bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolving treatment landscape in metastatic urothelial carcinoma (mUC) post-avelumab maintenance approval: Real-world insights from The US Oncology Network.
Authors: Li Haojie , Sura Sneha , Babcock Aram , Herms Lisa , Guo Jinhong , Conkling Paul , Franco Sonia , Singhal Puneet K. , Mamtani Ronac , Bupathi Manojkumar 
Published: January 2024

560 Background: Locally advanced/metastatic urothelial carcinoma (mUC) has poor prognosis and disproportionately affects the elderly, who often have coexisting illness and limited treatment options. According to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer (v3.2023), platinum-based chemotherapy (PBC) followed by avelumab maintenance therapy (maintA, only if there is no progression on first-line [1L] PBC), pembrolizumab (P, for platinum-ineligible), and P in combination with enfortumab vedotin (P+EV, for cisplatin-ineligible) are the preferred regimens. We evaluated real-world treatment patterns and overall survival (OS) among mUC patients during the period between maintA and P-EV approvals in the US. Methods: This retrospective cohort study was conducted using structured and chart review data from iKnowMed (iKM), The US Oncology Network electronic health record database. The cohort included adult mUC patients diagnosed between 30 April 2020 and 30 June 2021. Patients were followed from index date (date of 1L anticancer treatment) through 31 March 2023, last patient record or death, whichever occurred first. MaintA was defined as receiving avelumab after 1L PBC, with no documented progressive disease prior to avelumab start or as maintenance therapy indicated by physician notes. Descriptive statistics were used to report patient characteristics and treatment patterns. Kaplan-Meier analysis was implemented to assess OS. Results: A total of 207 patients initiated 1L treatments. The median age was 74 (range: 46 - 90+) years and 166 (80.2%) were male. Of 207 1L-treated patients, 107 (51.7%) received immune checkpoint inhibitor (ICI) monotherapy, 80 (38.6%) received PBC, and 20 (9.7%) received other treatments. The use of 1L ICI monotherapy increased with age, ranging from 15 (14.0%) among those younger than 65 to 57 (53.3%) among those aged 75 or older. Of patients who received 1L PBC, 28 (35.0%) received ICI maintenance therapy; majority of these (n = 26, 92.9%) received maintA (32.5% of patients received 1L PBC). During the follow-up, 71 (34.3%) patients received 2L treatment and 25 (12.1%) patients received 3L treatment. Majority of patients in 2L settings received antibody drug conjugates (n = 30, 42.2%) or ICI monotherapy (n = 27, 38.0%). Median (95% confidence interval) OS was 12.6 (8.5, 15.1) months for 1L-treated patients overall. Conclusions: Despite many recent advances in the therapy for mUC, these patients had poor prognosis. Notably, many 1L patients did not have the opportunities to receive 2L+ treatment, which demonstrated continuing unmet need for mUC patients. ICI monotherapy continues to be a prevalent option, especially for older patients.
Updated results from AVENANCE: Real-world effectiveness of avelumab first-line maintenance (1LM) in patients (pts) with advanced urothelial carcinoma (aUC) and analysis of subsequent treatment.
Authors: Barthelemy Philippe , Loriot Yohann , Thibault Constance , Gross-Goupil Marine , Eymard Jean Christophe , Voog Eric , Abraham Jaillon Christine , Le Moulec Sylvestre , Chasseray Matthieu , Gobert Aurélien , Auberger Benjamin , Viala Caroline , Cabart Mathilde , Kazan Eyad , Lorgis Veronique , Hilgers Werner , Josse Constant , Lambert Prisca , Solbes Marie-Noelle , Flechon Aude 
Published: January 2024

561 Background: Avelumab 1LM is the standard of care for aUC that has not progressed with 1L platinum-based chemotherapy based on level 1 evidence from the JAVELIN Bladder 100 phase 3 trial. Previous results from AVENANCE showed the effectiveness and safety of avelumab 1LM in a real-world population with aUC in France. We report updated data and analyses by subsequent (next-line) treatment. Methods: AVENANCE (NCT04822350) is a noninterventional, ambispective study. Eligible pts had aUC that had not progressed with 1L platinum-based chemotherapy and previous, ongoing, or planned avelumab 1LM treatment. The primary endpoint is overall survival (OS). Data reported are preliminary, and analysis is ongoing. Results: 594 pts were analyzed. At data cutoff (May 31, 2023), median follow-up was 24.2 mo (range, 0.6-43.7); 142 pts (23.9%) remained on avelumab. Median duration of avelumab treatment was 5.6 mo (95% CI, 4.9-6.9). Reasons for discontinuation were disease progression in 330 (73.2%), adverse event in 50 (11.1%), death in 42 (9.3%), and other reasons in 29 (6.4%) pts. 314 pts (52.9%) received subsequent treatment after avelumab: chemotherapy in 238 (75.8%), antibody-drug conjugate (ADC) in 52 (16.6%; enfortumab vedotin, 46 [14.6%]; other, 6 [1.9%]), immunotherapy in 12 (3.8%), and other in 12 (3.8%). Characteristics of pts who received ADC or chemotherapy are shown (Table). In the overall population, median OS from start of avelumab 1LM was 21.1 mo (95% CI, 17.3-23.8), and 1- and 2-y OS rates (95% CI) were 66.58% (62.57%-70.26%) and 45.41% (40.89%-49.82%), respectively. In pts who received subsequent ADC or chemotherapy, median OS (95% CI) from start of avelumab 1LM was 31.3 mo (22.2-not estimable) and 14.0 mo (13.2-15.6), 1-y OS rates (95% CI) were 85.93% (72.72%-93.04%) and 61.68% (55.13%-67.56%), and 2-y OS rates were 66.90% (49.85%-79.29%) and 25.43% (19.17%-32.14%), respectively. Conclusions: Updated results from the AVENANCE study confirm the effectiveness of avelumab 1LM in a real-world population. In pts with subsequent treatment (≈70% of pts who discontinued), a contemporary sequence of ADC after 1L platinum-based chemotherapy and avelumab 1LM treatment showed encouraging OS. Clinical trial information: NCT04822350 . [Table: see text]
Outcomes of enfortumab vedotin (EV) therapy in relation to prior immune checkpoint inhibitor (ICI) in patients (pts) with advanced urothelial cancer (aUC).
Authors: Vlachou Evangelia , Elias Roy , Hahn Noah M. , McConkey David James , Johnson Burles Avner , Hoffman-Censits Jean H. 
Published: January 2024

570 Background: EV is FDA approved for the treatment of aUC after disease progression with chemotherapy and/or ICI, and in combination with Pembrolizumab (P) for cisplatin ineligible pts in the first line. Reported response rate (RR) for EV+P is higher than EV alone and a retrospective study showed prior ICI is associated with higher grade of EV-related skin toxicity, suggesting immunogenic interaction. Herein we evaluated whether prior ICI correlates with improved response to EV monotherapy. Methods: This single-center retrospective study compared outcomes between pts with aUC who were treated with ICI immediately prior to EV (iICI) vs pts who did not receive immediate prior ICI (niICI). We also evaluated outcomes in pts who received ICI at any time prior to EV, with or without intervening treatments, compared to pts who never received ICI. Demographics and treatment details were extracted through chart review. RR (Complete Response + Partial Response) were compared between groups using χ2 test. Univariable and multivariable Cox regression models were used for comparing Progression free (PFS) and Overall (OS) survival. Multivariable models were adjusted for visceral metastasis presence and performance status (PS) at EV initiation (C1D1). Results: We identified 55 pts in the iICI group and 23 in the niICI. Table 1 summarizes patient characteristics. ICIs included Pembrolizumab, Atezolizumab, Nivolumab, and Avelumab. Median PFS for EV was 5.0 vs 2.0 months and OS 11.0 vs 7.1 months in iICI vs niICI group respectively. A statistically significant Hazard Ratio (HR) for PFS [HR: 1.72, 95% Confidence Interval (95CI): 1.03, 2.89, P=0.04] and OS (HR: 2.02, 95CI: 1.13, 3.60, P=0.02) was found in the univariable analysis. In the multivariable analysis HR was 1.56 (95CI: 0.91, 2.68, p= 0.11) for PFS and 1.79 (95CI: 0.97, 3.30, p=0.06) for OS. RR to EV was 43.6% (95CI: 0.33, 0.56) vs 43.5% (95CI: 0.14, 0.69), P= 0.99. In our cohort 70/78 (89.7%) pts received ICI prior to EV with or without intervening treatments. When comparing these pts to pts who never received ICI no significant difference was found in PFS, OS or RR. Conclusions: In our study, EV was associated with longer PFS and OS when given immediately after ICI compared to following other therapies. However, in the most parsimonious model examined, the p-value did not reach a significance threshold of p<0.05. Larger prospective studies are needed to better understand the mechanism behind this trend and identify the optimal sequence or combination of EV with other treatments in aUC. [Table: see text]
Sequencing of erdafitinib (erda) and enfortumab vedotin (EV) in patients (pts) with fibroblast growth factor receptor (FGFR2/3) altered (alt) advanced urothelial cancer (aUC): Analysis of UNITE database.
Authors: Jiang Cindy Y. , Hwang Hyunsoo , Jindal Tanya , Qiao Wei , Epstein Ilana , Nguyen Charles B , Gupta Shilpa , Shah Sumit , Bilen Mehmet Asim , Milowsky Matthew I. , Hoimes Christopher J. , Kilari Deepak , Zakharia Yousef , Emamekhoo Hamid , Grivas Petros , Bellmunt Joaquim , Alva Ajjai Shivaram , Koshkin Vadim S , Campbell Matthew T , Alhalabi Omar 
Published: January 2024

616 Background: The optimal therapy sequencing in aUC with FGFR2/3 alt is unclear. FGFR inhibition may increase Nectin-4 expression. We hypothesized that outcomes with EV would be more favorable when given after E compared to before E in pts with aUC harboring FGFR2/3 genomic alt. Methods: Pts with FGFR2/3 alts who received EV only (EVo), E then EV (E->EV), or EV then E (EV->E) were included. Overall survival (OS) measured from E or EV start (based on agent given first) and progression-free survival (PFS) measured from EV start were assessed with KM method and group comparison by log rank test with Cox proportional hazards regression model. Variables with p ≤0.2 were included in multivariate analysis (MVA). Wilcoxon rank sum and Fisher’s exact test were used to compare continuous and categorical variables, respectively. Observed response rate (ORR) was compared between groups using χ2 test. Results: Among 633 pts from 16 US sites, 487 had NGS data, and 94 (19%) had FGFR2/3 alterations with 24 receiving E->EV, 15 EV->E, and 55 EVo. Median age: 72 yrs; 87% Caucasian, 65% primary bladder tumor, 73% pure urothelial histology, 76% BMI <30, 83% ECOG PS 0-1, 60% visceral metastases (mets) with 23% liver mets, 93% prior IO, and 63% prior Plt. Pts treated with E->EV vs EV->E had similar baseline characteristics, but at EV start ECOG PS 0-1 was 93% in EV->E vs 67% in E->EV (p=0.04). ORR to EV for E->EV pts was 32% (CI- 12%-51%) vs 67% (CI 54%-91%) for EV->E pts (p=0.04). ORR for EVo was 49%. Median OS was 21 months (mo) E->EV, 19 mo EV->E, and 12 mo EVo; median PFS was 5, 5, 6 mo, respectively. Univariate analysis (UVA) and MVA results are shown in Table. In MVA, longer OS was seen in pts who received both EV and E vs EVo. Conclusions: We showed longersurvival in pts with FGFR2/3 alt aUC who received both EV and E regardless of sequence, which may reflect guarantee-time bias. Additional limitations include retrospective nature, modest sample size, no central scan review, lack of data for pts who received E only, selection and confounding biases. Larger prospective studies are needed to determine optimal sequencing and putative biomarkers. [Table: see text]
Infigratinib versus placebo in patients with resected urothelial cancer (UC) bearing FGFR3 mutation or fusion: Primary DFS analysis from the phase 3, randomized PROOF302 study.
Authors: Pal Sumanta Kumar , Grivas Petros , Gupta Shilpa , Valderrama Begoña Pérez , Rodriguez-Vida Alejo , Roghmann Florian , Sevillano Elena , Matin Surena F. , Loriot Yohann , Sridhar Srikala S. , Sonpavde Guru P. , Fleming Mark T. , Lerner Seth P. , Bellmunt Joaquim , Master Viraj A. , Tripathi Abhishek , Davis Kim , Van Veenhuyzen David Friedrich , Weng Richard , Daneshmand Siamak 
Published: January 2024

629 Background: In the subset of patients with UC bearing alterations in the fibroblast growth factor 3 ( FGFR3) gene, targeted therapies directed at this moiety have shown substantial antitumor effect in the metastatic setting. We examine infigratinib, a potent and selective inhibitor of FGFR3, as adjuvant therapy in patients with high-risk resected UC. Methods: In an international multicenter phase III clinical trial, we randomly assigned patients in a 1:1 ratio to receive either oral infigratinib (125 mg) or placebo daily for 21 days of a 28-day treatment cycle, for a maximum of 13 cycles or until disease recurrence. Eligible patients had confirmed invasive UC with susceptible FGFR3 alterations and had undergone radical surgery within 120 days of randomization. The primary endpoint of the study was centrally assessed disease-free survival (DFS), with secondary endpoints including investigator-assessed DFS, metastasis-free survival (MFS) and overall survival (OS). Results: Despite intensive efforts to enroll approximately 218 patients (with 822 patients consented to molecular pre-screening), only 39 patients were enrolled with 20 and 19 patients randomized to receive infigratinib and placebo, respectively. The frequency of FGFR3 alteration was significantly lower than anticipated, occurring in only 19% of patients overall; mutations were observed in 13% of patients with lower tract UC and 30% of patients with upper tract UC. No significant differences were observed in DFS, MFS or OS, and more frequent grade 3/4 adverse events were noted in the experimental arm (35% versus 16%). No fatal adverse events were observed. Conclusions: Our failure to accrue sufficient patients to the current trial precludes any definitive conclusions around the role of infigratinib as adjuvant therapy for FGFR3-altered UC. In the process of study conduct, however, we garnered substantial insights that may aid in the development of future precision oncology trials for adjuvant UC. Clinical trial information: NCT04197986 .
Role of tumor mutational burden (TMB) and microsatellite instability (MSI) in patients (pts) with advanced urothelial carcinoma (aUC) treated with immune checkpoint inhibitor (ICI).
Authors: Bakaloudi Dimitra Rafailia , Talukder Rafee , Makrakis Dimitrios , Diamantopoulos Leonidas Nikolaos , Patgunarajah Ubenthira , Mathew Thomas Vinay , Jindal Tanya , Brown Jason R , Miletic Marija , Johnson Jeffrey , Hui Gavin , Buznego Lucia Alonso , Morales-Barrera Rafael , Marmolejo Castañeda David Humberto , Nguyen Charles B , Barata Pedro C. , Stewart Tyler F. , Gupta Shilpa , Grivas Petros , Khaki Ali Raza 
Published: January 2024

654 Background: MSI and TMB correlate with ICI efficacy. We assessed the association between TMB and MSI with outcomes in pts with aUC treated with anti-PD1/L1 in a ‘real-world’ cohort. We hypothesize that pts with high TMB and MSI-high (H) have better outcomes with ICI. Methods: In this retrospective study we included pts from 13 sites treated with ICI for aUC. We calculated overall response rate (ORR), median overall and progression-free survival (mOS, mPFS) using KM method from ICI start. TMB and MSI were assessed by NGS. TMB was analyzed as dichotomous (≥10 vs <10 mut/Mb) and continuous variable. The analysis was stratified by therapy line (1L/upfront, 2+L). Multivariable models were adjusted by Khaki factors for 1L/upfront and Bellmunt factors for 2+L. We separately analyzed pts on maintenance avelumab (mAV). MSI is reported with descriptive statistics only. Results: 342 pts were treated with ICI 1L/upfront or 2+L (69% pure UC, median age at ICI start 69, 77% men, 90% White, 16% upper tract primary, 12% liver metastases [mets], 78% ECOG PS 0-1). Median f/u from ICI start was 34 months (mo). ORR was 36% (95%CI 26-46%) in pts with TMB≥10 vs 30% (95%CI 23-36%) with TMB<10 (OR=1.4 [95%CI 0.8-2.5] p=0.3). ORR was 75% (6/8) in pts with MSI-H and 30% (60/200) with MSI stable (MSI-S). mPFS was similar between TMB≥10 and <10 groups (6 vs 4 mo; HR=0.88 [95%CI 0.61-1.26] p=0.48) and between MSI-H and MSI-S (5 mo). mOS was numerically longer (not significant) in pts with TMB≥10 vs TMB<10: 25 vs 21 mo; (HR=0.7 [95%CI 0.50-1.09] p=0.12) and with MSI-H and MSI-S (NR and 20 mo). A significant association was found between TMB (continuous variable) and OS (HR=0.97 [95%CI 0.95-0.99] p=0.01). TMB analyses by therapy line are shown in Table. In the 1L/upfront setting (N=144), ORR 71% (5/7) vs 33% (45/135), mPFS 5 and 4 mo, mOS NR and 22 mo for MSI-H and MSI-S, respectively. Pts on mAV (n=77) were 77% men, 92% White, 16% upper primary, 13% liver mets, 84% ECOG PS 0-1 with median f/u 15 mo from avelumab start; mOS was NR for MSI-H and 24 mo for MSI-S; mPFS was 4 mo for both groups. Of 3 pts on mAV with MSI-H: 1 CR, 2 SD; of 58 pts with MSI-S: 4CR, 4PR, 24 SD, 21 PD, 5 unknown. Conclusions: MSI-H had numerically higher ORR and higher TMB was associated with longer OS with ICI, but further validation is needed. Limitations: retrospective design, small sample size for MSI-H cases, lack of randomization and central scan review, selection/confounding. [Table: see text]
Underutilization of androgen deprivation therapy (ADT) intensification for the treatment of men with metastatic hormone-sensitive prostate cancer (mHSPC): A systematic review of real-world database studies.
Authors: Raval Amit D , Chen Stephanie , Littleton Natasha , Constantinovici Niculae , Goebell Peter J. 
Published: January 2024

66 Background: In the last decade, intensification of ADT with chemotherapy or androgen receptor pathway inhibitors (ARPi) has shown clinical benefits for men with mHSPC compared to ADT alone and has been recommended for mHSPC in clinical guidelines. The transition of these guidelines into real-world practice was investigated by several studies; however, these data have not been systematically summarized across the globe. Thus, we conducted a systematic literature review of real-world database (RWD) studies to summarize treatment patterns in mHSPC. Methods: An electronic search was performed in PubMed and Embase (covering citations until July 2023) and for relevant conferences of the past 2 years to identify RWD studies examining treatment patterns in men with mHSPC. Treatment patterns were summarized by overall study population across major geographies and factors associated with ADT intensification were described. Results: Of 2,325 retrieved citations, 29 studies met the inclusion criteria, with a total of 344,473 men with mHSPC covering study periods from 2014 to 2021. Most were cohort studies (n=26), utilizing electronic medical records (EMR)/chart reviews (n=18), and with RWDs from the United States (US) (n=21), followed by Europe (n=8), and Asia (n=6). Most studies included men with a median age of ≥70 years (n=23) and >80% of men had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1 (n=5 of 8). In the US, most studies showed that ADT monotherapy was predominantly utilized (>50%), followed by ADT/ARPi (20-40%), and ADT/chemotherapy (10-20%). Abiraterone was the most frequently used ARPi followed by enzalutamide. In Europe, most studies also reported ADT monotherapy (>45%), followed by ADT/ARPi (11-25%), or ADT/chemotherapy (12-34%). In Asia, ADT monotherapy (>62%) was the most common treatment in most studies, with low use of ADT/ARPIs (<20%), and ADT/chemotherapy (<15%). A few studies with recent EMR data (covering the 2020-21 data period) from cancer centers/registries showed high use of ADT/ARPi (>40%) in both the US and Europe. Reported quantitative factors (n=13) associated with intensification beyond ADT were high disease burden (spread of metastases, high volume), young age, ECOG PS 0/1, low comorbidities, and treating physician specialty-oncologist; qualitative factors (n=2) were patient preference, unsatisfactory response to ADT treatment, ability to tolerate adverse events, and lack of cost barriers. Conclusions: This comprehensive review shows ADT monotherapy remained highly utilized across major geographies until 2021 despite new evidence and updated guideline recommendations. However, the utilization of intensified treatment with ARPi combinations is slowly increasing after the recent approvals in mHSPC.
Impact of homologous recombination repair (HRR) or nucleotide excision repair (NER) deficiency on sensitivity to antibody drug conjugate (ADC) payloads in urothelial cancer.
Authors: P Shanmugam Surish , Zhou Yuzhen , D'Andrea Vincent , Hanlon Timothy , Bekele Raie , Szallasi Zoltan , Bellmunt Joaquim , Mouw Kent William 
Published: January 2024

665 Background: Approximately 10% of urothelial cancer (UC) patients have defects in the NER pathway and at least another 10% have defects in the HRR pathway. Tumors with HRR or NER defects are more sensitive to platinum-based chemotherapy due to inability repair platinum-induced DNA damage. Two ADCs, sacituzumab govitecan (SG) and enfortumab vedotin (EV) are approved for treatment of metastatic UC. The cytotoxic payload attached to SG and EV are SN-38 and MMAE respectively. SN-38 directly damages DNA through inhibition of Topoisomerase 1 activity during DNA replication whereas MMAE is a potent microtubule disruptor but does not have any direct DNA damaging effects. Given the expanding clinical roles for EV and SG in UC, we wished to test the impact of HRR or NER deficiency on sensitivity to SN-38 and MMAE. We hypothesized that HRR or NER deficiency would result in a larger increase in sensitivity to SN-38 than MMAE. We also hypothesized that SN-38, but not MMAE, would result in synergistic cell killing when delivered with a PARP inhibitor. Methods: We assembled a series of isogenic NER- and HRR-proficient/deficient cell pairs and compared sensitivity to SN-38 and MMAE, as well as other clinically relevant agents including cisplatin, gemcitabine, and the PARP inhibitors olaparib and talazoparib. Results: HRR-deficient bladder cancer cell lines were significantly more sensitive to SN38 than their respective isogenic HRR-proficient counterpart whereas there was no significant difference in MMAE sensitivity between isogenic pairs of HRR-deficient and HRR-proficient cell lines. The largest difference in sensitivity between HRR-proficient vs HRR-deficient cell lines was observed with olaparib and talazoparib respectively. In contrast, NER-deficient cell lines were not more sensitive to SN38 or MMAE than their respective isogenic NER-proficient counterparts. Conclusions: HRR deficiency significantly increases sensitivity of bladder cancer cells to SN-38 but not MMAE. These findings suggest that UC patients with HRR deficiency may be more likely to benefit from treatment with SG than EV, and more generally with an ADC that has a Topoisomerase 1 inhibitor rather than a microtubule disruptor as the cytotoxic payload.