bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-effectiveness analysis of neoadjuvant immune checkpoint inhibition (ICI) versus cisplatin-based chemotherapy (CBC) in muscle-invasive bladder cancer (MIBC).
Authors: Khaki Ali Raza , Shan Yong , Nelson Richard , Kaul Sapna , Gore John L. , Grivas Petros , Williams Stephen B. 
Published: March 2021

419 Background: Multiple single-arm clinical trials have shown promising pathologic complete response (pCR) rates with neoadjuvant ICIs in MIBC. However, ICIs remain costly. We conducted a cost-effectiveness analysis comparing neoadjuvant ICIs with CBC. Methods: We applied a decision analytic simulation model with a health care payer perspective and two-year time horizon to compare neoadjuvant ICIs vs CBC. For the primary analysis we compared pembrolizumab with dose dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC). We performed a secondary analysis with gemcitabine/cisplatin (GC) as CBC and exploratory analyses with atezolizumab or nivolumab/ipilimumab as ICIs (vs both ddMVAC and GC). We input pCR rates from trials (ICIs) or a weighted average of prior studies (CBC) and costs from average sales price. Outcomes of interest included costs, 2-year recurrence-free survival (RFS), and incremental cost-effectiveness ratio (ICER) of cost per 2-year RFS. A threshold analysis estimated a pCR rate or price reduction for ICI to be cost-effective and one-way and probabilistic sensitivity analyses were performed. Results: Results of the cost effectiveness analysis are shown in the table. The incremental cost of pembrolizumab compared with ddMVAC was $8,042 resulting in an incremental improvement of 0.66% in 2-year RFS for an ICER of $1,218,485 per 2-year RFS. A pCR of 71% or a 26% reduction in cost of pembrolizumab would render it more cost-effective with an ICER of $100,000 per 2-year RFS. GC required a 96% pembrolizumab cost reduction to achieve an ICER of $100,000 per 2-year RFS. Atezolizumab appeared to be more cost-effective than ddMVAC, even though the 2yr RFS was 0.66% worse. Conclusions: ICIs were not cost-effective as neoadjuvant therapies, except when atezolizumab was compared with ddMVAC. Pembrolizumab would approach cost-effective thresholds with 26% or 96% reduction in cost when compared to ddMVAC and GC, respectively. Randomized clinical trials, larger sample sizes and longer follow-up are required to better understand the value of ICIs as neoadjuvant treatments. [Table: see text]
INTACT (S/N1806) phase III randomized trial of concurrent chemoradiotherapy with or without atezolizumab in localized muscle-invasive bladder cancer: Safety update on first 73 patients.
Authors: Singh Parminder , Efstathiou Jason A. , Tangen Catherine , Jhavar Sameer G. , Hahn Noah M. , Costello Brian Addis , Delacroix Scott Edward , Tripathi Abhishek , Sachdev Sean , Gills Jessie , Jani Ashesh B. , Bangs Rick , Plets Melissa , Vogelzang Nicholas J. , Thompson Ian Murchie , Feng Felix Y , Lerner Seth P. 
Published: March 2021

428 Background: Trimodality therapy (TMT) with maximal TURBT followed by chemoradiation(CRT) is a standard of care for select patients with muscle invasive bladder cancer (MIBC). This trial evaluates the activity of atezolizumab (atezo) in MIBC in combination with TMT. This trial was designed with pre-specified safety analyses of the first 80 patients (40 in each arm). At the time of SWOG fall 2020 DSMC report deadline we had enrolled 84 patients but data on only 73 patients were available. The same data are being submitted to ASCO GU meeting. Methods: This trial is testing atezo every 3 weeks for 6 months given concurrently and adjuvantly with CRT vs. CRT alone in 475 patients with MIBC T2-T4aN0M0 disease. Patients are stratified based on PS; T2 vs T3 or T4; choice of chemotherapy; and radiation field (bladder only vs small pelvis). Patients undergo biopsy 3 months after finishing CRT to assess treatment response. Patients are followed for 5 years for recurrence or survival. This trial was not preceded by a phase I study but was designed with a safety run in of 80 patients. Study team agreed on the study design based on available data from other tumor types and initial experience from investigators running smaller similar trials. It was pre-specified that if we observe more than 25% patients having grade 3-5 colitis or cystitis in the atezo arm or any other toxicity which is deemed clinically significant and related to atezo, the trial investigators and DSMC would consider stopping further enrollment. Results: 36 patients were enrolled on the TMT alone arm and 37 patients on the TMT + atezo arm. No grade 3 or higher colitis was reported in the atezo arm. Only one patient had treatment related grade 3 radiation cystitis which was diagnosed after finishing atezo treatment. No steroids were given. Overall 23 grade 3 or higher toxicity events were reported in the atezo arm vs 11 in non- atezo arm. Most common toxicity was hematological which was considered non-immune related. None of the grade 3 or higher toxicities were considered to be immune related by the treating investigator. Conclusions: There is no evidence of increased immune related grade 3-5 AEs.DSMC has recommended to continue enrollment. Adverse Events with No Entries for Grades 3 to 5 Have Been Suppressed Clinical trial information: NCT03775265 . [Table: see text]
Tailored immunotherapy approach with nivolumab in advanced transitional cell carcinoma (TITAN-TCC).
Authors: Grimm Marc-Oliver , Schmitz-Dräger Bernd , Zimmermann Uwe , Grün Barbara , Baretton Gustavo Bruno , Schmitz Marc , Foller Susan , Schostak Martin , Zengerling Friedemann , Schumacher Ulrike , Loidl Wolfgang C. , Meran Johannes 
Published: March 2021

446 Background: Several PD-1 immune-checkpoint inhibitors including Nivolumab (Nivo) are approved in urothelial cancer. Recently, in the front line setting, improved activity of combined PD-L1 and CTLA4 immune-checkpoint inhibition has been reported and a phase III trial with Nivolumab + Ipilimumab (Nivo+Ipi) is ongoing. Here we report a response-based tailored approach starting treatment with Nivo monotherapy using Nivo+Ipi as immunotherapeutic “boost”. Methods: Between July 2017 and April 2019 86 patients were enrolled and treated according to protocol version 3 (cohort 1). Patients started with Nivo 240 mg Q2W induction. After 4 dosings and tumor assessment at week 8 (i) responders (PR/CR) to Nivo monotherapy continued with maintenance while (ii) patients with stable (SD) or progressive disease (PD) received 2 cycles Nivo3+Ipi1 followed by another 2 cycles Nivo1+Ipi3 if not responding. Median follow-up is 8.7 months. The primary endpoint is confirmed investigator-assessed objective response rate (ORR) per RECIST1.1. Secondary endpoints include activity of Nivo monotherapy at week 8, remission rate with Nivo+Ipi “boosts”, safety, overall survival and quality of life. Results: Of the patients 42, 39 and 5 were first, second and third line, respectively. Median age was 67 years (range 45-84), 61 patients (71 %) were male and 25 female. ORR with Nivo monotherapy at first assessment (week 8) was 29 % and 23 % in first and second/third line, respectively. Of the patients 41 received Nivo+Ipi “boosts” after week 8 while 12 received later “boosts”. Best overall response (BOR) rate with Nivo induction ± Nivo+Ipi “boosts” was 48 % and 27 % in first and second/third line, respectively. In first line 7/17 (41 %) patients receiving Nivo+Ipi after week 8 had an improved response compared to 2/24 (8.3 %) in second/third line. Of the patients who continued with Nivo maintenance after week 8 and received later “boosts” 2/12 (17 %) had a PR and 2/12 (17 %) improved to SD. Treatment-related AEs will be presented. Conclusions: TITAN–TCC explores a response-driven use of Nivo+Ipi as an immunotherapeutic “boost”. In first line, this significantly improved ORR compared to the expected response rate of Nivo monotherapy, providing further evidence to the added value of Ipi in combination with Nivo. Further follow-up is ongoing to characterize duration and depth of response. Clinical trial information: NCT03219775 . Research Sponsor: Bristol-Myers Squibb[Table: see text]
Analysis of PFS2 by subsequent therapy in KEYNOTE-361: Pembrolizumab (pembro) plus chemotherapy (chemo) or pembro alone versus chemo as 1L therapy for advanced urothelial carcinoma (UC).
Authors: Ozguroglu Mustafa , Alva Ajjai Shivaram , Csőszi Tibor , Matsubara Nobuaki , Geczi Lajos , Cheng Susanna Y. , Fradet Yves , Oudard Stephane , Vulsteke Christof , Morales-Barrera Rafael , Flechon Aude , Gunduz Seyda , Loriot Yohann , Rodriguez-Vida Alejo , Mamtani Ronac , Yu Evan Y. , Nam Kijoeng , Imai Kentaro , Homet Moreno Blanca , Powles Thomas 
Published: March 2021

448 Background: 1L pembro + chemo did not show statistically superior PFS and OS vs chemo for pts with advanced UC in the phase III KEYNOTE-361 study; OS for pembro vs chemo was not formally tested. We analyzed PFS2 (time from randomization to progressive disease [PD] on first subsequent therapy, or death from any cause, whichever occurs first) by study treatment and subsequent therapy in KEYNOTE-361 (NCT02853305) to determine the effects, if any, of therapy sequence on PFS2. Methods: PFS2 was estimated for pts in each treatment arm, who received any subsequent therapy including any anti–PD-(L)1, any therapy other than anti–PD-(L)1, or no therapy. These were exploratory analyses; no formal comparisons were done. Results: 1010 pts were randomized: 351 pts to receive pembro + chemo, 307 to pembro, and 352 to chemo. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 31.7 (22.0-42.3) mo. Subsequent therapy was received by 124/351 (35%), 126/307 (41%), and 215/352 (61%) pts in the pembro + chemo, pembro, and chemo arms, respectively. Subsequent anti–PD-(L)1 therapy was received by 169/352 (48%) pts in the chemo arm vs 23/351 (7%) in the pembro + chemo arm and 14/307 (5%) in the pembro arm. Of pts in the pembro arm who received subsequent therapy, >90% received 2L cisplatin-based or carboplatin-based treatment. Median (m) PFS2 (95% CI) for all pts by treatment arm was 14.1 mo (12.6-16.2) with pembro + chemo, 10.9 mo (9.5-12.9) with pembro, and 10.4 mo (9.8-11.2) with chemo. Across treatment arms, pts in the pembro + chemo arm had the longest mPFS2 with any subsequent therapy (14.5 mo [95% CI 13.1-16.6]) (Table). Pts in the pembro arm who received no subsequent therapy had a longer mPFS2 (12.9 mo [95% CI 8.1-17.9]) vs pts in the chemo arm who received no subsequent therapy (9.4 mo [95% CI 7.6-10.6]). Finally, pts treated with 1L pembro in the trial followed by 2L therapy other than anti−PD-(L)1 had comparable mPFS2 (10.2 mo [95% CI 8.6-12.1]) to pts treated with 1L chemo in the trial followed by 2L anti−PD-(L)1 (11.1 mo [95% CI 10.2-12.9]). Conclusions: In this exploratory analysis, treatment sequence of chemo followed by anti−PD-(L)1 upon PD vs anti–PD-(L)1 followed by chemo upon PD did not appear to impact mPFS2. Among pts who did not receive 2L therapy, 1L pembro appeared to be associated with longer mPFS2 than chemo, potentially driven by long-term responders to pembro. Clinical trial information: NCT02853305 . [Table: see text]
Real-world utilization of docetaxel among men with de novo metastatic castration-sensitive prostate cancer: A population-based study in men aged 66 or older.
Authors: Shayegan Bobby , Wallis Christopher J.D. , Hamilton Robert James , Morgan Scott Carlyle , Cagiannos Ilias , Basappa Naveen S. , Ferrario Cristiano , Gotto Geoffrey , Fernandes Ricardo , Noonan Krista , Niazi Tamim , Hotte Sebastien J. , Saad Fred , Hew Huong , Chan Katherine , Park-Wyllie Laura , Malone Shawn 
Published: March 2021

47 Background: Docetaxel was the first agent, when added to androgen deprivation therapy (ADT), to demonstrate a survival benefit in men with metastatic castration-sensitive prostate cancer (mCSPC). It remains an important guideline recommendation approach in these men. However, real-world experience among patients with de novo metastatic disease is poorly understood. Using population-based data from Ontario Canada, we examined the real-world experience of using docetaxel in mCSPC. Methods: Men aged 66 years and older diagnosed with de novo metastatic prostate cancer between 2014-2019 were captured. The Cancer Activity Level Reporting system tracks information regarding the use of cancer treatments, including details of systemic therapy. We identified patients who received docetaxel intensification to ADT following diagnosis of de novo mCSPC and analyzed the proportion of patients who completed 6 cycles of treatment, required a dose decrease, and who visited the emergency department (ED) or were hospitalized for febrile neutropenia. Results: Over the 5-year study period, 399 men received docetaxel treatment among 3,556 identified with de novo mCSPC. The median age was 72 (IQR 68-76) and mean Charlson comorbidity index was 0.15 (SD +/- 0.72). Of the 399 men, 230 (58%), 202 (51%) and 175 (44%) patients completed at least 4, 5 and 6 cycles of docetaxel, respectively. Dose reduction during docetaxel treatment was required in 173 (43%) patients. Filgrastim was prescribed among 29 (7.3%) patients. Hospitalization or ED visit for febrile neutropenia was observed in 63 (16 %) of patients who received docetaxel. Conclusions: Among men age 66 years and over who received docetaxel and ADT for mCSPC, less than half were able to complete all six prescribed cycles. In addition, over two fifth required dose reductions and 16% experienced febrile neutropenia requiring hospitalization or ED visit. These data highlight the differences in expected outcomes between clinical trial populations (as reported in CHAARTED) and routine use.
HPV-16 positive clinically advanced squamous cell carcinoma of the urinary bladder (mBSCC): A comprehensive genomic profiling (CGP) study.
Authors: Jacob Joseph M , Spiess Philippe E. , Bratslavsky Gennady , Necchi Andrea , Grivas Petros , Danziger Natalie , Lin Douglas I. , Huang Richard , Mata Douglas A , Decker Brennan James , Sokol Ethan , Ross Jeffrey S. 
Published: March 2021

481 Background: mBSCC is an uncommon form of urinary bladder malignancy when compared with the much higher urothelial carcinoma incidence. We studied the genomic alteration (GA) landscape in a series of mBSCC based on the association with HPV-16 to determine if differences would be observed between the positive and negative groups. Methods: Using a hybrid capture-based FDA-approved CGP assay, a series of 171 mBSCC were sequenced to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining set at 1-49% and high staining at ≥50% expression. Results: Overall, 11 (6.4%) of the mBSCC were found to harbor HPV-16 sequences (Table). HPV-16+ status was identified slightly more often in women (NS) and in younger patients (P = .04); 2 female patients with mBSCC had prior history of SCC including 1 anal SCC and 1 vaginal SCC. HPV-16+ mBSCC had fewer GA/tumor (P < .0001), and fewer inactivating GA in CDKN2A (P < .0001), CDKN2B (P = .05), TERT promoter (P = .0004) and TP53 (P < .0001). GA in genes associated with urothelial carcinoma including FGFR2 and FGFR3 were similar in both HPV-16+ and HPV-16- mBSCC groups. MTOR and PIK3CA pathway GA were not significantly different in the 2 groups. MSI and TMB were also similar in the 2 groups. The 3 HPV-16+ mBSCC cases showed high positive PD-L1 IHC staining. Conclusions: HPV-16+ mBSCC tends to occur more often in women and younger patients. As reported in other HPV-associated squamous cell carcinomas, HPV-16+ mBSCC demonstrates significantly reduced frequencies of inactivating mutations in cell cycle regulatory genes with similar GA in MTOR and PIK3CA pathways. The implication of HPV in the pathogenesis of bladder cancer remains unknown but warrants further exploration and clinical validation. [Table: see text]
Real-world survival of men with metastatic hormone-sensitive prostate cancer (mHSPC) treated with abiraterone acetate (Abi) or docetaxel (Doc) and comparison with clinical trial outcomes.
Authors: Geynisman Daniel M. , Correa Andres F , Ramamurthy Chethan , Beck J Robert , Handorf Elizabeth A. 
Published: March 2021

53 Background: Multiple phase III trials have proven that Abi and Doc both improve overall survival (OS) in men with mHSPC. No randomized trials have compared the two approaches. Methods: We conducted a retrospective, observational study to compare OS in de novo M1 men, treated with Abi vs. Doc using patient-level data from the Flatiron health EHR-derived de-identified database. We also compared this real-world OS to trial level data using extracted data points along the OS curves from CHAARTED and LATITUDE trials. OS was compared via Kaplan-Meier curves. Analyses were adjusted via propensity score weighting for age, Gleason score, PSA at diagnosis, race, ethnicity, ECOG PS, insurance type and treatment setting. Results: The cohort included 418 Abi pts and 807 Doc pts (Table). Median follow-up was 13.5 mo for Abi and 31.6 mo for Doc. Unadjusted median OS for Abi and Doc were 31.6 mo (95% CI 28.1-NA) and 41.8 mo (95% CI 37.4-46.3) respectively (P=0.09). Twelve mo and 24 mo OS for Abi was 86.3% and 69%; for Doc it was 89.8% and 72.1 %. Median adjusted OS for Abi and Doc were 31.6 mo (95% CI 28.0-undefined) and 38.8 mo (95% CI 33.1-46.3) respectively (P=0.4). Twelve mo and 24 mo adjusted OS for Abi was 86.6% and 69.4%; for Doc it was 87.9% and 69.2%. Based on extracted trial data, in LATITUDE, Abi treated pts had 12 mo and 24 mo OS of 93.5% and 77.0%; in CHAARTED, Doc treated pts had 12 mo and 24 mo OS of 94.3% and 83.6%. Conclusions: Utilizing real-world data, we demonstrate that 12 and 24-months OS are clinically and statistically similar between Abi and Doc in men with mHSPC. Median OS is also similar, although due to limited follow-up, the estimate of median OS for Abi has large variability. In addition, we show that clinical trial pts had superior outcomes to those in a real-world clinic population. Recent meta-analyses of trial data have not found significant differences in OS for Abi vs. Doc; this analysis of real-world data confirms these findings and indicates that they may be generalizable to a broader patient population. Although this observational study is subject to residual confounding and missing data, it provides further evidence to support the use of both Abi and Doc in men with mHSPC. Differentiating costs, side-effects and QOL can thus become more prominent when making decisions about therapy. [Table: see text]
Outcomes in men with metastatic castrate-resistant prostate cancer treated with early platinum-based chemotherapy following an unsatisfactory response to androgen receptor (AR) inhibition as part of the phase II dynamic allocation modular sequential (DynAMo) trial.
Authors: Viscuse Paul Vincent , Zhang Miao , Liu Jingjing , Tidwell Rebecca , Subudhi Sumit Kumar , Zurita Amado J. , Corn Paul G. , Tu Shi-Ming , Araujo John C. , Wang Jennifer , Efstathiou Eleni , Wang Jianbo , Pilie Patrick Glen , Troncoso Patricia , Zhang Jianhua , Logothetis Christopher , Aparicio Ana 
Published: March 2021

83 Background: Most prostate cancers are driven by the androgen receptor (AR) and have significant responses to AR inhibition. However, approximately 20-30% respond poorly to AR signaling inhibitors and have an atypical and virulent clinical course. Previous studies have shown that early declines in PSA and CTC on treatment are linked with “AR-responsiveness” in metastatic castration resistant prostate cancer (mCRPC). Few non-androgen directed therapies are approved for AR-unresponsive patients though combination cabazitaxel and carboplatin showed efficacy in this patient population in a phase I/II trial (Corn et al. Lancet Oncol, 2019). We hypothesized that early addition of chemotherapy in AR-unresponsive patients would improve outcomes. Methods: In a modular phase II trial (NCT02703623), men with mCRPC treated with abiraterone acetate plus prednisone and apalutamide were classified at week 8 as having a ‘satisfactory’ decline in PSA (≥ 50% from baseline) and CTC (≤5/7.5mL) or ‘unsatisfactory’. Patients with ‘unsatisfactory’ declines had carboplatin and cabazitaxel added to the AR inhibitors. Primary objectives included the estimation of the overall survival (OS) of patients in this cohort. Results: 198 men were registered. 59 (31.5%) of 187 evaluable had ‘unsatisfactory’ marker declines. Patients were primarily white/non-Hispanic men (81%) over the age of 60 (78%) with ECOG score of 0 (75%). Median baseline PSA and CTC were 11.3 ng/mL and 9.0 cells/mL respectively. Median follow-up was 31.7 months with median OS 19.2 months (95% CI 14.8-27.8). Median TTF was 9.0 months (6.9-11.0). Related adverse events included decreased WBC (39%; 15% G3+), anemia (56%; 7% G3+), and lymphopenia (59%; 8% G3+). There was one grade 5 sepsis of unknown attribution. Conclusions: Although early platinum-based chemotherapy offers a durable response in a subset of AR unresponsive patients, there were patients that continued to have rapid progression. We will present additional clinical and molecular data (IHC, RNA-seq, WES) in an attempt to further differentiate AR responders from AR non-responders. Clinical trial information: NCT02703623.
Relationship between changes in serum androgen level measured by LC-MS/MS and therapeutic effect after enzalutamide treatment.
Authors: Miyazawa Yoshiyuki , Nakamura Toshiyuki , Takezawa Yutaka , Shimizu Nobuaki , Matsuo Yasushige , Ogura Haruyuki , Takei Tomoyuki , Arai Seiji , Nomura Masashi , Sekine Yoshitaka , Koike Hidekazu , Matsui Hiroshi , Shibata Yasuhiro , Suzuki Kazuhiro 
Published: March 2021

88 Background: Enzalutamide (ENZ) has proven efficacy against castration-resistant prostate cancer (CRPC) and is widely used in treatment. However, no useful biomarkers have yet been reported to predict the effects of ENZ. We examined the relationship between the efficacy of ENZ and changes in serum androgen levels after ENZ administration. Methods: This exploratory research was based on the data from our prospective clinical trial. Of a total of 104 cases, 67 with confirmed changes in androgen levels after 3 months of ENZ administration, compared to pretreatment levels, were included in this study to identify prognostic factors. Serum androgen levels were measured by liquid chromatography-mass spectrometry (LC-MS/MS). This study was approved by the institutional review board of Gunma University Hospital (No.1177). Results: The study population of 67 patients had a median age of 73 years. The median serum levels of testosterone (T), dihydrotestosterone (DHT), androstenedione (A-dione), and dehydroepiandrosterone sulfate (DHEA-S) before treatment were 56.8 pg/ml, 7.8 pg/ml, 253.5 pg/ml, and 502.2 pg/ml, respectively. The median increase rate(%) of T, DHT, A-dione andDHEA-S after 3 months of ENZ administration were +55.5%, +49.5%, +25.8%, and +24.9%, respectively. T, DHT, and A-dione levels were significantly increased after 3 months (p < 0.05). We performed Cox regression analysis to predict PSA-PFS and OS. Hemoglobin (Hb, ≥ 12.5 g/dl vs. < 12.5 g/dl) and T increase rate ( < 55.5% vs. ≥ 55.5%) were significant predictors of PSA-PFS (p < 0.05). ECOG performance status (0 vs. 1 - 2, respectively) and Hb (≥ 12.5 vs. < 12.5 g/dl, respectively) and T ( < 55.5% vs. ≥55.5%) were significant predictors of OS (p < 0.05). Conclusions: PSA-PFS and OS were significantly poor in the cases in which T increased significantly 3 months after ENZ administration. It was suggested that the change of hormonal environment after ENZ administration may be a prognostic factor.