, and discusses novel bladder-preservation strategies, including multimodality combinations and biomarker-driven studies of definitive chemotherapy., (Published by Elsevier Inc.)

Non-muscle-invasive bladder cancer is one of the most common malignancies. Patients with intermediate-risk or high-risk disease can be treated with intravesical Bacillus Calmette-Guerin, a vaccine against tuberculosis. However, many of these patients will experience tumor recurrence, despite appropriate treatment. 1 The standard of care in these patients is radical cystectomy (RC) with urinary diversion. 2 Patients diagnosed with muscle-invasive bladder cancer (MIBC) have traditionally faced 2 main treatment options: RC and urinary diversion, as in Bacillus Calmette-Guerin-unresponsive Non-muscle-invasive bladder cancer, or alternatively, trimodal therapy comprising maximal transurethral resection of bladder tumor plus chemoradiation. 3 For patients with MIBC and clinical (c)T2-T4a, neoadjuvant chemotherapy (NAC) preceding RC is supported by Level 1 evidence with a modest 5-year overall survival benefit of 5% with cisplatin-based regimens. 4-9 A number of factors preclude MIBC patients from standard treatment options. For example, patients with serious comorbidities might be unable to tolerate general anesthesia, while others might be unwilling to adapt to the lifestyle changes after RC. 10-12 Likewise, patients with extensive carcinoma in situ or poor bladder function might not be optimal candidates for trimodal therapy or be prepared for the ongoing risk that salvage RC might be ultimately required. Reasons for the underuse of NAC range from the fear of delaying potentially curative surgery in nonresponders to patient ineligibility to cisplatin-based NAC. 13,14 Despite best efforts, in both surgical and bladder-sparing approaches, the 5-year overall survival in treated patients with MIBC is only 35% to 50%. 3,15 Strategies to improve overall prognosis as well as to reduce the indications of RC are desperately needed. Trial results have demonstrated the unprecedented ability of immune-checkpoint inhibitors to induce durable remissions in some patients with metastatic urothelial carcinoma. 16-20 Furthermore, immune-checkpoint inhibitors have shown to be better tolerated than traditional chemotherapy. 16 These successful results have spearheaded the research on these agents in earlier curative settings, with the shared goal of improving overall outcomes, and potentially avoid surgery in patients who show complete response (pT0). Strategies to enhance the immune response by combining immunotherapy with immune sensitizers such as chemotherapy, immunotherapy, targeted therapy or radiation are on the rise., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The phase III CheckMate 9ER trial originally included a nivolumab plus ipilimumab plus cabozantinib triplet arm, which was discontinued early due to the evolving treatment landscape for first-line advanced renal cell carcinoma (aRCC). We report an exploratory analysis of patients randomised to the triplet regimen before enrolment discontinuation., Methods: Patients with clear-cell aRCC received nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) Q3W for four cycles with once-daily cabozantinib (40 mg), then nivolumab (240 mg) Q2W plus once-daily cabozantinib (40 mg). CheckMate 9ER primary (progression-free survival [PFS] by blinded independent central review [BICR]) and key secondary (overall survival [OS], objective response rate [ORR] by BICR, and safety) endpoints were applied, along with investigator-assessed PFS and ORR., Results: Fifty patients were randomised to the triplet regimen. After a median follow-up of 39.1 months (range, 33.4-44.5), median PFS (95% CI) was 9.9 (5.7-16.8) months by BICR and 13.9 (7.3-24.7) months by investigator; median OS (95% CI) was 37.0 (31.8-not estimable) months. ORR (95% CI) was 44.0% (30.0-58.7; complete response, 8.0%) by BICR and 48.0% (33.7-62.6; all partial responses) by investigator. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 84.0%, most commonly alanine aminotransferase increased (20.0%), aspartate aminotransferase increased (16.0%), and hepatotoxicity (16.0%). Grade 3-4 hepatic immune-mediated AEs occurred in 40.0%. There were no grade 5 TRAEs., Conclusions: These results suggest that the nivolumab plus ipilimumab plus cabozantinib triplet combination has clinical activity in patients with previously untreated aRCC, although monitoring of overlapping toxicities will be important in future studies of this regimen., Clinicaltrials: gov registration: NCT03141177., (Published by Elsevier Ltd.)

Background: Cabozantinib monotherapy is approved for the treatment of several types of solid tumors. Investigation into the use of cabozantinib combined with other therapies is increasing. To understand the evidence in this area, we performed a systematic review of cabozantinib combination therapy for the treatment of solid tumors in adults., Methods: This study was designed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses, and the protocol was registered with PROSPERO (CRD42020144680). On 9 October 2020, we searched for clinical trials and observational studies of cabozantinib as part of a combination therapy for solid tumors using Embase, MEDLINE, and Cochrane databases, and by screening relevant congress abstracts. Eligible studies reported clinical or safety outcomes, or biomarker data. Randomized and observational studies with a sample size of fewer than 25 and studies of cabozantinib monotherapy were excluded. For each study, quality was assessed using National Institute for Health and Care Excellence methodology, and the study characteristics were described qualitatively. This study was funded by Ipsen., Results: Of 2421 citations identified, 32 articles were included (6 with results from randomized studies, 24 with results from non-randomized phase I or II studies, and 2 with results from both). The most commonly studied tumor types were metastatic urothelial carcinoma/genitourinary tumors and castration-resistant prostate cancer (CRPC). Findings from randomized studies suggested that cabozantinib combined with other therapies may lead to better progression-free survival than some current standards of care in renal cell carcinoma, CRPC, and non-small-cell lung cancer. The most common adverse events were hypertension, diarrhea, and fatigue., Conclusion: This review demonstrates the promising efficacy outcomes of cabozantinib combined with other therapies, and a safety profile similar to cabozantinib alone. However, the findings are limited by the fact that most of the identified studies were reported as congress abstracts only. More evidence from randomized trials is needed to explore cabozantinib as a combination therapy further., Competing Interests: Competing Interests: DC has received institutional research funding from Janssen Oncology; has received travel and accommodation expenses from AstraZeneca (Spain), Bristol Myers Squibb, Pfizer and Roche; and has a consulting or advisory role with Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Ipsen, Janssen Oncology, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Sanofi. ABA has no interests to declare. CP has an advisory role with AstraZeneca, Bristol Myers Squibb, Eisai, EUSA Pharma, General Electric Healthcare, Ipsen, Janssen, MSD, Novartis, and Pfizer; has been a speaker for Bristol Myers Squibb, EUSA Pharma, General Electric Healthcare, Ipsen, and Pfizer; has been a protocol steering committee member for Bristol Myers Squibb, Eisai and EUSA Pharma; and has provided expert testimony for EUSA Pharma and Pfizer. JC has a scientific consultancy role (speaker and advisory roles) for Advanced Accelerator Applications, Amgen, Bayer, Eisai, Exelixis, Ipsen, ITM, Merck Serono, Novartis, Pfizer, Sanofi, and Sirlex, and has received research grants from Advanced Accelerator Applications, AstraZeneca, Bayer, Eisai, Novartis, and Pfizer. SV reports personal fees and non-financial support from Bristol Myers Squibb, personal fees and non-financial support from Roche, personal fees from MSD, personal fees from AbbVie, non-financial support from OSE PHARMA, and non-financial support from Merck. CR-A has no interests to declare. LM is an employee of Ipsen. PM is on advisory boards for Astellas, AstraZeneca, Bayer, Bristol, Ipsen, Janssen, Novartis, Pfizer, and Roche, and has received research grants from Bayer and Roche., (© The Author(s), 2022.)

Cancer immunotherapy has significantly improved patient survival. Yet, half of patients do not respond to immunotherapy. Gut microbiomes have been linked to clinical responsiveness of melanoma patients on immunotherapies; however, different taxa have been associated with response status with implicated taxa inconsistent between studies. We used a tumor-agnostic approach to find common gut microbiome features of response among immunotherapy patients with different advanced stage cancers. A combined meta-analysis of 16S rRNA gene sequencing data from our mixed tumor cohort and three published immunotherapy gut microbiome datasets from different melanoma patient cohorts found certain gut bacterial taxa correlated with immunotherapy response status regardless of tumor type. Using multivariate selbal analysis, we identified two separate groups of bacterial genera associated with responders versus non-responders. Statistical models of gut microbiome community features showed robust prediction accuracy of immunotherapy response in amplicon sequencing datasets and in cross-sequencing platform validation with shotgun metagenomic datasets. Results suggest baseline gut microbiome features may be predictive of clinical outcomes in oncology patients on immunotherapies, and some of these features may be generalizable across different tumor types, patient cohorts, and sequencing platforms. Findings demonstrate how machine learning models can reveal microbiome-immunotherapy interactions that may ultimately improve cancer patient outcomes., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2022 Liang et al.)

Background: Cabozantinib is approved, in various settings, for the treatment of renal cell carcinoma, medullary thyroid cancer, and hepatocellular carcinoma, and it has been investigated for the treatment of other cancers. With the available evidence and the real-world performance of cabozantinib compared with clinical trial data, we performed a systematic review of cabozantinib monotherapy as treatment for solid tumors in adults., Methods: This study was designed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and registered with PROSPERO (CRD42020144680). We searched for clinical and observational studies of cabozantinib monotherapy for solid tumors using Embase, MEDLINE, and Cochrane databases (October 2020), and screened relevant congress abstracts. Eligible studies reported clinical or safety outcomes, or biomarker data. Small studies ( n  < 25) and studies of cabozantinib combination therapies were excluded. Quality was assessed using National Institute for Health and Care Excellence methodology, and study characteristics were described qualitatively., Results: Of 2888 citations, 114 were included (52 randomized studies, 29 observational studies, 32 nonrandomized phase I or II studies or pilot trials, and 1 analysis of data from a randomized study and a nonrandomized study). Beyond approved indications, other tumors studied were castration-resistant prostate cancer, urothelial carcinoma, Ewing sarcoma, osteosarcoma, uveal melanoma, non-small-cell lung cancer, Merkel cell carcinoma, glioblastoma, pheochromocytomas and paragangliomas, cholangiocarcinoma, gastrointestinal stromal tumor, colorectal cancer, salivary gland cancer, carcinoid and pancreatic neuroendocrine tumors, and breast, endometrial and ovarian cancers. The most common adverse events were hypertension, diarrhea, and fatigue., Conclusion: The identified evidence demonstrates the positive efficacy/effectiveness of cabozantinib monotherapy in various solid tumor types, with safety findings being consistent with those observed with other VEGFR-targeting tyrosine kinase inhibitors. When available, real-world findings were consistent with the data reported from clinical trials. A limitation of this review is the high proportion of abstracts; however, this allowed us to capture the most up-to-date findings., Competing Interests: Conflict of interest statement: PM is on advisory boards for Astellas, AstraZeneca, Bayer, Bristol, Ipsen, Janssen, Novartis, Pfizer, and Roche, and has received research grants from Bayer and Roche. CP has an advisory role with AstraZeneca, Bristol Myers Squibb, Eisai, EUSA Pharma, General Electric Healthcare, Ipsen, Janssen, MSD, Novartis and Pfizer; has been a speaker for Bristol Myers Squibb, EUSA Pharma, General Electric Healthcare, Ipsen, and Pfizer; has been a protocol steering committee member for Bristol Myers Squibb, Eisai and EUSA Pharma; and has provided expert testimony for EUSA Pharma and Pfizer. JC has a scientific consultancy role (speaker and advisory roles) for Advanced Accelerator Applications, Amgen, Bayer, Eisai, Exelixis, Ipsen, ITM, Merck Serono, Novartis, Pfizer, Sanofi and Sirlex, and has received research grants from Advanced Accelerator Applications, AstraZeneca, Bayer, Eisai, Novartis, and Pfizer. ABA has no interests to declare. SV reports personal fees and nonfinancial support from Bristol Myers Squibb, personal fees and nonfinancial support from Roche, personal fees from MSD, personal fees from AbbVie, nonfinancial support from OSE PHARMA, and nonfinancial support from Merck. CR-A has no interests to declare. LM is an employee of Ipsen. DC has received institutional research funding from Janssen Oncology; has received travel and accommodation expenses from AstraZeneca (Spain), Bristol Myers Squibb, Pfizer and Roche; and has a consulting or advisory role with Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Ipsen, Janssen Oncology, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Sanofi., (© The Author(s), 2022.)

Background: In the primary analysis of CheckMate 9ER, nivolumab plus cabozantinib showed superior progression-free survival, overall survival, and objective response over sunitinib in patients with previously untreated advanced renal cell carcinoma (median follow-up of 18·1 months). Here, we report extended follow-up of overall survival and updated efficacy and safety., Methods: This open-label, randomised, phase 3 trial was done in 125 hospitals and cancer centres across 18 countries. We included patients aged 18 years or older with previously untreated advanced or metastatic clear-cell renal cell carcinoma, a Karnofsky performance status of 70% or higher, measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by the investigator, any International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk category, and available tumour tissue for PD-L1 testing. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks plus cabozantinib (40 mg) orally once daily or sunitinib (50 mg orally) once daily (4 weeks per 6-week cycle). Randomisation, stratified by IMDC risk status, tumour PD-L1 expression, and geographical region, was done by permuted block within each stratum using a block size of four, via an interactive response system. The primary endpoint was progression-free survival by blinded independent central review. Overall survival was a secondary endpoint (reported here as the preplanned final analysis according to the protocol). Efficacy was assessed in all randomly assigned patients; safety was assessed in all patients who received at least one dose of any study drug. This ongoing study, closed to recruitment, is registered with ClinicalTrials.gov, NCT03141177., Findings: Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to the nivolumab plus cabozantinib group and 328 to the sunitinib group. With an extended follow-up (data cutoff of June 24, 2021; median 32·9 months [IQR 30·4-35·9]), median overall survival was 37·7 months (95% CI 35·5-not estimable) in the nivolumab plus cabozantinib group and 34·3 months (29·0-not estimable) in the sunitinib group (hazard ratio [HR] 0·70 [95% CI 0·55-0·90], p=0·0043) and updated median progression-free survival was 16·6 months (12·8-19·8) versus 8·3 months (7·0-9·7; HR 0·56 [95% CI 0·46-0·68], p<0·0001). Grade 3-4 treatment-related adverse events occurred in 208 (65%) of 320 patients with nivolumab plus cabozantinib versus 172 (54%) of 320 with sunitinib. The most common grade 3-4 treatment-related adverse events were hypertension (40 [13%] of 320 patients in the nivolumab plus cabozantinib group vs 39 [12%] of 320 in the sunitinib group), palmar-plantar erythrodysaesthesia (25 [8%] vs 26 [8%]), and diarrhoea (22 [7%] vs 15 [5%]). Grade 3-4 treatment-related serious adverse events occurred in 70 (22%) of 320 patients in the nivolumab plus cabozantinib group and 31 (10%) of 320 in the cabozantinib group. One additional treatment-related death occurred with sunitinib (sudden death)., Interpretation: With extended follow-up and preplanned final overall survival analysis per protocol, nivolumab plus cabozantinib demonstrated improved efficacy versus sunitinib, further supporting the combination in the first-line treatment of advanced renal cell carcinoma., Funding: Bristol Myers Squibb and Ono Pharmaceutical., Competing Interests: Declaration of interests RJM reports advisory board fees from AstraZeneca, AVEO Pharmaceuticals, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer; and institutional funding from Bristol Myers Squibb (BMS), Eisai, Exelixis, Genentech/Roche, Merck, and Pfizer. TP reports grants from AstraZeneca, Roche, BMS, Exelixis, Ipsen, Merck, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas Pharma, Johnson & Johnson, and Eisai; consulting fees from BMS, Merck, AstraZeneca, Ipsen, Pfizer, Novartis, Incyte, Seattle Genetics, Roche, Exelixis, MSD, Merck Serono, Astellas Pharma, Johnson & Johnson, and Eisai; and travel support from Pfizer, MSD, AstraZeneca, Roche, and Ipsen. MB reports consulting fees from Roche/Genentech, BMS, MSD Oncology, Novartis, AstraZeneca; and speakers' bureau fees from Roche/Genentech, MSD Oncology, BMS, and AstraZeneca. BE reports an institutional research grant from BMS; consulting fees from Pfizer, BMS, Ipsen, AVEO, Oncorena, and Eisai; honoraria from Pfizer, BMS, Ipsen, Oncorena, and Eisai; and travel support from BMS, Ipsen, and MSD. MTB reports consulting fees from BMS, Asofarma, Eisai, MSD Oncology, Janssen Oncology, Novartis, Bayer, and Ferring; speakers' bureau fees from Asofarma, MSD Oncology, BMS, Bayer, Eisai, Janssen Oncology, Ipsen, Pfizer, Merck, Ferring, Tecnofarma, Medicamenta, AstraZeneca, and Astellas Pharma; honoraria from BMS and Tecnofarma; payment for expert testimony from Asofarma; travel support from Asofarma, Janssen-Cilag, MSD Oncology, BMS Mexico, Pfizer, Ipsen, and Sanofi; and steering committee honoraria from BMS. AYS reports research grants from BMS, Eisai, 4D Pharma, and EMD Serono; consulting fees from Exelixis, BMS, Pfizer, and EMD Serono; and honoraria from Eisai and Oncology Information Group. CSu reports research grants from AB Science, Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim España, BMS, Clovis Oncology, Exelixis, Genentech, GlaxoSmithKline, Hoffman-La Roche, Novartis Farmaceutica, Pfizer, and Sanofi-Aventis; speakers' bureau fees from Astellas Pharma, Bayer, BMS, EUSA Pharma, Hoffmann-La Roche, Ipsen, and Pfizer; and advisory board fees from Astellas Pharma, Bayer, BMS, EUSA Pharma, Hoffman-La Roche, Ipsen, MSD, Novartis, Pfizer, and Sanofi-Aventis. AH reports advisory board fees from MSD and Janssen. CP reports consulting fees from Angelini Pharma, AstraZeneca, BMS, Eisai, EUSA Pharma, Ipsen, Merck Serono, and MSD; speakers' bureau fees from BMS, EUSA Pharma, General Electric, Ipsen, and MSD; payment for expert testimony from EUSA Pharma and Pfizer; and travel support from Roche. CMH reports institutional research grant from BMS, and stock options from Telix Pharmaceuticals, Volpara Health Technologies, Alcidon, and Nanosonics. ERK reports a personal research grant from Medivation/Astellas; institutional research grant from BMS, Genentech/Roche, Pfizer, and Merck Serono; and stock options from Johnson & Johnson. HG reports advisory board fees from BMS, Ipsen, MSD, AstraZeneca, Janssen-Cilag, Pfizer, Roche, and Merck Serono; speakers' bureau fees from Merck Serono; and travel support from AstraZeneca. YT reports institutional research grants from Ono Pharmaceutical, Takeda, and Astellas; and honoraria from BMS, Pfizer, Ono Pharmaceutical, and Astellas. JB reports institutional research grants from BMS, Astellas Pharma, Ipsen, MSD Oncology, Novartis, Roche, Exelixis, Pfizer, and Seagen; consulting fees from BMS, Eisai, EUSA Pharma, Ipsen, MSD Oncology, AstraZeneca, Roche, Pfizer, and Merck; and speakers' bureau fees from MSD Oncology, BMS, Merck, Pfizer, Ipsen, and Roche. JZ and BS are employed by and have stock ownership in BMS. CSc is employed by and has stock ownership in Exelixis. TKC reports research grants, consulting fees, honoraria, and advisory board fees from AstraZeneca, Aravive, AVEO, Bayer, BMS, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVIA, Infinity, Ipsen, Janssen, Kanaph, Lilly, Merck, NiKang, Nuscan, Novartis, Pfizer, Roche, Sanofi-Aventis, Surface Oncology, Takeda, Tempest, UpToDate, and continuing medical education events (Peerview, OncLive, MJH, and others), outside the submitted work; institutional patents filed on molecular mutations and immunotherapy response, and circulating tumour DNA; leadership fees from the National Comprehensive Cancer Network, US NCI Genitourinary Steering Committee, American Society of Clinical Oncology, and European Society for Medical Oncology; stock ownership in Pionyr, Tempest, Osel, and NuscanDx; other financial or non-financial interests include medical writing and editorial assistance support that might in part have been funded by communications companies; potential funding (in part) from non-US sources or foreign institutions for mentoring of several non-US citizens on research projects; independent funding by drug companies or royalties potentially involved in research around the subject matter (institutional); and support in part by the Dana-Farber/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 the Dana-Farber Cancer Institute. ABA declares no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: This study investigated the efficacy and tolerability of cabozantinib plus nivolumab (CaboNivo) in patients with metastatic urothelial carcinoma (mUC) that progressed on checkpoint inhibition (CPI)., Patients and Methods: A phase I expansion cohort of patients with mUC who received prior CPI was treated with cabozantinib 40 mg/day and nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary goal was objective response rate (ORR) per RECIST v.1.1. Secondary objectives included progression-free survival (PFS), duration of response (DoR), overall survival (OS), safety, and tolerability., Results: Twenty-nine out of 30 patients enrolled were evaluable for efficacy. Median follow-up was 22.2 months. Most patients (86.7%) received prior chemotherapy and all patients received prior CPI (median seven cycles). ORR was 16.0%, with one complete response and three partial responses (PR). Among 4 responders, 2 were primary refractory, 1 had a PR, and 1 had stable disease on prior CPI. Median DoR was 33.5 months [95% confidence interval (CI), 3.7-33.5], median PFS was 3.6 months (95% CI, 2.1-5.5), and median OS was 10.4 months (95% CI, 5.8-19.5). CaboNivo decreased immunosuppressive subsets such as regulatory T cells (Tregs) and increased potential antitumor immune subsets such as nonclassical monocytes and effector T cells. A lower percentage of monocytic myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear MDSCs, lower CTLA-4 and TIM-3 expression on Tregs, and higher effector CD4+ T cells at baseline were associated with better PFS and/or OS., Conclusions: CaboNivo was clinically active, well tolerated, and favorably modulated peripheral blood immune subsets in patients with mUC refractory to CPI., (©2022 The Authors; Published by the American Association for Cancer Research.)

The role of adjuvant therapy in renal cell carcinoma and urothelial carcinoma is rapidly evolving. To date, the U.S. Food and Drug Administration has approved sunitinib and pembrolizumab in the adjuvant setting for renal cell carcinoma and nivolumab for urothelial carcinoma based on disease-free survival benefit. The U.S. Food and Drug Administration held a joint workshop with the National Cancer Institute and the Society of Urologic Oncology in 2017 to harmonize design elements, including eligibility and radiologic assessments across adjuvant trials in renal cell carcinoma and urothelial carcinoma. Considerations from the discussion at these workshops led the U.S. Food and Drug Administration to draft guidances to help inform subsequent adjuvant trial design for renal cell carcinoma and urothelial carcinoma. Patient-centered decision-making is crucial when determining therapeutic choices in the adjuvant setting; utility functions can be used to help quantify each patient's goals, values, and risk/benefit trade-offs to ensure that the decision regarding adjuvant therapy is informed by their preferences and the evolving outcomes data.

Background: In the CheckMate 9ER trial, patients with advanced renal cell carcinoma who received first-line nivolumab plus cabozantinib had significantly better progression-free survival compared with those given sunitinib. In this study, we aimed to describe the patient-reported outcome (PRO) results from CheckMate 9ER., Methods: In this open-label, randomised, phase 3 trial done in 125 cancer centres, urology centres, and hospitals across 18 countries, patients aged 18 years or older with previously untreated advanced renal cell carcinoma with a clear-cell component, a Karnofsky performance status of 70% or more, and available tumour tissue were randomly assigned (1:1) via interactive response technology to nivolumab 240 mg intravenously every 2 weeks plus oral cabozantinib 40 mg per day, or oral sunitinib 50 mg per day monotherapy for 4 weeks in 6-week cycles. The primary endpoint of progression-free survival was reported previously. PROs were analysed as prespecified exploratory endpoints at common timepoints (at baseline and every 6 weeks) until week 115. Disease-related symptoms were evaluated using the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and global health status was assessed with the three-level EQ-5D (EQ-5D-3L) visual analogue scale (VAS) and UK utility index. PRO analyses were done in the intention-to-treat population. Change from baseline was assessed using mixed-model repeated measures. A time-to-deterioration analysis was done for first and confirmed deterioration events. This study is registered with ClinicalTrials.gov, NCT03141177, and is closed to recruitment., Findings: Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to nivolumab plus cabozantinib and 328 to sunitinib. Median follow-up was 23·5 months (IQR 21·0-26·5). At baseline, patients in both groups reported low symptom burden (FKSI-19 disease-related symptoms version 1 mean scores at baseline were 30·24 [SD 5·19] for the nivolumab plus cabozantinib group and 30·06 [5·03] for the sunitinib group). Change from baseline in PRO scores indicated that nivolumab plus cabozantinib was associated with more favourable outcomes versus sunitinib (treatment difference 2·38 [95% CI 1·20-3·56], nominal p<0·0001, effect size 0·33 [95% CI 0·17-0·50] for FKSI-19 total score; 1·33 [0·84-1·83], nominal p<0·0001, 0·45 [0·28-0·61] for FKSI-19 disease-related symptoms version 1; 3·48 [1·58-5·39], nominal p=0·0004, 0·30 [0·14-0·47] for EQ-5D-3L VAS; and 0·04 [0·01-0·07], nominal p=0·0036, 0·25 [0·08-0·41] for EQ-5D-3L UK utility index), reaching significance at most timepoints. Nivolumab plus cabozantinib was associated with decreased risk of clinically meaningful deterioration for FKSI-19 total score compared with sunitinib (first deterioration event hazard ratio 0·70 [95% CI 0·56-0·86], nominal p=0·0007; confirmed deterioration event 0·63 [0·50-0·80], nominal p=0·0001)., Interpretation: PROs were maintained or improved with nivolumab plus cabozantinib versus sunitinib. Compared with sunitinib, nivolumab plus cabozantinib significantly delayed time to deterioration of patient-reported outcome scores. These results suggest a benefit for nivolumab plus cabozantinib compared with sunitinib in the treatment of patients with advanced renal cell carcinoma., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests DC reports consultant fees from AbbVie, Bristol Myers Squibb (BMS), Exelixis, Merck, Novartis, and Pfizer; reports licensing fees from FACIT.org; research grants (institutional) from AbbVie, Astellas, Aveo, BMS, GlaxoSmithKline, Merck, Novartis, and Pfizer; and is an officer of FACIT.org. RJM reports advisory board fees from AstraZeneca, Aveo Pharmaceuticals, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer; and principal investigator fees (institutional) from BMS, Eisai, Exelixis, Genentech/Roche, Merck, and Pfizer. CS reports advisory board fees from Astellas Pharma, Bayer, BMS, EUSA Pharma, Hoffmann-La Roche, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi-Aventis; speakers' bureau fees from Astellas Pharma, BMS, Hoffmann-La Roche, Ipsen, and Pfizer; and research grants (institutional) from AB Science, Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim España, BMS, Clovis Oncology, Exelixis, Genentech, GlaxoSmithKline, Hoffmann-La Roche, Novartis Farmaceutica, Pfizer, and Sanofi-Aventis. SIB is an employee of BMS, and has stock ownership in BMS and GlaxoSmithKline. FE, MH, BS, and JZ are employees of and have stock ownership in BMS. JFW is an employee and has stock ownership in Exelixis. CI is an employee of IQVIA. TKC reports advisory board fees from Aptitude Health, AstraZeneca, BMS, Calithera, EMD Serono, Exelixis, Infinity, Merck, Pfizer, and Surface Oncology; speaker's fees from Advent Health, ASCO-SITC, ASiM, CancerNet, Ipsen, MD Anderson Cancer Center (Houston, TX, USA), MJH Life Sciences, PeerView, Physicians Education Resources, Research To Practice, Springer, and WebMD; consulting fees from The Analysis Group; stock ownership in Pionyr and Tempest; a personal grant from Orien; royalties from Up-To-Date online textbook; funding (institutional) from Alliance Cooperative Group, AstraZeneca, BMS, Eisai, EMD Serono, Exelixis, Lilly, Merck, Peloton, Pfizer, Takeda, and Tracon; research grants (institutional) from BMS, Exelixis, and Roche; principal investigator fees (institutional) from GlaxoSmithKline, Roche, and Surface Oncology; a non-financial leadership role interest with Kidney Cancer Research Summit of KidneyCAN (meeting co-chair in 2019 and 2020); being a grant reviewer for the American Association for Cancer Research; being a track leader, session chair, speaker, and discussant for the American Society of Clinical Oncology; being a speaker and discussant for the European Society for Medical Oncology; access to the genomic database from Foundation Medicine; access to the genomic database (institutional) from Guardant; access to the genomic database (institutional) from Invitae; personal non-financial interests for medical writing and editorial assistance from Clinical Thinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, and Oxford PharmaGenesis; and personal non-financial interests for reviews of papers for various journals. ABA declares no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Patients treated with immune checkpoint inhibitors (ICIs) may experience pseudoprogression, which can be classified as progressive disease (PD) by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and could lead to inappropriate treatment discontinuation. Immune-response criteria were developed to better capture novel response patterns seen with ICIs., Methods: We pooled data from 1765 patients with 12 types of advanced solid tumors treated with avelumab (an anti-programmed death ligand 1 (PD-L1) monoclonal antibody) monotherapy in the JAVELIN Solid Tumor and JAVELIN Merkel 200 trials, conducted a comparative analysis of tumor assessments by investigators according to RECIST 1.1 and immune-related RECIST (irRECIST), and evaluated the correlation between progression-free survival (PFS) and overall survival (OS)., Results: In total, 147 patients (8.3%) had a best overall response (BOR) of PD by RECIST 1.1 but had immune-related disease control by irRECIST (defined as immune-related BOR (irBOR) of immune-related stable disease or better). This discordance was seen irrespective of PD-L1 status and observed across all tumor types. Overall, PFS and immune-related PFS showed similar imputed rank correlations with OS., Conclusions: The use of irRECIST identified a subset of patients with a BOR of PD by RECIST 1.1 but an irBOR of immune-related disease control by irRECIST with a distinctive survival curve, thereby providing more clinically relevant information than RECIST 1.1 alone. However, as a surrogate endpoint for OS in the whole population, immune-related PFS by irRECIST did not show improved predictive value compared with PFS by RECIST 1.1., Competing Interests: Competing interests: JLG has received research funding from Astellas Medivation, Bavarian Nordic, Bristol Myers Squibb, EMD Serono, an affiliate of Merck KGaA, NantBioScience, and Pfizer. SPD has provided consultancy or advisory services for Amgen, GlaxoSmithKline, Immune Design, Incyte, EMD Serono, an affiliate of Merck KGaA, and Nektar Therapeutics, and received travel expenses from Adaptimmune, EMD Serono, an affiliate of Merck KGaA, and Nektar Therapeutics. JM is an employee of EMD Serono Research & Development Institute, Billerica, Massachusetts, USA, an affiliate of Merck KGaA. SPE is an employee of Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA. MB is an employee of Merck. All other authors report no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

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.)

The success of the use of novel therapies in the treatment of advanced urothelial carcinoma has contributed to growing interest in evaluating these therapies at earlier stages of the disease. However, trials evaluating these therapies in the neoadjuvant setting must have clearly defined study elements and appropriately selected end points to ensure the applicability of the trial and enable interpretation of the study results. To advance the development of rational trial design, a public workshop jointly sponsored by the US Food and Drug Administration and the Bladder Cancer Advocacy Network convened in August 2019. Clinicians, clinical trialists, radiologists, biostatisticians, patients, advocates and other stakeholders discussed key elements and end points when designing trials of neoadjuvant therapy for muscle-invasive bladder cancer (MIBC), identifying opportunities to refine eligibility, design and end points for neoadjuvant trials in MIBC. Although pathological complete response (pCR) is already being used as a co-primary end point, both individual-level and trial-level surrogacy for time-to-event end points, such as event-free survival or overall survival, remain incompletely characterized in MIBC. Additionally, use of pCR is limited by heterogeneity in pathological evaluation and the fact that the magnitude of pCR improvement that might translate into a meaningful clinical benefit remains unclear. Given existing knowledge gaps, capture of highly granular patient-related, tumour-related and treatment-related characteristics in the current generation of neoadjuvant MIBC trials will be critical to informing the design of future trials., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Objective: Metastatic bladder cancer is an aggressive disease that can often be difficult to diagnose and stage with conventional cross-sectional imaging. The primary objective of this study was to determine the clinical value of fluorine-18 2-fluoro-2-deoxy-D-glucose ( 18 F-FDG) PET/MRI for surveillance and restaging of patients with muscle-invasive, locally advanced, and metastatic bladder cancer compared to conventional imaging methods., Materials and Methods: This retrospective study enrolled patients with muscle-invasive, locally advanced and metastatic bladder cancer in a single institute evaluated with 18 F-FDG PET/MRI. All patients also underwent conventional imaging with CT. Additional imaging may also have included 18 F-FDG PET/CT ( 18 F-FDG PET), or sodium fluoride (NaF) PET/CT in some patients. Images were reviewed by a diagnostic radiologist/nuclear medicine physician. Number of lesions and sites of disease were captured and compared between 18 F-FDG PET/MRI and conventional imaging. Lesions were confirmed by sequential imaging or lesion biopsy. All patients were followed for survival., Results: Fifteen patients (4 for surveillance; 11 for restaging) underwent 34 18 F-FDG PET/MRI scans. Each patient received a corresponding conventional CT around the time of the 18 F-FDG PET/MRI (median 6 days). The 15 patients (11 male; 4 female) had a median age of 61.5 years (range 37-73) and histologies of urothelial carcinoma (n = 13) and small-cell carcinoma of the bladder (n = 2) diagnosed as stage 4 (n = 13), stage 3 (n = 1), or stage 2 (n = 1). 18 F-FDG PET/MRI detected 82 metastatic malignant lesions involving lymph nodes (n = 22), liver (n = 10), lung (n = 34), soft tissue (n = 12), adrenal glands (n = 1), prostate (n = 1), and bone (n = 2) with a resultant advantage of 36% for lesion visibility in comparison with CT. Serial imaging or biopsy confirmed these lesions as malignant., Conclusion: 18 F-FDG PET/MRI can detect metastatic lesions which cannot be identified on conventional CT, and this can allow for better treatment planning and improved disease monitoring during therapy., (Published by Elsevier Inc.)

Comprehensive characterizations of bladder cancer (BCa) have established molecular phenotype classes with distinct alterations and survival trends. Extending these studies within the tyrosine kinase (TK) family to identify disease drivers could improve our use of TK inhibitors to treat specific patient groups or individuals. We examined the expression distribution of TKs as a class (n = 89) in The Cancer Genome Atlas (TCGA) muscle invasive BCa data set (n >400). Patient profiles of potentially oncogenic alterations (overexpression and/or amplification) clustered TKs into 3 groups; alterations of group 1 and 3 TKs were associated with significantly worse patient survival relative to those without alterations. Many TK pathways induce epithelial-to-mesenchymal transition (EMT), which promotes tumor invasiveness and metastasis. Overexpression and/or amplification among 9 EMT transcriptional activators occurred in 43% of TCGA cases. Co-occurring alterations of TKs and EMT transcriptional activators involved most group 1 TKs; 24% of these events were associated with significantly worse patient survival. Co-occurring alterations of receptor TKs and their cognate ligands occurred in 16% of TCGA cases and several BCa-derived cell lines. Suppression of GAS6, MST1 or CSF1, or their respective receptors (AXL, MST1R and CSF1R), in BCa cell lines was associated with decreased receptor activation, cell migration, cell proliferation and anchorage independent cell growth. These studies reveal the patterns and prevalence of potentially oncogenic TK pathway-related alterations in BCa and identify specific alterations associated with reduced BCa patient survival. Detection of these features in BCa patients could better inform TK inhibitor use and improve clinical outcomes., Competing Interests: D. Bottaro is an inventor on US Government held patents that are generally related to the subjects reported here: US 10,035,833: “Vascular Endothelial Growth Factor Antagonists and Methods of Making”; US 9,550,818 and related international publications WO/2013/163606: “Methods for Use of Vascular Endothelial Growth Factor Antagonists”; US 8,617,831: “Methods for Diagnosing and Monitoring the Progression of Cancer by Measuring Soluble c-Met Ectodomain”; US 7,964,365 and related international WO/2007/056523: “Methods for Diagnosing and Monitoring the Progression of Cancer”; US 8,304,199: Methods for Diagnosing and Monitoring the Progression of Cancer by Measuring Soluble c-Met Ectodomain”; US 8,569,360 and related international publications WO/2009/124024 and WO/2009/124013: “Compositions and Methods for Inhibition of Hepatocyte Growth Factor Receptor c-Met Signaling”: US 7,871,981 and related international WO/2001/028577: “Inhibition of Cell Motility, Angiogenesis and Metastasis”. This does not alter our adherence to PLOS ONE policies on sharing data and materials. No other authors have competing interests to disclose.

Purpose To compare Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 with volumetric measurement in the setting of target lymph nodes that split into two or more nodes or merge into one conglomerate node. Materials and Methods In this retrospective study, target lymph nodes were evaluated on CT scans from 166 patients with different types of cancer; 158 of the scans came from The Cancer Imaging Archive. Each target node was measured using RECIST 1.1 criteria before and after merging or splitting, followed by volumetric segmentation. To compare RECIST 1.1 with volume, a single-dimension hypothetical diameter (HD) was determined from the nodal volume. The nodes were divided into three groups: (a) one-target merged (one target node merged with other nodes); (b) two-target merged (two neighboring target nodes merged); and (c) split node (a conglomerate node cleaved into smaller fragments). Bland-Altman analysis and t test were applied to compare RECIST 1.1 with HD. On the basis of the RECIST 1.1 concept, we compared response category changes between RECIST 1.1 and HD. Results The data set consisted of 30 merged nodes (19 one-target merged and 11 two-target merged) and 20 split nodes (mean age for all 50 included patients, 50 years ± 7 [standard deviation]; 38 men). RECIST 1.1, volumetric, and HD measurements indicated an increase in size in all one-target merged nodes. While volume and HD indicated an increase in size for nodes in the two-target merged group, RECIST 1.1 showed a decrease in size in all two-target merged nodes. Although volume and HD demonstrated a decrease in size of all split nodes, RECIST 1.1 indicated an increase in size in 60% (12 of 20) of the nodes. Discrepancy of the response categories between RECIST 1.1 and HD was observed in 5% (one of 19) in one-target merged, 82% (nine of 11) in two-target merged, and 55% (11 of 20) in split nodes. Conclusion RECIST 1.1 does not optimally reflect size changes when lymph nodes merge or split. Keywords: CT, Lymphatic, Tumor Response Supplemental material is available for this article. © RSNA, 2021.

Objective: To evaluate multidisciplinary female representation at urologic oncology conferences, we reviewed speakership trends at contemporary Society of Urologic Oncology (SUO) and American Society of Clinical Oncology Genitourinary Symposium (GU-ASCO) annual meetings., Methods: Meeting programs from SUO and GU-ASCO from 2015 to 2019 were analyzed. Biographical information was determined by querying institutional websites and social/professional media platforms. Statistical analyses were performed to assess for differences and relationships between male and female authorship based on gender, specialty, professional, and educational factors., Results: We identified 1102 speakers at genitourinary oncology conferences. Overall, 222 (20%) were female. There was no significant difference between female speakership rates at SUO and GU-ASCO. The overall proportion of female speakers increased over time, but not when analyzing each individual subspecialty conference separately. Several professional and educational differences were noted between genders. Female speakers were more likely to be medical oncologists (P <.001), have more recent years of graduation (2001 vs 1996, P <.001), hold an additional advanced degree (OR 2.09, P = .005), and speak in sessions where other women served as chair (OR 1.42, P = .044). Conversely, female speakers had lower odds of delivering a plenary or keynote address (OR 0.28, P = .015)., Conclusion: We identified a significantly positive trend towards increased female representation within contemporary genitourinary conferences over time; these trends did not remain significant when analyzing each meeting separately. Several important disparities between men and women speakers were identified. Our data suggests that inclusion of women in planning committees may help reduce gender bias and promote diversity within urologic oncology., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known., Methods: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point., Results: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib., Conclusions: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.)., (Copyright © 2021 Massachusetts Medical Society.)

Purpose: Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of individual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy., Experimental Design: Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test., Results: From December 2016 to January 2019, 183 samples from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline ( P = 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with unique cellular features at baseline and on-therapy was associated with worse OS (0.9-2.3 vs. 28.2 months; P < 0.0001-0.013). Increasing CTC heterogeneity on-therapy had a trend toward worse OS ( P = 0.045). PD-L1 + CTCs on-therapy were associated with worse OS ( P < 0.01, cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category., Conclusions: Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1 + CTCs, and low %CD4/8 T cells in patients with metastatic genitourinary cancer. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies., (©2020 American Association for Cancer Research.)

Purpose: A prognostic model for overall survival of post-platinum patients with metastatic urothelial carcinoma receiving PD-1/PD-L1 inhibitors is necessary as existing models were constructed in the chemotherapy setting., Materials and Methods: Patient level data were used from phase I/II trials evaluating PD-L1 inhibitors following platinum based chemotherapy for metastatic urothelial carcinoma. The derivation data set consisted of 2 phase I/II trials evaluating atezolizumab (405). Two phase I/II trials that evaluated avelumab (242) and durvalumab (198) comprised the validation data sets. Cox regression analyses evaluated the association of candidate prognostic factors with overall survival. Stepwise selection was used to select an optimal model using the derivation data set. Discrimination and calibration were assessed in the avelumab and durvalumab data sets., Results: The 5 prognostic factors identified in the optimal model using the atezolizumab derivation data set were ECOG-PS (1 vs 0, HR 1.80, 95% CI 1.36-2.36), liver metastasis (HR 1.55, 95% CI 1.20-2.00), platelet count (HR 2.22; 95% CI 1.54-3.18), neutrophil-to-lymphocyte ratio (HR 1.94, 95% CI 1.57-2.40) and lactate dehydrogenase (HR 1.60, 95% CI 1.28-1.99). There was robust discrimination of survival between low, intermediate and high risk groups. The c-statistic was 0.692 in the derivation and 0.671 and 0.773 in the avelumab and durvalumab validation data sets, respectively. A web based interactive tool was developed to calculate the expected survival probabilities based on risk factors., Conclusions: A validated 5-factor model has satisfactory prognostic performance for survival across 3 PD-L1 inhibitors to treat metastatic urothelial carcinoma after platinum therapy and may assist in stratification, interpreting and designing trials incorporating PD-1/PD-L1 inhibitors in the post-platinum setting.

Purpose: We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances., Patients and Methods: Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS)., Results: Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC., Conclusion: CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.

Background: Adverse events (AEs) of special interest that arise during treatment with immune checkpoint inhibitors, including immune-related AEs (irAEs), have been reported to be associated with improved clinical outcomes. We analyzed patients treated with avelumab from the JAVELIN Solid Tumor and Merkel 200 trials, examining the association between AEs and efficacy while adjusting for confounding factors such as treatment duration and event order., Methods: We analyzed efficacy and safety data from 1783 patients treated with the programmed death ligand 1 inhibitor avelumab who were enrolled in expansion cohorts of the JAVELIN Solid Tumor and Merkel 200 trials. To analyze the association between irAEs and efficacy with regard to survival, we used a time-dependent Cox model with time-varying indicators for irAEs, as well as multistate models that accounted for competing risks and time inhomogeneity., Results: 295 patients (16.5%) experienced irAEs and 454 patients (25.5%) experienced infusion-related reactions. There was a reduced risk of death in patients who experienced irAEs compared with those who did not (HR 0.71, 95% CI 0.59 to 0.85) using the time-dependent Cox model. The multistate model did not suggest that the occurrence of irAEs could predict response; however, it predicted a higher chance of irAEs occurring after a response. No association was observed between response and infusion-related reactions., Conclusions: Patients who experience irAEs showed improved survival. Although irAEs are not predictors for response to immune checkpoint inhibitors, increased vigilance for irAEs is needed after treatment with avelumab., Trial Registration Numbers: NCT01772004 and NCT02155647., Competing Interests: Competing interests: KK has received research grants from EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany) and Merck & Co; has served on advisory boards for EMD Serono and Merck & Co; and has received an honorarium from Merck & Co. JM, MB and JW are employees of EMD Serono Research & Development Institute (an affiliate of Merck KGaA, Darmstadt, Germany). VK was an employee of EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany) at the time this analysis was conducted. IS is an employee of Merck KGaA, Darmstadt, Germany. SPD reports serving as a consultant or advisor for Amgen, EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany), GlaxoSmithKline, Immunocore, Immune Design, Incyte, Merck & Co, and Nektar; has received research grants from Amgen, Bristol Myers Squibb, Deciphera, EMD Serono, Incyte, Merck & Co, and Nektar; and has received reimbursement for travel and accommodation expenses from Adaptimmune, EMD Serono, Immunocore and Nektar. AR and JLG are employees of the National Cancer Institute, which has a cooperative research and development agreement with EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany)., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Anti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1). We report ≥2-year follow-up data for avelumab treatment and exploratory subgroup analyses in patients with urothelial carcinoma., Methods: Patients with previously treated advanced/metastatic urothelial carcinoma, pooled from two cohorts of the phase Ib JAVELIN Solid Tumor trial, received avelumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or withdrawal. End points included best overall response and progression-free survival (PFS) per RECIST V.1.1, overall survival (OS) and safety. Post hoc analyses included objective response rates (ORRs) in subgroups defined by established high-risk/poor-prognosis characteristics and association between time to response and outcome., Results: 249 patients received avelumab; efficacy was assessed in 242 postplatinum patients. Median follow-up was 31.9 months (range 24-43), and median treatment duration was 2.8 months (range 0.5-42.8). The confirmed ORR was 16.5% (95% CI 12.1% to 21.8%; complete response in 4.1% and partial response in 12.4%). Median duration of response was 20.5 months (95% CI 9.7 months to not estimable). Median PFS was 1.6 months (95% CI 1.4 to 2.7 months) and the 12-month PFS rate was 16.8% (95% CI 11.9% to 22.4%). Median OS was 7.0 months (95% CI 5.9 to 8.5 months) and the 24-month OS rate was 20.1% (95% CI 15.2% to 25.4%). In post hoc exploratory analyses, avelumab showed antitumor activity in high-risk subgroups, including elderly patients and those with renal insufficiency or upper tract disease; ORRs were numerically lower in patients with liver metastases or low albumin levels. Objective response achieved by 3 months versus later was associated with longer OS (median not reached (95% CI 18.9 months to not estimable) vs 7.1 months (95% CI 5.2 to 9.0 months)). Safety findings were consistent with previously reported 6-month analyses., Conclusions: After ≥2 years of follow-up, avelumab showed prolonged efficacy and acceptable safety in patients with platinum-treated advanced/metastatic urothelial carcinoma, including high-risk subgroups. Survival appeared longer in patients who responded within 3 months. Long-term safety findings were consistent with earlier reports with avelumab treatment in this patient population., Competing Interests: Competing interests: ABA has no relationships to disclose. JAE has no relationships to disclose. JRI has received research funding from Aileron Therapeutics, ARMO BioSciences, AstraZeneca, BioMed Valley Discoveries, Bristol Myers Squibb, Calithera Biosciences, Celldex, eFFECTOR Therapeutics, Genentech/Roche, GlaxoSmithKline, Immunocore, Janssen Oncology, MedImmune, Merck and Co., Novartis, Pfizer, Phosplatin Therapeutics, Roche, and TESARO. MA has no relationships to disclose. MSG reports having stocks and other ownership interests in Caremission and WCCT Global; has received research funding from AbbVie, Acetylon, Aduro Biotech, Advaxis, Amgen, Array BioPharma, BeiGene, BioLineRx, Calithera Biosciences, CanBas, Celgene, Celldex, Corcept Therapeutics, CtyomX Therapeutics, Deciphera, Driver Group, Endocyte, ESSA, Five Prime Therapeutics, FujiFilm, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Halozyme, Hengrui Therapeutics, Inanovate, Incyte, Lilly, Lilly/ImClone, MabVax, Macrogenics, MedImmune, Merck KGaA (Darmstadt, Germany), Merrimack, Millennum, Minneamrita Therapeutics, Nektar, Novartis, Novita Pharmaceuticals, OncoMed, Pfizer, Phoenix Biotech, Plexxikon, Proderm IQ, Samumed, Seattle Genetics, Sirtex Medical, Strategia Therapeutics, Syndax, SynDevRx, TESARO, Tokai Pharmaceuticals, Tolero Pharmaceuticals, Toray Industries, TRACON Pharma, Trovagene, and Verastem; and reports patents, royalties or other intellectual property for patient-on-patient selection for clinical trials. RA has no relationships to disclose. TG has received research funding from Ferring Pharmaceuticals. LD has no relationships to disclose. K-WL has received research funding from Array BioPharma, ASLAN Pharmaceuticals, AstraZeneca/MedImmune, Five Prime Therapeutics, Green Cross Corp., LSK BioPharma, MacroGenics, Merck KGaA (Darmstadt, Germany), MSD, Ono Pharmaceutical, Pfizer, and Pharmacyclics. MHT reports serving as a consultant or advisor for ArQule, Array BioPharma, Bayer, Blueprint Medicines, Bristol Myers Squibb, Eisai, Loxo, and Novartis; and is a member of a speaker’s bureau for Bristol Myers Squibb, and Eisai. PS reports serving as a consultant or advisor for Blueprint Medicines, Eisai, Ellipses Pharma, Epizyme, Ipsen, Lilly, Loxo, PIQUR Therapeutics, and Plexxikon; and has received research funding from Blueprint Medicines, Boehringer Ingelheim, CoBioRes, Eisai, Exelixis, G1 Therapeutics, Lilly, Novartis, PharmaMar, and Plexxikon. DW reports serving as a consultant or advisor for Merck and Co.; and has received reimbursement for travel, accommodation and expenses from Merck and Co. AR has received honoraria from Bristol Myers Squibb, Ipsen, Merck KGaA (Darmstadt, Germany), MSD, Novartis, and Pfizer; reports serving as a consultant or advisor for Bristol Myers Squibb, Ipsen, Novartis, Pfizer, and Roche; has received research funding from Novartis and Pfizer; and has received reimbursement for travel, accommodation and expenses from Bristol Myers Squibb, MSD, Novartis, and Pfizer. JM reports employment at EMD Serono Research & Development Institute, Inc.; a business of Merck KGaA, Darmstadt, Germany. GP reports employment at EMD Serono, Inc.; a business of Merck KGaA, Darmstadt, Germany. MR reports employment at EMD Serono Research & Development Institute, Inc.; a business of Merck KGaA, Darmstadt, Germany. JLG has received research funding from Astellas/Medivation, Bavarian Nordic, Bristol Myers Squibb, EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Incyte, Janssen, Merck & Co, Immunity Bio, and Pfizer. MRP is a member of a speaker’s bureau for Celgene, Exelixis, Genentech/Roche, and Taiho Pharmaceutical., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To report the clinical features, severity, and management of ocular immune-related adverse events (irAEs) in the setting of immune checkpoint inhibitor therapy for metastatic malignancies., Methods: Retrospective chart review at three tertiary ophthalmology clinics. Electronic medical records were reviewed between 2000 and 2017 for patients with new ocular symptoms while undergoing checkpoint inhibition therapy., Results: Eleven patients were identified. Ocular irAEs ranged from keratoconjunctivitis sicca to Vogt-Koyanagi-Harada-like findings. Average timing of irAEs from starting checkpoint inhibitor therapy was 15.7 weeks. Ocular inflammation was successfully controlled with corticosteroids in most cases, however three patients discontinue treatment as a result of ocular inflammation with decreased visual acuity, two discontinued due to progression of metastatic disease, and one discontinued due to severe systemic irAEs., Conclusion: We found a wide spectrum of ocular irAEs associated with immune checkpoint inhibitors. In most cases, ocular AEs did not limit ongoing cancer treatment.

Background: Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL, and RET, which also has an effect on the tumour immune microenvironment by decreasing regulatory T cells and myeloid-derived suppressor cells. In this study, we examined the activity of cabozantinib in patients with metastatic platinum-refractory urothelial carcinoma., Methods: This study was an open-label, single-arm, three-cohort phase 2 trial done at the National Cancer Institute (Bethesda, MD, USA). Eligible patients were 18 years or older, had histologically confirmed urothelial carcinoma or rare genitourinary tract histologies, Karnofsky performance scale index of 60% or higher, and documented disease progression after at least one previous line of platinum-based chemotherapy (platinum-refractory). Cohort one included patients with metastatic urothelial carcinoma with measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Two additional cohorts that enrolled in parallel (patients with bone-only urothelial carcinoma metastases and patients with rare histologies of the genitourinary tract) were exploratory. Patients received cabozantinib 60 mg orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate by RECIST in cohort one. Response was assessed in all patients who met the eligibility criteria and who received at least 8 weeks of therapy. All patients who received at least one dose of cabozantinib were included in the safety analysis. This completed study is registered with ClinicalTrials.gov, NCT01688999., Findings: Between Sept 28, 2012, and Oct, 20, 2015, 68 patients were enrolled on the study (49 in cohort one, six in cohort two, and 13 in cohort three). All patients received at least one dose of cabozantinib. The median follow-up was 61·2 months (IQR 53·8-70·0) for the 57 patients evaluable for response. In the 42 evaluable patients in cohort one, there was one complete response and seven partial responses (objective response rate 19%, 95% CI 9-34). The most common grade 3-4 adverse events were fatigue (six [9%] patients), hypertension (five [7%]), proteinuria (four [6%]), and hypophosphataemia (four [6%]). There were no treatment-related deaths., Interpretation: Cabozantinib has single-agent clinical activity in patients with heavily pretreated, platinum-refractory metastatic urothelial carcinoma with measurable disease and bone metastases and is generally well tolerated. Cabozantinib has innate and adaptive immunomodulatory properties providing a rationale for combining cabozantinib with immunotherapeutic strategies., Funding: National Cancer Institute Intramural Program and the Cancer Therapy Evaluation Program., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Importance: Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for an ever-increasing number of cancers. However, their use has also led to the emergence of immune-related adverse events, such as ICI-induced inflammatory arthritis. A reproducible, reliable, and accessible modality is needed to assess and distinguish early ICI-induced inflammatory arthritis and help in management. Magnetic resonance imaging (MRI) of joints may be helpful for early diagnosis, guiding therapeutic decision-making, and identifying patients at high risk for erosive disease., Objective: To assess the role of MRI of joints in patients with ICI-induced inflammatory arthritis., Design, Setting, and Participants: This retrospective case series included patients enrolled at the National Institutes of Health Clinical Center in Bethesda, Maryland. Patients were evaluated by the rheumatology consultation service between December 27, 2016, and May 28, 2019. A retrospective health record review was performed to determine demographic characteristics, clinical characteristics of inflammatory arthritis and malignant tumors, and imaging findings. Inclusion criteria were patients who were enrolled on various institutional review board-approved protocols of ICIs, developed joint-related symptoms, and had MRI data for at least 1 joint. Data were analyzed from June 1, 2019, to September 1, 2019., Exposures: Undergoing MRI of at least 1 joint., Main Outcomes and Measures: All MRIs were reviewed for synovitis, tenosynovitis, bone marrow edema, and soft tissue conditions., Results: A total of 8 patients (mean [SD] age, 58.8 [5.2] years; 6 women and 2 men) between the ages of 50 and 65 years who were undergoing ICI therapy for a variety of malignant tumors were included in this study. Only 1 patient was receiving combined ICI therapy. The results of 13 separate MRI examinations were reviewed. The most commonly performed MRIs were of the hands and wrists (9 MRIs), followed by knee examinations (3 MRIs). Tenosynovitis and synovitis were frequently seen in the hands and wrists. Bone marrow edema and erosions were also found in 3 patients, suggesting early damage. In larger joints (ie, knees and ankles), joint effusions and synovial thickening were characteristic. Most patients (5 patients) were treated with corticosteroids and had good responses. In patients with high-risk features on MRI imaging (eg, bone marrow edema, erosions), disease-modifying antirheumatic drug therapy was also discussed as a treatment option., Conclusions and Relevance: These findings suggest that advanced imaging may help to distinguish ICI-induced inflammatory arthritis from other causes of joint pain, aid in identifying patients at increased risk of joint damage, and provide utility in monitoring inflammatory arthritis treatment response in patients receiving ICI therapy.

Purpose: To harmonize the eligibility criteria and radiologic disease assessment definitions in clinical trials of adjuvant therapy for renal cell carcinoma (RCC)., Method: On November 28, 2017, US-based experts in RCC clinical trials, including medical oncologists, urologic oncologists, regulators, biostatisticians, radiologists, and patient advocates, convened at a public workshop to discuss eligibility for trial entry and radiologic criteria for assessing disease recurrence in adjuvant trials in RCC. Multiple virtual meetings were conducted to address the issues identified at the workshop., Results: The key workshop conclusions for adjuvant RCC therapy clinical trials were as follows. First, patients with non-clear cell RCC could be routinely included, preferably in an independent cohort. Second, patients with T3-4, N+M0, and microscopic R1 RCC tumors may gain the greatest advantages from adjuvant therapy. Third, trials of agents not excreted by the kidney should not exclude patients with severe renal insufficiency. Fourth, therapy can begin 4 to 16 weeks after the surgical procedure. Fifth, patients undergoing radical or partial nephrectomy should be equally eligible. Sixth, patients with microscopically positive soft tissue or vascular margins without gross residual or radiologic disease may be included in trials. Seventh, all suspicious regional lymph nodes should be fully resected. Eighth, computed tomography should be performed within 4 weeks before trial enrollment; for patients with renal insufficiency who cannot undergo computed tomography with contrast, noncontrast chest computed tomography and magnetic resonance imaging of the abdomen and pelvis with gadolinium should be performed. Ninth, when feasible, biopsy should be undertaken to identify any malignant disease. Tenth, when biopsy is not feasible, a uniform approach should be used to evaluate indeterminate radiologic findings to identify what constitutes no evidence of disease at trial entry and what constitutes radiologic evidence of disease. Eleventh, a uniform approach for establishing the date of recurrence should be included in any trial design. Twelfth, patient perspectives on the use of placebo, conditions for unblinding, and research biopsies should be considered carefully during the conduct of an adjuvant trial., Conclusions and Relevance: The discussions suggested that a uniform approach to eligibility criteria and radiologic disease assessment will lead to more consistently interpretable trial results in the adjuvant RCC therapy setting.

OBJECTIVE. The objective of our study was to evaluate the utility of ferumoxytol-enhanced MR lymphography (MRL) in detection of metastatic lymph nodes (LNs) in patients with prostate, bladder, and kidney cancer. SUBJECTS AND METHODS. This phase 2 single-institution study enrolled patients with confirmed prostate (arm 1), bladder (arm 2), and kidney (arm 3) cancer and evidence of suspected LN involvement. Participants underwent ferumoxytol-enhanced MRL 24 and 48 hours after IV injection of 7.5 mg Fe/kg of ferumoxytol. A retrospective quantitative analysis was performed to determine the optimal timing for ferumoxytol-enhanced MRL using percentage change in normalized signal intensity (SI) from baseline to 24 and 48 hours after injection, which were estimated using the linear mixed-effects model in which time (24 vs 48 hours), diseases status, and time and disease status interaction were the fixed-effects independent variables. Differences in normalized SI values between subgroups of lesions were estimated by forming fixed-effects contrasts and tested by the Wald test. RESULTS. Thirty-nine patients ( n = 30, arm 1; n = 6, arm 2; n = 3, arm 3) (median age, 65 years) with 145 LNs (metastatic, n = 100; benign, n = 45) were included. LN-based sensitivity, specificity, positive predictive value, and negative predictive value of ferumoxytol-enhanced MRL was 98.0%, 64.4%, 86.0%, and 93.5%, respectively. Sensitivity and specificity of ferumoxytol-enhanced MRL did not vary by LN size. Metastatic LNs showed a significantly higher percentage decrease of normalized SI on MRL at 24 hours after ferumoxytol injection than at 48 hours after ferumoxytol injection ( p = 0.023), whereas the normalized SI values for nonmetastatic LNs were similar at both imaging time points ( p = 0.260). CONCLUSION. Ferumoxytol-enhanced MRL shows high sensitivity in the detection of metastatic LNs in genitourinary cancers independent of LN size. The SI difference between benign and malignant LNs on ferumoxytol-enhanced MRL appears similar 24 and 48 hours after ferumoxytol injection, suggesting that imaging can be performed safely within 1 or 2 days of injection. Although ferumoxytol-enhanced MRL can be useful in settings without an available targeted PET agent, issues of iron overload and repeatability of ferumoxytol-enhanced MRL remain concerns for this method.