bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II trial combining tumor-targeting TP53 gene therapy with gemcitabine/nab-paclitaxel as a second-line treatment for metastatic pancreatic cancer.
Authors: Leung Chris Poki , Barve Minal A. , Wu Ming-Shiang , Pirollo Kathleen F. , Strauss James F. , Liao Wei-Chih , Yang Shih-Hung , Nunan Robert Alan , Adams Jana , Harford Joe B. , Chang Esther H. 
Published: June 2021

4139 Background: Nearly all stage IV pancreatic adenocarcinoma (PAC) patients progress after first-line treatment, and second-line options are limited. SGT-53 is an investigational product for tumor-targeted TP53 gene therapy that has completed phase Ia/Ib trials [Senser et al (2013), Mol Ther 21:1096; Pirollo et al (2016) Mol Ther 24:1697]. Methods: Here we provide an interim analysis of a Phase II trial (SGT53-02-1; NCT02340117) combining SGT-53 with gemcitabine/nab-paclitaxel (GEM/ABX). Eligible were first-line patients or those who had progressed after FOLFIRINOX (FFX) and/or gemcitabine-based therapy (second-line). In a 7-week treatment cycle, SGT-53 (3.6 mg DNA) was given once or twice weekly with GEM/ABX (1000 mg/m2/wk and 125 mg/m2/wk, respectively, for 3 of 4 weeks). Progression-free survival (PFS) and objective response rate (ORR) are primary endpoints.Overall survival (OS) and PFS are estimated by Kaplan-Meier analysis. Results: Of all evaluable patients (n=20), best response in 7 patients was determined to be partial response (PR) and 13 had stable disease (SD); none had progressive disease. In the second-line patients (n=11) there were 5 PR and 6 SD after 9 had failed FFX treatment, 3 had failed gemcitabine-based treatment and 1 had failed both. For patients with elevated CA19-9, SGT-53 + GEM/ABX resulted in marked reductions in the tumor marker. Published data for patients with PAC after therapy failure [Mita et al (2019) J Clin Med 8: 761; Portal et al (2015) Br J Cancer 113:989; Wang-Gillam et al (2016) Lancet 387:545] are shown for comparison. Notably, mPFS in our second-line patients was 7.4 months versus 3.1 months for the approved second-line therapy [Wang-Gillam et al (2016)]. This improvement in PFS exceeds the benchmark proposed to predict a clinically meaningful Phase III trial [Rahib et al (2016) Lancet Oncol 2:1209]. Conclusions: Our data suggest a clinically meaningful benefit of adding SGT-53 to GEM/ABX particularly for second-line PAC patients, most of whom had failed prior FFX treatment. Clinical trial information: NCT02340117. [Table: see text]
Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: Results of a phase 2 trial.
Authors: Lee Chung-Han , Voss Martin H , Carlo Maria Isabel , Chen Ying-Bei , Reznik Eduard , Knezevic Andrea , Lefkowitz Robert A , Shapnik Natalie , Tassone Diana , Dadoun Chloe , Shah Neil J. , Owens Colette Ngozi , McHugh Deaglan Joseph , Aggen David Henry , Laccetti Andrew Leonard , Kotecha Ritesh , Feldman Darren R. , Motzer Robert J. 
Published: June 2021

4509 Background: Cabozantinib plus nivolumab (CaboNivo) improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) over sunitinib in a phase 3 trial for metastatic clear cell renal cell carcinoma (RCC). (Choueiri, abstract 6960, ESMO 2020) We report the results of a phase 2 trial of CaboNivo in patients (pts) with non-clear cell RCC. Methods: Pts had advanced non-clear cell RCC, 0 or 1 prior systemic therapies excluding prior immune checkpoint inhibitors, and measurable disease by RECIST. Cabo 40 mg/day plus Nivo 240 mg every 2 weeks or 480 mg every 4 weeks was given across two cohorts. Cohort 1: papillary, unclassified, or translocation associated RCC; Cohort 2: chromophobe RCC. The primary endpoint was ORR by RECIST; secondary endpoints included PFS, OS, and safety. Cohort 1 was a single stage design that met its primary endpoint and was expanded to produce more precise estimates of ORR. Cohort 2 was a Simon two-stage design that closed early for lack of efficacy. Correlative analyses by next generation sequencing were performed and to be presented. Results: A total of 40 pts were treated in Cohort 1, and 7 pts were treated in Cohort 2 (data cutoff: Jan 20, 2021). Median follow up time was 13.1 months (range 2.2 – 28.6). In Cohort 1, 26 (65%) pts were previously untreated, and 14 (35%) pts had 1 prior line: 10 (25%) received prior VEGF-targeted therapy and 8 (20%) received prior mTOR-targeted therapy. ORR for Cohort 1 was 48% (95% CI 31.5–63.9; Table). Median PFS was 12.5 months (95% CI 6.3–16.4) and median OS was 28 months (95% CI 16.3–NE). No responses were seen among 7 patients in Cohort 2 with chromophobe histology (Table). Grade 3/4 treatment emergent adverse events were consistent with that reported in the phase 3 trial; Grade 3/4 AST and ALT were 9% and 15%, respectively. Cabozantinib and nivolumab were discontinued due to toxicity in 17% and 19% of pts, respectively. Conclusions: CaboNivo had an acceptable safety profile and showed promising efficacy in metastatic non-clear cell RCC pts with papillary, unclassified, or translocation associated histologies whereas activity in patients with chromophobe RCC was limited. Clinical trial information: NCT03635892. [Table: see text]
Clinical activity of durvalumab and savolitinib in MET-driven, metastatic papillary renal cancer.
Authors: Suarez Rodriguez Cristina , Larkin James , Patel Poulam M. , Valderrama Begoña P. , Rodriguez-Vida Alejo , Glen Hilary , Thistlethwaite Fiona , Ralph Christy , Srinivasan Gopalakrishnan , Mendez-Vidal Maria Jose , Carter Abigail , Tyson Charlotte , Prendergast Aaron , Mousa Kelly , Powles Thomas 
Published: June 2021

4511 Background: Savolitinib is a potent and selective MET inhibitor with activity in MET-driven papillary renal cancer (PRC). Durvalumab is a PD-L1 inhibitor which has been tested in combination with savolitinib in metastatic PRC with response rates of 29% (12/41). Here we describe the efficacy of this combination in MET-driven metastatic PRC. Methods: This single arm phase I/II trial explored durvalumab (1500mg Q4W) and savolitinib (600mg OD) together in metastatic PRC, with a 4wk savolitinib run in. Biomarker analysis results were compared with responses to treatment as planned in the protocol. The analysis presented here focuses on those patients with MET DNA alterations (central analysis:chromosome 7 gain/MET or HGF amplification/MET kinase domain mutations). Confirmed response rate (RR) (RECIST v1.1), progression-free survival (PFS), tolerability (CTCAE v4.03) and overall survival (OS) were analysed. Results: 42 patients were enrolled in the metastatic papillary cohort, of which 41 patients received treatment. The median follow up was 26.8 months. The confirmed RR was 29% (12/41) and median PFS was 4.9 months (95% CI 2.5-10.0). 14/41 (34%) of these patients had MET-driven disease. 71% (10/14) of MET-driven patients had not previously received systemic therapy and 7% (1/14) were PD-L1 positive. IMDC good, intermediate, and poor risk disease occurred in 36% (5/14), 57% (8/14), and 7% (1/14) of MET-driven patients respectively. Confirmed RR in MET-driven patients was 57% (8/14) with duration of response at 9.4 months (95% CI 3.9-Not reached [NR]). Median PFS and OS in MET-driven patients were 10.5 months (95% CI 2.9-15.7) and 27.4 months (95% CI 7.3-NR) respectively. No new safety signals were seen. Conclusions: The combination of savolitinib and durvalumab has clinical activity in MET-driven PRC. A randomised phase III study is planned based upon these data. Clinical trial information: NCT02819596.
First results of a randomized phase IB study comparing nivolumab/ipilimumab with or without CBM-588 in patients with metastatic renal cell carcinoma.
Authors: Meza Luis A , Dizman Nazli , Bergerot Paulo Gustavo , Dorff Tanya B. , Lyou Yung , Frankel Paul Henry , Mira Valerie , Llamas Marian , Hsu Joann , Zengin Zeynep Busra , Salgia Nicholas , Salgia Sabrina , Malhotra Jasnoor , Chawla Neal Shiv , Chehrazi-Raffle Alex , Gillece John D , Reining Lauren J , Trent Jeffrey M. , Highlander Sarah K , Pal Sumanta K. 
Published: June 2021

4513 Background: Recent evidence suggests that the gut microbiome is a potent mediator of immune checkpoint inhibitor (ICI) activity in metastatic renal cell carcinoma (mRCC), with both specific bacterial species and cumulative microbial diversity driving response (Routy et al Science 2018; Salgia et al Eur Urol 2020). We examined whether the butyrate-producing bacterium Clostridium butyricum, the key constituent of CBM-588, could modulate the gut microbiome in patients (pts) with mRCC receiving nivolumab/ipilimumab (N/I) and secondarily improve clinical outcome. Methods: An open-label, randomized study was conducted, with key eligibility criteria including confirmed clear cell and/or sarcomatoid mRCC, intermediate/poor risk by IMDC criteria and no systemic therapy for metastatic disease. Patients were randomized 2:1 to receive either N/I+CBM-588 or N/I alone. N/I was dosed at 3 mg/kg and 1 mg/kg IV every 3 weeks for 12 weeks, followed by N at 480 mg IV every 4 weeks. CBM-588 was dosed orally at 80 mg bid. Stool was collected for bacteriomic profiling at baseline and 12 weeks. Metagenomic sequencing was employed using previously published methods (Dizman et al Cancer Med 2020). The primary endpoint of the study was change in Bifidobacterium spp. from baseline to week 12. Secondary endpoints included change in microbial diversity and clinical outcomes including response rate (RR) and progression-free survival (PFS). Results: 30 pts were randomized between April 2019 and Nov 2020; 1 pt was excluded after genomic sequencing clarified a diagnosis of sarcoma. Among 29 evaluable patients (21:8 M:F), median age was 66, 10 pts (34%) had sarcomatoid features and 24 pts (83%) were intermediate risk. Metagenomic sequencing of paired stool specimens showed an 8-fold increase in B. bifidum and a 6-fold increase in B. adolescentis in pts receiving N/I+CBM-588 from baseline to week 12. C. butyricum was detected only in pts receiving CBM-588. Pathogenic species (e.g., Escherichia. coli and Klebsiella spp.) were more prevalent in pts not receiving CBM-588. RR was significantly higher among pts receiving N/I+CBM-588 vs N/I alone (59% vs 11%; P = 0.024). Median PFS was also prolonged with the addition of CBM-588 to N/I (NR vs 11 weeks; P < 0.001). No significant difference in grade 3/4 toxicities were observed between study arms. Conclusions: This is the first randomized, prospective study to suggest enhancement of ICI response with a live bacterial product. The observed clinical impact is corroborated by biologic findings supporting gut modulation by CBM-588. Clinical trial information: NCT03829111.
Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): Analysis of clinical and genomic subgroups from the JAVELIN Bladder 100 trial.
Authors: Powles Thomas , Petrylak Daniel P. , Park Se Hoon , Sridhar Srikala S. , Caserta Claudia , Thiery Vuillemin Antoine , Lee Hyo Jin , Bellmunt Joaquim , Yamamoto Yoshiaki , Aragon-Ching Jeanny B. , Huang Bo , Ching Keith A. , Davis Craig B. , Di Pietro Alessandra , Loriot Yohann , Grivas Petros 
Published: June 2021

4520 Background: In the phase 3 JAVELIN Bladder 100 trial, avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) vs BSC alone in patients (pts) with advanced UC that had not progressed on 1L platinum-based chemotherapy (HR, 0.69 [95% CI: 0.56, 0.86; 1-sided P= 0.0005]). We report post hoc analyses in previously unreported clinical and genomic subgroups. Methods: In JAVELIN Bladder 100 (NCT02603432), eligible pts had unresectable locally advanced or metastatic UC without progression after 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin, and were randomized to receive avelumab + BSC (n = 350) or BSC alone (n = 350). The primary endpoint was OS, in all randomized pts and pts with PD-L1+ tumors (Ventana SP263 assay). In this exploratory analysis, we analyzed OS in disease stage and site subgroups, in pts with PD-L1+ tumors who received 1L gemcitabine + carboplatin, and in genomic subtypes (RNAseq whole-transcriptome profiling of tumor tissue) defined using data from The Cancer Genome Atlas (TCGA 2017). Interaction tests were not performed. Results: Prolonged OS was observed in the avelumab + BSC arm vs the BSC alone arm in pts with upper or lower tract tumors, metastatic or locally advanced (LA) and unresectable disease (prior to chemotherapy), and lymph node-only disease post-chemotherapy (Table). OS was also prolonged with avelumab + BSC in pts in PD-L1+ tumors who had received 1L gemcitabine + carboplatin, consistent with findings in the overall population. In genomic subtypes, the OS benefit for avelumab + BSC was apparent across TCGA subtypes except luminal. Conclusions: An OS benefit was seen for avelumab 1L maintenance + BSC vs BSC alone across subgroups of interest. Results are consistent with previously reported findings, further supporting avelumab 1L maintenance as a standard of care for pts with advanced UC that has not progressed with 1L platinum-containing chemotherapy. Clinical trial information: NCT02603432. [Table: see text]
Health care disparities and barriers to palliative care among metastatic renal cell carcinoma patients: An NCDB analysis.
Authors: Wadiwala Janvi , Patel Mausam , Li Chenghui , Maraboyina Sanjay , Safar Ahmed , Kim Thomas 
Published: June 2021

4545 Background: Palliative care improves quality of life for both patients and caregivers but may be underutilized due to socioeconomic barriers to access. An NCDB analysis was performed to analyze the effect of socioeconomics on palliative care receipt among patients with metastatic renal cell carcinoma. Methods: A retrospective hospital-based analysis was performed using the National Cancer Database to identify variables that significantly affect receipt of palliative care among patients diagnosed with metastatic renal cell carcinoma diagnosed between 2004 and 2016. Sub-cohort analysis was also performed among patients with the most severe disease. Multivariate binominal logistic regression was performed to determine the association of underlying socioeconomics with receipt of palliative care. The odds of receiving palliative care based on socioeconomic factors was reported as odds ratios (OR) with 95% CI. Results: There were 50405 patients meeting inclusion criteria with 40448 (80.2%) undergoing no palliation and 9957 (19.8%) undergoing palliative care. Both Black and Spanish/Hispanic patients had decreased odds of receiving palliative care (OR, 0.816, 95% CI, 0.753 to 0.885 and OR, 0.599, 95% CI, 0.540 to 0.665, respectively). Increasing age, papillary histology, increasing income, and increasing distance were also significantly associated with decreased odds of receiving palliation while treatment at an integrated network cancer program or comprehensive community cancer program and higher educational attainment were associated with increased odds of receiving palliative care. Similar findings were demonstrated among patients with the most severe disease. Limitations include the retrospective design and potential underlying selection biases of this study. Conclusions: Significant associations between receipt of palliative care and socioeconomic factors exist among patients with metastatic renal cell carcinoma. In this study among patients with metastatic renal cancer, we found associations between socioeconomics and palliative care access including age, race, Spanish/Hispanic origin, income, education, and other factors.
Real-world outcomes in patients with metastatic clear cell renal cell carcinoma receiving front-line axitinib plus pembrolizumab versus ipilimumab plus nivolumab.
Authors: Zarrabi Kevin , Handorf Elizabeth A. , Miron Benjamin , Zibelman Matthew R. , Anari Fern , Ghatalia Pooja , Plimack Elizabeth R. , Geynisman Daniel M. 
Published: June 2021

4551 Background: Front-line treatment for patients (pts) with metastatic clear cell renal cell carcinoma (mRCC) has undergone rapid advances in the last five years. This evolution has led to uncertainty about the optimal first line combination regimen. Herein, we compare real-world outcomes in pts treated with either axitinib/pembrolizumab (A/P) or ipilimumab/nivolumab (I/N) reported by International Metastatic RCC Database Consortium (IMDC) score. Methods: The nationwide Flatiron Health electronic health records-derived database was used to select pts diagnosed with mRCC and treated with front-line A/P or I/N from 2018-2020. The primary endpoints were overall-survival (OS) and real-world progression free survival (rwPFS). The survival analyses were adjusted using propensity score-based Inverse Probability of Treatment weighting, providing balance on age, gender, insurance, race, IMDC, practice type, and nephrectomy. Survival was assessed from beginning of therapy, and survival by treatment groups was compared using weighted and unweighted Kaplan-Meier curves with log-rank tests and weighted Cox proportional hazards regressions. Disease characteristics between the treatment groups were compared using chi-square and T-tests. Results: 821 pts received frontline A/P (n=259) or I/N (n= 562). Demographics and clinical parameters were similar between the two cohorts. Median age was 66 years, 73% were male, and 54.9% had a nephrectomy. 459 pts had all IMDC criteria factors available, 242 pts had missing factors but enough to define as intermediate/poor risk, 120 pts had unknown IMDC risk. Adjusted median OS was not statistically different: mOS for A/P was not reached (NR) while I/N was 22 mo (95% CI, 19.8-NR; p=0.40). Twelve-month survival was 68.5% for A/P treated pts and 65.8% for I/N treated pts (P=0.41). Twelve-month rwPFS was 41.4% for A/P treated pts and 39.7% for I/N treated pts (P=0.14). No statistical difference in survival was seen within IMDC risk strata (see table). Conclusions: In this retrospective, real-world study of pts treated with front-line A/P or I/N, 12-month survival was not statistically different irrespective of IMDC risk. Longer follow-up will be necessary to discern any significant differences.[Table: see text]
Nivolumab plus cabozantinib (N+C) versus sunitinib (S) for advanced renal cell carcinoma (aRCC): Outcomes by baseline disease characteristics in the phase 3 CheckMate 9ER trial.
Authors: Apolo Andrea B. , Powles Thomas , Burotto Mauricio , Bourlon Maria Teresa , Hsieh James J , Basso Umberto , Shah Amishi Yogesh , Suarez Cristina , Porta Camillo , Barrios Carlos H. , Gurney Howard , Kessler Elizabeth R , Retz Margitta , George Saby , Escudier Bernard , Zhang Joshua , Simsek Burcin , Scheffold Christian , Motzer Robert J. , Choueiri Toni K. 
Published: June 2021

4553 Background: First-line N+C significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) vs S in aRCC patients (pts) in the phase 3 CheckMate 9ER trial, leading to FDA approval of N+C in this setting. A deeper understanding of how baseline disease characteristics may impact clinical outcomes with N+C vs S may inform clinical decision making. Methods: Pts with clear cell aRCC were randomized to N 240 mg IV Q2W + C 40 mg PO QD vs S 50 mg PO QD (4 weeks of 6-week cycles). In this post hoc exploratory analysis, PFS, OS, and ORR were evaluated across pt subgroups defined by baseline IMDC risk status, organ sites of metastases (mets), number of organs with any lesions, or target lesion size. Consistent with primary/secondary efficacy endpoints in ITT pts, PFS and ORR were evaluated per RECIST v1.1 by blinded independent central review in subgroups. Results: Median follow-up in ITT pts was 23.5 months. PFS, OS, and ORR (including complete response [CR]) outcomes are summarized in the table across subgroups: IMDC risk (favorable [FAV], intermediate [I], poor [P]); number of organs with ≥ 1 target/nontarget lesion (T/NT; 1 and ≥ 2); sum of diameters of target lesions (sDTL; < and ≥ median [72.1 mm]), and in pts with liver, bone, or lung mets. The PFS HR favored N+C vs S and median (m) PFS was longer with N+C vs S across all subgroups. The OS HR also favored N+C vs S across most subgroups. ORR ranged from 38%–66% (N+C) vs 10%–44% (S) across subgroups, and CR benefits were seen with N+C in most subgroups. Additional outcomes including landmark OS and response details in subgroups will be reported. Conclusions: Consistent with outcomes in ITT pts, efficacy benefits with N+C vs S were observed regardless of IMDC risk status, organ site of mets, or extent of tumor burden at baseline. These results support N+C as a new first-line treatment option for pts with aRCC. Clinical trial information: NCT03141177. [Table: see text]
Dynamic changes of the immune infiltrate after neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx).
Authors: Bex Axel , Abu-Ghanem Yasmin , Van Thienen Johannes V. , Graafland Niels , Lagerveld Brunolf , Zondervan Patricia , Beerlage Harrie , van Moorselaar Jeroen , Kockx Mark , Van Dam Pieter-Jan , Szabados Bernadett , Blank Christian U. , Powles Thomas , Haanen John B. A. G. 
Published: June 2021

4573 Background: Antibodies targeting PD-1/PD-L1 combined with vascular endothelial growth factor (VEGF) inhibitors are a front-line standard of care for metastatic RCC. Neoadjuvant use of these combinations is associated with tumor downsizing, but dynamic effects on key immune biomarkers are uncertain. We report early dynamic changes in the tumour immune environment after neoadjuvant treatment with avelumab/axitinib. Methods: Neoavax is an open label, single arm, phase II trial, investigating 12 weeks of neoadjuvant avelumab/axitinib prior to nephrectomy in patients with high-risk non-metastatic clear-cell (cc) RCC (cT1b-4N0-1M0). Partial primary tumour response (RECIST 1.1) occurring in ≥25% is the primary endpoint. Biomarker analysis on sequential tissue is an exploratory endpoint. Expression of PD-L1 (SP263), CD8+, CD8-granzyme-B (CD8/GZMB)+, Foxp3+ cells, CD8/CD39+ and major histocompatibility complex class I (MHC-I) were compared on paired samples (pre-treatment biopsy and nephrectomy) (NCT03341845). Results: Paired, sequential tissue from the first 24 patients was analysed for immune biomarker expression. Of these patients, 70% were ≥pT3a, 30% pN1, 58% had ISUP/WHO grade ≥3 with 8% sarcomatoid features. Compared to pre-treatment biopsy there was a significant increase in PD-L1 (p = 0.0002) and CD8+ expression (p = 0.0003) after therapy, whereas changes in CD8/GZMB+, MHC-I and CD8/CD39+ were not significant. Furthermore, neoadjuvant avelumab/axitinib therapy was associated with a significant decrease in Foxp3+ cells (p = 0.009). Conclusions: 12 weeks of neoadjuvant axitinib/avelumab treatment in ccRCC leads to significant dynamic changes in the tumour microenvironment for CD8+, PD-L1 and Foxp3+ expression. High baseline Foxp3+ infiltration is associated with an unfavorable outcome in the majority of solid tumours. The significant on-treatment decrease in Foxp3+ may account for the positive interaction seen between VEGF targeted therapy and immune checkpoint inhibitors in mRCC. If these cells represent regulatory T cells (Tregs), activated CD4 T cells or fragile Tregs remains to be determined. Clinical trial information: NCT03341845.