bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world treatment patterns and clinical outcomes among patients with metastatic urothelial carcinoma.
Authors: Geynisman Daniel M. , Broughton Edward , Alhasani Hasan , Hao Yi , Zhang Ying , Stwalley Brian , Le Trong Kim , Huo Stephen 
Published: June 2021

4538 Background: Knowledge of large-scale real-world treatment patterns and clinical outcomes in patients (pts) with metastatic urothelial carcinoma (mUC) is limited. We conducted this study to address the lack of knowledge and identify unmet needs in pts with mUC in real-world clinical practice. Methods: The US nationwide Flatiron Health electronic health records–derived, de-identified database, comprised of 280 oncology practices across the US, was utilized to conduct a retrospective cohort analysis of pts diagnosed with mUC between Jan 1, 2011, and Aug 31, 2020. Baseline pt characteristics were assessed descriptively, and treatment patterns were classified by cisplatin (CIS) eligibility. Kaplan–Meier methods were used to evaluate overall survival (OS) and progression-free survival (PFS). In a subgroup analysis of cisplatin-ineligible (CIS-inelig) pts, a multivariable model adjusting for baseline covariates was used to assess survival outcomes. Results: Of 8183 pts with mUC, median age was 73.0 years at diagnosis. Primary tumor sites were bladder (78.5%), upper tract (20.6%), and urethra (0.9%). Median (range) follow-up from mUC diagnosis was 9.7 (0.2-116.6) months. Of 5855 (71.6%) pts who received first-line (1L) systemic therapy, 1764 (30.1%) were CIS eligible (CIS-elig), 2293 (39.2%) were CIS-inelig, and 616 (10.5%) did not receive CIS despite qualifying ECOG PS (0–1) and renal function; CIS eligibility was unknown in 1182 (20.2%). Among all 1L pts, 4380 (74.8%) received chemotherapy and 1410 (24.1%) received immunotherapy (IO); of the IO users, 1345 (95.4%) received monotherapy. Among CIS-elig pts, CIS plus gemcitabine (GC) and methotrexate, vinblastine, doxorubicin, CIS (MVAC) accounted for 1562 (88.5%) of 1L therapy. Among CIS-inelig pts, carboplatin plus gemcitabine (GCa; 36.1%), pembrolizumab (pembro) monotherapy (18.5%), and atezolizumab (atezo) monotherapy (15.1%) were the most common 1L therapies. Across CIS eligibility groups, the most common second-line therapies included pembro, atezo, and GCa; the most common third-line therapies included atezo, pemetrexed, paclitaxel, and GCa. Median OS (95% CI) was longer in pts who received ≥ 1 line of systemic therapy (14.5 [14.0–15.2] months) than in those who did not receive therapy (6.8 [6.2–7.3] months). Median (95% CI) OS and PFS were also longer in CIS-elig pts (OS, 19.7 [18.2–21.4] months; PFS, 11.5 [10.8–12.1] months) than in CIS-inelig pts (OS, 11.4 [10.8–12.0] months; PFS, 7.0 [6.7–7.4] months), irrespective of receiving treatment. In a subgroup analysis of CIS-inelig pts, 1L IO monotherapy was associated with worse OS than 1L chemotherapy (HR, 1.26; 95% CI, 1.13–1.40, P < 0.0001). Conclusions: This study of > 8000 mUC pts, of whom almost 30% never received systemic therapy, demonstrates real-world treatment patterns in mUC and highlights the substantial unmet need in this population, in particular for CIS-inelig pts.
TIVO-3: Durability of response and updated overall survival of tivozanib versus sorafenib in metastatic renal cell carcinoma (mRCC).
Authors: Verzoni Elena , Escudier Bernard , Hutson Thomas E. , McDermott David F. , Pal Sumanta K. , Porta Camillo , Rini Brian I. , Needle Michael N. , Atkins Michael B. 
Published: June 2021

4546 Background: Tivozanib is a potent and highly selective VEGF receptor (R) tyrosine kinase inhibitor in clinical development for mRCC. Methods: The TIVO-3 study enrolled subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI, stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized 1:1 to T or sorafenib. Tivozanib demonstrated PFS and ORR advantages over sorafenib. Here we report long term durability of response based on investigator assessment and updated overall survival. Results: There were 41 responders (23%) to tivozanib and 20 responders (11%) to sorafenib. The median duration of response (mDoR) was 20.3 months (95% CI: 9.8, 29.9) and 9.0 months (95% CI: 3.7, 16.6) for tivozanib and sorafenib, respectively. With prolonged follow up there were 270 deaths; the HR for overall survival favored tivozanib at 0.91 (95% CI: 0.716, 1.165). Clinical trial information: NCT02627963 . Conclusions: Tivozanib treatment in third and fourth line mRCC results in longer PFS, higher objective response rate and more durable responses compared to sorafenib. There is no difference in overall survival.[Table: see text]
An FDA-pooled analysis of frontline combination treatment benefits by risk groups in metastatic renal cell carcinoma (mRCC).
Authors: Lee Daniel , Gittleman Haley , Weinstock Chana , Suzman Daniel L. , Bloomquist Erik , Agrawal Sundeep , Brave Michael Holman , Brewer Jamie Renee , Singh Harpreet , Tang Shenghui , Pazdur Richard , Beaver Julia A. , Ibrahim Amna , Amiri-Kordestani Laleh 
Published: June 2021

4559 Background: The International Metastatic RCC Database Consortium (IMDC) risk model was developed for prognosis of patients with mRCC treated with vascular endothelial growth factor (VEGF)-targeted monotherapy in the first-line setting. Efficacy in trials of anti-VEGF therapy has been generally consistent across risk groups, including for overall survival (OS). For trials of immunotherapy combinations, the small numbers of OS events for the favorable risk group in each trial limited reliable conclusions; however, there was a suggestion of possible differential effects on OS between favorable risk and other risk groups. Methods: We pooled individual patient data (n=3447) from four phase III randomized trials of combinations of immunotherapy + immunotherapy (n=1) or immunotherapy + anti-VEGF therapy (n=3) submitted to the US Food and Drug Administration in support of marketing applications. All trials calculated IMDC risk group for each patient and used a control arm of sunitinib. We combined intermediate and poor prognostic groups (“intermediate/poor”) and compared their OS to that of the favorable risk group using Kaplan-Meier and Cox Proportional Hazards methods. Results: In this pooled analysis, treatment with combination immune checkpoint therapy did not demonstrate an improvement in OS compared to sunitinib in the favorable risk group (HR 0.953; 95% CI: 0.72, 1.27). An improvement in OS was observed in the intermediate/poor risk group (HR 0.696; 95% CI: 0.62, 0.78). Conclusions: Our analysis of OS in patients treated with immunotherapy combinations compared to sunitinib suggests possible differential benefit in the favorable risk compared to the intermediate/poor risk group. These results are not conclusive and considered exploratory due to the relative immaturity of OS in the favorable risk group. Follow-up for survival continues in each study to allow for more definitive results.[Table: see text]
Efficacy of avelumab + axitinib (A + Ax) versus sunitinib (S) by IMDC risk group in advanced renal cell carcinoma (aRCC): Extended follow-up results from JAVELIN Renal 101.
Authors: Haanen John B. A. G. , Larkin James , Choueiri Toni K. , Albiges Laurence , Rini Brian I. , Atkins Michael B. , Schmidinger Manuela , Penkov Konstantin , Thomaidou Despina , Wang Jing , Mariani Mariangela , Di Pietro Alessandra , Motzer Robert J. 
Published: June 2021

4574 Background: In the phase 3 JAVELIN Renal 101 trial (NCT02684006), treatment-naive patients with aRCC receiving A + Ax showed improved progression-free survival (PFS) and objective response rate (ORR) across International Metastatic RCC Database Consortium (IMDC) risk groups (favorable [F], intermediate [I], and poor [P]) compared with patients receiving S. Here we report updated efficacy results for A + Ax vs S by IMDC risk groups from the third interim analysis. Methods: Patients were randomized 1:1 to receive either A (10 mg/kg intravenously every 2 weeks) plus Ax (5 mg orally twice daily) or S (50 mg orally once daily) for 4 weeks (6-week cycle). Patients were categorized per IMDC risk group into F, I, and P subgroups, and outcomes were assessed for F, I, P, and I + P. Overall survival (OS) and PFS, ORR, complete response (CR), and duration of response (DoR) per investigator assessment (RECIST v1.1) were assessed. Results: The study enrolled 886 patients with aRCC. At data cutoff (Apr 2020), median (95% CI) follow-up for OS in the A + Ax was NR (42.2-NE) vs 37.8 (31.4-NE) months with S. The Table shows OS, PFS, ORR, CR, and DOR by IMDC risk group. A + Ax generally showed improved efficacy compared with S across IMDC groups. Conclusions: Consistent with previously reported results from prior interim analyses, extended follow-up confirms the efficacy benefits of A + Ax vs S across IMDC risk groups in patients with aRCC. Patients continue to be followed up for the final OS analysis. Clinical trial information: NCT02684006. [Table: see text]
Efficacy outcomes of nivolumab + cabozantinib versus pembrolizumab + axitinib in patients with advanced renal cell carcinoma (aRCC): Matching-adjusted indirect comparison (MAIC).
Authors: McGregor Bradley Alexander , Geynisman Daniel M. , Burotto Mauricio , Porta Camillo , Suarez Rodriguez Cristina , Bourlon Maria Teresa , Barata Pedro C. , Gulati Shuchi , Stwalley Brian , Del Tejo Viviana , Du Ella X. , Wu Aozhou , Chin Andi , Betts Keith A. , Huo Stephen , Choueiri Toni K. 
Published: June 2021

4578 Background: Nivolumab in combination with cabozantinib (N+C) has demonstrated significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS), compared with sunitinib as a first-line (1L) treatment for aRCC in the phase 3 CheckMate (CM) 9ER trial. As there are no head-to-head trials comparing N+C with pembrolizumab in combination with axitinib (P+A), this study compared the efficacy of N+C with P+A as 1L treatment in aRCC. Methods: An MAIC was conducted using individual patient data on N+C (N = 323) from the CM 9ER trial (median follow-up: 23.5 months) and published data on P+A (N = 432) from the KEYNOTE (KN)-426 trialof P+A (median follow-up: 30.6 months). Individual patients within the CM 9ER trial population were reweighted to match the key patient characteristics published in KN-426 trial, including age, gender, previous nephrectomy, International Metastatic RCC Database Consortium risk score, and sites of metastasis. After weighting, hazards ratios (HR) of PFS, duration of response (DoR), and OS comparing N+C vs. P+A were estimated using weighted Cox proportional hazards models, and ORR was compared using a weighted Wald test. All comparisons were conducted using the corresponding sunitinib arms as an anchor. Results: After weighting, patient characteristics in the CM 9ER trial were comparable to those in the KN-426 trial. In the weighted population, N+C had a median PFS of 19.3 months (95% CI: 15.2, 22.4) compared to a median PFS of 15.7 months (95% CI: 13.7, 20.6) for P+A. Using sunitinib as an anchor arm, N+C was associated with a 30% reduction in risk of progression or death compared to P+A, (HR: 0.70, 95% CI: 0.53, 0.93; P = 0.015; table). In addition, N+C was associated with numerically, although not statistically, higher improvement in ORR vs sunitinib (difference: 8.4%, 95% CI: -1.7%, 18.4%; P = 0.105) and improved DoR (HR: 0.79; 95% CI: 0.47, 1.31; P = 0.359). Similar OS outcomes were observed for N+C and P+A (HR: 0.99; 95% CI: 0.67, 1.44; P = 0.940). Conclusions: After adjusting for cross-trial differences, N+C had a more favorable efficacy profile compared to P+A, including statistically significant PFS benefits, numerically improved ORR and DoR, and similar OS.[Table: see text]
Circulating tumor DNA (ctDNA) in patients with advanced adrenocortical carcinoma.
Authors: Nazha Bassel , Dada Hiba I. , Drusbosky Leylah , Brown Jacqueline T , Ravindranathan Deepak , Carthon Bradley Curtis , Kucuk Omer , Master Viraj A. , Bilen Mehmet Asim 
Published: June 2021

4585 Background: Adrenocortical Carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis and limited treatments in the advanced setting. Molecular pathways with tumor suppressor genes (e.g. TP53, CDKN2A) and oncogenes (e.g. CTNNB1 and RAS) are implicated in oncogenesis. To our knowledge, the genomic landscape of ctDNA alterations for ACC has not been described in a large cohort. We report plasma-based ctDNA alterations in patients with advanced ACC. Methods: We retrospectively evaluated genomic data from 102 patients with ACC who had ctDNA testing between 12/2016 – 10/2020 using Guardant360 (Guardant Health, CA). ctDNA analysis interrogated single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 83 genes. We evaluated the frequency of genomic alterations, the landscape of co-occurring mutations, and pathogenic or likely pathogenic alterations with potential targeted therapies. The prevalence of alterations identified in ctDNA were compared to those detected in tissue using a publicly available database (cBioPortal). Results: The median age was 54 years (range 24-81), and 55% of patients were male. Among the entire cohort, 84 pts (82.4%) had ≥1 somatic alteration detected. Mutations were most frequently detected in TP53 (52%), EGFR (23%), CTNNB1 (18%), MET (18%), and ATM (14%). The frequencies detected in ctDNA were similar to the results detected in tissue. Pathogenic and/or likely pathogenic mutations in therapeutically relevant alterations were observed in 36 patients (35%), including EGFR, BRAF, MET, CDKN2A, and CDK4/6 (Table 1). The most frequently co-occurring mutations were EGFR + TP53 (14%), EGFR + MET (11%), BRAF + MET (10%). Conclusions: Blood-based ctDNA profiling in advanced ACC provided comprehensive genomic data in most patients, with a similar profile to tumor tissue analyses. Over one third of patients had actionable mutations with approved therapies in other cancers. This approach might inform the development of personalized treatment options for this aggressive malignancy.[Table: see text]
Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide versus enzalutamide alone: An updated safety analysis.
Authors: Gillessen Silke , Choudhury Ananya , Rodriguez-Vida Alejo , Nole Franco , Gallardo Diaz Enrique , Roumeguere Thierry Andre , Daugaard Gedske , Loriot Yohann , Saad Fred , McDermott Raymond S. , Neven Anouk , Fournier Beatrice , TOMBAL Bertrand F. 
Published: June 2021

5002 Background: The randomized phase III EORTC-1333-GUCG (NCT02194842) trial compares enzalutamide vs. a combination of Radium 223 and enzalutamide in asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC) patients. The premature unblinding of ERA223 (NCT02043678) in Nov 2017 due to a significant increase in the rate of fractures in the combination of abiraterone and Ra223 arm led to the implementation of the mandatory use of bone protecting agents (BPA) in the EORTC-1333-GUCG trial. Skeletal fractures, pathological or not, are a frequent and underestimated adverse event of systemic treatment of advanced prostate cancer. Whether this mandated use of BPA (zoledronic acid or denosumab) would mitigate the risk of fractures in this patient population was unclear. An early safety analysis (Tombal, ASCO, 2019) suggested that the risk of fractures was well controlled in both arms when patients receive BPA. We present here an updated analysis of fracture incidence with longer follow-up. Methods: As of 28/01/2021, a total of 253 patients (134 after making BPA mandatory) were randomized between enzalutamide/Ra223 and enzalutamide. The fracture rate was estimated with the cumulative incidence method in the safety population of 237 (122 after making BPA mandatory) treated patients. Death in absence of fracture was analyzed as competing risk and censoring was applied at last follow-up. Results: Overall, 69.5% of enzalutamide/Ra223 patients (95.2% after making BPA mandatory) and 73.1% of enzalutamide patients (95% after making BPA mandatory) received BPA on treatment: 13.6% in the enzalutamide/Ra223 arm and 21.8% in the enzalutamide arm did not use BPA at registration, but started during protocol treatment and 55.9% and 51.3% respectively, received BPA since entry. At 36.7 months median follow-up in patients without BPA and 23.1 months median follow-up in patients receiving BPA, a total of 39 patients reported a fracture. Among them, 30 patients (20 in enzalutamide/Ra223 arm) did not receive BPA and 9 (4 in the enzalutamide/Ra223 arm) received BPA (see table). Conclusions: The updated safety analysis confirms the early fracture rate results. In the absence of BPA, the risk of fracture is increased when RA223 is added to enzalutamide. Strikingly, in both arms, the risk remains almost abolished by a preventive continuous administration of BPA, thus stressing the importance of complying to international recommendations in terms of giving BPA to mCRPC patients. This study is sponsored by EORTC and supported by Bayer and Astellas. Clinical trial information: NCT02194842. [Table: see text]
COMBAT-CRPC: Concurrent administration of bipolar androgen therapy (BAT) and nivolumab in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Markowski Mark Christopher , Taplin Mary-Ellen , Aggarwal Rahul Raj , Wang Hao , Lalji Aliya , Paller Channing Judith , Marshall Catherine Handy , Carducci Michael Anthony , Eisenberger Mario A. , De Marzo Angelo M , Denmeade Samuel R. , Antonarakis Emmanuel S. 
Published: June 2021

5014 Background: During BAT, intramuscular (IM) testosterone (T) is administered, which results in rapid cycling of serum T levels from supraphysiologic to near-castrate in men with metastatic castration resistant prostate cancer (mCRPC). We previously observed anecdotal clinical responses to immune checkpoint blockade (ICB) in mCRPC patients (pts) previously treated with BAT and hypothesized that that a BAT/ICB combination would be synergistic. Here we report a prospective phase 2 study of men with mCRPC treated with BAT in combination with nivolumab. Methods: This was a multi-center, single arm, open label phase 2 trial (NCT03554317) of men with mCRPC who received T cypionate 400mg IM (BAT) every 28 days and nivolumab 480mg IV every 28 days. LHRH agonist treatment was continued. All pts received BAT as single agent therapy for a 12-week lead-in prior to the addition of nivolumab. Eligible pts were those with asymptomatic mCRPC who had soft tissue disease amenable to biopsy and progressed on at least one prior novel AR targeted therapy. Up to one line of chemotherapy was allowed for the treatment of mCRPC disease. The primary endpoint was confirmed PSA50 response rate. Key secondary endpoints included safety, objective response rate (ORR), and radiographic progression-free survival (rPFS). The trial was designed to detect a 20% absolute increase in PSA50 response rate from the null of 25%. Results: 45 pts were enrolled on study and treated. The confirmed PSA50 response rate was 40.0% (N=18/45, 95% CI: 26-56%, P=0.02 against the 25% null hypothesis). For pts with measureable disease, the ORR was 23.8% (N=10/42). Median rPFS on BAT and nivolumab was estimated at 5.7 months (95% CI: 4.9-7.8 months). 11.1% (N=5/45) of pts were free from radiographic progression for 11 or more months. One patient achieved a complete radiographic response, which is ongoing (>13 months). The majority of adverse events (AE) were Grade <2. The most common AEs were edema (20%), nausea (20%), and back pain (13%). Immune related AE (irAE) were generally mild (Grade <2) with N=2 Grade 3 irAE observed (pericarditis, lipase elevation). Serial biopsies were obtained on trial for translational studies. Conclusions: BAT plus nivolumab was well tolerated without concerning safety signals. The combination met the pre-specified primary endpoint of confirmed PSA50 response in a heavily treated population. Durable responses were observed in a subset of pts. Biomarker analysis is ongoing to identify a molecular signature predictive of response. Clinical trial information: NCT03554317. [Table: see text]
Characterization of findings on prostate cancer tumor sequencing that should prompt consideration for germline testing.
Authors: Truong Hong , Breen Kelsey , Kemel Yelena , Lenis Andrew Thomas , Reisz Peter , Benfante Nicole , Ehdaie Behfar , Touijer Karim A. , Laudone Vincent Paul , Scardino Peter T. , Eastham James Andrew , Joseph Vijai , Birsoy Ozge , Mandelker Diana , Stadler Zsofia Kinga , Offit Kenneth , Morris Michael J. , Abida Wassim , Robson Mark E. , Carlo Maria Isabel 
Published: June 2021

5022 Background: Tumor sequencing is increasingly used for therapeutic selection in men with advanced prostate cancer (PC). If tumor-only sequencing is performed without matched germline, identified mutations could be of somatic or germline origin. Germline mutations could confer additional risk for other cancers to the patient and at-risk family members. The objective of this study is to determine the overall and gene-specific probability of pathogenic/likely pathogenic germline mutations based on tumor-only sequencing. Methods: We investigated mutations found in a cohort of men with PC who underwent targeted next generation sequencing of PC tumor and matched peripheral blood using the MSK-IMPACT assay between 01/2015 and 01/2020. A germline probability for each gene was determined by dividing the number of germline mutations by the total number of somatic and germline mutations. Cancer susceptibility genes commonly sequenced on tumor-based tests for PC were assessed, including ATM, BRCA1/ 2, BRIP1, CHEK2, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2 (henceforth referred to as PC genes). Results: A total of 1883 men with PC were included, with median age of diagnosis of 62.0 ± 8.8 years. 84% had high risk PC, 52% had metastasis, 38% had family history of PC. A total of 364 (19%) men had at least one mutation (either somatic or germline) in PC genes. Overall, 189 (10%) men had at least one germline mutation that would not have been reported as germline without matched normal. The average germline probability of PC genes was 40% (range: 0% in MLH1 to 83% in CHEK2). The number of total mutations, germline mutations, and germline probability of genes found in > 0.5% of the study cohort are summarized in Table. All these genes are moderate/high penetrance autosomal dominant genes with established guidelines for cascade testing, enhanced cancer screening, or potential risk-reducing surgery. Conclusions: In this study, an average of 40% of mutations found in cancer susceptibility genes on PC tumor sequencing were germline mutations. Men undergoing tumor-only sequencing should be counseled on the possibility of uncovering a germline mutation. In addition to BRCA1/ 2, mutations in certain genes, such as CHEK2 and PALB2, have a high probability of being germline and should prompt referral for genetic counseling and germline testing.[Table: see text]