bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world treatment patterns and sequencing for metastatic renal cell carcinoma (mRCC): Results from the Flatiron database.
Authors: George Saby , Faccone Jillian , Huo Stephen , Zhang Ying , Stwalley Brian , Hamilton Melissa , Le Trong Kim , Ejzykowicz Flavia
Published: March 2021

286

Background: RCC accounts for ~80%‒90% of all kidney cancers worldwide. The mRCC treatment landscape is rapidly changing with the approval of new therapies; data describing real-world (RW) treatment patterns and sequencing are limited. This study investigates the characteristics, treatment patterns, and sequencing for mRCC patients in the RW (December 2015‒May 2020) and post-dual immuno-oncology therapy (IO-IO) approval in the United States (April 2018‒May 2020). Methods: Adults diagnosed with mRCC between December 2015 and May 2020 were selected from the Flatiron electronic medical record database for this retrospective study. The study cohort was required to have ≥ 1 month of medical data from the initial mRCC diagnosis date (index date). We used descriptive statistics to analyze baseline patient characteristics, treatment patterns, and sequencing. Results: Of 3,524 patients with mRCC (overall cohort, December 2015–May 2020), most were male (68.5%) and had clear cell histology (68.2%). The median age at metastatic diagnosis was 68 years (range, 23–85) and the median follow-up from index date was 328 days. Based on IMDC risk score, 75.8% of patients were categorized as intermediate/poor risk and 23.2% as favorable risk (1% missing). Systemic therapy for RCC was initiated in 79.1% (N = 2788) of patients. The most common treatments for first-line (1L) therapy were tyrosine kinase inhibitor (TKI) monotherapy (mono; 56.4%), IO-IO (19.1%), IO-TKI (9.5%), IO mono (6.9%), and others (8.1%). Second-line (2L) therapy was received by 1303 patients; treatment sequences are presented in the table below. Among patients who received IO-based therapy in the 1L (N = 990), 11% were retreated with IO on any subsequent line. When stratified by clear cell and non-clear cell histology, similar treatment patterns and sequences were observed. Among patients who initiated 1L treatment post-April 2018 (N = 1395), the most common treatments for 1L therapy were IO-IO (36.9%) and TKI mono (32.7%). Among patients who received 2L treatment after initiating 1L post-April 2018 (N = 486), TKI mono followed by IO mono, and IO-IO followed by TKI mono were the most prescribed sequences (Table). Conclusions: Following approval of IO-based therapies for 1L, RW treatment patterns for mRCC are evolving; IO-IO has become the most common 1L therapy received by all patients initiating treatment for mRCC. [Table: see text]
Use of nivolumab (N) and cabozantinib (C) for treatment of the metastatic renal cell carcinoma (mRCC) in the Veneto region: Results of AMOUR study.
Authors: Maruzzo Marco , Bortolami Alberto , Palleschi Dario , Zivi Andrea , Nicodemo Maurizio , Sartori Donata , De Vivo Rocco , Zustovich Fable , Bimbatti Davide , Pastorelli Davide , Vultaggio Giuseppe Dione , Soraru' Mariella , Ballestrin Melissa , Zanchetta Giulia , Modonesi Caterina , Randisi Paola , Barile Carmen , Perri Gino , Basso Umberto , Zagonel Vittorina
Published: March 2021

290

Background: Second (2L) or third-line (3L) treatment options for mRCC have dramatically changed in the last years. The standard of care as per Italian Regulatory Agencies approvals is N or C. To date, there are no criteria for the choice between N and C, which both demonstrated OS gain in the pivotal trials. Methods: We planned a retrospective, real world analysis of the use of N and C as 2L and 3L treatment in 17 Oncology Units of Veneto Region. All consecutive patients (pts) with mRCC treated in advanced setting in 2017-2018 were included. Results: We identified 170 pts, 73% males, median age 68.4 years. All pts started a 2L treatment while only 59% received a 3L treatment. In our cohort, patients with NLR > 3 at treatment start had a shorter OS (43 vs 90 months (mos), p < 0.0001); IMDC classification maintained its prognostic role. In 2L, N was administrated in 108 pts (63%), C in 29 pts (17%); in 3L N was administrated in 42 pts (25%), C in 49 pts (29%). Reported oncologists’ reasons for 2L choice were: change of mechanism of action compared to first line (28%), response to previous TKI (21.2%), intolerance to TKI (17.6%), previous toxicity (12.9%), tumor burden (11.2%), age of the patient (4.1%). Median OS and PFS in 2L were 28.4 and 6.6 mos for N, 16.8 and 6.6 mos for 2L C. Median OS and PFS in 3L were 27 and 5.2 mos for N, 16.6 and 7.5 mos for C. 46 pts received the sequence of drugs N > C, 12 the opposite sequence C > N. Median OS for N > C vs C > N were 96.6 vs 36 mos (p > 0.0001); median PFS for both the sequences were similar at 5.7 mos (p = ns). The cost per patient of the sequence N > C is 51.606 € while for the sequence C > N is 31.480,00 €. Between the two sequences a cost effectiveness per month of survival analysis was performed: the cost per month of OS for the sequence N > C was 534,18 € while for the sequence C > N was 874,46 €, heavily higher. Conclusions: In our real-world setting cohort, most of the pts received N as 2L treatment and a minority received C. Outcome of single drug are superimposable to published literature. With the limits of the retrospective nature of the study, with a cost per month of OS lower a much longer OS, the sequence N > C appear to be a better treatment strategy.
Evaluation of germline genetic testing criteria in early-onset kidney cancer.
Authors: Truong Hong , Sheikh Rania , Kotecha Ritesh , Kemel Yelena , Khurram Aliya , Reisz Peter , Lenis Andrew Thomas , Joseph Vijai , Mandelker Diana , Lee Chung-Han , Feldman Darren R. , Voss Martin H , Coleman Jonathan , Russo Paul , Stadler Zsofia Kinga , Hakimi A. Ari , Motzer Robert J. , Offit Kenneth , Patil Sujata , Carlo Maria Isabel
Published: March 2021

296

Background: An estimated 5% of kidney cancers are associated with hereditary RCC syndromes. Current germline genetic testing guidelines for patients with kidney cancer were developed to identify carriers of known RCC-associated genes and have evolved in the panel-testing era. We evaluated the utility of the recent National Comprehensive Cancer Network (NCCN) recommendation of testing all patients with early-onset RCC (defined as age of diagnosis ≤ 46 years) for germline variants in genes implicated in hereditary RCC syndromes. Methods: We retrospectively identified patients with RCC diagnosed at age ≤ 46 years who underwent targeted germline testing at our institution through referral to clinical genetics service (n = 68, 29%) or through broad germline testing of ≥77 cancer susceptibility genes using next generation sequencing as part of a prospective matched tumor-normal genomic profiling initiative (n = 165, 71%). Diagnostic performance of referral criteria was assessed by the presence of pathogenic/likely pathogenic (P/LP) germline variants in RCC-associated genes and incidental cancer susceptibility genes. Results: Of 233 patients, 61% were male, 74% were Caucasian, 15% had family history of RCC, 15% had RCC-syndromic features, including 9% with multifocal renal tumors. Most patients (54%) had clear cell RCC (ccRCC). P/LP germline variants were identified in 42 (18%) patients but only 21 (9%) had mutations in RCC genes (12 FH, 4 VHL, 2 SDHB, 1 each in BAP1, TSC1, and FLCN). All 21 early-onset patients with germline variants in an RCC-associated gene also had one of the following risk factors: non-ccRCC histology, family history, or syndromic features. In 91 patients (39%) with a non-RCC germline variants or no alteration, none of these three risk factors were found. Of 21 patients with non-RCC P/LP germline variants, 9 had mutations in moderate/high penetrance genes ( BRCA1 [2], ATM [2], CHEK2 [1], TP53 [2] , PALB2 [1], and RET [1]); 8/9 (89%) met standard criteria for testing for those genes independent of early-onset RCC diagnosis. Conclusions: Patients with early-onset clear cell RCC and no suspicious personal or family history are unlikely to have an RCC-associated germline mutation. RCC-gene panel testing has highest utility in early-onset patients with either non-ccRCC histology, family history of RCC, or RCC-associated syndromic features. Given the high frequency of non-RCC P/LP variants, early-onset RCC patients should be counseled regarding broader testing beyond RCC-associated genes.
Efficacy of avelumab plus axitinib (A + Ax) versus sunitinib (S) by number of IMDC risk factors and tumor sites at baseline in advanced renal cell carcinoma (aRCC): Extended follow-up results from JAVELIN Renal 101.
Authors: Tomita Yoshihiko , Motzer Robert J. , Choueiri Toni K. , Rini Brian I. , Miyake Hideaki , Oya Mototsugu , Albiges Laurence , Fujii Yosuke , Umeyama Yoshiko , Wang Jing , Di Pietro Alessandra , Schmidinger Manuela
Published: March 2021

302

Background: In the phase III JAVELIN Renal 101 trial (NCT02684006), A + Ax demonstrated progression-free survival (PFS) and objective response rate (ORR) benefit across IMDC risk groups (favorable, intermediate, and poor) vs S in patients with previously untreated aRCC. Here we report efficacy of A + Ax vs S by number of IMDC risk factors (0, 1, 2, 3, and 4-6) and target tumor sites (1, 2, 3, and ≥4) at baseline from the second interim analysis of overall survival (OS). Methods: Patients were randomized 1:1 to receive A 10 mg/kg intravenously every 2 wk + Ax 5 mg orally twice daily or S 50 mg orally once daily for 4 wk (6-wk cycle). PFS and ORR per independent central review (RECIST 1.1) and OS were assessed. Results: At data cut-off (Jan 2019), median (m) follow-up for OS and PFS was 19.3 vs 19.2 mo and 16.8 vs 15.2 mo for the A + Ax vs S arm, respectively. The table shows OS, PFS, and ORR by number of IMDC risk factors and target tumor sites at baseline. A + Ax generally demonstrated efficacy benefit vs S across subgroups. Conclusions: With extended follow-up, A + Ax generally demonstrated efficacy benefit vs S across the number of IMDC risk factors and tumor sites at baseline in aRCC. OS was still immature; follow-up for the final analysis is ongoing. Clinical trial information: NCT02684006 . [Table: see text]
The efficacy of bevacizumab plus erlotinib (B+E) in patients (pts) with renal medullary carcinoma (RMC).
Authors: Wiele Andrew James , Surasi Devaki Shilpa , Rao Priya , Sircar Kanishka , Bathala Tharakeswara , Shah Amishi Yogesh , Jonasch Eric , Cataldo Vince David , Genovese Giannicola , Karam Jose A. , Wood Christopher G. , Tannir Nizar M. , Msaouel Pavlos
Published: March 2021

303

Background: RMC is a rare and highly aggressive malignancy with a median overall survival (OS) of only 13 months from diagnosis. RMC is thought to be completely refractory to the targeted therapies used against clear cell renal cell carcinoma and the recommended standard of care therapy is platinum-based cytotoxic chemotherapy, which only produces a best response rate of 29% in the first line setting (Shah et al. BJU Int., 2017). Comprehensive molecular profiling of RMC tissues revealed a decrease in genes related to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation and an increase in genes involved in fatty acid synthesis, demonstrating a reliance on aerobic glycolysis to meet cellular bioenergetics needs (Msaouel et al. Cancer Cell, 2020). The combination of B+E is particularly effective in tumors such as fumarate hydratate – deficient renal cell carcinomas, which also rely on aerobic glycolysis. We therefore hypothesized that B+E would show clinical efficacy against RMC. Methods: We analyzed 10 pts with RMC treated with B+E at our institution. A blinded board-certified radiologist reviewed all restaging images to assess best radiographic response as defined by RECIST v1.1 and, when applicable, date of progression. Adverse events (AEs) were evaluated using the CTCAE version 5.0 grading estimated from chart documentation. Clinical-grade next generation genome sequencing for gene mutations, copy number alterations and fusions was performed in 6/10 pts using the Oncomine platform. Results: Between 05/2005 and 09/2020, we identified 10 pts with RMC that were treated with B+E (Table). B+E produced a partial response in 2/10 pts (20%) and stable disease as best response in 6/10 pts (60%), resulting in a median progression-free survival of 3.5 months (mo) with 95% CI 1.8 – 5.2 mo. Decrease in tumor burden was noted even in patients that had received 3+ prior therapies and irrespective of genomic alterations. The median overall survival (OS) from B+E initiation was 7.3 mo (95% CI 5.4 – 9.1) and the median OS from diagnosis was 20.8 mo (95% CI 15.4 – 26.1). B+E was well tolerated with no grade ≥ 4 AEs and only one grade 3 AE (skin rash). Dose reduction was only needed in 1/10 pts. Conclusions: B+E is clinically active and well tolerated in heavily pre-treated pts with RMC and is therefore a viable therapeutic option for this lethal disease. However, pts ultimately relapse and further investigation is needed to elucidate mechanisms of resistance and determine how to optimally target metabolic vulnerabilities in RMC. [Table: see text]
Activity and safety of cabozantinib (cabo) in brain metastases (BM) from metastatic renal cell carcinoma (mRCC): An international multicenter study.
Authors: Hirsch Laure , Martinez Chanza Nieves , Farah Subrina , Flippot Ronan , Rathi Nityam , Collier Katharine , de Velasco Guillermo , Seront Emmanuel , Beuselinck Benoit , Xu Wenxin , Bowman Isaac Alexander , Lam Elaine Tat , Dzimitrowicz Hannah Elizabeth , Zakharia Yousef , McKay Rana R. , Bilen Mehmet Asim , Albiges Laurence , Xie Wanling , Harshman Lauren C , Choueiri Toni K.
Published: March 2021

310

Background: Cabo shows robust clinical activity in mRCC. Patients (pts) with BM have been underrepresented in clinical trials and effective systemic therapy is lacking. We retrospectively characterized the clinical activity and toxicity of cabo in pts with BM from RCC. Methods: Consecutive medical records from mRCC pts with BM treated with cabo monotherapy across 15 institutions were reviewed. Pts were grouped by radiologic presence (cohort 1) or absence (cohort 2) of progressing intracranial metastases. Brain-directed local therapy was allowed but radiological confirmation of intracranial progression at cabo start was required in cohort 1. Radiological response rate was investigator-assessed by modified RECIST 1.1 for intracranial and RECIST 1.1 for extracranial responses. Time to treatment failure (TTF) and overall survival (OS) were estimated by Kaplan-Meier. Results: We identified 69 pts with BM from RCC, 25 (36%) in cohort 1 and 44 (64%) in cohort 2. Majority were IMDC intermediate/poor (87%) and received cabo as ≥2nd line (75%). Median time from mRCC diagnosis to BM was 19.1 months (mos) (IQR 4.4-39.5). Overall, median number of BM was 3 (range 1-27) and median size of largest lesion was 1.2 cm (range 0.2-6.6) with frontal (62%) and parietal (48%) as the most frequent localizations. Prior brain directed therapy was used in 65% and 93% of pts in cohort 1 and 2 respectively. Median follow-up after cabo initiation was 11 mos (range 4-72). Twenty three percent of pts remained on therapy while 52% discontinued for progression and 9% for toxicity. Intracranial response rate was 61% (95%CI 39%-80%), with 3 complete responses, for cohort 1 and 57% (95%CI 41%-72%) for cohort 2. Only 10% (n = 7) had intracranial progression as best response. For cohort 1, extracranial response was 52% (95%CI 31%-72%), median TTF was 9.9 mos (95%CI 5.9-14.0) and OS was 14.7 mos (95%CI 7.7-23.0). For cohort 2, extracranial response was 41% (95%CI 26%-57%), TTF was 9.0 mos (95%CI 4.6-11.4) and OS was 14.1 mos (95%CI 11.0-22.0). Most common adverse events were fatigue (77%) and diarrhea (46%). Eight pts received concomitant brain-directed treatment during cabo therapy without neurological toxicities. Conclusions: Cabo shows significant intracranial activity and acceptable safety profile in pts with BM from RCC. [Table: see text]
A pilot study of preoperative nivolumab in high-risk nonmetastatic renal cell carcinoma.
Authors: Carlo Maria Isabel , Attalla Kyrollis , Patil Sujata , Murray Samuel J. , Chen Ying-Bei , Kotecha Ritesh , Durack Jeremy C. , Motzer Robert J. , Hakimi A. Ari , Voss Martin H
Published: March 2021

323

Background: Immunotherapy improves survival in patients with advanced renal cell carcinoma (RCC), but has no established role for perioperative use in patients with localized RCC. Neoadjuvant immunotherapy is a promising strategy in several cancers, and may leverage the primary tumor as antigen source. Methods: We conducted a single institution pilot study of neoadjuvant nivolumab in patients with RCC undergoing nephrectomy with curative intent. Patients were eligible if their risk of metastatic recurrence within the first 12 years was >20% by an established nomogram. After confirmatory biopsy and renal MRI, patients were treated with standard dose nivolumab every 2 weeks for 4 treatments, with a follow-up renal MRI prior to nephrectomy. The primary end points of the study were safety and feasibility defined as being able to complete 3/4 treatments without surgical delay. We evaluated adverse events by CTCAE, surgical safety by Clavien-Dindo classification, and tumor radiographic response by RECIST 1.1. Results: Eighteen (11 men, 7 women; median age 60) were enrolled. All patients had clear cell RCC, median tumor size at baseline was 8.8cm (range 6.4-14.2cm). Median predicted 12-year probability of recurrence was 45% (range 25-71%). All received at least 1 dose of nivolumab; 16/18 patients completed all 4 doses. 17/18 (94%) patients completed at least 3 doses. No patient had notable delay in the timing of their nephrectomy. 4 patients had surgical complications per Clavien-Dindo classification, including 2 with grade 3a chylous ascites after lymphadenectomy. Two patients had nivolumab discontinued for immune-related adverse events, including grade 3 transaminitis and grade 2 arthralgias; a third patient developed grade 4 colitis 4 months after completing nivolumab. All patients had stable disease as the best response prior to surgery. Recurrence-free survival at 2 years was 0.74 (95%CI 0.45-0.90). We analyzed an additional 21 patients with metastatic RCC (20 ccRCC, 1 epithelioid AML) who subsequently had nephrectomy after standard immunotherapy. 15 patients had received ipilimumab+nivolumab, 6 received single-agent PD-1 or PD-L1 inhibitors. 3 (14%) patients achieved a near or complete pathologic response, including a patient with epithelioid AML. Analysis of radiologic and pathologic biomarkers of response are ongoing and will be presented at conference. Conclusions: In this pilot study, there were no new safety signals or delays in surgery with preoperative nivolumab. Neoadjuvant immunotherapy shows preliminary evidence of safety, feasibility and efficacy; biomarker studies may help identify individuals who may have a higher likelihood of response. Clinical trial information: NCT02595918 .
First assessment of the stool mycobiome in patients (pts) with metastatic renal cell carcinoma (mRCC) receiving targeted therapy (TT) or immunotherapy (IO).
Authors: Dizman Nazli , Hsu Joann , Gillece John D , Folkerts Megan , Reining Lauren J , Bergerot Paulo Gustavo , Meza Luis A , Zengin Zeynep Busra , Muddasani Ramya , Chawla Neal , Karimi Misagh , Trent Jeffrey M. , Highlander Sarah K , Pal Sumanta K.
Published: March 2021

337

Background: Previous studies have associated specific stool bacterial species with response to both targeted therapy and immunotherapy (Routy et al Science 2018; Dizman et al Cancer Med 2020). Abundant fungal elements also constitute the human microbiome (the so-called “mycobiome”); we explore whether these could be related to clinical benefit (CB) from TT. Methods: Pts from 2 simultaneously conducted studies were included in the analysis. Both studies enrolled patients with histologically confirmed RCC with metastatic disease; in one study, pts received standard of care (SOC) TT, while in the other pts received SOC IO. In both studies, stool was collected at baseline and at multiple timepoints thereafter. Whole metagenome sequencing was performed for fungal microbiome composition (TGen North, AZ). Linear discriminant analysis (LDA) effect size (LEfSe) was used for comparison of the gut mycobiome in patients who obtained clinical benefit (CB; complete response, partial response or stable disease > 6mos) versus no clinical benefit (NCB; progressive disease or stable disease ≤6mos) from TT or IO. Results: A total of 50 samples from 24 pts (19:5 M:F) were included in the analysis. The majority of pts (19; 79%) had clear cell histology. 15 pts received TT while 9 pts received IO. The fungal genera demonstrating the highest abundance was Saccharomyces with a median relative abundance of 86.9% (range, 11%-99%). LEfSe performed in different taxonomic levels revealed Malassezia globosa (LDA = 4.93; P = 0.038) and Alternaria infectoria (LDA 4.94; P = 0.018) as gut mycobiome components associated with NCB, and order Russulales associated with CB from TT (LDA = 4.93; P = 0.018). In contrast, no association was identified between mycobiome profile and CB in the IO-treated group. The presence of several pathogenic fungi such as Candida albicans and Aspergillus fumigatus was noted in a minority of pts and did not have any bearing on clinical outcome. In pts with serial samples, a trend towards decreasing Saccharomyces spp. (the most abundant species) and increasing fungal diversity was noted. Conclusions: Our study is the first to highlight potential associations between the mycobiome and CB with TT. Our finding of Malassezia spp resulting in lack of CB with TT bolsters findings from Aykut et al (Nature 2019), implicating the same genera in progression of pancreatic cancer. Confirmation of these findings in larger series is underway.
Plasma exosome microRNAs in patients with advanced renal cell carcinoma treated with nivolumab and ipilimumab: Potential biomarkers of response to therapy.
Authors: Soleimani Maryam , Thi Marisa , Saxena Neetu , Khalaf Daniel Joseph , Eigl Bernhard J. , Chi Kim N. , Kollmannsberger Christian K. , Nappi Lucia
Published: March 2021

338

Background: There is a critical unmet need for predictive biomarkers in the management of metastatic renal cell carcinoma (mRCC). We sought to quantify plasma exosome microRNAs (miRNAs) and correlate with response to first line nivolumab and ipilimumab (N/I) to potentially serve as such a biomarker. Methods: We evaluated the expression of 11 miRNAs in 19 patients with mRCC (prior to initiation of N/I) and in 32 healthy volunteers. Exosomes were extracted from 500 uL of plasma (qEV original, Izon Science) and once confirmed, were used for miRNAs extraction. MiRNAs expression was evaluated by real time polymerase chain reaction using a TaqMan miRNA assay (Applied Biosystems). The relative quantity of each miRNA in patients was compared to healthy volunteers. The expression of each miRNA was correlated to the best response to N/I, categorizing patients as either responders or non-responders. Results: Clinical characteristics are summarized in the table below. Median age at the start of systemic therapy was 64.3 years. MiR200b demonstrated a significantly higher expression in mRCC patients than in healthy volunteers (unpaired t-test; p=0.04). We observed a variable pattern of miRNA expression based on response to N/I. Although not statistically significant, 4 miRNA (miR138, 155, 200b, 221) were upregulated in non-responders, while two (miR200a and 497) were upregulated in responders. Of note, the only patient to achieve a complete response had the lowest expression of miR138 and the highest expression of miR497. Conclusions: Although preliminary and limited by a small number of patients, these initial observational results are promising and suggest a potential role for miRNAs as predictive biomarkers in mRCC. MiR138 and 497 are known to regulate CTLA-4 and PD-L1, respectively. We speculate that these miRNA are potentially involved in response to immune checkpoint therapy. Ongoing work in evaluating expression of these and other miRNAs in blood and in tissue along with clinical correlation continues. [Table: see text]
The very favorable metastatic renal cell carcinoma (mRCC) risk group: Data from the International Metastatic RCC Database Consortium (IMDC).
Authors: Schmidt Andrew Lachlan , Xie Wanling , Gan Chun Loo , Wells Connor , Dudani Shaan , Donskov Frede , Porta Camillo , Suarez Cristina , Szabados Bernadett , Wood Lori , Ruiz Morales Jose Manuel , Tran Ben , Bjarnason Georg A. , Yuasa Takeshi , Beuselinck Benoit , Hansen Aaron Richard , Agarwal Neeraj , Bakouny Ziad , Heng Daniel Yick Chin , Choueiri Toni K.
Published: March 2021

339

Background: The IMDC criteria have been used as a prognostic tool for patients with mRCC receiving single agent VEGF-targeted drugs, and more recently combination immuno-oncology (IO) +/- VEGF-targeted agents, which improve outcomes over VEGF TKI monotherapy. We sought to identify a subset of patients with very favorable outcomes, for which less intensive therapy might be considered. Methods: Utilizing the IMDC dataset, 1638 patients with IMDC favorable risk disease received first-line systemic therapy. Patients were randomly selected in a 2:1 ratio to the training and testing sets, stratified by year of systemic therapy initiation. Multivariable Cox regression estimated prognostic factors for overall survival (OS). Results: Median age was 63 (range 21-95) years and 98% had received prior nephrectomy. First-line systemic therapy consisted of targeted therapy (91%), IO-combination regimens (8%), or other (1%). From the training data, three variables (primary diagnosis to systemic therapy <3 vs ≥3yr; Karnofsky Performance Status 80 vs >80; presence of brain, liver, or bone metastasis) significantly predicted for OS in the multivariable model (hazard ratio 1.4~1.5, p-values<0.05). The model had similar performance in the test dataset (C-index=0.64). Using the 3 included risk factors, patients were classified to very favorable risk (0 risk factors, 29% of patients) or favorable risk disease (≥1 risk factors, 71% of patients). Clinical outcomes for the two risk groups are presented in the table below. Conclusions: We identified a very favorable risk group in the IMDC criteria in RCC patients treated with first-line therapy. External validation including populations receiving IO containing therapies is ongoing. [Table: see text]
Associations between plasma cytokine levels and gut microbiota composition in metastatic renal cell carcinoma (mRCC).
Authors: Chehrazi-Raffle Alex , Dizman Nazli , Bergerot Paulo Gustavo , Karimi Misagh , Hsu Joann , Gillece John D , Folkerts Megan , Reining Lauren J , Highlander Sarah K , Pal Sumanta K.
Published: March 2021

351

Background: Plasma cytokines and the gut microbiome have been shown separately to influence the response to systemic therapy in mRCC. We sought associations between serum cytokines and gut microbial composition in patients (pts) with mRCC. Methods: Eligibility requirements included histologically proven mRCC and an intent to receive either vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or immune checkpoint inhibitor (ICI). Blood samples were collected prior to treatment initiation and immunologic profiles were evaluated using a Human Cytokine 30-plex protein assay (Invitrogen). Stool was collected at baseline and shotgun metagenomic sequencing was performed to quantify gut microbial populations using previously published methods (Salgia et al Eur Urol 2020). Results: A total of 50 pts were studied (36:14 M:F) with a median age of 67 (range, 32-85). Twenty pts and 30 pts had subsequent initiation of VEGF-TKI and ICI therapy, respectively. Levels of Akkermansia spp were significantly higher in pts who were IL-6 low (P = 0.023). In contrast, pts who were IL-6 high had higher levels of enteric pathogens, including Salmonella spp and Enterococcus spp. Both Akkermansia spp and Bacteroides spp levels were higher in pts who were IL-8 low. Associations between cytokine levels, microbiome composition, and treatment response will be presented. Conclusions: Given studies suggesting the role of Akkermansia spp in enhancing ICI response (Routy et al Science 2018), our data provide a critical link between the gut microbiome and systemic immunomodulation.
18F-DCFPyL PSMA PET imaging compared to conventional imaging in the detection of pelvic nodal metastases in patients with locally advanced or oligometastatic prostate cancer.
Authors: Esdaille Ashanda Rosetta Patrice , Lawrence Edward , Kyriakopoulos Christos , Johnson Brian , Roldán-Alzate Alejandro , Huang Wei , Beebe David J. , Emamekhoo Hamid , Wells Shane , Lang Joshua Michael , Cho Steve Y. , Jarrard David Frazier
Published: March 2021

36

Background: Interest has arisen in the use of prostate specific membrane antigen (PSMA) PET/CT imaging to detect prostate cancer at metastatic sites using different tracers. Here, we examined the ability of 18F-DCFPyL (DCFPyL) PSMA-based PET imaging to detect nodal disease in comparison to conventional imaging in a cohort of men with locally advanced or oligometastatic prostate cancer (PC). Methods: UW17009 is an IRB-approved open-label, single-arm trial that enrolled 26 patients with newly diagnosed advanced PC. Patients received androgen deprivation therapy and docetaxel for 3 months followed by radical prostatectomy (RP) and pelvic lymph node dissection (PLND). Exploratory interventions include PSMA PET/CT and MRI imaging as a method for determining treatment response and heterogeneity in primary PC and metastatic lesions performed before and after chemohormonal therapy. Prior to randomization, patients received DCFPyL PET/CT and PET/MR imaging as well as CTs and Bone Scans. A mean dose of 7.86 mCi DCFPyL was administered. Whole-body PET/CT images were acquired starting at approximately 60 minutes after radiotracer injection followed by dedicated pelvic PET/MR and whole-body PET/MR. PET imaging findings were compared to conventional dedicated CT imaging and were correlated to the results of final pathologic examination of each pelvic nodal dissection. Results: 26 patients underwent conventional and exploratory imaging with subsequent neoadjuvant treatment, RP and PLND. The mean diagnostic PSA was 32.1 ng/dl and 88.5% had Gleason 9 PCa. Using conventional imaging, pelvic nodal disease was identified in 6/26 patients. Pelvic lymph node uptake was identified in 12/26 patients using DCFPyL-based PSMA PET. Initial correlation of the pathologic specimens with pretreatment PSMA PET imaging revealed pelvic nodal metastatic PC in 10/12(83%) patients. On a per-lymph node packet basis (6 per patient), there were 156 evaluable regions, including 65 from patients with positive nodes. PSMA detected 14 packets that were positive for PC and 102 packets that were negative on imaging and final pathology. PC was missed in 5 packets. The mean tumor size in the missed nodes was 2.3 mm(range 1-4 mm). Calculated sensitivity was 73.7%(95% CI [48.8, 90.8]), 85.7 % specificity(95% CI[78.1, 91.4]), and 95.3 % negative predictive value(95% CI[90.5, 97.7]). Conclusions: In comparison to conventional imaging, in this cohort, DCFPyL PSMA-based PET imaging identified nodal positive disease at twice the rate and when evaluating on a per-packet basis, there was high negative predictive value. Ongoing analysis of post-chemohormonal therapy PET imaging may provide more information regarding tumor response in this cohort.
Australia and New Zealand (ANZ) outcomes of high-dose chemotherapy and stem cell transplantation for relapsed or refractory germ cell tumors (GCT) from 1999 to 2019: Multicenter registry-based study with ABMTRR.
Authors: Connolly Elizabeth Anne , Weickhardt Andrew James , Grimison Peter S. , Heller Gillian , Lewin Jeremy Howard , Liow Elizabeth Chien Hern , Tung Iris , Tran Ben , Hill Sean , Walpole Euan Thomas , McKenzie Jane , Kuchel Anna , Forgeson Garry , Tan Alvin Boon Tee , Joshi Abhishek , Wickham Alistair , Tan Thean Hsiang , Wang Yang , Hamad Nada , Wong Vanessa ,   Australasian Bone Marrow Transplant Recipient Registry
Published: March 2021

382

Background: High dose chemotherapy (HDCT) with autologous stem-cell transplant (ASCT) is effective in advanced germ cell tumours (GCT) that are refractory to, or progress after, first-line therapies. Five-year overall survival in North American and European series range from 48-60%1,2,3. This study aimed to assess ANZ outcomes for quality assurance. Methods: Retrospective multi-centre audit of all male patients with GCT who underwent HDCT and ASCT from 1999-2019. Patients were identified from the Australasian Bone Marrow Transplant Recipient Registry. Primary outcomes included overall and progression- free survival (OS, PFS). Results: 111 patients were identified at 13 centres, each treating a median (range) of 7 (1-27) patients. Median (range) age was 30 (14-68) years. 88 (79%) had testicular primary. 16% were pure seminoma. Median time from first diagnosis to first stem cell cycle was 11 months (range 3 months-38 years). Prior to ASCT, 35% had primary refractory disease and 65% had relapsed. IPFSG risk score was very low in 5%, low in 13%, intermediate in 36%, high in 25%, and very high in 21%. HDCT regimen was CE in 78% (as part of TI-CE regimen in 38%), Carbop-EC-T in 6%, ICE in 6%, CEC in 5% and other in 4%. 89% completed all planned HDCT and ASCT cycles. Five treatment related deaths occurred. Progressive disease on treatment occurred in 14%. At median follow-up time 4.4 years (95% CI: 2.9 to 6.0), 51% were disease-free, 13% alive with disease, 34% deceased. 3 patients displayed late progression over 2 years after ASCT. The estimated 1, 2 and 5-year PFS rates were 62%, 57% and 52% respectively and OS rates were 73%, 65% and 61%. Survival by IPFSG and IGCCG risk categories are displayed in the table below. Conclusions: This is the first registry-based audit of HDCT for metastatic GCT from ANZ, which has demonstrated our outcomes are comparable with best international practice. References: Gossi Bone Marrow Transplant 2018;53:820-825. Adra J Clin Onc 2017; 35(10):1096-1102. Feldman J Clin Onc 2010; 28(10):1706-13. [Table: see text]
Real-world application of pre-orchiectomy miR-371a-3p test in testicular germ cell tumor (GCT) management.
Authors: Badia Rohit R , Abe Dreaux , Wong Daniel , Singla Nirmish , Savelyeva Anna , Chertack Nathan , Jia Liwei , Kapur Payal , Murray Matthew , Amatruda James F. , Lafin John T. , Bagrodia Aditya
Published: March 2021

387

Background: Current serum tumor markers (STMs) for testicular germ cell tumor (GCT) are limited by low sensitivity. Growing evidence supports the use of circulating miR-371a-3p as a superior marker for malignant (viable) GCT management. We evaluated the real-world application of serum miR-371a-3p levels in detecting viable GCT among patients undergoing partial or radical orchiectomy. Methods: Serum samples were collected from 69 consecutive patients pre-orchiectomy. Performance characteristics of serum miR-371a-3p were compared with conventional STMs (AFP/β-hCG/LDH) between viable GCT patients and those without viable GCT on orchiectomy pathology. Relative miR-371a-3p levels were correlated with clinical course. Kruskal-Wallis test and linear and ordinal regression models were used for analysis. Results: For detecting viable GCT, combined conventional STMs had a specificity of 100%, sensitivity of 58%, and area under the curve (AUC) of 0.79 (Table). The miR-371a-3p test showed a specificity of 100%, sensitivity of 93%, and AUC of 0.978. Median relative expression of miR-371a-3p in viable GCT patients was >6,800-fold higher than in patients lacking viable GCT. MiR-371a-3p levels correlated with composite stage (CS) (p=0.006), and, among CS I patients, independently associated with embryonal carcinoma percentage (p=0.0012) and tumor diameter (p<0.0001). Six patients received orchiectomy after chemotherapy and were correctly predicted to have presence or absence of viable GCT by the miR-371a-3p test. Conclusions: If validated, the miR-371a-3p test can be used in conjunction with conventional STMs to aid clinical decision-making. A positive miR-371a-3p test in patients after preoperative chemotherapy or with solitary testes could potentially guide subsequent orchiectomy or observation. [Table: see text]
Socio-environmental conditions associated with geospatial clusters of urothelial carcinoma: A multi-institutional analysis.
Authors: Edwards Daniel C. , Yankelevich Gabrielle R , Dreher Paulette C , Narowska Gabriela , Kim Daniel , Taylor Zachariah , Larson Sharon H , Buckley Meghan , Belkoff Laurence H , Bernstein Guy T
Published: March 2021

392

Background: Industrial byproducts and environmental pollutants (IBP/EP) are associated with the development of urothelial carcinoma (UC). While tobacco exposure (TE) is the major risk factor for UC, the interaction between sources of IBP/EP and incidence of UC in surrounding communities has been infrequently explored. We seek to identify high-density microregions of UC prevalence and spatially-related industrial and environmental risk factors. Methods: We queried a multi-institutional database for patients diagnosed with UC between 2008-2018. Geocoded addresses and ArcGIS software were used to calculate the Getis-Ord-Gi* statistic and perform hotspot analysis on the census-block level to identify UC hotspots. Demographics, clinicopathologic disease characteristics, and proximity to sources of IBP/EP were compared using Pearson’s chi-square and Student’s T-test. Univariate analyses and multivariable multilevel logistic random-intercept regression models were fitted to test the association between patient and census block-level factors and living in a UC hot spot. Results: Of 5,080 patients meeting inclusion/exclusion criteria, 148 patients (2.9%) were associated with one of three UC hotspots. In univariate analyses, hotspot patients were less likely to be tobacco users (OR 0.24, p=0.004) or of white race (OR 0.10, p<0.001) and less likely to have higher income (OR 0.73, p=0.005). They were more likely to be associated with IBP/EP exposure (OR 8.24, p=0.001) (Table). Multivariable analysis confirmed increased likelihood of residing in a UC hotspot and proximity to high-traffic density (OR >999, p=<0.001) and sites of IBP/EP contamination (OR 106.90, p=0.009), with decreased likelihood of tobacco use (OR 0.11, p=0.045) and white race (OR 0.02, p=0.004). Conclusions: Patients residing in geospatial hotspots of UC prevalence are less likely to be white, higher income or tobacco users and more likely to reside in proximity to sources of IBP/EP. Further research is necessary to investigate the interplay between socioeconomic status, race and environmental risk factors in order to better identify at-risk populations and improve screening, referral, diagnosis and timely intervention. [Table: see text]
Cost-effectiveness analysis of pembrolizumab for BCG-unresponsive carcinoma in situ of the bladder.
Authors: Sharma Vidit , Wymer Kevin , Saigal Christopher , Chamie Karim , Litwin Mark S. , Packiam Vignesh T. , Mossanen Matthew , Pagliaro Lance C. , Borah Bijan J , Boorjian Stephen A.
Published: March 2021

395

Background: Patients with BCG-unresponsive carcinoma in situ (CIS) are treated with radical cystectomy (RCx) or salvage intravesical chemotherapy (SIC). Recently, the FDA approved pembrolizumab for BCG-unresponsive CIS +/- papillary tumors. Given the costs and toxicities of pembrolizumab, it remains unclear whether its benefits are sufficient to warrant widespread use for BCG-unresponsive CIS. To that end, we conducted a cost-effectiveness analysis comparing pembrolizumab with RCx and SIC (using gemcitabine-docetaxel as the prototypical regimen) for patients with BCG-unresponsive CIS. Methods: A decision-analytic Markov model compared pembrolizumab, SIC (with gemcitabine-docetaxel), and RCx for patients with BCG-unresponsive CIS +/- papillary tumors who are RCx candidates (index patient 1) or are unwilling/unable to undergo RCx (index patient 2). Each treatment option was a Markov node containing distinct variations of the following health states: surveillance, recurrence, progression to MIBC, progression to metastasis, treatment toxicity, and death. Incremental Cost-Effectiveness Ratios (ICERs) were compared using a willingness-to-pay threshold of $100,000/Quality-adjusted life year (QALY). The model used a US Medicare perspective with a 5-year time horizon for the base case. One-way and probabilistic sensitivity analyses were performed for all model parameters. Results: For index patient 1, pembrolizumab was not cost-effective vs. RCx (ICER $1,403,008) or SIC (ICER $2,011,923). One-way sensitivity analysis revealed that pembrolizumab only became cost-effective relative to RCx with a > 93% price reduction. Relative to RCx, SIC was cost-effective for time horizons < 5 years and nearly cost-effective at 5 years (ICER $118,324). One-way sensitivity analysis revealed that SIC became cost-effective relative to RCx if its risk of recurrence or metastasis at 2 years was less than 55% or 5.9%, respectively. For index patient 2, pembrolizumab required > 90% price reduction to be cost-effective vs. RCx (ICER $1,073,240). Probabilistic sensitivity analyses revealed that pembrolizumab was unlikely to be cost-effective even at high willingness-to-pay thresholds. Further sensitivity analyses found that no two-way combination of extrapolated values resulted in pembrolizumab being favored over RCx or SIC for either index patient. Conclusions: Based on decision-analytic Markov modeling of treatment options for patients with BCG-unresponsive CIS, pembrolizumab was unlikely to be cost-effective without a > 90% price reduction. While both RCx and SIC were more cost-effective than pembrolizumab, further studies may validate the cost-effectiveness of gemcitabine-docetaxel relative to RCx if the recurrence and metastasis thresholds are met. Overall, our model supports the preferential use of RCx and SIC over pembrolizumab for BCG-unresponsive CIS.
Associations of education, residence, and travel distance to oncology center on survival outcomes in patients with penile cancer: A tertiary care referral center experience.
Authors: GARG VIKAS , Ray Mukurdipi , Haresh KP , Sahoo Ranjit Kumar , Sharma Atul , Kaushal Seema , Batra Atul
Published: March 2021

4

Background: Rural residence, educational status & longer travel distance are variably associated with suboptimal cancer treatment and outcomes. There are limited data on impact of these factors on treatment patterns & survival outcomes in penile cancer. Methods: Patients with a histological diagnosis of carcinoma penis during 2015 to 2019 were identified from the database of a large tertiary care center in India. Chart reviews were performed to retrieve demographic, clinicopathological and treatment details. Educational status was categorized as no formal education and any educational attainment, while travel distance was dichotomized at 500 km. Logistic regression analyses were performed to examine the associations with cancer treatments. Relapse free survival (RS) and overall survival (OS) were calculated by plotting Kaplan Meir curves and compared using log rank test. Multivariable Cox regression analysis were used to determine the associations of socioeconomic status and residence on survival outcomes. Results: A total of 100 patients were eligible for the current analysis. The median age was 56 (interquartile [IQR]range, 42-65) years. The median duration of symptoms was 6 (IQR, 4-12) months. Ulcero-proliferative growth (65%) was the most common presenting symptom followed by pain (57%) and dysuria (36%). Most patients had grade 2 tumor (60%), while stage was equally distributed from I-IV. Three-fourths of patients had clinically enlarged inguinal lymph nodes, while, 42 % were pathologically involved. Of all patients, 58% were from rural communities, 44% patient didn’t receive any formal education, and 36% had travelling distance of over 500 km from the hospital. Surgery, radiotherapy, and chemotherapy were administered in 53%, 42% and 24%, respectively. On multivariable logistic regression analysis, lower education, rural residence and longer travel distance were not associated with a lower likelihood of receiving any treatment. At a median follow-up of 50.7 months, median RFS and OS were 59.8 (95% CI, 15.8-NR) and 83.9 (95% CI, 29.2–NR) months, respectively. After adjusting for tumor stage, involvement of lymph nodes, PS, and grade, education status, primary residence (urban vs rural), and distance from the treatment center were not associated with RFS and OS. However, advanced stage was the only factor predictive of worse RFS and OS (Table). Conclusions: Rural residence, educational status and travel time were not associated with treatment administration and survival outcomes in patients with penile cancer treated in a publicly funded tertiary care center in India. [Table: see text]
Reliability, validity, and clinically important differences (CIDs) on the NCCN/FACT Bladder Symptom Index (NFBISI-18) among individuals with locally advanced or metastatic urothelial cancer (UC).
Authors: Peipert John , Chang Jane , Li Si , Di Pietro Alessandra , Cislo Paul , Cappelleri Joseph C , Cella David
Published: March 2021

408

Background: The NFBlSI-18 is a measure of advanced bladder cancer–specific symptoms composed of a total scale and 3 subscales representing physical disease–related symptoms (DRS-P), emotional disease–related symptoms (DRS-E), treatment side effects (TSE), and function/well-being (F/WB). There is evidence for the reliability and content validity of this instrument, but a full psychometric evaluation of the full 18-item format has not been done. In addition, CIDs have not been estimated. Methods: With the exception of test-retest (TRT) analyses, baseline data (n=651) from the JAVELIN Bladder 100 trial (NCT02603432), which compared maintenance treatment with avelumab + best supportive care (BSC) vs BSC alone in patients with unresectable, locally advanced or metastatic UC that did not progress with first-line platinum-containing chemotherapy, were used for this study. Since we focused on baseline, we did not analyze the TSE. We estimated internal consistency reliability (Cronbach coefficient α), tested convergent validity by estimating Spearman ρ correlations with the EQ-5D-5L utility index (UI) and visual analog score (VAS) scales, and estimated known group validity using age (<65, ≥65 years), ECOG performance status rating (PSR), and number of comorbidities/symptoms (1-9, ≥10) as anchors. We estimated TRT reliability using data from treatment cycles 2-3 with intraclass correlation coefficients (ICCs). To estimate and compare CIDs, we calculated differences in means between categories of the known group anchors for which Cohen’s d was >0.2 (ie, at least a small effect). To provide context for the CIDs, we calculated distributional properties of the scales (1/2 standard deviation [SD], 1 standard error of measurement [SEM]). Results: The table shows the reliability, convergent validity, and CID estimates. Reliability estimates often exceeded thresholds for reliability generally considered acceptable. Cohen’s d for NFBlSI-18 scale score differences between known groups ranged between 0.05 and 0.25 (age), 0.35 and 0.6 (ECOG PSR 0 vs 1), and 0.1 and 0.41 (number of comorbidities/symptoms). Conclusions: This analysis demonstrated that the NFBlSI-18 is a reliable and valid instrument to measure symptoms in patients with advanced UC. The CID estimates can help clinicians and researchers to understand what difference in patient symptoms are clinically meaningful, as measured by NFBlSI-18, to inform clinical practice. [Table: see text]