bluuebunny/crossref_metadata_2025_split huggingface dataset:
Avelumab first-line (1L) maintenance + best supportive care (BSC) versus BSC alone in Asian patients with advanced urothelial carcinoma (UC): JAVELIN Bladder 100 subgroup analysis.
Authors: Eto Masatoshi , Lee Jae-Lyun , Park Se Hoon , Tsuchiya Norihiko , SU Po-Jung , Chan T.W. , Desai Chirag Jyotiker , Di Pietro Alessandra , Wang Jing , Laliberte Robert J , Gao Seasea , Gurney Howard 
Published: February 2022

486 Background: In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), avelumab 1L maintenance therapy + BSC showed significantly longer overall survival (OS) vs BSC alone in patients with advanced UC that had not progressed with 1L platinum-based chemotherapy. We report efficacy and safety results in patients enrolled in Asia. Methods: Patients with unresectable locally advanced or metastatic UC without disease progression after 4-6 cycles of gemcitabine + cisplatin or carboplatin were randomized 1:1 to receive avelumab 1L maintenance + BSC or BSC alone, stratified by best response to 1L chemotherapy and visceral vs nonvisceral disease when initiating 1L chemotherapy. The primary endpoint was OS, assessed from randomization in all patients and patients with PD-L1+ tumors (Ventana SP263 assay). Results: 147 Asian patients were enrolled at sites in Japan, South Korea, Taiwan, Hong Kong, and India; 73 and 74 were randomized to receive avelumab + BSC or BSC alone, respectively. Median OS (95% CI) was 25.3 mo (18.6 mo-not estimable [NE]) with avelumab+ BSC vs 18.7 mo (12.8 mo-NE) with BSC alone (HR, 0.74 [95% CI, 0.434-1.260]) in all patients, and 26.1 mo (18.2 mo-NE) vs 19.4 mo (11.9 mo-NE), respectively (HR, 0.66 [95% CI, 0.279-1.541]), in the PD-L1+ subgroup (n = 71). With avelumab + BSC vs BSC alone, median (95% CI) progression-free survival was 5.6 (2.0-7.5) vs 1.9 (1.9-1.9) months (HR, 0.58 [95% CI, 0.383-0.864]) in all patients and 6.8 (1.9-11.2) vs 1.9 (1.9-3.8) months (HR, 0.63 [95% CI, 0.336-1.172]) in the PD-L1+ subgroup; objective response rates (95% CI) were 9.6% (3.9%-18.8%) vs 2.7% (0.3%-9.4%) and 12.5% (4.2%-26.8%) vs 3.2% (0.1%-16.7%), respectively. The most common treatment-emergent adverse events (TEAEs) of any grade (any causality) in the avelumab + BSC arm were pyrexia (23.6%), constipation, nasopharyngitis, and rash (19.4% each); grade ≥3 TEAEs were anemia (9.7%), amylase increased (5.6%), and urinary tract infection (4.2%). Conclusions: Efficacy and safety data support the use of avelumab 1L maintenance as the standard of care in Asian patients with advanced UC that has not progressed with 1L platinum-based chemotherapy. Clinical trial information: NCT02603432.
Reduction of residual tumors by photodynamic diagnosis-assisted TURBT using 5-aminolevulinic acid for high-risk nonmuscle-invasive bladder cancer (BRIGHT study).
Authors: Kawai Taketo , Kume Haruki , Inoue Keiji , Fujimoto Kiyohide , Oyama Masafumi , Miyake Hideaki , Azuma Haruhito , Nishiyama Hiroyuki , Shinohara Nobuo , Ohyama Chikara , Mitsui Takahiko , Mizokami Atsushi , Kawakita Mutsushi , Matsuyama Hideyasu 
Published: February 2022

489 Background: High-risk non-muscle invasive bladder cancer (NMIBC) has high tumor residual rate of 40–60% after TURBT, and second TUR is strongly recommended. Photodynamic diagnosis-assisted TURBT (PDD-TURBT) using 5-aminolevulinic acid (5-ALA) has been reported to reduce residual tumors and intravesical recurrence. The purpose of this study is to investigate the residual tumor-reducing effect of PDD-TURBT for high-risk NMIBC and to explore the possibility that second TUR could be omitted by PDD-TURBT. Methods: We conducted an investigator-initiated multicenter prospective observational study (BRIGHT study; UMIN000035712) involving patients who underwent PDD-TURBT using 5-ALA and second TUR for high-risk NMIBC (high-grade UC or pT1 or concurrent CIS). The primary endpoint was tumor residual rate and the secondary endpoint was recurrence-free survival, which were compared with historical data (conventional TURBT) using propensity score-matching (PSM; caliper: 0.2). Assuming that the difference between the two groups was 20%, the planned number of cases was statistically set to 200 PDD-TURBT cases and 300 historical data cases, and the registration period was 2 years from January 2019 to December 2020, and the follow-up period was 2 years after second TUR. Results: In this study, 188 patients in the PDD-TURBT group and 313 patients in the historical group were enrolled, and 177 patients and 306 patients were included in the final analysis, respectively. After PSM adjustment, 167 patients in both groups were compared, and no significant differences were observed in age, gender, history of bladder cancer, tumor diameter, number of tumors, history of upper tract urothelial cancer, and period from initial TURBT to second TUR. The tumor residual rate was 25.8% in the PDD-TURBT group compared with 47.3% in the historical group, showing a significant decrease (odds ratio 0.39 [95% CI: 0.24–0.63]; p = 0.000064). Logistic regression analysis revealed that significant factors predicting residual tumors in PDD-TURBT were current or past smoking history, multiple tumors, and non-pTa (pT1 or pTis) tumors. Focusing on these three factors, patients with 0–1 of these three factors have a significant less tumor residual rate compared with patients with 2–3 factors (8.33% vs. 33.3%; odds ratio 5.46 [95% CI: 1.81–22.3]; p = 0.00052). Conclusions: PDD-TURBT for high-risk NMIBC significantly reduced the tumor residual rate at the second TUR compared to the conventional TURBT. PDD-TURBT using 5-ALA may enable to omit second TUR in some high-risk NMIBC cases. Clinical trial information: UMIN000035712.
Atezolizumab (atezo) with or without Bacille Calmette-Guérin (BCG) in patients (pts) with high-risk nonmuscle-invasive bladder cancer (NMIBC): Results from a phase Ib/II study.
Authors: Hahn Noah M. , Steinberg Gary D. , Stratton Kelly Lynn , Kopp Ryan P. , Sankin Alexander , Skinner Eila C. , Pohar Kamal S. , Gartrell Benjamin Adam , Pham Song , Rishipathak Deepali , Mariathasan Sanjeev , Davarpanah Nicole N. , Carter Corey , Inman Brant Allen 
Published: February 2022

493 Background: Standard treatment (tx) for high-risk NMIBC is transurethral resection of bladder tumor (TURBT) followed by BCG induction and maintenance. However, ≈50% of pts experience recurrence and/or progression after tx and may be ineligible for or refuse cystectomy. The PD-L1/PD-1 pathway may be involved with immune escape in NMIBC following BCG exposure. Here, we report results of atezo (antiPD-L1) ± BCG in BCG-unresponsive, high-risk NMIBC. Methods: This multicenter study (NCT02792192) enrolled pts with BCG-unresponsive NMIBC with carcinoma in situ who had repeat TURBT. Cohort 1A and 1B pts received atezo 1200 mg IV q3w for ≤96 wk. Cohort 1B pts also received standard BCG induction (qw × 6 doses) and maintenance (qw × 3 doses at 3 mo), with optional maintenance courses at 6, 12, 18, 24, and 30 mo. For cohort 1B only, de-escalation was allowed for ≤3 BCG dose levels (full dose 50 mg, 66% and 33% of full dose). Co-primary outcomes were safety and complete response (CR) rate at 6 mo (6-mo bladder biopsy required). Duration of CR and 3-mo CR rate (key secondary outcomes) and 12-mo CR rate (exploratory) were also shown. Results: Cohorts 1A and 1B enrolled 12 pts each. Median age was 74 y; most pts had ECOG PS 0 (n = 7 [58%] in each cohort). At data cutoff (Sep 29, 2020), median atezo tx duration was 22.7 wk in cohort 1A and 31.6 wk in 1B. Following dose de-escalation in cohort 1B, the recommended BCG dose was 50 mg. BCG dose modification/interruption occurred in 4 pts (33%) due to an AE. The most common reason for tx discontinuation was disease recurrence or progression in both cohorts. Three pts (25%) in cohort 1A had atezo-related Gr 3 AEs (most common: maculopapular rash, n = 2); no atezo- or BCG-related Gr ≥3 AEs were seen in cohort 1B. Three dose-limiting toxicities occurred (1 [8%] in cohort 1A and 2 [17%] in cohort 1B), all reported as AEs of special interest. No Gr 4/5 AEs were reported. CRs, which appeared durable, were seen in both cohorts (Table). Conclusions: In this first report of atezo + BCG in NMIBC, atezo as mono- and combination therapy was well tolerated, with no new safety signals or tx-related deaths. Preliminary data suggested clinically meaningful activity, especially with atezo + BCG, requiring confirmation in a larger setting. Clinical trial information: NCT02792192. [Table: see text]
Futibatinib plus pembrolizumab in patients (pts) with advanced or metastatic urothelial carcinoma (mUC): Preliminary safety results from a phase 2 study.
Authors: Koshkin Vadim S , Sonpavde Guru P. , Hwang Clara , Mellado Begona , Tomlinson Gareth , Shimura Masashi , Chisamore Michael Jon , Gil Maciej , Loriot Yohann 
Published: February 2022

501 Background: Immune checkpoint inhibitors (ICIs), including pembrolizumab, are among the few treatment options available for platinum-ineligible pts with mUC, but only 25–30% of pts achieve responses with ICIs. FGFR DNA alterations (in 15–20% of mUCs) may contribute to poor responses to ICIs, and FGFR inhibition may sensitize tumors to ICIs by direct action on cancer cells or by altering the tumor microenvironment. In an open-label phase 2 study (NCT04601857), futibatinib, a highly selective, potent, irreversible FGFR1–4 inhibitor with activity in FGFR-deregulated tumors, is being assessed in combination with pembrolizumab in pts with mUC. Here, we report preliminary findings from the safety lead-in phase. Methods: Eligible pts (≥18 y; ECOG PS ≤1) had mUC, were treatment naive in the advanced/metastatic setting, and unfit for, intolerant to, or refusing platinum-based chemotherapy. Prior anti–PD-1/PD-ligand 1/2 or FGFR inhibitor therapy were not permitted. Pts (regardless of FGFR alteration status) were first enrolled in a safety lead-in and received futibatinib 20 mg orally once daily (QD) and pembrolizumab 200 mg IV every 21 d. Dose-limiting toxicities (DLTs) were assessed during the first 21-d treatment cycle. Results: As of September 27, 2021, 6 pts were enrolled in the safety lead-in. Median age was 73.5 y (range, 46–84 y) and 17% (1/6) of pts had an ECOG PS of 1. Median duration of treatment was 48 d (range, 21–141 d) with futibatinib and 35 d (1–114 d) with pembrolizumab. Two pts (33%) remained on treatment at data cutoff. Adverse events (AEs) were reported in all 6 pts; AEs in > 2 pts were diarrhea (83%), hyperphosphatemia (67%), increased aspartate aminotransferase (50%), and pruritis (50%). Grade 3 AEs were reported in 2/6 pts: increased aspartate aminotransferase, maculopapular rash, myositis (17% each). There were no grade 4–5 AEs. AEs led to any study drug discontinuation in 3 pts, dose interruption in 3 pts, and dose modification in 3 pts. All 6 pts were evaluated for DLTs after 1 treatment cycle; no DLTs were reported. Conclusions: Preliminary safety results support tolerability of futibatinib plus pembrolizumab in platinum-ineligible pts with mUC. As no DLTs were observed in the safety lead-in, the recommended dose of futibatinib in combination with pembrolizumab is 20 mg QD. Enrollment in pts with or without FGFR alterations is ongoing to evaluate antitumor activity by FGFR alteration status. Clinical trial information: NCT04601857.
Interim results of a phase Ib single-center study of pembrolizumab in combination with chemotherapy in patients with locally advanced or metastatic small cell/neuroendocrine cancers of the prostate and urothelium.
Authors: Chin Arnold I. , Drakaki Alexandra , Rodriguez Sara , Sachadeva Ankush , Bradley Margaret , Zomorodian Nazy , Zhang Hanwei , Li Shanpeng , Li Gang , Rettig Matthew , Liu Sandy 
Published: February 2022

510 Background: Small cell/neuroendocrine cancers irrespective of origin share aggressive phenotypes. Pembrolizumab (MK-3475) is a humanized antibody targeting programmed cell death protein 1 (PD-1) that has shown activity against small cell lung cancers. Preclinical studies showed molecular commonality amongst small cell/neuroendocrine cancers across multiple tissue types. This study evaluated the safety and efficacy signals of pembrolizumab and chemotherapy in patients with small cell/neuroendocrine cancer of the prostate and urothelium. Methods: Patients with locally advanced or metastatic small cell cancer of the bladder or upper urinary tract (cohort 1) and primary small cell or treatment-derived neuroendocrine prostate cancer (NEPC) (cohort 2) received pembrolizumab and standard of care chemotherapy (etoposide and cisplatin/carboplatin for cohorts 1 and 2, with option of docetaxel and carboplatin for cohort 2) with maintenance pembrolizumab for 2 years until unequivocal progressive disease or unacceptable toxicity. The primary endpoint was to estimate ORR and PFS compared to historical controls as well as safety and tolerability. Pretreatment targeted gene mutation sequencing was performed. Results: 14 patients were enrolled (7 cohort 1, 7 cohort 2) with mean age 64.9 (range 53 to 81). ORR across cohorts was 43% (95% CI: (0.17, 0.69)), and 43% (95% CI: (0.06, 0.80)) within each cohort. PFS rate at 12 months (proportion of patients who have not progressed at 12 month) was 61% (95% CI: (0.40,0.95)) across cohorts, 86% (95% CI: (0.63,1.00)) within cohort 1, and 36% (95% CI: (0.12,1.00)) within cohort 2. 3 patients in cohort 1 with locally advanced disease exhibited SD and underwent radical cystectomy, with one patient pT0 and no PD at a mean follow up of 20 months. Grade 3 or higher AEs occurred in 71% of patients, while 29% of patients experienced grade 3 or higher AEs related to pembrolizumab. No patients died or discontinued therapy secondary to adverse treatment effects. In 12 patients where tissue was sufficient, all patients had genomic alterations in either p53 (75%) or Rb (58%). Of the 5 available patients with NEPC, 60% had alternations in DNA damage response genes. Conclusions: In patients with locally advanced or metastatic small cell/neuroendocrine prostate and bladder cancers, combination pembrolizumab with standard of care chemotherapy and maintenance pembrolizumab showed promising efficacy with tolerable adverse events. Clinical trial information: NCT03582475.
Safety lead-in of phase II SBRT and durvalumab with or without tremelimumab for unresectable and cisplatin-ineligible, locally advanced or metastatic bladder cancer.
Authors: Kundu Palak , Lee Alan , Drakaki Alexandra , Liu Sandy , Shen John , Chin Arnold I. , Chamie Karim , Chang Albert 
Published: February 2022

517 Background: Many patients with muscle-invasive bladder cancer are not ideal candidates for chemotherapy or radical cystectomy. Moreover, local progression may further impair quality of life. Bladder preservation with maximal transurethral resection of bladder tumor (TURBT) and stereotactic body radiotherapy (SBRT) is a viable treatment option for such patients, offering durable local control while potentiating the effect of immunotherapy. Herein, we report on the safety profile of SBRT in combination with durvalumab (anti-PDL1) and tremelimumab (anti-CTLA4) in the safety lead-in cohort of an institutional Phase II trial for cisplatin-ineligible, unresectable locally advanced or metastatic bladder cancer patients. Methods: Patients with locally advanced or metastatic urothelial carcinoma, who were unwilling or unable to undergo radical cystectomy and/or systemic chemotherapy were eligible. Patients received maximal TURBT, followed by durvalumab 1500mg IV every 4 weeks and bladder SBRT 33Gy in 5 fractions between the first 2 cycles. After 6 such patients did not experience a dose limiting toxicity, tremelimumab 75mg IV was added for cycles 1-2. Patients were followed with CT Chest/Abdomen/Pelvis and cystoscopy every 3 months. Treatment-related adverse events (TRAEs) were assessed per CTCAE 5.0 and progression was assessed per RECIST 1.1. Results: Between January 2019 and May 2020, 10 patients received TURBT followed by SBRT and durvalumab (Age 73-96, 3 Female, 7 ECOG 1, 3 ECOG 0). Five patients had localized disease and 5 had nodal or distant metastases. Median cycles of durvalumab was 12.5 (2-13), and 4 patients received 2 cycles of tremelimumab. At a median follow-up of 16.8mo (6.4-30mo), there were 2 Grade 3+ immunotherapy-related TRAEs (1 Grade 3 lipase elevation self-resolved, 2 Grade 3 myositis treated with steroids). The most common TRAEs of any grade included pancreatic enzyme elevation (3 patients), rash (3 patients), and urinary symptoms related to RT (3 patients). Disease control rate 70% and local control was 90%. There were 3 non-treatment related deaths. Conclusions: Bladder SBRT with durvalumab and tremelimumab was well tolerated and demonstrated promising local control in the safety lead-in cohort. Clinical trial information: NCT03601455.
Association of TMB and PD-L1 with efficacy of first-line pembrolizumab (pembro) or pembro + chemotherapy (chemo) versus chemo in patients (pts) with advanced urothelial carcinoma (UC) from KEYNOTE-361.
Authors: Morales-Barrera Rafael , Powles Thomas , Ozguroglu Mustafa , Csoszi Tibor , Loriot Yohann , Flechon Aude , Matsubara Nobuaki , Rodriguez-Vida Alejo , Geczi Lajos , Cheng Susanna Y. , Fradet Yves , Oudard Stephane , Gunduz Seyda , Ma Junshui , Rajasagi Mohini , Vajdi Amir , Cristescu Razvan , Imai Kentaro , Homet Moreno Blanca , Alva Ajjai Shivaram 
Published: February 2022

540 Background: The 3-arm, open-label, phase 3 KEYNOTE-361 study (NCT02853305) evaluated first-line pembro ± chemo vs chemo in advanced UC regardless of PD-L1 status. The trial did not meet its primary end points of superior PFS and OS with pembro + chemo vs chemo and thus analysis of pembro monotherapy (mono) vs chemo was exploratory. We explored the association of TMB status and PD-L1 combined positive score (CPS) with clinical outcomes in KEYNOTE-361. Methods: In pts with TMB and/or PD-L1 data, the association between TMB (via whole exome sequencing) and PD-L1 (via PD-L1 IHC 22C3 pharmDx) and clinical outcomes (ORR, PFS, and OS) was evaluated. In each treatment arm, the hypotheses regarding the associations were evaluated using logistic regression (ORR) and Cox proportional hazards regression (PFS; OS), and 1-sided (pembro; pembro + chemo) and 2-sided (chemo) P values were calculated; significance was prespecified at α = 0.05 without multiplicity adjustment. Clinical utility was assessed using prespecified cutoffs of 175 mut/exome (TMB) and CPS 10 (PD-L1). Clinical data cutoff was April 29, 2020. Results: 820/993 pts (82.6%) had evaluable TMB data (pembro, 252; pembro + chemo, 282; chemo, 286). TMB (log10) was significantly positively associated with ORR, PFS, and OS for pembro ( P < 0.001, < 0.001, and 0.007, respectively) and PFS and OS for pembro + chemo ( P= 0.007 and 0.010, respectively). The area under the receiver operating characteristics (AUROC) curve (95% CI) for discriminating response was 0.64 (0.56-0.71) for pembro, 0.53 (0.46-0.60) for pembro + chemo, and 0.52 (0.45-0.59) for chemo. Efficacy by TMB cutoff is reported in the Table. All 993 pts had PD-L1 data (pembro, 302; pembro + chemo, 349; chemo, 342). PD-L1 was significantly positively associated with PFS for pembro ( P= 0.006) and ORR for pembro + chemo ( P= 0.042) but not chemo. Efficacy by PD-L1 CPS is reported in the Table. Conclusions: Strong associations were observed between TMB and all 3 clinical outcomes (ORR, PFS, and OS) with pembro mono in the first-line setting and a reduced association was observed between TMB and clinical outcomes with pembro + chemo. No consistent associations were observed between PD-L1 and clinical outcomes with pembro mono or pembro + chemo. Clinical trial information: NCT02853305. [Table: see text]
IRONMAN: The international registry for men with advanced prostate cancer.
Authors: George Daniel J. , Mucci Lorelei A , Kantoff Philip W. , Villanti Paul , Vinson Jake , Gerke Travis A. , Hyslop Terry , Rencsok Emily 
Published: February 2022

TPS190 Background: Men with advanced prostate cancer (APC) experience high mortality and severely impacted quality of life due to the disease itself as well as its therapies, with Black men facing the highest disease burden. The treatment landscape for APC is rapidly changing; however, little is known about the real-life experience of men receiving new therapies. There is an urgent need to identify disparities in treatment patterns and outcomes in advanced disease, based on patient and country demographics. The International Registry for Men with Advanced Prostate Cancer (IRONMAN) is uniquely equipped to meet these needs. Methods: IRONMAN is a population-based prospective cohort of men with newly diagnosed metastatic hormone-sensitive (mHSPC) and castration-resistant (CRPC) prostate cancer aiming to enroll 5,000 men across 16 countries (Australia, the Bahamas, Barbados, Brazil, Canada, Ireland, Jamaica, Kenya, Nigeria, Norway, South Africa, Spain, Sweden, Switzerland, United Kingdom, Untied States). Patients are followed prospectively for overall survival, clinically significant adverse events, changes in cancer treatments, biomarkers, and Patient-Reported Outcome Measures (PROMs). Data is collected via longitudinal electronic questionnaires from patients and providers as well as blood samples and medical records. IRONMAN is currently enrolling in 10 countries at 103 sites. Sites were selected to create a diverse cohort across race/ethnicity, rural/urban populations, socioeconomic factors, and geographic regions. Of the first 1,865 men enrolled to date, 60% have mHSPC and 40% have CRPC; overall, 9% of men (18% in the US) self-identify as Black and 82% identify as white (78% in the US). 60% (N = 1,111) of this cohort has been enrolled outside of the US, and the median age at study entry is 70 years. The distribution and demographics of patients are continuously monitored to inform ongoing enrollment efforts. The IRONMAN Diversity Working Group meets monthly to discuss barriers and strategies to enhance enrollment of a racially and ethnically diverse population. The Low- and Middle-Income Country Working Group addresses the unique needs of men being recruited from the Caribbean and African sites in addition to supporting broad oncology efforts in these regions. These efforts support IRONMAN’s larger goal to investigate disparities in the care of patients with APC, having potential implications for decreasing racial disparities in survival outcomes. Clinical trial information: NCT03151629.