bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing IMDC prognostic groups in contemporary first-line combination therapies for metastatic renal cell carcinoma (mRCC).
Authors: Ernst Matthew Scott , Navani Vishal , Wells J Connor , Donskov Frede , Basappa Naveen S. , Labaki Chris , Pal Sumanta K. , Meza Luis A , Wood Lori , Ernst D. Scott , Szabados Bernadett , McKay Rana R. , Parnis Francis , Suárez Cristina , Yuasa Takeshi , Kapoor Anil , Alva Ajjai Shivaram , Bjarnason Georg A. , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: February 2022

308 Background: The combination of immuno-oncology agents (IO) ipilimumab and nivolumab (IPI-NIVO) and combinations of IO with vascular endothelial growth factor targeted therapies (IOVE) have demonstrated efficacy in clinical trials for the first-line treatment of mRCC. This study seeks to establish real-world clinical benchmarks based on the International mRCC Database Consortium (IMDC) criteria using vascular endothelial growth factor targeted therapy (VEGF-TT) treated patients for context. Methods: The IMDC database (IMDConline.com) was used to identify patients with mRCC who received first-line IPI-NIVO, IOVE (axitinib/pembrolizumab, lenvatinib/pembrolizumab, cabozantinib/nivolumab, or axitinib/avelumab) and VEGF-TT (sunitinib or pazopanib) from 2002-2021. The primary endpoint was overall survival (OS) and was calculated from time of initiation of first-line therapy to death or last follow up. Log-rank tests were conducted to compare favorable, intermediate, and poor risk OS outcomes within treatment groups. Overall response rates (ORR) and complete response (CR) rates were calculated based on physician assessment of best clinical response. Results: In total, 692 patients received IPI-NIVO, 244 received IOVE, and 7152 received VEGF-TT. Baseline characteristics for IPI-NIVO, IOVE, and VEGF-TT, respectively, were as follows: median age (interquartile range) 63 (56-69), 64 (57-70), and 63 (56-70); male 72%, 74%, and 72% (p=0.74); non-clear cell histology 15%, 10%, and 13% (p=0.15); sarcomatoid features 24%, 15%, and 13% (p<0.0001); brain metastasis 8%, 4%, and 8% (p=0.04); liver metastasis 18%, 14%, and 18% (p=0.17); underwent nephrectomy 61%, 79% and 80% (p<0.0001). OS and ORR are reported in the table. P-values (log rank) for OS between risk groups were significant for IPI-NIVO (p<0.0001), IOVE (p=0.0005), and VEGF-TT (p<0.0001). Conclusions: These findings provide real-world survival and response benchmarks for contemporary first-line mRCC treatments and could be helpful for patient counselling. In addition, these findings mirror the efficacy of combination therapies established in clinical trials against VEGF-TT monotherapy. IMDC criteria continue to risk stratify patients in these novel combination therapies.[Table: see text]
Nemvaleukin alfa in patients with advanced renal cell carcinoma: ARTISTRY-1.
Authors: Calvo Emiliano , Boni Valentina , Chaudhry Arvind , Debruyne Philip R. , Rosen Seth D , Wang Yan , Sun Lei , Desai, MD Monali , Dalal Rita P. , Du Yangchun , Graham Julie R. , Tomczak, MD Piotr 
Published: February 2022

330 Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel engineered cytokine that selectively binds to the intermediate-affinity IL-2 receptor, preferentially activating and expanding antitumor CD8+ T and NK cells, with minimal expansion of Tregs. Nemvaleukin is under investigation for the treatment of advanced solid tumors, including renal cell carcinoma (RCC), in the ARTISTRY-1 trial (NCT02799095). Demonstration of single-agent activity is essential to validate the potential therapeutic benefit of nemvaleukin, both as monotherapy and in combination with a checkpoint inhibitor (CPI), particularly in patients (pts) with limited treatment options, such as CPI-experienced pts with RCC. Methods: Pts with advanced RCC who had previously responded (either objective response or stable disease [SD]) to a CPI alone or as part of a combination were enrolled into an RCC-specific cohort of ARTISTRY-1 Part B. Nemvaleukin 6 µg/kg IV monotherapy was administered daily for 5 days every 14 days in cycle 1 and every 21 days in cycles 2+. Pts with disease progression (PD; after ≥2 cycles) or SD (after ≥4 cycles) could be enrolled into Part C to receive nemvaleukin and pembrolizumab combination therapy. Outcomes presented include antitumor activity (RECIST v1.1), pharmacodynamics, and safety as of August 2021. Results: Twenty-seven pts with RCC received nemvaleukin monotherapy in Part B. Median age was 69 y (range, 39-77); median prior lines of therapy was 2 (range, 1-7). Four of 21 evaluable pts had a best overall response of partial response (1 confirmed, 1 unconfirmed, 2 awaiting confirmation); 11 had SD. Nemvaleukin induced robust expansion of CD8+ T and NK cells with minimal effect on Tregs. The most frequently reported adverse events (AEs), regardless of causality (N = 27), were pyrexia (59.3%), chills (55.6%), nausea (29.6%), and anemia (29.6%). The most frequently reported grade ≥3 nemvaleukin-related AEs are shown in the table. One pt had an AE (nemvaleukin-related bronchospasm) resulting in treatment discontinuation. There were no deaths due to treatment-related AEs. Four pts are continuing monotherapy in Part B (up to 1 y) and 10 have rolled over to Part C (combination therapy). Of the 8 evaluable pts with PD on Part B who subsequently received combination therapy in Part C, 1 had a confirmed partial response and has now been on treatment for almost 1 y and 5 had SD. No additional safety signals were observed. Conclusions: Nemvaleukin was generally well tolerated as monotherapy and in combination with pembrolizumab, and provided evidence of single-agent tumor response and disease control in CPI-experienced pts with advanced RCC. Clinical evaluation of nemvaleukin among pts with advanced RCC is ongoing. Clinical trial information: NCT02799095. [Table: see text]
Prolonging utilization of systemic therapy in oligoprogressive metastatic renal cell carcinoma using stereotactic body radiation therapy.
Authors: Muddasani Ramya , Govindarajan Ameish , Salgia Sabrina , Salgia Nicholas , Zengin Zeynep Busra , Meza Luis A , Hsu Joann , Chehrazi-Raffle Alex , Dizman Nazli , Chawla Neal Shiv , Malhotra Jasnoor , Bergerot Cristiane Decat , Philip Errol James , Castro Daniela V. , Dandapani Savita V. , Tripathi Nishita , Sayegh Nicolas , Pal Sumanta K. 
Published: February 2022

336 Background: SBRT in indicated for the management of locally recurrent and oligometastatic mRCC as per National Comprehensive Cancer Network guidelines. Our study evaluates both the efficacy of radiotherapy (RT) in prolonging systemic treatment along with RT toxicity in the oligoprogressive RCC setting. Methods: A single institution retrospective data collection was performed in which we identified mRCC patients who experienced oligoprogression (defined as <1 sites of progressive disease) while on an FDA approved systemic therapy and were concurrently treated with SBRT, while remaining on the same therapy. Clinicopathologic characteristics and SBRT-related data along with duration of systemic therapy (DOT) were collected. DOT was then quantified into two categories which included the duration of systemic therapy prior to oligoprogression (DOT[P]) and duration of systemic therapy after completion of SBRT (DOT[S]). The ratio of DOT[S]/DOT[P] was calculated to determine the impact of SBRT on systemic treatment prolongation. Results: 23 patients diagnosed with mRCC meeting criteria were identified, 91% (n = 21) with clear cell histology and 9% (n = 2) with papillary histology. At the time of oligoprogression, 15 patients (65%) were on immunotherapy, 7 patients (30%) were on targeted therapy, and 1 patient (5%) was on combination therapy. We noted the preponderance of patients were on a first-line therapy at the time of oligoprogression (n = 10, 43%). A median of 2 (range, 1-3) lesions were treated per patient, with lung being the most frequent site (n = 14, 40%). The median total dose of SBRT was 30 Gy (range, 27-50 Gy) with a median dose per fraction of 6 Gy (range, 3-12 Gy). SBRT related toxicities, all of which were grade <2, were noted in 5 patients (22%), of which fatigue was the most frequent side effect (n = 3, 13%). Median DOT[S] was 13.4 months (range, 0.5-37.7 months) and the median DOT[P] was 12.8 months (range, 0.4-46.3 months). Results demonstrated a median DOT[S]/DOT[P] ratio to be 1.3 (range, 0.01-25.8). Conclusions: Based on our data, we discovered the addition of SBRT to systemic therapy during oligoprogression is not only well-tolerated, but that this treatment had clinical benefit in prolonging time on systemic therapy for patients with mRCC. The utilization of SBRT may prolong lines of therapy, thereby decreasing additional toxicities associated with exposure to new regimens.
Phase 2 study of neoadjuvant cabozantinib in patients with locally advanced non-metastatic clear cell renal cell carcinoma.
Authors: Bilen Mehmet Asim , Liu Yuan , Nazha Bassel , Brown Jacqueline T , Osunkoya Adeboya O. , Williams Sierra , Session Wilena , Yantorni Lauren Beth , Russler Greta , Caulfield Sarah , Joshi Shreyas S. , Narayan Vikram M. , Filson Christopher Paul , Ogan Kenneth , Kucuk Omer , Carthon Bradley Curtis , Kissick Haydn , Master Viraj A. 
Published: February 2022

340 Background: Cabozantinib is a small molecule inhibitor of the tyrosine kinases c-Met, AXL and VEGFR2 that has been shown to reduce tumor growth, metastasis, and angiogenesis. After the promising results from the METEOR, CABOSUN and Checkmate-9ER trials, cabozantinib was approved for use in patients with advanced renal cell carcinoma (RCC). The increased response rates with cabozantinib in metastatic RCC, along with the other neoadjuvant TKI data, support an expanded role for cabozantinib in the neoadjuvant setting. Methods: Patients with clinical stage ≥ T3Nx or TanyN+ or deemed unresectable by the surgeon with biopsy-proven clear cell RCC were eligible for this study, and received cabozantinib at a starting dose of 60 mg daily for 12 weeks. The primary outcome was objective response rate per RECIST v1.1 (complete and partial responses) at week 12 after the administration of cabozantinib as determined by independent radiologist review. Secondary outcomes included safety, tolerability, clinical outcome (DFS, OS), surgical outcome and quality of life. Results: As of 20 September 2021, 16 biopsy-proven clear cell RCC patients were treated with neoadjuvant cabozantinib. The median age was 56 years (range: 41-84 years) and 81.2% male. All patients completed 12 weeks of treatment, and 15 of them underwent surgery as planned without any delay after completion of 4 weeks wash-out. One patient refused to undergo surgery due to personal reasons and received further systemic treatment. Five patients (31.2%) experienced a partial response, and 11 patients had stable disease. There was no progression of disease while on cabozantinib. Median reduction of primary renal tumor size was 24% (range: 6-45%). The one patient who was deemed to be unresectable became resectable at the end of treatment. Two patients were converted from radical to partial nephrectomy. The most common AEs were diarrhea, nausea, fatigue, hypertension, anorexia, and palmar-plantar erythrodysesthesia syndrome. Intraoperatively, we did not experience any immediate complications. Postoperatively, no surgical complications related to the drug were noted. No treatment related grade 4 or 5 AEs related to cabozantinib or surgery occurred. Two patients had died at the time of analysis (1 due to COVID and 1 unknown cause). Conclusions: Cabozantinib was clinically active and safe in the neoadjuvant setting in patients with locally advanced non-metastatic clear cell RCC. Additional data will be reported including long term outcomes, correlative studies, quality of life, and frailty/sarcopenia indices. Clinical trial information: NCT04022343.
A multicenter real-world study reviewing systemic anticancer treatment choices and drop off rates between treatment lines for metastatic renal cell carcinoma in the United Kingdom: In the immunotherapy era.
Authors: McGrane John , Frazer Ricky , Challapalli Amarnath , Ratnayake Gihan , Lydon Anna , Parslow Dominique Siobhan , Sharma Anand , Moon Niall , Gupta Senjuti , Walters Sara , Driver Megan , Alexander Rebecca , Kingdon Sarah , Khan Muhammad , Bahl Amit 
Published: February 2022

358 Background: The treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved over the last few years with several systemic anti-cancer therapies (SACT) licensed across different lines of treatment. A previous real world study in the UK had demonstrated a significant attrition rate between each line of therapy suggesting less than half of patients who received first line SACT then received second line therapy and less than a fifth of first line SACT patients reach third line. Methods: We conducted a retrospective analysis of all patients treated between January 2018 and end of June 2021 to see if advancement in treatment options had impacted on the drop-off rates. Data was collected from 5 UK sites. Patients were identified from electronic SACT database. All reimbursed treatment options including the COVID interim treatment guidelines options were included. Patients who received SACT as part of a clinical trial were also included. Patients who remained on the respective lines of treatment were censored. Results: Data for 515 patients (372 male: 143 female) who received first-line SACT for mRCC were included in the analyses. IMDC prognostic groups were 103 favourable, 236 intermediate, 127 poor (49 not available). On progression 69% of patients were able to receive second-line therapy and 34% were able to receive third-line therapy. Of the 515 first-line therapies, 24% of patients received frontline ipilimumab and nivolumab, 10% received TKI and IO combination and 63% received single agent VEGF TKI. Second-line nivolumab or cabozantinib (43% and 40% respectively) were the most commonly prescribed options. Third-line cabozantinib 61% and nivolumab 16% remain the most used options. Across all lines of therapy progressive disease was the primary reason for discontinuation. 5% switched treatment due to toxicity. Conclusions: These results suggest that, with more treatment options available, including combination/ immunotherapy therapies, more patients are able to receive second and third-line therapies. Despite this, nearly one third of patients only receive one line of treatment which highlights the need to deliver the most efficacious treatments first to optimise patient outcomes. Moreover, single agent TKI was the most commonly used first-line SACT despite advances in the management pathway. Data analysing the impact of COVID on treatment selection will be presented.[Table: see text]
A prospective randomized parallel-controlled pilot trial of stereotactic body radiation therapy versus radiofrequency ablation for the management of small renal masses.
Authors: Hoogenes Jen , Swaminath Anand , Mironov Oleg , Tajzler Camilla , Cassim Raees , Millan Braden , Matsumoto Edward , Kapoor Anil 
Published: February 2022

363 Background: The potential of ablative technologies as an alternative to surgery for the treatment of small renal masses (SRMs) ≤4cm is unclear. Our objective was to evaluate the feasibility and toxicity of stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) for SRMs in a prospective randomized pilot trial. Methods: Patients scheduled for renal cell carcinoma (RCC) treatment at a single academic center were approached for the pilot trial, with the aim of recruiting 24 patients. Participants were assigned 1:1 to SBRT or RFA. Imaging (CT or MRI) using a renal tumor protocol is completed at 3, 6, 9, and 12 months post-procedure. Biopsies were completed prior to the procedure and at 12 months. Multiple clinical parameters were collected. Follow-up visits will occur at 6 month intervals following the trial up to 5 years. SBRT included an initial simulation session and a single image-guided treatment session with a prescribed dose of 25 Gy. RFA was conducted by either percutaneous or laparoscopic access with 2 cycles of 8 minutes duration each upon reaching target temperature. Results: Beginning in December 2019, 24 patients were recruited and randomized (SBRT = 11; RFA = 13). Eleven had SBRT, 8 RFA, 3 have not yet had treatment, and 2 became ineligible. Median age for all patients was 67 (53,85) and 17 were male. A total of 17 patients had clear cell RCC, 6 had papillary RCC (type 1), and 1 had chromophobe RCC. All patients had T1a disease. Mean procedure length (minutes) for SBRT and RFA was 15.5±7.4 and 10.5±3.9, respectively. Two patients (both SBRT) had a 12-month biopsy showing no evidence of recurrence or metastases, while two patients (1 RFA, 1 SBRT) had a 9-month CT showing no recurrence. Data are pending for the remaining patients. An early grade 2 flare-up occurred in one SBRT patient. Conclusions: Recruitment and randomization of patients with SRMs in a SBRT vs. RFA prospective trial is feasible on a timeline that allows for regular follow-up and imaging. To date, both treatment modalities have been shown to have excellent short-term safety profiles.
Complimentary transcriptomic-metallomic analysis identifies risk of relapse for clear-cell renal cell carcinoma (ccRCC) patients.
Authors: Gulati Shuchi , Vemuri Bhargav , Secic Dina , Shamsaei Behrouz , Plas David R. , Cunningham John T. , Meller Jarek , Landero Julio Alberto , Czyzyk-Krzeska Maria F. 
Published: February 2022

378 Background: Patients with localized or locally advanced ccRCC undergo surgical resection by partial or radical nephrectomy. Approximately 50% of tumors recur within five years after surgery. Currently the only FDA approved drug in the adjuvant setting is sunitinib. However, the absence of an overall survival benefit and the prevalence of side effects limit widespread use of sunitinib. Accurate identification of patients at high risk of recurrence would enhance targeted adjuvant therapy, while sparing low-risk patients from side effects. A single scoring system, transcriptomic signature or genomic classifier, is unlikely to accurately define prognosis. Here, we describe an integrated transcriptomic-metallomic classifier to assess the risk of relapse in localized ccRCC. Methods: We investigated the transcriptomic landscape of Caucasian male patients with stage III ccRCCs who remained disease free (S3DF) or relapsed (S3RL) within 24 months after surgery using the TCGA Firehose Legacy cohort. In a separate cohort of S3RL and S3DF ccRCCs, copper (Cu) content and molecular distribution were analyzed by size exclusion chromatography coupled to inductively coupled plasma mass spectrometry (SEC-ICP-MS). Results: Transcriptomic analysis identified that S3RL tumors were enriched for genes encoding subunits of mitochondrial electron transport chain (ETC) and mitochondrial ribosomal proteins (MRPs), an indication that mitochondrial activity may contribute to the relapse. In contrast, S3DF tumors were enrichedfor genes related to immune responses, including genes encoding members ofMHC-II, suggesting tumor control by the immune system. We established a setof 23 genes (23G) as a signature that stratified ccRCCsinto distinct groups characterized by low, intermediateand high risk of relapse after surgery. Importantly, SEC-ICP-MS analysis identified augmented distribution of Cu to the Cu cytochrome c oxidase complex (Cu-COX) in tumor mitochondria from S3RL, consistent with the prediction of increased ETC activity in the transcriptomic analysis. Conclusions: Integration of the 23G transcriptomic signature and Cu-COX complex measurements in locoregional ccRCC can serve as a prognostic biomarker for recurrence, and as a predictive classifier for novel treatments, including inhibitors of ETC for the S3RL tumors. In particular, a combination classifier using both measurements may have a stronger prognostic/predictive power as compared to either biomarker alone.
Characterization of aberrant alternative splicing landscape in patients with renal cell carcinoma (RCC).
Authors: Govindarajan Ameish , Hegde Apurva M. , Chawla Neal Shiv , Dizman Nazli , Zengin Zeynep Busra , Meza Luis A , Muddasani Ramya , Chehrazi-Raffle Alex , Malhotra Jasnoor , Castro Daniela V. , Salgia Sabrina , Bergerot Cristiane Decat , Tripathi Nishita , Sayegh Nicolas , Philip Errol James , Hsu Joann , Byron Sara A. , Pirrotte Patrick , Pal Sumanta K. 
Published: February 2022

386 Background: Aberrant alternative splicing (AS) events have been implicated in the initiation and progression of various cancers; however, the detailed nature of their role in RCC is yet to be fully elucidated. Our study aims to characterize AS events in RCC tumors using a novel AS pipeline (Bisbee). Methods: We retrospectively identified patients (pts) with RCC who had tumor-normal whole exome sequencing and tumor whole transcriptome sequencing (GEMExtra, Ashion Analytics) performed as part of their routine clinical care. AS events from RNA sequencing data were identified and further characterized as (1) alternative splice 3’ site (A3), (2) alternative splice 5’ site (A5), (3) exon skipping (ES), (4) intron retention (IR), and (5) mutually exclusive exons splice events (MUT). The Bisbee outlier analysis was performed against normal kidney tissues from the GTEx tissue library to further identify tumor-associated splice events. Outlier splice events were categorized as either non-coding/protein loss/silent, isoform switch, novel, or unknown. Results: Overall, 147 RCC pts (77% male) with RNA sequencing data were included in this analysis. Median age at diagnosis was 60 (range 31-94) and 97% of pts had metastatic RCC. The distribution of histology was 85% clear cell RCC followed by 11% papillary RCC. The AS analysis identified 25,928 outlier splice events. Approximately 60% of these were predicted to be protein-coding events, with the majority arising from IR and ES. These were followed by A3, A5, and MUT, in descending order of frequency. We also examined tumor-associated novel outlier events where 70% of analyzed RCC tumor samples noted 34 tumor-associated novel events were present, shared in most of the cohort and found an enrichment for IR events leading to frame disruptions. Data of splice variants will be presented at the meeting. Conclusions: In depth examination of this large cohort suggests that IR resulting from AS events occur frequently within RCC. Further efforts to investigate the association of AS events and clinical outcomes are underway.