bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does concurrent COX inhibition and immune checkpoint blockade improve clinical outcomes in patients with metastatic renal cell carcinoma (mRCC)?
Authors: Kumar Premsai , Zhang Yumeng , Li Jiannong , Manley Brandon J. , Chahoud Jad , Spiess Philippe E. 
Published: February 2022

354 Background: Cyclooxygenase (COX) inhibition is postulated to restore the immune environment and synergizes with immune checkpoint inhibitors (ICI). The concurrent use of COX inhibitors (COXi) and ICI was associated with longer disease control in metastatic melanoma and non-small cell lung cancer. However, its role in mRCC remains unclear. Methods: We retrospectively reviewed 194 patients with mRCC treated with ICI (PD-(L)1 inhibitors +/- CTLA-4 inhibitors or TKIs) at Moffitt Cancer Center between 6/2014-7/2019. Concurrent use of COXi (aspirin [ASA] or NSAIDs) was defined as at least 3 weeks of COXi use during the first ICI course. Clinical characteristics of both arms were compared using Chi-squared or Kruskal-Wallis Rank Sum test. Time to progression (TTP) and Overall survival (OS) were compared using Kaplan Meier’s estimates. Univariate and multivariate Cox proportional hazards model was performed to evaluate the association between clinical factors, TTP, and OS. Results: Of 194 patients, 126 patients (64.9%) took COXi. Median age was 59.7 years and 80.4% were male. COXi arm had fewer patients with < 1 year from diagnosis to systemic treatment (45.9% vs 69.5%, p=0.006) and more advanced age (median: 66 years vs 60 years, p=0.01). IDMC risk group, number of prior therapies, neutrophil to lymphocytes ratio were similar between both arms. Median TTP was 8 months (m) for COXi arm and 12m for ICI only (HR 1.38; 95% CI [0.98, 1.94]). Median OS was 27m for COXi arm and 33m for ICI only (HR 1.05, 95% CI [0.69, 1.59]). Early mortality rate (within 3m of ICI treatments) were similar between both arms. Conclusions: In contrast to melanoma and lung cancer, concurrent use of COXi and ICI did not improve TTP and OS in patients with mRCC. The dual blockade showed a trend for shorter TTP and OS. Further validation studies with larger cohorts are needed to confirm this finding.[Table: see text]
Assessing physician prescribing behaviors in first-line (1L) advanced renal cell carcinoma (aRCC): A case-based study.
Authors: Gajra Ajeet , Jeune-Smith Yolaine , Vaishampayan Ulka N. , Rupard Skyler 
Published: February 2022

355 Background: Over the past decade, immune checkpoint inhibitors (ICIs) have become foundational to aRCC management. Tyrosine kinase inhibitors (TKIs) remain a mainstay, resulting in the potential for ICI/TKI combination regimens. Four ICI/TKI combinations (pembrolizumab/axitinib [PA], nivolumab/cabozantinib [NC], pembrolizumab/lenvatinib [PL], and avelumab/axitinib [AA]) have shown promising results compared to single-agent sunitinib in randomized clinical trials (KEYNOTE-426 [KN426], CheckMate 9ER [CM9ER], CLEAR, and JAVELIN RENAL 101 [JR101], respectively); national guidelines recommend them as 1L options. Further, an ICI-based regimen of nivolumab/ipilumumab (NI) is a treatment option for poor-risk RCC based on CheckMate 214 (CM214) results. We sought to understand how community oncologists perceive data from these trials and what aspects influence their clinical decisions. Methods: In May 2021, medical oncologists experienced in treating aRCC were presented with key results from these trials and 2 clinical vignettes. Treatment preferences and reasons for decisions were captured via an audience response system. Responses were aggregated and analyzed using descriptive statistics. Results: A total of 103 U.S. medical oncologists participated; most risk-stratify their patients with either IMDC (44%), MSKCC (34%), or both (14%). When presented with simulated case studies, most (76%) indicated they are not likely to order PD-L1 testing, yet 81% will treat with an ICI-based regimen. Participants are more likely to prescribe ICI/TKI over ICI/ICI (65% vs 47%) in favorable-risk aRCC. Yet in poor-risk RCC, they are more likely to prescribe ICI/ICI over ICI/TKI (52% vs 15%). Among ICI/TKI regimen, participants showed a small preference toward PA over NC for both the poor-risk (21% vs 20%) and intermediate-risk (30% vs 23%) patient case. In the favorable-risk case, PA was significantly preferred over NC, 46% vs 19%. Most participants were aware of the trial data (91% KN426, 82% CM9ER, 57% CLEAR, 96% CM214); and more found the data from CM9ER most compelling compared to KN426 and CM214 (32%, 29%, and 23%, respectively). The participants viewed trials that met primary or survival endpoints as strong. Major limitations in each trial commonly identified were trial design (KN426, 27%); short follow-up (CM9ER, 48%); short follow-up and no OS data (CLEAR, 39% and 38%, respectively), and high discontinuation rate (CM214, 42%). Conclusions: Providers typically will treat aRCC patients with ICI-based regimens regardless of PD-L1 status and are more likely to prescribe an ICI/TKI regimen for favorable-risk and an ICI/ICI regimen for poor-risk aRCC. Meeting primary endpoints is a strong influencer in providers’ decision-making. Given the nonsignificant difference in preference for PA over NC, further research is needed to assess factors influencing providers’ decisions.
Safety and differential clinical activity of nivolumab plus ipilimumab (nivo-ipi) in patients (pts) with non-clear cell renal cell carcinoma (nccRCC).
Authors: Alhalabi Omar , Wilson Nathaniel , Ajufo Helen , Lehner Michael , Hasanov Elshad , Campbell Matthew T , Shah Amishi Yogesh , Wang Jennifer , Jonasch Eric , Araujo John C. , Wang Jianbo , Gao Jianjun , Goswami Sangeeta , Msaouel Pavlos , Tannir Nizar M. 
Published: February 2022

356 Background: Pembrolizumab monotherapy recently showed promising efficacy in nccRCC. The objective response rate (ORR) by histology was 28.8% for papillary, 9.5% for chromophobe, and 30.8% for unclassified RCC (McDermott, JCO 2021). However, combination immunotherapy data are limited in nccRCC. Methods: We retrospectively evaluated the efficacy and safety of nivo-ipi in pts with nccRCC treated at our institution. ORR and progression-free survival (PFS) were determined using RECIST. Overall survival (OS) was measured from therapy start to death or last follow up. Results: Between November 2017 and July 2020, 27 pts with nccRCC were treated with nivo-ipi at our institution; 25 pts (93%) received nivo-ipi as first-line therapy and 14 pts (52%) had prior nephrectomy. Histology subtypes included 13 (48%) papillary (4 with sarcomatoid features [SF]), 7 (26%) chromophobe (4 with SF), and 7 (26%) unclassified. Sites of metastases included lung in 52%, bone in 37%, and liver in 22% of pts. IMDC risk was favorable (8%), intermediate (48%) and poor (44%). ORR in all pts was 30%; 7 pts achieved a partial response (PR), and 1 patient achieved a complete response (CR). ORR by histology subtype was 54% for papillary, 14% for chromophobe, and 0% for unclassified (table). Clinical benefit (defined as PR, CR, or stable disease [SD] for > 6 months) was achieved in 62% for papillary, 57% for chromophobe, and 29% for unclassified. At a median follow-up time of 17.1 months, for all 27 pts, median PFS was 7.2 months, and median OS was 18.5 months. Median OS per each variant histology subtype was not reached in papillary, 25.7 months in chromophobe, and 7.4 months in unclassified. Median PFS per variant histology subtype was 11.8 months in papillary, 4.0 months in chromophobe, and 2.8 months in unclassified. Seven pts (26%) developed Grade ≥3 toxicity: pneumonitis (2), colitis (2), hepatitis (1), rash (1), and immune-mediated glomerulonephritis (1). Conclusions: In this small retrospective study, nivo-ipi was well-tolerated in pts with nccRCC and yielded high ORR and prolonged PFS in papillary RCC but disappointing efficacy results in chromophobe and unclassified RCC. Molecular studies are ongoing to understand the mechanisms of response and resistance to nivo-ipi in these tumor subtypes.[Table: see text]
Quantifying absolute benefit of adjuvant treatments in renal cell carcinoma: A systematic review and network-meta-analysis.
Authors: Sipra Qurat Ul Ain Riaz , Naqvi Syed Arsalan Ahmed , Islam Mahnoor , Asghar Noureen , Siddiqi Rabbia , Ikram Waleed , Singh Parminder , Xu Wenxin , Ho Thai Huu , Bryce Alan Haruo , Riaz Irbaz Bin 
Published: February 2022

360 Background: Pembrolizumab has been established as an effective treatment option in adjuvant renal cell carcinoma after the publication of KEYNOTE-564. However, the magnitude of benefit based on different risk categories is not well defined. Methods: We included full-text publications of phase II/III randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors or tyrosine kinase inhibitors (TKIs) in adjuvant renal cell carcinoma after a systematic search. The outcomes of interest included disease free survival (DFS), overall survival (OS), all grade or grade ≥3 treatment related, and all cause adverse events. Mixed treatment comparisons were computed through a fixed-effect multivariate meta-regression within the frequent framework. Relative treatment rankings were assessed using P-scores. We used stratified baseline risks of disease progression from observational data and at 5, 10, 15 years from the Leibovich risk stratification system (based on risk scores ranging from 0 to ≥15). Corresponding intervention risks (CIRs) were then approximated using relative effect estimates (from NMA) and baseline risks. The difference between CIRs and baseline risks were calculated to present absolute risk differences in each baseline category. Results: This NMA included six RCTs with a total of 7525 participants and five unique treatment options. Mixed treatment comparisons showed significant DFS and OS benefit with pembrolizumab (rank 1) when compared against sunitinib (DFS HR 0.74 [0.55-0.99]; OS HR 0.51 [0.27-0.94]). However, there were no significant differences with pembrolizumab compared to pazopanib (DFS HR 0.81 [0.60- 1.09]; OS HR 0.54[0.29-1.01]) and axitinib (DFS HR 0.78 [0.54-1.14]; OS HR 0.52 [0.24-1.16]). The safety profiles were comparable. Absolute benefit of TKIs in adjuvant setting was minimal whereas this benefit increased with higher T and N patients in patients treated with pembrolizumab (Table). Similarly, the treatment benefit increased with higher Leibovich’s risk scores at 5, 10 and 15 years of follow up. Conclusions: The current analysis suggests that a risk adapted approach may be useful when considering adjuvant pembrolizumab in RCC patients.[Table: see text]
Long-term PFS from TIVO-3: Tivozanib (TIVO) versus sorafenib (SOR) in relapsed/refractory (R/R) advanced RCC.
Authors: Atkins Michael B. , Verzoni Elena , Escudier Bernard , McDermott David F. , Hutson Thomas E. , Pal Sumanta K. , Porta Camillo , Asnis-Alibozek Aviva G. , Kasturi Vijay , Rini Brian I. 
Published: February 2022

362 Background: The TIVO-3 trial supported FDA-approval of TIVO in R/R advanced RCC, demonstrating significantly improved PFS over SOR in the primary independent review committee [IRC] analysis (HR: 0.672, 95% CI: 0.52-0.87). Long-term survival without disease progression (LT-PFS) is a clinically meaningful outcome among patients with R/R mRCC and ≥2 lines of prior therapy. We assessed the proportion of TIVO-3 patients living progression-free with R/R mRCC at 6-month intervals up to 4 years post-initiation of TIVO or SOR. Methods: Exploratory analysis of LT-PFS was calculated using investigator-assessment [INV] with a data cut-off of May 24, 2021. PFS hazard ratio and landmark values of LT-PFS at 6, 12, 18, 24, 30, 36, 42 and 48 months are reported. Results include the ITT population, with censoring for missing assessments and discontinuation without PD. Cox proportional hazards and log-rank statistics were used to estimate the HR and 95% CI for INV-PFS; odds ratios (ORs) are reported for landmark timepoints up to 36-months. LT-PFS across prespecified subgroups were analyzed descriptively. Results: 350 patients were randomized to TIVO (n=175) or SOR (n=175). INV PFS was superior with TIVO vs SOR (HR: 0.624, 95% CI: 0.49-0.79). Landmark LT-PFS rates up to 48-months are consistently higher with TIVO vs SOR, with 12% vs 2% and 7.6% vs 0% at 3- and 4-years, respectively (Table). Despite low numbers of patients at risk with extended follow-up, subgroups with ≥15% LT-PFS at 3-years include IMDC favorable risk, female gender, ECOG PS0, age ≥65 years, and region NA – all confined to the TIVO arm. Conclusions: INV PFS with long-term follow-up is consistent with primary IRC PFS. Patients treated with TIVO were up to 5X more likely to experience LT-PFS compared to SOR. A clinically relevant minority of patients are alive and progression-free on TIVO at 3- and 4-years. Clinical trial information: NCT02627963. [Table: see text]
Novel predictive biomarkers of response to immune checkpoint blockade with nivolumab ± ipilimumab in the TITAN-RCC phase 2 trial.
Authors: Grimm Marc-Oliver , Kesselmeier Miriam , Leucht Katharina , Schumacher Ulrike , Tunger Antje , Röber Nadja , Conrad Karsten , Sommer Ulrich , Baretton Gustavo Bruno , Scherag André , Albiges Laurence , Esteban Emilio , Barthélémy Philippe , Schmidinger Manuela , Busch Jonas , Pérez-Valderrama Begoña , de Velasco Guillermo , Duran Ignacio , Schmitz Marc , Wehner Rebekka 
Published: February 2022

367 Background: Despite promising therapeutic efficacy of immune checkpoint inhibitors in renal cell carcionoma (RCC) response varies significantly between individual patients. Therefore, predictors of response are urgently needed. To identify novel predictive biomarkers, we explored the characteristics of blood-circulating immune cell subsets within the population of the TITAN-RCC trial (NCT02917772) applying a tailored approach with nivolumab (nivo) and ipilimumab (ipi). Methods: In TITAN-RCC, patients with intermediate and poor risk advanced clear cell RCC started nivo Q2W induction. Upon early progressive disease (PD, week 8) or non-response (stable disease or PD) at week 16, patients received 2-4 nivo+ipi “boost” cycles. Responders (complete or partial response) to nivo induction continued with maintenance but could receive nivo+ipi for later PD. Blood samples for biomarker analyses were taken at baseline, during nivo induction and nivo+ipi “boost” cycles. Samples from 198 RCC patients (105 first line, 93 second line) were analyzed by multi-parametric flow cytometry for frequency and phenotype of T cell, monocyte, myeloid-derived suppressor cell (MDSC) and dendritic cell (DC) subsets. Baseline data were associated to response upon nivo induction and data from samples taken prior to first “boost” to response to nivo+ipi. We applied uni- and multivariable logistic regression modelling to investigate the association between treatment response and immune parameters. Here we report on single marker models (adjusted for age and gender). Results: Higher percentages of blood-circulating 4-1BB+ CD4+ T cells (adjusted odds ratio (ORadj) 1.05, 95% CI 1.02-1.08), 4-1BB+ CD8+ T cells (ORadj 1.03, 95% CI 1.01-1.07) and LAG3+ CD4+ T cells (ORadj 1.03, 95% CI 1.01-1.05) were found in responders to nivo induction compared to non-responders. Moreover, in patients receiving nivo+ipi “boosts”, a higher proportion of PD-L1+ CD14+ monocytes (ORadj 1.22, 95% CI 1.06-1.58), PD-L1+ early-stage MDSC (ORadj 1.14, 95% CI 1.02-1.41) and PD-L1+ plasmacytoid DC (ORadj 1.08, 95% CI 1.01-1.17) was observed in responders compared to non-responders. Conclusions: We identified various immune cell-related parameters that are associated with increased or poor therapeutic efficacy in RCC patients which are currently investigated in multi-marker models. These parameters may represent novel predictive biomarkers for response to nivo±ipi in clear cell RCC. Clinical trial information: NCT02917772.
Validation of a 22-gene epithelial-mesenchymal transition (EMT) prognostic signature in clear cell renal cell carcinoma.
Authors: Cotta Brittney , Nallandhighal Srinivas , Stangl-Kremser Judith , Pham Trinh , Tosoian Jeffrey J. , Marchetti Kathryn , Berends Joel , Maruf Mahir , Tomlins Scott A. , Morgan Todd Matthew , Palapattu Ganesh S. , Adbulfatah Eman , Udager Aaron M. , Salami Simpa 
Published: February 2022

377 Background: Current predictors of metastatic progression after radical nephrectomy for localized clear cell renal cell carcinoma (ccRCC) include clinicopathologic features such as tumor stage and grade. The addition of molecular tumor characteristics in a prognostic score may improve risk stratification and patient selection for enhanced follow up strategies or adjuvant therapies. Methods: We retrospectively identified consecutive patients with ccRCC who underwent radical nephrectomy (RNx) for localized disease. Those who developed metastasis were identified. Whole-transcriptome mRNA sequencing of primary tumors was performed followed by gene set enrichment analysis (GSEA) for the most significant cancer hallmark pathways enriched in patients who did or did not develop metastasis. For each patient, the 22-gene epithelial mesenchymal transition (EMT) score was calculated (high vs. low), using cut-offs from a prior study using TCGA data. The prognostic impact of the EMT score was evaluated by performing multivariable cox-proportional hazard testing and Kaplan-Meier (KM) survival analysis. Results: We analyzed 82 patients with median age 62 years and median tumor size 6 ±2.9 cm. The median time to metastasis after radical nephrectomy for patients who developed metastasis (n = 12) was 18.2 months and 31.1 months for patients who did not develop metastasis (n = 70). We observed a significant enrichment of EMT, myogenesis, inflammatory response and hypoxia hallmark pathways in patients with metastasis vs. those without metastasis. Multivariable analysis controlling for relevant clinicopathologic features such as age, sex, tumor size, tumor stage etc. revealed high EMT score to be significantly associated with development of metastasis [hazard ratio (HR) 7.2; 95% CI 1.15-44.8; ]. Conclusions: Here we validate a prognostic 22-gene epithelial mesenchymal transition (EMT) score in patients treated with radical nephrectomy for localized ccRCC. Pending further studies, the EMT score may improve risk stratification and select patients for adjuvant therapy.
Characteristics and outcomes of patients managed with surgical resection of brain metastasis from renal cell carcinoma.
Authors: Drescher Max , Patel Sunil H. , Alam Ridwan , De La Calle Claire , Yerrapragada Anirudh , Bettegowda Chetan , Matoso Andres , Ged Yasser , Singla Nirmish 
Published: February 2022

392 Background: For patients with metastatic renal cell carcinoma (mRCC), the presence of brain metastases (BM) confers a poor prognosis compared with alternative metastatic sites. Being an uncommon site of spread, granular data regarding BM in RCC is relatively sparse. We retrospectively reviewed the clinical features and outcomes of patients with surgically-resected BM from mRCC at our institution. Methods: Patients with mRCC and BM were identified within our institutional experience. Clinical and treatment data was obtained from electronic records. A diagnosis of mRCC to the brain was determined by pathological confirmation obtained via metastasectomy or rarely biopsy. Baseline patient demographics, clinicopathological disease characteristics and survival data were extracted. Overall survival (OS) was calculated from the date of BM intervention using Kaplan–Meier methods. Results: 54 patients were identified with surgically resected BM. Median age at RCC diagnosis was 58 years (IQR 49-67) and most patients were male (n = 39, 73%). 30 patients (56%) presented with de novo metastatic disease without any prior localized treatment, and most developed or presented with multiple metastatic sites. The most common histologic subtype was clear cell carcinoma (n = 51, 94%) and high grade disease was common (n = 39, 73%). The initial treatment of BM for the majority of patients was with neurosurgical resection (94%) followed by post-operative stereotactic radiosurgery (SRS) (87%) and systemic therapy (75%). For patients receiving systemic therapy, most received multiple agents (median 2, range 1-5). 32% of patients had received systemic therapy prior to developing BM. 19 patients (35%) received immune-checkpoint inhibitors. The median overall survival for patients from the date of neurosurgical intervention was 14.5 months (95% CI 9.2- 25 months). Conclusions: We present a large institutional series of patients with BM from mRCC treated with surgical resection. While BM remains a poor prognostic factor in mRCC, surgical resection in selected patients remains a viable strategy. Comprehensive molecular profiling of BM and their corresponding primary RCC tumors will shed light on biological tropism of this phenomenon and underscore prognostic and therapeutic implications.[Table: see text]
Comparison of quality of life (QoL) in survivors of testicular nonseminomatous germ cell tumor (NSGCT) with age-matched controls using EORTC QLQ-C30 questionnaire.
Authors: VARSHNEY ANKUR NANDAN , Raj Abhishek , Singh Prabhjot , Nayak Brusabhanu , KP Haresh , Sahoo Ranjit Kumar , Batra Atul 
Published: February 2022

413 Background: Testicular NSGCT is typically diagnosed in young males, and is a highly curable cancer. Data pertaining to the quality of life of testicular NSGCT survivors are limited. Methods: Patients aged 18 or more years with a diagnosis of testicular NSGCT treated in a large tertiary care centre in New Delhi, India between January 2015 and July 2019 were eligible to participate. Patients had to be disease free for at least two years for QoL assessment using EORTC QLQ-C30 questionnaire. Raw scores were transformed as per the EORTC scoring manual. Controls were healthy age-matched adults recruited from the patient accompanying population. Results: We identified 55 survivors and 100 controls. Median age was 32 (range, 18-65) years and 58.2% of patients stage III disease, while the rest were equally divided in stage I and II. Chemotherapy was administered in 94% patients, while 25% had retroperitoneal lymph node resection for residual disease and relapse occurred in 11%, who were treated with salvage chemotherapy and resection of the residual disease. Emotional, social and global scores were significantly lower in survivors as compared to controls. Among symptom scales, fatigue, pain, dyspnoea, insomnia, appetite loss, and financial difficulty were significantly increased in patients as compare to survivors (Table). On a multivariate analysis, neither stage of disease nor treatment were found to be associated significantly with QOL scores. Conclusions: Survivors of testicular NSGCT have lower emotional, social and global functioning and a higher symptom burden. Since NSGCT affects young males, aggressive measures may be needed to improve the QoL in such patients.[Table: see text]