bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retrospective analysis of the safety and efficacy of immune checkpoint inhibitors (CPI) among patients (pts) with pre-existing autoimmune disorders (AD) and renal cell carcinoma (RCC) or urothelial carcinoma (UC).
Authors: Martinez Chanza Nieves , Xie Wanling , Issa Majd , Dzimitrowicz Hannah Elizabeth , Tripathi Abhishek , Beuselinck Benoit , Lam Elaine Tat , Zakharia Yousef , McKay Rana R. , Shah Sumit , Mortazavi Amir , Harrison Michael Roger , Choueiri Toni K. , Harshman Lauren Christine 
Published: May 2019

4571 Background: RCC and UC pts with clinically significant AD were generally excluded from CPI trials due to potential AD exacerbation. Thus, the safety and clinical activity of CPI in AD pts are not well characterized. Methods: We retrospectively collected data from RCC and UC pts with AD treated with CPI at 9 centers. Adverse events (AEs) were assessed using CTCAEv5 criteria. Objective response rate (ORR) was assessed by RECIST principles. Overall survival (OS) was estimated by Kaplan Meier. Results: Of 103 pts (57 RCC & 46 UC) with a broad spectrum of AD such as psoriasis (22%), thyroiditis (20%), rheumatoid arthritis (13%), polymyalgia rheumatica (8%), inflammatory bowel disease (6%), multiple sclerosis (3%) and lupus (3%), most received CPI as 1st or 2nd line (77% RCC, 93% UC) and anti-PD-1/L1 monotherapy (65% RCC, 98% UC). At CPI start, 36 had clinically active AD (all grade 1-2) and 4(11%) requiring systemic immunosuppression. AD exacerbations occurred in 37% (n = 38); most frequent: arthritis (12% RCC, 24% UC), rash (11% RCC, 9% UC). New onset immune related (ir) AEs occurred in 36% (n = 37); most frequent: colitis (12% RCC, 4% UC), rash (11% RCC, 9% UC), hypothyroid (each 7%), nephritis (7% UC). Table details timing and management. Median followup was 12.5 (1-52) mos for RCC and 14.5 (1-53) mos for UC. Median time on CPI was 6 mos (1-36) RCC and 4 mos (0.5-40) UC. At data cutoff, 39 RCC & 36 UC had discontinued CPI; 16% for toxicity. ORR was 31% for RCC and 35% for UC. 1 yr-OS rate was 74% (95%CI 58-84) for RCC and 60% (95%CI 43-74) for UC. Conclusions: AD exacerbations or new irAEs occurred in 37% and 36% respectively and were generally manageable. Only a minority required CPI cessation due to toxicity. [Table: see text]
Systemic therapy for advanced clear cell renal cell carcinoma (ccRCC) after progression on immune-oncology plus VEGF targeted therapy combinations (IO-VEGF).
Authors: Ged Yasser , Gupta Ruby , Duzgol Cihan , Shapnik Natalie , Redzematovic Almedina , Kotecha Ritesh , Voss Martin Henner , Feldman Darren R. , Akin Oguz , Patil Sujata , Motzer Robert J. , Rini Brian I. , Lee Chung-Han 
Published: May 2019

4576 Background: IO-VEGF combinations are the backbone for current and future therapeutic developments in RCC with several IO-VEGF regimens reporting positive results in phase 3 trials. However, limited data exists on outcomes to subsequent therapy in patients progressing on IO-VEGF regimens. Methods: A retrospective analysis was performed on patients with ccRCC at the Memorial Sloan Kettering Cancer Center and Cleveland Clinic Cancer Institute who initiated systemic therapy post IO-VEGF regimens including combinations with VEGFR tyrosine kinase inhibitors (IO-TKI) and combinations with anti-VEGF monoclonal antibodies (IO-mAB). Patients treated on unreported clinical trials were excluded from the outcomes analysis. The primary objective was to evaluate the overall survival (OS) post IO-VEGF. The secondary objectives included objective response rate (ORR) and progression-free survival (PFS) according to RECIST v1.1. Kaplan-Meier methods and the log-rank test were used to evaluate time from start of systemic therapy post IO-VEGF to the event of interest. Results: Fifty-nine patients were treated after discontinuation of IO-VEGF regimens. Prior IO-VEGF regimens included IO-mAB (n = 35, 59%) and IO-TKI (n = 24, 41%). IMDC scores at the start of next line of therapy were favorable in 20%, intermediate in 60% and poor in 20%. Next line of therapy included VEGFR-TKI monotherapy (n = 45, 76%), VEGFR-TKI based combinations (n = 6, 10%), mTOR inhibitors (n = 3, 5%), and unreported clinical trials (n = 5, 9%). VEGFR-TKI containing regimens (n = 51) included cabozantinib (n = 22), axitinib (n = 17), lenvatinib/everolimus (n = 4), pazopanib (n = 4), and others (n = 4). Median OS was 24.5 months (95% CI 12-NE) with a 12 months OS rate of 63%. The ORR was 27% (14/51) and the median PFS was 6.8 months (95% CI 4.8-11). No difference in post IO-VEGF OS was observed when comparing IO- TKI vs IO-mAB (log rank p = 0.7). Conclusions: Post combination IO-VEGF treatment, most patients received VEGFR-TKIs. In this setting, VEGFR-TKIs continue to show clinical activity similar to historic experiences of patients post VEGF monotherapy.
First-line (1L) immuno-oncology (IO) combination therapies in metastatic renal-cell carcinoma (mRCC): Results from the international mRCC database consortium (IMDC).
Authors: Dudani Shaan , Graham Jeffrey , Wells Connor , Bakouny Ziad , Pal Sumanta K. , Dizman Nazli , Donskov Frede , Porta Camillo , de Velasco Guillermo , Hansen Aaron Richard , Iafolla Marco Adelmo James , Beuselinck Benoit , Vaishampayan Ulka N. , Wood Lori , Liow Elizabeth Chien Hern , Yan Flora , Yuasa Takeshi , Bjarnason Georg A. , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: May 2019

4577 Background: In mRCC, ipilimumab and nivolumab (ipi-nivo) is a 1L treatment option. Recent data have also shown efficacy of 1L IO-VEGF (IOVE) inhibitor combinations. Comparative data between these two strategies are limited and the efficacy of subsequent therapies remains unknown. Methods: Using the IMDC dataset, patients (pts) treated with any 1L IOVE combination were compared to those treated with ipi-nivo. Multivariable Cox regression analysis was performed to control for imbalances in IMDC risk factors. Results: 188 pts received 1L IO combination therapy: 113 treated with IOVE combinations and 75 with ipi-nivo. Baseline characteristics and IMDC risk factors were comparable between groups. When comparing IOVE combinations vs ipi-nivo, 1L response rate (RR) was 33% vs 40% (p=0.39), time to treatment failure (TTF) was 14.3 (95% CI 9.2-16.1) vs 10.2 months (95% CI 6.7-15.1, p=0.23), and median overall survival (OS) was not reached (NR) (95% CI 22.3-NR) vs NR (95% CI 35.1-NR, p=0.17). When adjusted for IMDC risk factors, the hazard ratio (HR) for TTF was 0.71 (95% CI 0.46-1.12, p=0.14) and the HR for death was 1.74 (95% CI 0.82-3.68, p=0.14). Second-line (2L) treatments were varied. In pts receiving subsequent VEGF-based therapy, 2L RR was lower in the IOVE (n=20) versus ipi-nivo (n=20) cohort (15% vs 45%; p=0.04), though 2L TTF was not significantly different (3.7 vs 5.4 months, p=0.40, n=55). The use of IO post IOVE was uncommon and 3/5 pts had PD as best response; 2/5 had PR/SD but their 1L IOVE exposure was short at <3 months. Conclusions: There does not appear to be a superior 1L IO combination strategy in mRCC, as lOVE combinations and ipi-nivo have comparable 1L RR, TTF and OS. Most pts received VEGF-based therapy in the 2L. In this group, 2L RR was greater in pts who received ipi-nivo, though there was no difference in 2L TTF. [Table: see text]
Meta-analysis of randomized clinical trials (RCT) for the adjuvant treatment of renal cell carcinoma (RCC) with vascular endothelial growth factor receptor tyrosine-kinase inhibitors (VEGFR TKIs).
Authors: Almeida Daniel Vargas , Oliveira Cleyton Z. , Soares Andrey , MARIANO RODRIGO COUTINHO , Jardim Denis L , Bastos Diogo Assed , Maluf Fernando C. , Werutsky Gustavo , Monteiro Fernando Sabino M , Souza Vinicius Carrera , de Velasco Guillermo , Fay Andre P. , Sasse Andre Deeke , Schutz Fabio A. B. ,   Latin America Cooperative Oncology Group - Genitourinary (LACOG-GU)
Published: May 2019

4579 Background: Although surgery is the cornerstone in the treatment of most cases of localized kidney cancer, up to 30% of patients will experience disease recurrence at three years of follow-up. Three RCTs with VEGFR TKIs (ASSURE, PROTECT and ATLAS) failed to demonstrate improvement in disease-free survival (DFS). Only S-TRAC trial showed a significant improvement in DFS, and was approved by the Food and Drug Administration (FDA). However, the matter remains controversial among genitourinary oncologists. Therefore, we performed a meta-analysis to better evaluate the potential benefit of adjuvant VEGFR TKIs after curative intent nephrectomy. Methods: Eligible studies were searched in PubMed databases and limited to phase 3 RCT published from January 1996 to December 2018 of US FDA-approved VEGFR TKIs reporting on patients with RCC treated in the adjuvant setting. A summary hazard-ratio (HR) of disease-free survival (DFS) was calculated using 95% CIs by random-effects or fixed-effects models on the basis of the heterogeneity of included studies. Results: Four RCT (ASSURE, S-TRAC, PROTECT and ATLAS trials) were selected for analysis, including a total of 4,820 patients. A VEGFR TKI (sunitinib, sorafenib, pazopanib or axitinib) was administered in 2,737 patients, and 2,083 received placebo. The summary DFS HR for the overall population was 0.89 (95% CI 0.79-1.00; p = 0.06). When including the report of the ASSURE with the sub-group analysis with high-risk patient population (n = 3,946), the summary HR for DFS was 0.84 (95% CI 0.75-0.95, p = 0,0044). No evidence of publication bias was found. Conclusions: This is the first meta-analysis including the four RCTs in RCC adjuvant setting. This meta-analysis failed to demonstrate improvement in DFS for patients receiving a VEGFR TKI after curative intent nephrectomy. A modest benefit in DFS was observed in a selected sub-group of patients with higher risk for recurrence. There is no data regarding overall survival.
Metastatic penile (mPSCC), uterine cervical (mCSCC), and skin (mSSCC) squamous cell carcinomas: A comparative genomic profiling (CGP) study.
Authors: Jacob Joseph , Bratslavsky Gennady , Shapiro Oleg , Liu Nick , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Ngo Nhu , Lin Douglas I. , Ramkissoon Shakti , Severson Eric Allan , Ali Siraj Mahamed , Chung Jon , Schrock Alexa Betzig , Reddy Prasanth , Alexander Brian , McGregor Kimberly , Miller Vincent A. , Necchi Andrea , Ross Jeffrey S. 
Published: May 2019

4585 Background: We compared the genomic alteration (GA) profiles of mCSCC, mPSCC and mSSCC to study impact on the targeted and immunotherapy options for the men and women suffering from these refractory cancers. Methods: 78 mPSCC, 604 mCSCC and 338 mSSCC underwent CGP using a hybrid-capture based assay. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and and microsatellite instability (MSI) was determined on 114 loci. Results: The HPV+/CDKN2A- status was significantly more frequent in the mCSCC than mPSCC or mSSCC (P < 0.0001). The GA/tumor frequencies were similar for mCSCC and mPSCC, but significantly higher in mSSCC (P < 0.0001). TP53 mutations were more common in mSSCC (UV light exposure) and mPSCC (likely due to loss of an original HPV+ status). TERT, NOTCH1 and FAT1 GA were more frequent in mPSCC and mSSCC whereas PIK3CA GA were more common in mCSCC. MTOR pathway targets (GA in STK11, FBXW7 and PTEN) were more common in mCSCC than mPSCC or mSSCC. MSI high status was extremely rare in all cases. TMB ≥ 10/20 mut/Mb frequencies were noteworthy in mPSCC and mCSCC but extraordinarily high in mSSCC. Examples of patients with mCSCC, mPSCC and mSSCC responding to targeted and immunotherapies will be presented. Conclusions: Although mCSCC, mPSCC and mSSCC share a variety of clinicopathologic features, the 3 tumor types can be sharply differentiated on CGP. The TP53, CDKN2A and HPV status of the tumor types differ significantly with HPV+ higher in the mCSCC group. There are opportunities for targeted therapies in all groups predominantly identified in the MTOR pathway. The relatively high numbers of cases with significantly elevated TMB in all 3 tumor types suggest that immunotherapies would be beneficial in a large subset of patients. [Table: see text]
Impact of darolutamide (DARO) on pain and quality of life (QoL) in patients (Pts) with nonmetastatic castrate-resistant prostate cancer (nmCRPC).
Authors: Fizazi Karim , Shore Neal D. , Tammela Teuvo , Kuss Iris , Le Berre Marie-Aude , Mohamed Ateesha F. , Odom Dawn , Bartsch Jennifer , Snapir Amir , Sarapohja Toni , Smith Matthew Raymond 
Published: May 2019

5000 Background: DARO is a structurally distinct androgen receptor antagonist for which in vitro and phase 1/2 studies suggest low risk of adverse events (AEs) and drug–drug interaction. In the ARAMIS study of DARO in nmCRPC, metastasis-free survival (MFS) was significantly prolonged vs placebo (PBO) (40.4 vs 18.4 mo; hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.34–0.50; P < 0.001) and interim overall survival (OS) favored DARO (HR 0.71; 95% CI 0.50–0.99; P = 0.045). Methods: 1509 pts were randomized 2:1 to DARO 600 mg (two 300 mg tablets) twice daily (n = 955) or PBO (n = 554) while continuing androgen deprivation therapy (ADT). Primary endpoint was MFS. Secondary endpoints included OS and time to pain progression (assessed by Brief Pain Inventory Short Form). QoL was assessed by European Organisation for Research and Treatment of Cancer QoL Prostate Cancer module (EORTC-QLQ-PR25) at baseline (BL) and every 16 wks until end of treatment. Analysis of time to deterioration in EORTC-QLQ-PR25 subscales, defined as first occurrence of a minimally important difference (half the standard deviation of BL value), used Kaplan–Meier estimators and stratified Cox proportional hazard models. Results: DARO significantly delayed pain progression vs PBO (40.3 vs 25.4 mo; HR 0.65; 95% CI 0.53–0.79; P < 0.001); this was maintained beyond end of study treatment. Time to deterioration of EORTC-QLQ-PR25 outcomes showed statistically and clinically significant delays with DARO vs PBO for urinary symptoms (25.8 vs 14.8 mo; HR 0.64; 95% CI 0.54–0.76; P < 0.01). Time to deterioration of hormonal treatment-related symptoms was comparable with DARO vs PBO (18.9 vs 18.4 mo; HR 1.06; 95% CI 0.88–1.27; P = 0.52). DARO was well tolerated. Exposure-adjusted incidences (pts per 100 years’ exposure) of AEs of interest were similar/lower with DARO vs PBO (fatigue/asthenic conditions [11.3 vs 11.1], hypertension [4.7 vs 5.1], hot flush [3.7 vs 4.1], fracture [3.0 vs 3.5], falls [2.7 vs 4.1], cognitive disorder [0.3 vs 0.2], and seizure [0.2 vs 0.2]). Conclusions: For nmCRPC pts, DARO prolongs MFS, is well tolerated, maintains QoL, and delays worsening of pain and disease-related symptoms compared with PBO. Clinical trial information: NCT02200614.
PSMA heterogeneity and DNA repair defects in prostate cancer.
Authors: Paschalis Alec , Sheehan Beshara , Riisnaes Ruth , Nava Rodrigues Daniel , Gurel Bora , Bertan Claudia , Ferreira Ana , Lambros Maryou B. , Seed George , Yuan Wei , Dolling David , Welti Jon , Neeb Antje , Sumanasuriya Semini , Rescigno Pasquale , Bianchini Diletta , Tunariu Nina , Carreira Suzanne , Sharp Adam , De Bono Johann S. 
Published: May 2019

5002 Background: Prostate-specific membrane antigen (PSMA) is a promising target for theranostics in metastatic castration resistant prostate cancer (mCRPC). Methods: Membranous PSMA (mPSMA) expression was immunohistochemically evaluated in castration sensitive (CSPC) (n = 38) and mCRPC (n = 60) tissue biopsies, and associations with molecular aberrations (next-generation sequencing; NGS) and clinical outcome were determined. Results: mPSMA expression was significantly higher (p = 0.005) in mCRPC biopsies (median H-score [interquartile range]; 55.0 [2.8-117.5]) compared to CSPC biopsies (17.5 [0.0-60.0]). Furthermore, patients with higher mPSMA expression ( > median H-score) at diagnosis had higher Gleason Grade (p = 0.04) and shorter OS (p = 0.006). Critically, 42% (16/38) of CSPC biopsies and 27% (16/60) of mCRPC biopsies were completely negative for mPSMA expression. In addition, CSPC and mCRPC biopsies expressing mPSMA demonstrated marked intra-tumor heterogeneity in expression levels, commonly exhibiting areas without detectable PSMA (CSPC – 100%; mCRPC – 84%), while heterogeneous mPSMA expression between metastases from the same patient was also observed. Subsequent genomic analysis showed that mCRPC patients with deleterious DNA damage repair (DDR) aberrations have higher (p = 0.016) mPSMA expression (87.5 [25.0-247.5]) than those without these (20 [0.3-98.8]). Furthermore, 9 of the 11 patients (82%) responding to PARP inhibition had a mPSMA H-Score above the median. The association between mPSMA expression and DDR aberrations was validated in an independent cohort with known DDR aberrations. Tumors with DDR aberrations had significantly higher mPSMA (ATM 212.5 [136.3-300] p = 0.005; BRCA2 300 [165-300] p = < 0.001) than unselected mCRPC biopsies (55.0 [2.75-117.5]). Finally, analyses of 122 mCRPC biopsy transcriptomes confirmed a negative correlation between PSMA and BRCA2 mRNA expression (p = 1.5x10-5). Conclusions: mPSMA expression in CSPC and mCRPC exhibits marked intra- and inter-patient heterogeneity, limiting the clinical utility of PSMA-targeted theranostics. We show for the first time that DDR gene aberrations associate with high mPSMA expression and may serve as predictive biomarkers for PSMA-targeted therapies.
TAXOMET: A French prospective multicenter randomized controlled phase II study comparing docetaxel plus metformin versus docetaxel plus placebo in mCRPC.
Authors: Pujalte Martin MARC , Borchiellini Delphine , Viotti Julien , Guillot Aline , Paoli Jean Baptiste , Besson Dominique , Hilgers Werner , El Kouri Claude , Cavaglione Gerard , Priou Frank , Lharidon Tifenn , Largillier Remy , Deville Jean-Laurent , Hoch Benjamin , Schiappa Renaud , Tanti Jean François , Bost Frederic , Ferrero Jean-Marc 
Published: May 2019

5004 Background: Docetaxel (DOCE) is a standard of care in metastatic castration-resistant prostate cancer (mCRPC). Several retrospective cohort studies suggest a decrease in PC incidence and mortality with metformin (MET). MET has also demonstrated anti-tumor activity in PC preclinical models, with increase apoptosis when added to DOCE. The addition of MET could enhance DOCE efficacy in mCRPC patients (pts). Methods: TAXOMET is a phase II prospective multicentric randomized controlled trial. Non-diabetic mCRPC pts were assigned 1:1 to receive DOCE 75mg/m2 every 21 days + prednisone (P) 5 mg twice a day and either MET 850mg twice a day (arm A) or placebo (arm B), up to 10 cycles. The primary end point was PSA response rate (≥50% decrease). Main secondary endpoints included objective response rate (ORR, according to RECIST v1.1), clinical and biological progression-free survival (PFS), overall survival (OS), toxicity and quality of life (QoL). Comparisons between arm A and B were performed using Chi² test for qualitative data and Log-rank test for survival data. Results: From January 2013 to December 2015, 99 pts were randomized (50 pts in arm A and 49 pts in arm B) in 10 french centers, and 95 pts were evaluable. No difference was observed between arm A and arm B in PSA-response rate (72% in both arms), ORR (28% in both arms), clinical or biological mPFS (7.3 months vs 5.8 months p = 0.848) and mOS (24.2 months (95CI: 17.2 – 33.7) vs 19.7 months (95CI: 14.8 – 36.8), p = 0.53), respectively. There was no difference between arms in adverse events, except a trend for diarrhea to be more common with MET (70% in arm A vs 50% in arm B, p = 0.072), but few grade 3-4 events. There was no difference in QoL according to QLQ-C30 score between the two arms during the treatment period. Conclusions: This is the first prospective randomized controlled trial to evaluate the combination of MET with DOCE+P in mCRPC. The addition of MET has no meaningful clinical benefit in this setting. Clinical trial information: NCT01796028.
TOPARP-B: A phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations.
Authors: Mateo Joaquin , Porta Nuria , McGovern Ursula Brigid , Elliott Tony , Jones Robert J , Syndikus Isabel , Ralph Christy , Jain Suneil , Varughese Mohini Anna , Parikh Omi , Crabb Simon J. , Miranda Susana , Seed George , Bertan Claudia , Espinasse Aude , Chatfield Peter , Bianchini Diletta , Hall Emma , Carreira Suzanne , De Bono Johann S. ,   on behalf of the TOPARP Investigators Group
Published: May 2019

5005 Background: We previously reported the antitumor activity of olaparib (400mg BID) against molecularly unselected mCRPC (TOPARP-A; Mateo et al NEJM 2015). We now report TOPARP-B, a phase II trial for patients with mCRPC preselected for putatively pathogenic DDR alterations. Methods: Patients with mCRPC progressing after ≥ 1 taxane chemotherapy underwent targeted sequencing of tumor biopsies and were deemed eligible when alterations (germline or somatic; mono- or bi-allelic) in any DDR gene were detected. Patients were randomized 1:1 under a “pick-the-winner” design to 400mg or 300mg of olaparib BID, aiming to exclude ≤30% response rate (RR) in either arm. The primary endpoint RR was defined as radiological response (RECIST 1.1) and/or PSA50% fall and/or CTC count conversion (Cellsearch; ≥5 to < 5), confirmed after 4-weeks. Analyses of RR per gene alteration subgroup was pre-planned. Secondary endpoints included progression-free survival (PFS), tolerability. Results: Overall, 98 patients (median age 67.6y) were randomized, with 92 patients treated and evaluable for the primary endpoint (70 RECIST-evaluable; 89 PSA50%-evaluable; 55 CTC-evaluable). All had progressed on ADT; 99% were post-docetaxel, 90% post-abiraterone/enzalutamide, 38% post-cabazitaxel. The overall RR was 54% (95%CI 39-69%, meeting threshold for primary endpoint) in the 400mg cohort and 37% (95%CI 23-53%) in the 300mg cohort. With a median follow-up of 17.6 months (mo), the overall median PFS (mPFS) was 5.4 mo. Subgroup analyses per altered gene identified indicated response rates for: BRCA1/2 of 80% (24/30; mPFS 8.1mo); PALB2 57% (4/7; mPFS 5.3mo); ATM 37% (7/19; mPFS 6.1mo); CDK12 25% (5/20; mPFS 2.9mo); others [ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, WRN] 20% (4/20; mPFS 2.8mo). The highest PSA50% response rates were observed in the BRCA1/2 (22/30; 73%) and PALB2 (4/6; 67%) subgroups. Conclusions: Olaparib has antitumor activity against heavily pre-treated mCRPC with DDR gene defects, with BRCA1/2 aberrant tumors being most sensitive but with confirmed responses in patients with other DDR alterations. Clinical trial information: NCT01682772.