bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC)
Authors: Motzer Robert J. , Powles Thomas , Atkins Michael B. , Escudier Bernard , McDermott David F. , Suarez Cristina , Bracarda Sergio , Stadler Walter Michael , Donskov Frede , Lee Jae-Lyun , Hawkins Robert E. , Ravaud Alain , Alekseev Boris Y. , Staehler Michael D. , Uemura Motohide , Donaldson Francis , Li Shi , Huseni Mahrukh A. , Schiff Christina , Rini Brian I. 
Published: February 2018

578 Background: Atezolizumab (atezo; anti–PD-L1) + bevacizumab (bev; anti-VEGF) showed first-line (1L) anti-tumor activity with a manageable safety profile in PD-L1+ mRCC pts in a Phase II study (McDermott ASCO-GU 2017). Here we describe the first randomized Phase III trial of a PD-L1/PD-1 pathway inhibitor combined with an anti-VEGF agent in 1L mRCC. Methods: IMmotion151 (NCT02420821) enrolled treatment-naïve pts regardless of prognostic risk group randomized 1:1 to receive atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sunitinib (sun) 50 mg PO QD 4 wk on/2 wk off. Pts were stratified by PD-L1 status (< 1% vs ≥ 1% PD-L1 expression on tumor-infiltrating immune cells [IC]; SP142 IHC assay). Coprimary endpoints: progression-free survival (PFS; by investigator per RECIST v1.1) in PD-L1+ pts (≥ 1% IC) and overall survival (OS) in intent-to-treat (ITT) pts. Secondary endpoints included PFS in ITT pts, ORR and DOR. Results: Baseline characteristics were comparable between arms within PD-L1+ (40% of ITT) and ITT pts. Median survival follow-up was 15 mo. PFS HR for atezo + bev vs sun was 0.74 (95% CI 0.57, 0.96) in PD-L1+ pts and 0.83 (95% CI 0.70, 0.97) in ITT pts. OS was immature at first interim analysis. PFS benefit was consistent across analyzed subgroups, including MSKCC risk, liver metastases and sarcomatoid histology. In PD-L1+ pts, ORR was 43% and DOR was not reached for atezo + bev vs 35% and 12.9 mo for sun. 40% of atezo + bev–treated pts and 54% of sun-treated pts had treatment-related Gr 3-4 AEs; 12% and 8% of treatment-related all-Gr AEs led to discontinuation, respectively. Conclusions: The study showed longer PFS for atezo + bev vs sun in PD-L1+ pts. Improved PFS was also observed in ITT pts. Safety was consistent with that of the individual agents. These results support the use of atezo + bev as a 1L treatment option in mRCC. Clinical trial information: NCT02420821. [Table: see text]
Cabozantinib versus sunitinib for previously untreated patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk: Subgroup analysis of progression-free survival (PFS) and objective response rate (ORR) in the Alliance A031203 CABOSUN trial.
Authors: George Daniel J. , Hessel Colin , Halabi Susan , Sanford Ben L. , Michaelson M. Dror , Hahn Olwen Mary , Walsh Meghara K. , Olencki Thomas , Picus Joel , Small Eric Jay , Dakhil Shaker R. , Feldman Darren R. , Mangeshkar Milan , Scheffold Christian , Morris Michael J. , Choueiri Toni K. 
Published: February 2018

582 Background: The randomized phase 2 CABOSUN trial (NCT01835158) compared cabozantinib (C) with sunitinib (S) as initial systemic therapy in patients (pts) with RCC of intermediate or poor risk. Compared with S, C improved both PFS and ORR as assessed by independent radiology review committee (IRC). Median PFS per IRC was 8.6 mo for C vs 5.3 mo for S (HR 0.48, 95% CI 0.31-0.74 two-sided p = 0.0008), and ORR per IRC was 20% vs 9%. Methods: 157 patients were randomized 1:1 to receive C (60 mg qd) or S (50 mg qd, 4 weeks on/2 weeks off) stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group and the presence of bone metastases. Subgroup analyses of PFS per IRC and ORR per IRC are presented based on stratification factors, age, sex, baseline ECOG status, and MET tumor expression by immunohistochemistry. The primary endpoint was investigator-assessed PFS. PFS and ORR were evaluated by IRC in a post-hoc analysis. Results: 45% of pts were ≥65 years, 78% were male, 54% were ECOG 1 or 2, 19% were poor risk, and 36% had bone metastases. MET status was determined in 131 pts; of these 47% were MET positive. The HR for PFS per IRC favored C over S across all subgroups analyzed (Table). Subgroups with poor prognostic characteristics (poor risk, ECOG 1 or 2, presence of bone metastases) had shorter median PFS for both C and S. Odds ratios for ORR also favored C over S, with the highest C ORR in the MET positive subgroup (34% C vs 10% S). Conclusions: C was associated with improved PFS and ORR compared with S in previously untreated pts with advanced RCC irrespective of baseline characteristics. Clinical trial information: NCT01835158. [Table: see text]
Self-reported quality of life as a predictor of survival in renal cell carcinoma.
Authors: Alam Ridwan , Patel Hiten , Pierorazio Phillip M. 
Published: February 2018

595 Background: Quality of life (QOL) in cancer patients has gained increasing attention and may provide prognostic value above and beyond traditional demographic and disease parameters. We evaluate the utility of self-reported QOL to predict mortality in patients with renal cell carcinoma (RCC). Methods: The Medicare Health Outcomes Survey was linked to SEER data to identify patients who completed a QOL questionnaire after the diagnosis of RCC from 1998-2014. Mental component summary (MCS) and physical component summary (PCS) scores were classified as high (≥50) or low ( < 50) based on a population mean score of 50 points. Patients were classified into four groups: 1) high MCS, high PCS; 2) high MCS, low PCS; 3) low MCS, high PCS; and 4) low MCS, low PCS. Multivariable Cox proportional hazards regression evaluated associations between QOL and all-cause mortality (ACM). The Harrell’s concordance statistic (C-index) estimated predictive accuracy. Fine and Gray competing risks models adjusted for stage, demographics, and comorbidities evaluated RCC-specific and non-RCC-specific mortality. Results: A total of 1494 patients with a median age of 73.4 years (IQR 68.8-79.3) at survey completion were included. Median follow-up was 5.6 years (IQR 4.0-8.3). There were 747 deaths, of which 139 were due to RCC. Models showed that each additional MCS and PCS point reduced the hazard of ACM by 1.3% (95% CI 0.981-0.993, P< 0.001) and 2.2% (95% CI 0.972-0.985, P< 0.001), respectively. The C-index was 72.1%. In the competing risks model, the subdistribution hazard ratio (SHR) of RCC mortality in Groups 2, 3, and 4 were 2.71 (95% CI 1.18-6.22, P= 0.02), 4.55 (95% CI 1.57-13.18, P= 0.005), and 3.11 (95% CI 1.35-7.16, P= 0.008), respectively, compared to Group 1. The SHR for non-RCC mortality were 1.50 (95% CI 1.16-1.94, P= 0.002), 1.03 (95% CI 0.59-1.78, P= 0.9), and 1.83 (95% CI 1.41-2.38, P< 0.001), respectively, relative to Group 1. Conclusions: Self-reported QOL metrics can be used to predict ACM in RCC patients with good accuracy; lower PCS and MCS scores led to higher rates of ACM, even after accounting for differences in disease, demographics, and comorbidity. Furthermore, non-RCC mortality was associated more with low physical health rather than low mental health.
Antibiotic use and outcomes with systemic therapy in metastatic renal cell carcinoma (mRCC).
Authors: Lalani Aly-Khan A. , Xie Wanling , Lin Xun , Steinharter John A. , Martini Dylan J. , Duquette Audrey , Bosse Dominick , McKay Rana R. , Simantov Ronit , Wei Xiao X. , McGregor Bradley A , Harshman Lauren Christine , Choueiri Toni K. 
Published: February 2018

607 Background: Antibiotic (Abx) use is shown to alter commensal gut microbiota, a key regulator of immune homeostasis. We conducted the largest investigation to date on the impact of Abx use on outcomes in mRCC patients treated with systemic agents. Methods: Two cohorts were analyzed: an institutional cohort (DFCI, n = 146) of patients receiving PD-1/PD-L1-based immune checkpoint inhibitors (ICI), and an external cohort from pooled phase II/III clinical trials (Pfizer, n = 4144) of patients treated with interferon (IFN, n = 510), mTOR inhibitors (n = 660), and VEGF inhibitors (n = 2974). Abx use was defined as Abx treatment at any time between 8-weeks pre- and 4-weeks post the start of systemic therapy. We examined the associations of Abx use and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) using Cox/logistic regression models, adjusted for prognostic factors including risk groups. Results: In the DFCI cohort, 15% had non-clear cell histology, 43% had first-line ICI, 45% had combotherapy. Baseline characteristics were balanced between Abx users (n = 31, 21%) and non-users (p > 0.15). Abx users had a lower ORR (12.9 vs 34.8%, p = 0.026) and shorter PFS compared to non-users (Table). In the external cohort, Abx users (n = 709) had lower ORR (19.3 vs 24.2%, p = 0.005). IFN treated patients (current or prior cytokines) had worse OS if they received Abx compared to those who did not. However, there was no OS difference by Abx use in mTOR or VEGF treated patients without prior cytokines. Conclusions: Abx use was independently associated with worse outcomes in mRCC patients receiving contemporary ICI or historic cytokine immunotherapy. We hypothesize that concurrent use of Abx may reduce the efficacy of ICI due to a complex interplay with the host microbiome. [Table: see text]
Impact of hypertension on recurrence and survival of patients with renal cell carcinoma after surgery.
Authors: Suyama Takahito , Kanesaka Manato , Otsuka Kotaro , Fujimoto Ayumi , Hou Kyokushin , Kato Tomonori , Araki Kazuhiro , Masuda Hiroshi , Kojima Satoko , Naya Yukio 
Published: February 2018

611 Background: Hypertension (HT) is an established risk factor for developing renal cell carcinoma (RCC), and a relationship between the renin-angiotensin system and RCC has been emphasized. However, information about the impact of HT on treatment outcomes of patients after RCC surgery is limited. The present study aimed to clarify the impact of HT on the recurrence and survival of patients with RCC after surgery. Methods: Relationships between HT and clinical data including treatment outcomes were retrospectively analyzed in 149 patients (male, n = 112; female, n = 37; median age, 63 y; range, 29-86 y at the time of surgery) who underwent surgery between 2010 and 2016 at our hospital. Data were statistically analyzed using JMP version 9.0. Results: During a median follow-up period of 30.9 months, 28 and 16 patients experienced recurrence and died, respectively. Patients (n = 15) with Stage IV RCC were excluded from the analysis of recurrence. Five-year overall (OS) and recurrence-free (RFS) survival rates of the entire cohort were 80.8% and 76.1%, respectively. Kaplan-Meier analysis did not uncover a relationship between HT and OS, but the RFS rate was significantly lower for patients with HT than without HT (P = 0.0468). Tumor stage and the prevalence of proteinuria were significantly higher in the group with HT. The prevalences of vessel invasion (P = 0.0582) and low pre-surgical hemoglobin values (P = 0.0585) tended to be significantly higher for patients with HT. Conclusions: Patients with HT had significantly worse RFS rates, a more advanced stage of disease at the time of surgery, and a tendency towards a higher rate of vessel invasion. Further investigations are warranted to determine how HT promotes cancer progression.
Tivozanib combined with nivolumab: Phase Ib/II study in metastatic renal cell carcinoma (mRCC).
Authors: Escudier Bernard , Barthelemy Philippe , Ravaud Alain , Negrier Sylvie , Needle Michael N. , Albiges Laurence 
Published: February 2018

618 Background: Tivozanib is a VEGFR-TKI with high specificity and lower incidence of class effect adverse events. As combinations of vascular endothelial growth factor receptor tyrosine kinase inhibitiors (VEGFR-TKIs) and checkpoint inhibitors have proven to be toxic, alternatives with an improved AE profile are required. We present safety data from a phase Ib/II combination of tivozanib and nivolumab Methods: In this phase Ib/II study, tivozanib was administered orally at two dose levels, 1.0 mg and 1.5 mg, once daily for 21 days every 28 day cycle in combination with nivolumab 240 mg every 14 days intravenously. Results: Eighteen patients have been enrolled. Phase Ib is complete. Safety data is available for 13, 3 at 1.0 mg tivo; 10 at 1.5 mg tivo. The median age was 62; 11 patients were ECOG 0 and 5 ECOG 1; and there were 13 males. 16 had clear cell histology No patient in phase Ib experienced an DLT in cycle 1. Patients in phase II are receiving tivozanib at 1.5 mg. All patients experienced at least one AE. The most common adverse events were hypertension, asthenia, mucositis, diarrhea, hand foot syndrome, arthralgia, and pruritis. Five patients (38%) had grade 3-4 AEs. One patient had both elevated serum lipase and amylase and one patient had an SAE of symptomatic malignant hypertension complicated by a seizure. The other grade 3-4 AEs were pneumonitis, stomatitis, and elevated ALT. Conclusions: As expected from a VEGFR-TKI with high specificity and a preferable toxicity pattern as a single agent, the combination of tivozanib with nivolumab is safe and manageable at full dose of both drugs. Efficacy is pending. This data is based on limited exposure and should be interpreted with caution. Additional patients are being enrolled and treated. This begs the question if tivozanib could be added to a triple combination with ipilimumab and nivolumab. Clinical trial information: NCT03136627. [Table: see text]
Outcomes and patterns of disease progression in metastatic renal cell carcinoma patients treated with nivolumab.
Authors: Zahoor Haris , Barata Pedro C. , Allman Kimberly D , Martin Allison , Ornstein Moshe Chaim , Grivas Petros , Gilligan Timothy D. , Garcia Jorge A. , Rini Brian I. 
Published: February 2018

654 Background: Nivolumab (nivo) has been approved for the treatment of refractory metastatic renal cell carcinoma (mRCC). Data regarding the characteristics and outcomes of patients (pts) who progress on nivo are lacking. Methods: A retrospective analysis of pts with clear cell mRCC who received nivo at Cleveland Clinic (2015-2017) was performed. Pts were divided into two groups; 1) PD group; pts with progressive disease (PD) per RECIST v1.1 or clinical PD, and 2) NPD group; pts with non-progressive disease on nivo. Results: Ninety pts (PD group n = 55, NPD group n = 35) with median age of 67 (33-83), 74% men, and 79% ECOG 0-1 were included. Pts had received 1 (44%), 2 (29%), or ≥ 3 (27%) prior systemic treatments, most commonly with sunitinib (71%), axitinib (39%) and pazopanib (33%). Pts in the PD group had a greater incidence of baseline liver metastases (PD, 40% vs. NPD, 14%; p = 0.01), with other baseline characteristics not significantly different. Median follow up was similar in both groups (PD group, 8.0 months (95% CI, 5.5-10.5) and NPD group, 7.1 months (95% CI, 4.9-9.3); p = 0.87). Median duration of treatment for PD group was 8.7 months (95% CI, 7.3-10.1) compared to 16.1 months (95% CI, 8.6-23.6) for NPD group (p = 0.02). In the PD group, 50 (91%) pts developed PD per RECIST v1.1 whereas 5 (9%) pts had clinical PD. New organ sites of metastases were found in 20/55 (36%) pts; brain (8/20; 40%), liver (4/20; 20%), soft tissue (4/20; 20%), and locoregional (4/20; 20%) were the most common new organ sites, whereas lungs, lymph nodes and pancreas were never involved at PD as new organ sites. Twelve pts received treatment beyond progression (TBP) with a median duration of TBP of 2.8 months (95% CI, 0.6-5.0) and 50% of pts had stable disease as their best response. Median overall survival (OS) and progression free survival (PFS) on nivo were 10.1 months (95% CI, 6.6-13.6) and 5.5 months (95% CI, 2.9-8.1), respectively. Conclusions: Pts with PD on nivo have a higher incidence of hepatic metastases at baseline, and one third of these pts develop new sites of metastases at PD, most commonly brain.
Accumulation of tumor infiltrating myeloid-derived suppressor cells associates with changes in the immune landscape of clear cell renal cell carcinoma.
Authors: Lin Lin , Pavicic Paul G , Rayman Patricia A. , Tannenbaum Charles , Rini Brian I. , Hamilton Thomas , Finke James , Diaz-Montero C. Marcela 
Published: February 2018

655 Background: Myeloid-derived suppressor cells (MDSC) are capable of inducing profound immune suppression of anti-tumor T cell responses. Here we examined the ability of intratumoral MDSC accumulation to alter the immune landscape of RCC and to identify the factors involved. Methods: Using flow cytometry, 41 clear cell RCC nephrectomy samples were assessed for their total MDSC infiltrate and the percentage of granulocytic (PMN-MDSC) or monocytic (M-MDSC) subsets. RNA isolated from these tumor samples and 4 non-tumor samples was also evaluated for expression levels of immune-related genes using a Nanostring PanCancer immune panel. A multiple linear regression model was used to identify which immune-related genes might be significantly associated with PMN-MDSC intratumoral accumulation. Log-Rank test was used for comparison of survival curves. Results: Genes encoding cytokines, cancer-testis antigens, interleukins, and T cell function were differentially expressed by clear cell RCC and the non-tumor samples. The transcription of 55 immune-related genes was significantly associated (FDR adjusted p < 0.05) with PMN-MDSC infiltration, including mediators of MDSC recruitment such as CXCL1, CXCL3, CXCL5, CXCR2, IL8, LIF, S100A8, CSF3R, and CCR3, and molecules governing MDSC expansion and function such as IL10, C/EBPB, CD44, COX2, and NFATC3. When a statistically significant 10 gene signature was analyzed in the context of patient survival using the TCGA database of clear cell RCC patients (n = 945), a strong association between the expression of these genes and reduced survival was observed. Moreover, this association seemed to be additive, with expression of 7-10 of these genes correlating with poorer survival when compared to patients expressing 3 or less (p < 0.0001). Conclusions: Consistent with previous studies defining the immunoregulatory role of MDSCs, these results suggest that MDSC accumulation can alter the inflammatory state of the tumor, and indicate that mediators associated with the function of PMN-MDSCs can have a negative impact on outcome. Mechanistic studies aimed at identifying the functionally relevant mediators are ongoing.
Relationship of tumor mutational burden (TMB) to immunotherapy response in metastatic renal cell carcinoma (mRCC).
Authors: Maia Manuel C. , Almeida Lorena , Bergerot Paulo Gustavo , Dizman Nazli , Pal Sumanta K. 
Published: February 2018

662 Background: Multiple studies across histologies (e.g., lung cancer, melanoma and bladder cancer) have linked TMB to response to checkpoint inhibition (CPI). However, the association in patients with mRCC remains unclear. Methods: From an institutional database, consecutive patients (pts) with mRCC who had comprehensive genomic profiling (CGP) done in the course of routine clinical care were assessed. Data pertaining to systemic therapy was collected, and for each patient, duration of therapy (DOT) on 1st immunooncology agent (DOT-IO) was computed. Furthermore, best response data (using a RECIST v1.1 defintion) was collected, and patients were characterized as either having clinical benefit (CB; defined as complete/partial response or stable disease) or no clinical benefit (NCB; progressive disease). CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 718X for up to 315 cancer-related genes plus introns from up to 28 genes frequently rearranged in cancer. TMB was estimated using the cumulative number of non-variant of unknown significance (non-VUS) and VUS genomic alterations (GAs). The correlation between TMB and DOT-IO as well as CB rate was assessed. Results: Of 31 patients (26:5 M:F) who received IO, 25 pts and 6 pts had clear cell and non-clear cell (papillary = 4; sarcomatoid = 1; chromophobe = 1) histologies, respectively. The most common 1st IO agent rendered was nivolumab (77%), and this was administered most commonly in the post-2nd-line setting (60%). The median number of GAs in the cohort was 10, with the most frequent GAs encountered being VHL (21%), TERT (10%) and PBRM1 (10%). When segregated in groups by estimate of TMB, DOT-IO was similar in high TMB and low TMB pts (71 days and 70 days, respectively; P = 0.39). The median estimated TMB was similar in pts with CB and NCB (11 and 10, respectively; P = 0.84). Conclusions: While previous studies in other histologies have suggested an association between TMB and IO response, our study fails to confirm these findings in mRCC. Given our limited sample size, this association warrants exploration in larger series.
Phase II trial of pexa-vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, in patients with metastatic, refractory renal cell carcinoma (RCC).
Authors: Kim Seong-Geun , Ha Hong Koo , Lim Sung-nam , De Silva Naomi S. , Pelusio Adina , Mun Jae Hee , Patt Richard H. , Breitbach Caroline J. , Burke James M. 
Published: February 2018

671 Background: Pexa-Vec is a vaccinia virus engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), thereby stimulating anti-tumor immunity, direct oncolysis, and tumor vascular disruption. ( Nat Rev Cancer 2009). Pexa-Vec was shown to replicate in metastatic tumors following intratumoral (IT) or intravenous (IV) administration ( Lancet Oncol 2008; Nature 2011). Methods: RCC patients failing at least 1 prior VEGF/R-targeted therapy received five weekly IV Pexa-Vec infusions. Starting at Week 6, patients with disease control or otherwise clinically benefitting from treatment could continue to receive IV infusions every 3 weeks. The primary study objective was radiographic response based on modified Response Evaluation Criteria (RECIST) 1.0. Secondary objectives included disease control rate, progression free survival and safety. Results: All seventeen patients enrolled received the initial 5 weekly Pexa-Vec infusions. Twelve patients received at least one additional infusion (median Pexa-Vec infusions = 8; range 5-12). The treatment regimen was well-tolerated. Transient influenza-like illness (100%), asthenia (47%), anemia (29%) and nausea (29%) were the most common adverse events. All patients were evaluable radiographically at Week 6. The RECIST disease control rate was 76% at Week 6 including 1 complete response. Conclusions: Pexa-Vec was well-tolerated and associated with one complete RECIST response and 76% disease control at Week 6 in patients with advanced RCC. Further trials of Pexa-Vec in RCC patients are warranted.