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There is a paucity of data on the safety of cabozantinib use in combination with radiotherapy.To report the practice patterns, safety, and efficacy of cabozantinib with radiotherapy in metastatic renal cell carcinoma (mRCC).An international multicenter retrospective study was conducted. Patients with mRCC treated with cabozantinib at any line of therapy and who received radiotherapy between 30 d prior to the start date of cabozantinib and 30 d following discontinuation of cabozantinib, from 2014 to 2020, were included. Concurrent use was defined as the use of cabozantinib on radiotherapy treatment days during any course of radiotherapy.The primary outcomes of interest were the rate of grade ≥3 adverse events (AEs) occurring within 90 d of receipt of radiotherapy. Secondary outcomes included hospitalization rate and patterns of cabozantinib and radiotherapy use. Baseline characteristics and AEs were presented descriptively.A total of 127 consecutive patients were included. Most patients had clear cell histology (88%), had International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk disease (57%), and had received at least one prior line of therapy (93%). Of 127 patients, 67 (53%) received concurrent cabozantinib with radiotherapy, while the remaining held cabozantinib on radiotherapy days. Overall, grade 3-4 AEs occurred in 6.3% (n = 8/127) of patients. No grade 5 events were observed. In patients treated with conventional palliative radiotherapy (n = 88), the rate of grade 3-4 AEs in those who had concurrent versus those who had nonconcurrent cabozantinib was 6.3% (n = 3/48) versus 5.0% (n = 2/40). No patient was hospitalized due to radiotherapy-related toxicity. In patients treated with stereotactic ablative body radiotherapy (SABR; n = 50), the rate of grade 3-4 AEs in those who had concurrent versus those who had nonconcurrent cabozantinib was 3.6% (n = 1/28) versus 9.1% (n = 2/22). One patient in the nonconcurrent group was hospitalized due to muscle weakness suspected to be related to associated vasogenic edema 19 d after SABR for multiple brain metastases.In this real-world study of patients with mRCC treated with cabozantinib, 53% of patients received radiotherapy concurrently, with few grade 3-4 AEs reported within 90 d of receiving radiotherapy. The use of radiotherapy and cabozantinib requires a risk-benefit assessment of patient and disease characteristics to optimize therapy regimens.Our study reports the real-world experience of using radiotherapy in patients receiving cabozantinib for metastatic kidney cancer. Over half of the patients continued taking cabozantinib while receiving radiotherapy, and few patients developed serious side effects. The combined use of radiotherapy and cabozantinib requires a careful risk-benefit assessment to achieve optimal treatment outcomes.

Since the approval of the COVID-19 vaccines, their safety and efficacy has been widely demonstrated in patients with cancer. However, there remain patients with reservations regarding vaccination. We aimed to assess genitourinary cancer patients' perceptions of the vaccines as well as barriers and influencers of decision-making through the completion of a questionnaire. While vaccine-associated concerns were observed, most patients with genitourinary cancers were willing to receive the vaccine. Moving forward, differing strategies could be considered to enhance patient education on the utility of vaccination in the setting of cancer and beyond.

Collecting duct carcinoma of the kidney is a rare and aggressive subtype of renal cell carcinoma (RCC) arising from the distal convoluted tubules. At the time of diagnosis, patients are more frequently symptomatic, with advanced locoregional stage, and have metastatic disease. The 2016 WHO Classification of Tumours of the Urinary System defined diagnostic criteria for this entity. However, the diagnostic features continue to evolve, with typical, but not entirely specific, histologic and immunophenotypic characteristics. In addition, the lack of consistent molecular alterations makes collecting duct carcinoma a diagnosis of exclusion, with historical cases being re-classified as fumarate hydratase deficient RCC, ALK rearranged RCC, renal medullary carcinoma or high-grade urothelial carcinoma. The rarity and poor prognosis of the tumor makes it difficult to reach consensus guidelines to guide therapy. In this manuscript we review the clinicopathologic features of collecting duct carcinoma including pathologic diagnostic criteria, molecular characteristics and differential diagnosis, and their possible implications for management.

Tivozanib, vascular endothelial growth factor receptor inhibitor, met the primary endpoint of improved progression free survival compared to sorafenib in the phase 3 TIVO-3 study in patients with previously treated metastatic renal cell carcinoma. In this study we sought to understand the temporal characteristics of treatment related adverse events (TRAEs) and frequency and timing of the dose modifications.In this open label, randomized, phase 3 TIVO-3 study, previously treated patients with a diagnosis of metastatic renal cell carcinoma and with measurable disease were included. Patients were randomized to receive either tivozanib 1.5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily continuously. Based on updated safety analysis data (cutoff date of August 15, 2019), time to onset of the most commonly reported TRAEs, duration of toxicity, rate of dose modifications was calculated for each treatment arm.Overall, 350 patients were randomly assigned to receive tivozanib or sorafenib;173 patients from the tivozanib arm and 170 patients from the sorafenib arm were included in this analysis. Patients received a median of 11.9 cycles (336 days) and 6.7 cycles (192 days) of tivozanib and sorafenib, respectively. Dose reductions, interruptions and treatment discontinuations were 25%, 50%, and 21%, and 39%, 50%, and 30% in the tivozanib and sorafenib arms, respectively, with a longer time to onset of TRAEs in the tivozanib arm.Tivozanib was associated with less TRAEs, fewer dose modifications, a longer time to onset and a shorter duration of TRAEs compared to sorafenib.

PROOF 302 is an ongoing randomized, double-blind, placebo-controlled, adjuvant phase III trial (NCT04197986) in approximately 218 patients from 120 centers worldwide. Eligibility criteria include post-surgical high-risk muscle-invasive upper tract urothelial cancer (85% of patients) or urothelial bladder cancer (15%), susceptible FGFR3 alterations (activating mutations, gene fusions or rearrangements), ≤120 days following radical surgery and ineligible for/or refusing cisplatin-based (neo)adjuvant chemotherapy. Patients receive either oral infigratinib 125 mg or placebo daily on days 1–21 of a 28-day cycle for up to 52 weeks or until recurrence, unacceptable toxicity or death. Primary end point: centrally determined disease-free survival (DFS); secondary end points: investigator-assessed DFS, metastasis-free survival, overall survival and safety/tolerability; exploratory end points: correlative biomarker analysis, quality-of-life and infigratinib pharmacokinetics.

PURPOSE Circulating tumor DNA (ctDNA) has been validated across multiple indications in the adjuvant and surveillance settings. We evaluated whether targeted digital sequencing (TARDIS) may distinguish a partial response (PR) from a complete response (CR) among patients with metastatic renal cell carcinoma (mRCC) receiving immune checkpoint inhibitor (ICI) therapy. MATERIALS AND METHODS Eligible patients had mRCC that yielded a PR or CR to ICI therapy. Peripheral blood was obtained at a single time point for ctDNA analysis. TARDIS was used for quantification of average variant allele fractions (VAFs). Our primary objective was to determine the association between VAFs and depth of response (PR v CR). A secondary objective was to determine whether VAFs were associated with disease progression. RESULTS Twelve patients were analyzed, nine of whom achieved a PR (75%). Patients received either nivolumab monotherapy (50%) or nivolumab plus ipilimumab (50%). ctDNA analysis incorporated an average of 30 patient-specific mutations (range, 19-35); average coverage depth was 103,342 reads per target. TARDIS quantified a significant difference in VAFs between PR and CR (median, 0.181% [IQR, 0.077%-0.420%] v 0.007% [IQR, 0.0%-0.028%], respectively [ P = .014]). Of the 12 patients in the series, six patients demonstrated radiographic progression subsequent to ctDNA assessment. Patients who progressed on subsequent scans had significantly higher ctDNA than those who maintained their response (median, 0.362% [IQR, 0.181%-2.71%] v 0.033% [IQR, 0.007%-0.077%], respectively [ P = .026]). CONCLUSION In this pilot study, TARDIS accurately differentiated PR from CR among patients with mRCC receiving immunotherapy, and also prospectively identified patients at risk for subsequent progression. Given these findings, we envision subsequent studies that validate these results and investigate the utility of this assay to discern appropriate candidates for discontinuation of immunotherapy.

Introduction To describe the efficacy of infigratinib, a potent, selective fibroblast growth factor receptor (FGFR) 1-3 tyrosine kinase inhibitor, across lines of therapy (LOT) in patients with metastatic urothelial cancer (mUC). Patients and Methods Eligible patients had mUC and prior platinum-based chemotherapy, unless contraindicated, and activating FGFR3 mutation/fusion. Patients received infigratinib 125 mg orally daily (3 weeks on/1 week off) in a single-arm, open-label study. Primary endpoint: investigator-assessed confirmed objective response rate (ORR). Disease control rate (DCR), progression-free survival (PFS), best overall response (BOR) that included unconfirmed responses, and overall survival (OS) were also assessed. Subgroup analysis of efficacy and safety outcomes by LOT was performed. Results Sixty-seven patients were enrolled; 13 (19.4%) received infigratinib as early-line therapy for mUC due to ineligibility to receive platinum-based chemotherapy. Overall, ORR was 25.4% (95% CI 15.5-37.5) and DCR was 64.2% (95% CI 51.5-75.5). ORR was 30.8% (95% CI 9.1-61.4) with early-line infigratinib and 24.1% (95% CI 13.5-37.6) for ≥2 LOT. DCR was 46.2% (95% CI 19.2-74.9) for early-line and 68.5% (95% CI 54.4-80.5) for ≥2 LOT. PFS and OS appeared similar in both groups. Thirteen of 59 patients with a bladder primary tumor received early-line treatment with an ORR of 30.5% (95% CI 9.1-61.4), and 46 received ≥2 LOT with an ORR of 20.3% (95% CI 9.4-33.9); BOR was 38.5% (95% CI: 13.9-68.4%) and 42.6% (95% CI: 29.2-56.8%) in the early-line and salvage settings, respectively. Eight patients with upper tract urothelial carcinoma received salvage therapy (ORR, 50.0%; DCR, 100.0%). No significant differences in toxicities between LOT were observed. Conclusion Infigratinib has notable activity in patients with mUC regardless of LOT. The findings support the evaluation of infigratinib across different settings in mUC.

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.

Treatment options for metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC) have increased dramatically over the past decade. However, even when novel approaches have proven to be effective as monotherapy, many patients still develop progressive disease, and different strategies are needed to increase clinical response and quality of life. Strategies combining targeted therapy (TT) and immunotherapy (IO) have emerged as a way to shorten the gap between responders and nonresponders to monotherapy and have reported promising results. In this review, we discuss the current role of cabozantinib in combination with IO agents in the treatment of metastatic RCC and UC and go over future directions in the field.Lay abstract Treatment options for both advanced kidney and bladder cancers have increased significantly over the last decade. However, even when these new approaches have proven to be effective, many patients still experience disease progression. Therefore, different strategies are needed to increase the response to treatment and quality of life. Strategies combining therapies directed to reduce the tumor's blood supply (targeted therapies) and therapies that increase the ability of the body to recognize and attack tumor cells (immunotherapy) have emerged as a way to increase the effectiveness obtained when using these drugs on their own. In this review, we discuss the current role of cabozantinib, a targeted therapy, in combination with immune-based agents in the treatment of advanced kidney and bladder cancers and go over future directions in the field.

BACKGROUND: There are limited data evaluating the activity of cabozantinib (CABO) as second line (2L) therapy post standard of care ipilimumab-nivolumab (IPI-NIVO) or immuno-oncology(IO)/vascular endothelial growth factor inhibitor (VEGFi) combinations (IOVE). MATERIALS AND METHODS: Using the IMDC database, we sought to identify the objective response rate, time to treatment failure (TTF) and overall survival (OS) of 2L CABO after IPI-NIVO, IOVE combinations, pazopanib or sunitinib (PAZ/SUN) or other first line (1L) therapies. Multivariable Cox regression, adjusted for underlying differences in IMDC groups, was used to compare differences in OS for 2L CABO based on preceding therapy. RESULTS: Three hundred and forty-six patients received 2L CABO (78 post IPI NIVO, 46 post IOVE, 161 post PAZ/SUN, 61 post Other). Of the entire cohort, 12.6%, 62.6%, and 24.8% were IMDC favourable, intermediate, and poor risk, respectively. Patients that received 1L IPI-NIVO had a median OS of 21.4 (95% CI, 12.1 - NE [Not evaluable]) months compared to 15.7 (95% CI, 9.3 - NE) months in 1L IOVE and 20.7 (95% CI, 15.6 - 35.6) months in 1L PAZ/SUN, P = .28. Median TTF from the initiation of 2L CABO in the overall population was 7.6 (95% CI, 6.6 - 9.0) months. We were unable to detect a significant difference in 2L CABO OS based on type of 1L therapy received: 1L IPI-NIVO (reference group) vs. 1L IOVE HR 1.73 (95% CI, 0.83 - 3.62 P = .14), 1L PAZ/SUN 1.16 (95% CI, 0.67 - 2.00 P = .60), however given the retrospective observational nature of this work a lack of sufficient power may contribute to this. CONCLUSION: In a large real world dataset, we identified clinically meaningful activity of 2L CABO after all evaluated contemporary 1L therapies, irrespective of whether the 1L regimen included a VEGFi. These are real world benchmarks with which to counsel our patients. ispartof: CLINICAL GENITOURINARY CANCER vol:21 issue:1 ispartof: location:United States status: published

Stereotactic body radiation therapy (SBRT) has been shown to be safe and effective for delaying systemic treatment change among patients with metastatic renal cell carcinoma (mRCC). In this study, we sought to assess the genomic signatures of patients with mRCC who underwent SBRT for oligoprogression. A total of 30 patients with oligoprogressive disease were identified, the majority of whom had clear cell renal cell carcinoma (83.3%) and were receiving first-line treatment (53.3%). Genomic and transcriptomic sequencing were available in 20 and 16 patients, respectively. Duration of systemic treatment (DOT) was categorized as that prior (DOT[P]) and subsequent (DOT[S]) to radiation treatment. The median DOT(P) and DOT(S) were 15.1 and 18.3 mo, respectively, with a median DOT(S)/DOT(P) ratio of 1.4. Patients who had a DOT(S)/DOT(P) ratio of ≥1 had increased expression in pathways related to cell proliferation and development. In contrast, among patients with a ratio of ≤1, the reactive oxygen species pathway was enriched. This study highlights the potential role of genomics and transcriptomics to refine radiation treatment selection in patients with mRCC. PATIENT SUMMARY: In this study, we looked at mutations and genomic expressions among kidney cancer patients who responded better to stereotactic body radiotherapy. We found that enriched expression of certain pathways might play a role in response to radiotherapy.

The association between tobacco use and urothelial cancer of the bladder is well known. Given the worsening tobacco epidemic, here we make the case for systematic targeted points of intervention for urologists and other professionals to intervene against bladder cancer. Awareness of contemporary checkpoints where we can intervene for counseling patients may help medical education in a tobacco-pandemic difficult setting.

Context Bladder and kidney cancers require invasive procedures for definitive diagnosis, and bladder cancer requires repeated procedures to monitor for disease recurrence. Given the recent work to identify molecular alterations in liquid biopsies to diagnose and monitor these diseases, a synthesis of the growing body of evidence is merited. Objective To review current data on cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) and to synthesize their roles in the diagnosis, monitoring, and prognostication of bladder and kidney cancer. Evidence acquisition A literature review was conducted through August 15, 2020 including prospective and retrospective studies. Keywords included “cell-free DNA”, “circulating tumor DNA”, “kidney cancer”, “renal cell carcinoma”, “bladder cancer”, “upper tract urothelial carcinoma”, and “urothelial carcinoma”. Evidence synthesis Urine tumor DNA (utDNA) has sensitivity of 91% and specificity of 96% for detecting bladder cancer, outperforming cystoscopy and cytology. Increased utDNA and ctDNA are associated with progression from non–muscle-invasive to muscle-invasive disease. In patients undergoing cystectomy, ctDNA detection is associated with worse overall survival and disease recurrence, and with persistent tumor on surgical pathology in those who received neoadjuvant chemotherapy. cfDNA is significantly higher in patients with kidney cancer than in healthy controls or in those with benign lesions, and detectable ctDNA and increased cfDNA are associated with decreased survival. Conclusions Combined data from small studies provide evidence that cfDNA and ctDNA may have the ability to detect, monitor, and prognosticate in patients with bladder, upper tract urothelial, and kidney cancers. Patient summary In this review, we looked at the work that has been published so far on cell-free and circulating tumor DNA in bladder and kidney cancers. We found that while many of the studies were small, there is evidence that cell-free tumor DNA can emerge as a tool for the diagnosis and monitoring of treatment response for patients with these cancers.

BackgroundPatients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have a poor prognosis and limited therapeutic options. First-line nivolumab plus ipilimumab (NIVO+IPI) provided efficacy benefits over sunitinib (SUN) in patients with intermediate/poor-risk sRCC at 42 months minimum follow-up in the phase 3 CheckMate 214 trial. In this exploratory post hoc analysis, we report clinical efficacy of NIVO+IPI in sRCC after a minimum follow-up of 5 years.MethodsIn CheckMate 214, patients with clear cell advanced RCC were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg every 3 weeks (four doses), then NIVO 3 mg/kg every 2 weeks versus SUN 50 mg once daily (4 weeks; 6-week cycles). Randomized patients with sRCC were identified via independent central pathology review of archival tumor tissue or histological classification per local pathology report. Overall survival (OS), as well as progression-free survival (PFS) and objective response rate (ORR) per independent radiology review using Response Evaluation Criteria in Solid Tumors V.1.1, were evaluated in all International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk sRCC patients and by baseline tumor PD-L1 expression level (≥1% vs ResultsIn total, 139 patients with intermediate/poor-risk sRCC were identified (NIVO+IPI, n=74; SUN, n=65). At 5 years minimum follow-up, more patients remained on treatment with NIVO+IPI versus SUN (12% vs zero). Efficacy benefits with NIVO+IPI versus SUN were maintained with median OS of 48.6 vs 14.2 months (HR 0.46), median PFS of 26.5 vs 5.5 months (HR 0.50), and ORR 60.8% vs 23.1%. In addition, median duration of response was longer (not reached vs 25.1 months), and more patients had complete responses (23.0% vs 6.2%) with NIVO+IPI versus SUN, respectively. Efficacy was better with NIVO+IPI versus SUN regardless of tumor PD-L1 expression, but the magnitude of OS, PFS, and ORR benefits with NIVO+IPI was greater for sRCC patients with tumor PD-L1 ≥1%. No new safety signals emerged in either arm with longer follow-up.ConclusionsAmong patients with intermediate/poor-risk sRCC, NIVO+IPI maintained long-term survival benefits and demonstrated durable and deep responses over SUN at minimum follow-up of 5 years, supporting NIVO+IPI as a preferred first-line therapy in this population.Trial registration numberNCT02231749.

Background Genomic testing of somatic and germline DNA has transformed cancer care. However, low genetic knowledge among patients may compromise care and health outcomes. Given the rise in genomic testing, we sought to understand patients’ knowledge of their genetic test results. Materials and Methods We conducted a survey‐based study with 85 patients at a comprehensive cancer center. We compared self‐reported recall of (a) having had somatic/germline testing and (b) their specific somatic/germline results to the genomic test results documented in the medical record. Results Approximately 30% of patients did not recall having had testing. Of those who recalled having testing, 44% of patients with pathogenic/likely pathogenic germline mutations and 57% of patients with reported somatic alterations did not accurately recall their specific gene or variant‐level results. Conclusion Given significant knowledge gaps in patients’ recall of genomic testing, there is a critical need to improve patient‐directed education and return‐of‐results strategies., Considering the increase in genomic testing for cancer care, this study aimed to better understand patients’ knowledge of their genetic test results.

BRCA1-mutated prostate cancer has been shown to be less responsive to poly (ADP-ribose) polymerase (PARP) inhibitors as compared to BRCA2-mutated prostate cancer. The reason for this differential response is not clear. We hypothesized this differential sensitivity to PARP inhibitors may be explained by distinct genomic landscapes of BRCA1 versus BRCA2 co-segregating genes. In a large dataset of 7,707 men with advanced prostate cancer undergoing comprehensive genomic profiling (CGP) of cell-free DNA (cfDNA), 614 men harbored BRCA1 and/or BRCA2 alterations. Differences in the genomic landscape of co-segregating genes was investigated by Fisher’s exact test and probabilistic graphical models (PGMs). Results demonstrated that BRCA1 was significantly associated with six other genes, while BRCA2 was not significantly associated with any gene. These findings suggest BRCA2 may be the main driver mutation, while BRCA1 mutations tend to co-segregate with mutations in other molecular pathways contributing to prostate cancer progression. These hypothesis-generating data may explain the differential response to PARP inhibition and guide towards the development of combinatorial drug regimens in those with BRCA1 mutation.

Background In phase III TIVO-3 trial, tivozanib improved progression-free survival (PFS) compared to sorafenib for patients with metastatic renal cell carcinoma (mRCC). However, the effectiveness of this drug after exposure to other selective VEGFR agents has not yet been defined. Herein, we characterize the clinical efficacy of tivozanib in patients with mRCC previously treated with axitinib. Methods We identified patients from the intention to treat (ITT) population, in the TIVO-3 trial, who received treatment with axitinib before enrolment in the study and evaluated PFS, response rate (RR), and safety. Results Out of 350 patients, 172 (83:89, tivozanib:sorafenib) had received prior treatment with axitinib in TIVO-3. In this subgroup, PFS was 5.5 months with tivozanib and 3.7 months with sorafenib (HR 0.68). RR was 13% and 8% favoring tivozanib. Conclusions Tivozanib is active in the treatment of patients with mRCC who have progressed on prior therapies, including axitinib.

In less than 5years immune checkpoint inhibitors (ICI) went from first FDA approval to become first-line options in advanced renal cell carcinoma. Despite that many patients have benefited from ICI, a significant fraction of individuals are refractory to these new immunological treatments. In this review, we discussed using intratumoral (i.t.) route of drug administration as an alternative to systemic therapy to increase the response rates and to circumvent potential drug-induced systemic adverse events. We provided a historic account of i.t. drug treatments in cancer and reviewed the contemporary experience in local drug delivery. We discussed the potential for enhancing the therapeutic impact of ICI by leveraging hydrogels as drug delivery vehicles and presented an outlook for implementing i.t. in renal cell carcinoma.

5068 Background: Anti-PD-1/PD-L1 immune-checkpoint inhibitors (ICI) are now a standard of care in metastatic renal cell carcinoma (mRCC). Older adults were underrepresented in registration trials and given that immunological senescence may affect the anti-tumor activity of ICIs, there is uncertainty about the efficacy of ICIs in this population. Here we provide real world data on outcomes of older adults with mRCC treated with ICIs. Methods: Patients with mRCC treated with a PD-1/PD-L1 ICI either as monotherapy or as a combination treatment from 2000 to 2019 were included. Older adult was defined as ≥ 70-years at the time of ICI treatment. Descriptive statistics were summarized in means, medians and proportions. Efficacy was assessed by survival analysis, including overall survival (OS), time to treatment failure (TTF), and overall response rate (ORR). Multivariate analyses adjusted for imbalances in IMDC risk factors. P < 0.05 was considered statistically significant. Results: Of 1427 patients, 397 (28%) were older adults. Mean age of older vs. younger adults was 74 (70-92) vs. 60 (22-69) years. Groups were comparable in terms of gender (Female 28.5% vs. 26.1%, p = 0.36), rates of nephrectomy (21% vs. 18.3%, p = 0.24) and presence of sarcomatoid features (12.3% vs. 17.8%, p = 0.14). Proportion of IMDC risk-groups between older vs. younger adults were as follows: 15.4% vs. 18.2% for favorable, 61.2% vs. 59.1% for intermediate, and 23.4% vs. 22.7% for poor; there was no statistical difference (p = 0.55). ICI was used as 1st line in 40%, 2nd line in 48.5% and 3rd line in 11.5% patients; older adults were less likely to be treated with ICI in 1st line (32.2% vs. 43%, p < 0.01). In terms of survival, older adults had poorer median OS (25.1m vs. 30.8m, p < 0.01) but similar median TTF (6.9m vs. 6.9m, p = 0.40) compared to younger adults. In multivariate analyses, older age was not a predictor of either worse OS (aHR = 1.02, p = 0.86) or TTF (aHR = 0.95, p = 0.59). Older adults had a lower ORR compared to younger (24% vs. 31%, p = 0.01), which was mainly driven by responses in 1st line (31% vs. 44%, p = 0.02) and not observed in 2nd/3rd line (20% vs. 20%, p = 0.86). Conclusions: On multivariate analyses, older adults with mRCC treated with ICI had no difference in OS and TTF when compared to younger adults, despite having lower ORR in 1st line. Our data supports that older age is not an independent risk factor for survival; thus, treatment selection should not be based solely on chronological age.

Background The use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively. Objective To evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC. Design, setting, and participants IMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab. Intervention Patients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy. Outcome measurements and statistical analysis The secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods. Results and limitations Fifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19–37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6–13.7) mo. The median event follow-up duration was 19.4 (12.9–21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors. Conclusions The atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC. Patient summary Patients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.

OBJECTIVE Emotional problem-related distress is a common issue faced by patients with cancer. However, patients suffering with this emotional burden do not typically seek assistance. This study sought to determine the prevalence of emotional problem-related distress by cancer type, and identify factors correlated with the level of assistance requested. METHODS Using the SupportScreen®, patients were screened for emotional problem-related distress at their first or second visit to an NCI designated Comprehensive Cancer Center. General Linear Model was used to test the association between emotional problem-related distress and type of cancer, and the relationship between level of assistance requested and patients' characteristics. RESULTS A total of 2,421 patients were included in this analysis. Patients were mostly female (62%), diagnosed with breast (24%), gynecological (16%) or gastrointestinal (15%) cancers. Highest levels of emotional problem-related distress were reported by patients diagnosed with lung, gynecological, breast and gastrointestinal cancers. Level of assistance requested were significantly associated with problem-related distress scores (p

Context Bladder urothelial carcinoma (BUC) and upper tract urothelial carcinoma (UTUC) have genetic differences, which may influence therapy. Objective The aim of the current review was to summarize the current genetic understanding of upper tract and BUC. Evidence acquisition PubMed, Cochrane, and Web of Science online databases were searched systematically up to February 2020, using the following keywords: urothelial carcinomas, upper urinary tract, renal pelvis, ureter, bladder cancer, and genetics. Evidence synthesis UTUC and BUC share mutations in similar genes, such as FGFR3, TP53, and HRAS, and epigenetic genes, such as KDM6A and KMT2A-C, but at varying frequencies. Furthermore, subtyping of UTUC and BUC has identified similar expression subtypes, but UTUC is more often luminal with more T-cell depletion. Clonal studies indicate that BUC after UTUC is also likely luminal, while UTUC after BUC is often basal. Conclusions UTUC and BUC share many genomic alterations, but at different frequencies, which recapitulate with their metachronous recurrences. These differences likely contribute to the behavior of these two cancers and imply that they and their metachronous recurrences should be treated as two related yet distinct entities. Patient summary Urothelial carcinoma of the bladder has distinct genomic features, which are different from distinct genomic features of urothelial carcinoma of the renal pelvis and/or ureter. These features can be used for tailored treatment options specific to tumors of different locations.

Although predominantly urothelial, some bladder cancer and upper tract urothelial cancer (BC/UTUC) harbor histologic variants. Small cell BC (SCBC) variants comprised ˜5% of The Cancer Genome Atlas BC cohort, with a poor prognosis. We describe genomic profiles of BC/UTUC with small cell/neuroendocrine features identified in the Foundation Medicine database from June 2012 to September 2018. Of 3368 BC/UTUC samples, 3.92% (132) harbored small cell/neuroendocrine features by immunohistochemistry. Mutations were noted in: TP53 (92%), RB1 (75%), combined TP53/RB1 (72%), and TERT promoter (68%). Of the samples, 6.5% had TMB ≥ 10 mutations/Mb. RNA expression profiling of 24 pure SCBC and 51 urothelial BC (UBC) muscle-invasive samples evaluated from a separate cohort revealed a large number of differentially expressed genes with suppression of several inflammatory pathways in SCBC compared with UBC. This largest reported SCBC dataset to date confirms enrichment of signatures in SCBC similar to small cell lung cancer and describes unique gene expression compared with UBC. These findings may explain aggressive SCBC phenotype. Patient summary Small cell bladder cancer (SCBC) is an aggressive subtype that microscopically resembles aggressive small cell lung cancer (SCLC). This study confirms that SCBC shares DNA changes similar to SCLC and that SCBC expresses many genes that urothelial bladder cancer does not, possibly explaining aggressive SCBC activity.

SummaryTAS0728 is an oral covalent binding inhibitor of human epidermal growth factor receptor 2 (HER2). A first-in-human open-label, dose-escalation, phase I study (NCT03410927) was initiated to investigate the safety and dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) and/or recommended phase II dose of TAS0728 in adults with advanced solid tumors with HER2 or HER3 overexpression, amplification or mutation. In total, 19 patients received TAS0728 at escalating doses from 50 to 200 mg BID for 21-day cycles. Following escalation of the dose to 200 mg BID, a total of two DLTs were observed, both cases of Grade 3 diarrhea (lasting >48 h and not responsive to aggressive antidiarrheal treatment). Following de-escalation of the dose to 150 mg BID, another DLT of Grade 3 diarrhea was observed in one patient. Additionally, at 150 mg BID, one patient had a fatal cardiac arrest after receiving 1 cycle (21 days) of TAS0728. The etiology of the cardiac arrest event was not clear, however causal relationship to TAS0728 could not be excluded due to the temporal association observed. Partial responses were observed in 2 of 14 patients evaluable for TAS0728 treatment response. The study was stopped due to unacceptable toxicity during the dose-escalation as the overall risk-benefit ratio no longer favored the dose level being tested, therefore the MTD was not determined. ClinicalTrials.gov registration number: https://clinicaltrials.gov/ct2/show/NCT03410927; registered on January 25, 2018.

Background Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature. Methods This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival. Results Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST. Conclusions AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.

In recent years, incredible progress has been made in the treatment of metastatic renal cell carcinoma, with a paradigm shift from the use of cytokines to tyrosine kinase inhibitors, and more recently, immune checkpoint inhibitors (ICIs). Despite advances in the metastatic setting, effective therapies in the adjuvant setting are a largely unmet need. Currently, sunitinib (Sutent, Pfizer) is the only therapy for the adjuvant treatment of RCC included in the National Comprehensive Cancer Network guidelines, which was approved by the FDA based on the improvement in disease-free survival (DFS) seen in the S-TRAC trial. However, improvement in DFS has not translated into an overall survival (OS) benefit for patients at high-risk of relapse post-nephrectomy, illustrating the need for more effective therapies. This manuscript will highlight attributes of both historical and current drug trials and their implications on the landscape of adjuvant therapy. Additionally, we will outline strategies for selecting patients in whom treatment would be most beneficial, as optimal patient selection is a crucial step towards improving outcomes in the adjuvant setting. This is especially critical, given the financial cost and pharmacological toxicity of therapeutic agents. Furthermore, we will review the design of clinical trials including the value of utilizing OS as an endpoint over DFS. Finally, we will discuss how the incorporation of genomic data into predictive models, the use of more sensitive imaging modalities for more accurate staging, and more extensive surgical intervention involving lymph node dissection, may impact outcomes.

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.

Emerging efficacy data have led to the emergency use authorization or approval of COVID-19 vaccines in several countries worldwide. Most trials of COVID-19 vaccines excluded patients with active malignancies, and thus data on the safety, tolerability and efficacy of the vaccines in patients with cancer are currently limited. Given the risk posed by the COVID-19 pandemic, decisions regarding the use of vaccines against COVID-19 in patients participating in trials of investigational anticancer therapies need to be addressed promptly. Patients should not have to choose between enrolling on oncology clinical trials and receiving a COVID-19 vaccine. Clinical trial sponsors, investigators and treating physicians need operational guidance on COVID-19 vaccination for patients with cancer who are currently enrolled or might seek to enrol in clinical trials. Considering the high morbidity and mortality from COVID-19 in patients with cancer, the benefits of vaccination are likely to far outweigh the risks of vaccine-related adverse events. Herein, we provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials. In our perspective, continued quality oncological care requires that patients with cancer, including those involved in trials, be prioritized for COVID-19 vaccination, which should not affect trial eligibility., Patients with cancer have a high risk of morbidity and mortality from COVID-19. The rapid development of COVID-19 vaccines has provided new hope of mitigating the disease. Herein, the COVID19 and Cancer Clinical Trials Working Group calls for prioritization of patients with cancer, importantly including those participating in oncology clinical trials, for COVID-19 vaccination. The authors also provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials.

Purpose: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC. Patients and Methods: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics. Results: Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3–22.9); n = 65; HR, 0.45 (95% CI, 0.3–0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33–0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged. Conclusions: NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population. See related commentary by Hwang et al., p. 5

Background Cabozantinib is approved for metastatic renal cell carcinoma (mRCC) based on the METEOR and CABOSUN trials. However, real‐world effectiveness and dosing patterns of cabozantinib are not well characterized. Methods Patients with mRCC treated with cabozantinib between 2011 and 2019 were identified and stratified using the International mRCC Database Consortium (IMDC) risk groups. First‐ (1L), second‐ (2L), third‐ (3L), and fourth‐line (4L) overall response rate (ORR), time to treatment failure (TTF), and overall survival (OS) were analyzed. Dose reduction rates and their association with TTF and OS were determined. Results A total of 413 patients were identified. The ORRs across 1L to 4L were 32%, 26%, 25%, and 29%, respectively, and the median TTF rates were 8.3, 7.3, 7.0, and 8.0 months, respectively. The median OS (mOS) rates in 1L to 4L were 30.7, 17.8, 12.6, and 14.9 months, respectively. For patients treated with 1L PD(L)1 combination agent (n = 31), 2L cabozantinib had ORR of 22%, median TTF of 5.4 months, and mOS of 17.4 months. About 50% (129/258) of patients required dose reductions. The TTF and mOS were significantly longer for patients who required dose reduction vs. patients who did not, with an adjusted hazard ratio of 0.37 (95% CI 0.202–0.672, p, Cabozantinib demonstrates activity for use in real‐world patients with metastatic renal cell carcinoma across the first‐ to fourth‐line treatment settings.

This commentary highlights the potential relevance of including patient-reported outcomes in early phase trials and the barriers to such inclusion.

Over the last decade, the treatment paradigm of metastatic renal cell carcinoma has rapidly evolved, with notable changes in the front-line setting. Combination therapies involving the use of either doublet therapy with immune checkpoint inhibitors or combination VEGFR-directed therapies with immune checkpoint inhibitors have significantly improved clinical outcomes, including prolonged overall survival and durable response to treatment. We aim to highlight the Food and Drug Administration-approved front-line therapy options, the navigation of treatment selection, and the future directions of metastatic renal cell carcinoma therapies.

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.

PURPOSE Evidence-based somatic and germline sequencing has transformed cancer care and improves patient outcomes. However, patients’ low genetic literacy and misunderstanding of their own genomic results poses a threat to the realization of precision oncology. To optimize patient genomic comprehension, we developed a Web-based, patient-directed, genomic sequencing education and return-of-results tool, HOPE-Genomics. METHODS The HOPE-Genomics prototype included somatic and germline sequencing results, embedded multimedia genomic education, and interactive features (eg, request for genetic counseling). Between January and April 2018, we elicited feedback on tool usability and comprehensiveness through participant surveys, 4 focus groups of patients with cancer and their family members, and 3 provider focus groups (comprising 8 patients, 5 family members, and 19 providers). RESULTS We identified themes in patient/family tool-related responses, including the desire to view a patient-friendly report, a desire to receive multiple types of genomic information (eg, prognostic and uncertain), high acceptability of report content, and interest in tool-enabled access to genetic counseling. Major themes from the clinician focus groups included believing the tool could help patients formulate questions and facilitate patients’ communication of results to family members. However, there were diverse responses from all participants in terms of tool implementation (ie, timing and nature of report release). Some participants preferred report release before meeting with the provider, and others preferred it during the appointment. Additionally, some clinicians were concerned about providing prognostic and treatment information through the tool. CONCLUSION There was high acceptability and interest from patients, family members, and providers in a patient-directed genomics report. Future work will determine whether direct-to-patient reporting of genomic results improves patient knowledge, care engagement, and compliance with genomically guided interventions.

PURPOSE: Patients with cancer commonly report distress and fear of cancer recurrence (FCR) impacting quality of life and clinical outcomes. This study aims to test the association between emotional well-being and clinical characteristics of survivors with localized renal cell carcinoma (RCC). MATERIALS AND METHODS: Survivors with localized RCC were invited to participate in this study through social media by the Kidney Cancer Research Alliance. Participants self-reported clinical characteristics, distress (Distress Thermometer), and FCR (Fear of Cancer Recurrence-7). Ordinal regression was used to test the association between emotional well-being and patient characteristics. RESULTS: A total of 412 survivors were included in this analysis. Participants were mostly female (79.4%) and well educated (58.3%), with a median age of 54 years (range, 30-80 years) and median time since diagnosis of 17.5 months. More than one half were diagnosed with stage I disease (56.1%). Most patients (62.3%) had a clear understanding of their diagnosis. A high prevalence of moderate to severe distress (67.0%) and FCR (54.9%) was reported across all survivors of RCC. Higher FCR was associated with female gender, younger age, and lack of understanding of their diagnosis ( P = .001), whereas more recent diagnosis was associated with higher distress levels ( P = .01). CONCLUSION: Our findings suggest that FCR is a common problem that is persistent after therapy and that certain individuals, including female and younger patients, may be at particular risk of experiencing clinically relevant FCR.

Studies suggest a link between the gut microbiome and metastatic renal cell carcinoma (mRCC) outcomes, including evidence that mRCC patients possess a lower abundance of Bifidobacterium spp. compared to healthy adults. We sought to assess if a Bifidobacterium‐containing yogurt product could modulate the gut microbiome and clinical outcome from vascular endothelial growth factor‐tyrosine kinase inhibitors (VEGF‐TKIs). mRCC patients initiating VEGF‐TKIs, regardless of the line of therapy, were randomized to probiotic‐supplemented (two 4 oz. servings of the probiotic yogurt product daily) or probiotic‐restricted arms. Stool samples were collected prior to therapy and at weeks 2, 3, 4, and 12. Microbiome composition was assessed using whole‐metagenome sequencing. A total of 20 patients were randomized. Bifidobacterium animalis, the active ingredient of the probiotic supplement, reached detectable levels in all patients in the probiotic‐supplemented arm versus two patients in the probiotic‐restricted arm. Clinical benefit rate was similar in probiotic‐supplemented versus probiotic‐restricted arms (70% vs. 80%, p = 0.606). Linear discriminant analysis (LDA) effect size analysis of MetaPhIAn2 abundance data predicted 25 enriched species demonstrating an LDA score >3 in either clinical benefit or no clinical benefit. In patients with clinical benefit (vs. no clinical benefit), Barnesiella intestinihominis and Akkermansia muciniphila were significantly more abundant (p = 7.4 × 10−6 and p = 5.6 × 10−3, respectively). This is the first prospective randomized study demonstrating modulation of the gut microbiome with a probiotic in mRCC. Probiotic supplementation successfully increased the Bifidobacterium spp. levels. Analysis of longitudinal stool specimens identified an association between B. intestinihominis, A. muciniphila, and clinical benefit with therapy. Trial Registration: NCT02944617, Our study provides novel evidence regarding gut microbiome modulation with a Bifidobacterium‐containing yogurt in metastatic renal cell carcinoma patients receiving targeted therapies and specifies the microbiota members (Barnesiella intestinihominis, Akkermansia muciniphila) associated with clinical benefit from targeted therapies in mRCC.

BACKGROUND Patient-reported outcomes have been used to assess treatment effectiveness and actively engage patients in their disease management. This study was designed to describe the patient-reported performance status (PS) and the provider-reported PS. METHODS Patients with metastatic genitourinary cancers were recruited from a single cancer center before the initiation of a new line of treatment. PS (Eastern Cooperative Oncology Group [ECOG]), quality of life (Functional Assessment of Chronic Illness Therapy-General), and distress (Patient-Reported Outcomes Measurement Information System Anxiety and Depression) were self-reported by patients. Clinical data (eg, age, sex, diagnosis, and physician-reported ECOG PS) were extracted from medical records. Multivariate analysis was used to determine the association between PS, quality of life, and psychological symptoms. RESULTS One hundred forty-five patients were enrolled (76.6% male, 70.3% White, 81.4% married, and 76.6% well educated). The median age was 67 years; 66.9% were diagnosed with renal cell carcinoma, 20.0% were diagnosed with urothelial carcinoma, and 13.1% were diagnosed with prostate cancer. Clinicians more frequently classified patients' ECOG PS as 0 in comparison with the patients themselves (92.4% vs 64.1%; P = .001). Higher clinician-reported ECOG PS was associated with poorer physical and functional well-being and higher rates of depression (P < .01), whereas higher patient-reported ECOG PS was associated with worse psychosocial outcomes (P < .01). CONCLUSIONS Discrepancies were noted between the patient- and provider-reported ECOG PS, with clinicians overestimating the ECOG PS in comparison with the patients themselves. This study's findings suggest that patients incorporate their social and emotional well-being into their PS score in addition to their physical well-being. This information is not immediately accessible to most clinicians from just a standard patient interview and likely accounts for the overestimation of the patients' ECOG PS by the clinicians.

Precision medicine approaches for managing patients with metastatic castrate-resistant prostate cancer (mCRPC) are lacking. Non-invasive approaches for molecular monitoring of disease are urgently needed, especially for patients suffering from bone metastases for whom tissue biopsy is challenging. Here we utilized baseline blood samples to identify mCRPC patients most likely to benefit from abiraterone plus prednisone (AAP) or enzalutamide. Baseline blood samples were collected for circulating tumor cell (CTC) enumeration and qPCR-based gene expression analysis from 51 men with mCRPC beginning treatment with abiraterone or enzalutamide. Of 51 patients (median age 68 years [51–82]), 22 received AAP (abiraterone 1000 mg/day plus prednisone 10 mg/day) and 29 received enzalutamide (160 mg/day). The cohort was randomly divided into training (n = 37) and test (n = 14) sets. Baseline clinical variables (Gleason score, PSA, testosterone, and hemoglobin), CTC count, and qPCR-based gene expression data for 141 genes/isoforms in CTC-enriched blood were analyzed with respect to overall survival (OS). Genes with expression most associated with OS included MSLN, ARG2, FGF8, KLK3, ESRP2, NPR3, CCND1, and WNT5A. Using a Cox-elastic net model for our test set, the 8-gene expression signature had a c-index of 0.87 (95% CI [0.80, 0.94]) and was more strongly associated with OS than clinical variables or CTC count alone, or a combination of the three variables. For patients with a low-risk vs. high-risk gene expression signature, median OS was not reached vs. 18 months, respectively (HR 5.32 [1.91–14.80], p = 0.001). For the subset of 41 patients for whom progression-free survival (PFS) data was available, the median PFS for patients with a low-risk vs high-risk gene expression signature was 20 vs. 5 months, respectively (HR 2.95 [1.46–5.98], p = 0.003). If validated in a larger prospective study, this test may predict patients most likely to benefit from second-generation antiandrogen therapy.

Preclinical models and early clinical data suggest an interplay between the gut microbiome and response to immunotherapy in solid tumors including metastatic renal cell carcinoma (mRCC). We sought to characterize the stool microbiome of mRCC patients receiving a checkpoint inhibitor (CPI) and to assess treatment-related changes in microbiome composition over the course of CPI therapy. Stool was collected from 31 patients before initiation of nivolumab (77%) or nivolumab plus ipilimumab (23%) therapy, of whom 58% experienced clinical benefit. Greater microbial diversity was associated with clinical benefit from CPI therapy (p = 0.001), and multiple species were associated with clinical benefit or lack thereof. Temporal profiling of the microbiome indicated that the relative abundance of Akkermansia muciniphila increased in patients deriving clinical benefit from CPIs. This study substantiates results from previous CPI-related microbiome profiling studies in mRCC. Temporal changes in microbiome composition suggest potential utility in modulating the microbiome for more successful CPI outcomes. Patient summary We compared the composition and diversity of the gut microbiome in patients receiving immunotherapy for renal cell carcinoma. We found that higher microbial diversity is associated with better treatment outcomes. Treatment response is characterized by changes in microbial species over the course of treatment.

BACKGROUND: No study to date has assessed the relationship between treatment-specific therapeutic outcomes and race/ethnicity in metastatic renal cell carcinoma (mRCC). As targeted therapies have formed the backbone of first-line treatment options for mRCC until very recently, we assessed the relationship between race/ethnicity and targeted therapy-related outcomes in mRCC. OBJECTIVE: To retrospectively compare response rates and survival outcomes across ethnicities in patients who received first-line targeted therapies for mRCC. METHODS: Patients with mRCC receiving a first-line targeted therapy were identified from an institutional database encompassing consecutive patients treated between 2009 and 2019. Patient demographics, clinical characteristics and survival outcomes were recorded. The racial/ethnic groups included for analysis were Caucasian American, Hispanic American, and Asian American. Survival and response outcomes including progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) were calculated and compared across ethnic groups using Kaplan-Meier method and Chi-square test, respectively. RESULTS: In total, 295 patients were included for analysis. There were 184 (62.4%) Caucasian American patients, 82 (27.8%) Hispanic American patients, and 29 (9.8%) Asian American patients. No statistically significant differences in PFS nor OS were found between groups (PFS: 5.6 vs. 4.7 vs. 4.7 months, respectively) (OS: 32 vs. 31.7 vs. 51.7 months, respectively). No significant difference was found in ORR nor DCR across groups. Univariate cox regression analyses demonstrated no independent effect of race/ethnicity on PFS or OS. CONCLUSIONS: The apparent lack of differences in treatment-related outcomes across racial/ethnic groups is encouraging. However, further validation is required in larger series.

LAY SUMMARY Despite longer survival with immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1), metastatic urothelial carcinoma remains lethal. There is an unmet need to further improve the efficacy of these agents. In their phase 2 trial, Zhang et al. evaluated the combination of pembrolizumab (a PD-1 inhibitor) plus acalabrutinib (a novel agent inhibiting an enzyme considered relevant to immunotherapy resistance) based on strong rationale but did not demonstrate clinical benefit compared with pembrolizumab alone. Future trials that examine such promising rational combinations may be able to evaluate selected patients based on validated biomarkers to optimize benefit in an endless pursuit of personalizing therapies.

In an era of several therapeutic options available, optimal treatment sequencing is crucial to providing patients the most effective therapy and promoting quality of life. In clear cell renal cell carcinoma, a combination approach with an immunotherapy backbone, such as nivolumab/ipilimumab or axitinib/pembrolizumab, has a key role in the first-line setting. Safety and activity data support the transition to single-agent targeted therapies in the second-line setting. Nivolumab monotherapy possesses clinical and mechanistic rationale as a second-line therapeutic option for patients treated with targeted therapies in the first-line setting. Gene expression models are being generated from large prospective clinical trial data sets.

The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis.Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1-positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population.Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490-0.777]}; one-sided P0.0001; median 13.8 (95% CI 10.1-20.7) versus 7.0 months (95% CI 5.7-9.6); overall population: HR 0.69 (95% CI 0.574-0.825); one-sided P0.0001; median 13.3 (95% CI 11.1-15.3) versus 8.0 months (95% CI 6.7-9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596-1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616-1.027); one-sided P = 0.0392].Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature.NCT02684006.

Intra- and inter-tumor heterogeneity (TMH) among colorectal cancer patients is considered as major hurdles to develop precise, potent, and personalized cancer therapeutics. The discernible factors that contribute to the existence of TMH and associated problems are suggested as genetic, molecular, epigenetic, and environmental pressures including shifts in trend from high-fiber diet to high-fat/processed sugar diet. In essence, components of high fat/processed sugar diet potentiate metabolic re-programing of inherent cellular heterogeneity of cancer stem cells (CSCs) by genetic and epigenetic pathways intersected by the farnesoid X receptor (FXR) nuclear receptor. Therefore, choices of dietary components shape up protumor or antitumor microenvironment by the modulation of FXR regulated transcriptional and epigenetic events in CSCs. In this article, we highlight the major understanding emanated from preclinical and clinical studies that indicate the potential contribution of high fiber/saturated sugar diet toward carcinogenesis of colorectal cancer.

BACKGROUND: Twitter has emerged as an important platform for conversation surrounding cancer-related topics. As use has proliferated, a better classification of physicians engaging in cancer discussions on Twitter is warranted. OBJECTIVES: To better characterize the medical specialists involved in disseminating kidney cancer information on social media through academic and Twitter metrics. METHODS: Clinical practitioners with an expertise in kidney cancer were identified. Demographics, metrics of academic rank and productivity, and Twitter usage data were collected. Correlations were calculated for the generation of a model predictive of the number of Twitter followers. Analysis of the experts’ Twitter content was performed. RESULTS: Among 59 kidney cancer experts identified, 14 (23.7%) were assistant professors, 24 (40.7%) were associate professors, and 21 (35.6%) were full professors. A total of 5424 tweets were analyzed, 86% of which were medically-related. We identified several differences between academic rank and Twitter variables. Associate professors registered a greater median number of followers subscribed to their Twitter accounts (2360) versus assistant professors (1253) and full professors (934) (p = 0.03) and a greater median number of accounts they themselves followed (752 vs. 290 vs. 235, respectively; p = 0.0009). Use of a more generalized approach (ANCOVA) showed that the most predictive variables for the number of followers are number of tweets, H-index, and percentage of medical tweets (R2 = 0.70). CONCLUSIONS: This study supported correlations between metrics of academic and Twitter activity. The generation of a model to predict the number of followers on Twitter is novel – future work will validate this in other disease types.