bluuebunny/crossref_metadata_2025 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.
Occurrence of NECTIN4 amplification in solid tumors and enfortumab vedotin response in metastatic urothelial cancer.
Authors: Klümper Niklas , Tran Ngoc Khanh , Zschaebitz Stefanie , Hahn Oliver , Zengerling Friedemann , Nagy Dora , Kristiansen Glen , Ivanyi Philipp , Grunewald Camilla Marisa , Darr Christopher , Schlack Katrin , Rausch Steffen , Ritter Manuel , Junker Kerstin , Hartmann Arndt , Grünwald Viktor , Hölzel Michael , Eckstein Markus
Published: January 2024

673

Background: The anti-NECTIN4 antibody-drug conjugate (ADC) enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains are frequent genomic events in mUC leading to NECTIN4 amplifications. Here, we aimed to evaluate the potential of NECTIN4 amplification as a genomic biomarker to predict EV response in patients with mUC. Methods: We established a NECTIN4-specific fluorescence in-situ hybridization (FISH) assay to assess NECTIN4 copy number variations (CNVs) in a multicenter EV-treated mUC patient cohort (UC-EV, N=77), and CNV data were correlated with membranous NECTIN4 protein expression (H-score) assessed via immunohistochemistry, EV treatment responses and outcomes. Next, we conducted a pan-cancer analysis of the The Cancer Genome Atlas (TCGA) datasets, comprising 10,712 patients across 32 cancer types, to investigate the relationship between NECTIN4 CNV, mRNA expression (RNAseq) and protein levels (RPPA) across entities. Results: In TCGA cohorts, NECTIN4 amplification occurs frequently across different solid cancer types, especially in 15-20% of bladder cancers (17% in TCGA-BLCA), as well as 5-10% in breast cancer (TCGA-BRCA) and lung adenocarcinoma (TCGA-LUAD). We confirmed the amplification frequency in our UC-EV cohort (18%). NECTIN4 amplification is significantly associated with both increased NECTIN4 mRNA expression (e.g., TCGA-BLCA, BRCA, LUAD) and membranous NECTIN4 protein expression (UC-EV), and represents a stable genomic alteration during metastatic progression. In the UC-EV cohort, all patients with NECTIN4 amplification (N=14) responded to EV. In multivariable Cox adjusted for age and sex, NECTIN4 amplifications led to a 93% risk reduction for death compared to a NECTIN4non-amplified status (HR=0.07, 95%-CI 0.01–0.53; P<0.001). Conclusions: Our study highlights the value of NECTIN4 amplifications to predict EV responses in patients with mUC. NECTIN4 amplifications occur frequently in different cancer types and therefore have the potential to be a novel tumor-agnostic genomic biomarker that enables tailored NECTIN4-targeted therapies in various entities.
Effect of neutrophil to lymphocyte ratio (NLR) on outcomes with immune checkpoint inhibitors (ICIs) in patients (pts) with metastatic urothelial carcinoma (mUC) in real-world setting.
Authors: Lynn David , Dawsey Scott , Patgunarajah Ubenthira , Pramod Nikhil , Wei Wei , Hobeika Charbel , Nair Monica , Maroli Kimberly , Martin Allison , Ornstein Moshe Chaim , Wee Christopher Eing , Gilligan Timothy D. , Nizam Amanda , Bonham Amanda , Mian Omar Y. , Pavicic Paul G. , Diaz-Montero C. Marcela , Gupta Shilpa
Published: January 2024

678

Background: Elevated inflammatory biomarkers like the neutrophil to lymphocyte ratio (NLR) has been associated with poor prognosis in several cancers, including UC but there is limited evidence on its role as a prognostic biomarker in patients (pts) with mUC treated with ICIs. We studied the effect of baseline (pre-treatment) NLR on outcomes with ICI in mUC pts in our large cohort of patients with mUC treated with ICIs. Methods: We identified 335 adult pts with mUC at the Cleveland Clinic treated who received >/= 2 cycles of ICI with pembrolizumab (P) or atezolizumab (A) between 2015 and 2023. Patient characteristics including age, sex, race, primary site (bladder vs upper tract UC (UTUC)), tumor histology and pre-ICI treatment NLR values were collected and divided into four quartiles: (NLR <2.7, 2.7-4.0, 4.0-7.1, and >7.1). Impact of NLR on overall survival (OS) and progression free survival (PFS) post ICI start date was studied. OS and PFS were estimated using the Kaplan Meier method and compared by log rank test. Results: Of the 335 pts, NLR values were available for 320 pts. Median age was 73 yrs (35-95) and 76% pts were males. 247 pts (74%) received P and 88 (26%) received A. We found that in the 320 patients with available NLR values, the highest quartile values of NLR >/= 7.1 was significantly associated with worse OS (p=0.01). We did not find a statistically significant impact of NLR on PFS (p=0.06). (Table). Conclusions: In our large real-world cohort of pts with mUC receiving ICI, we report the effect of baseline NLR on outcomes with ICI and that NLR >/=7.1 was associated with significantly worse OS. Further validation studies are warranted to risk-stratify pts with mUC planned for ICI treatment. [Table: see text]
Real-world outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) and tumors harboring androgen receptor (AR) ligand-binding domain (LBD) mutations.
Authors: Stewart Tyler F. , Chandiwana David , Doyle Ashley , Boame Nana , Saha Jayati , Zhang Nicole , Benjumea Darrin , Rava Andrew , Parameswaran Janaki , Edwards Michelle L. , Lang Joshua Michael
Published: January 2024

77

Background: In mCRPC, AR T878 and/or H875 and L702H mutations have been associated with disease progression and poor prognosis. This study characterized real-world overall survival (rwOS), testing practices, mutation prevalence, and treatment patterns in patients with mCRPC with and without tumors with missense mutations in the AR LBD (amino acids 671–920). Methods: In this retrospective analysis of the Guardant Inform Database (Mar 11, 2014–Jun 30, 2022), men (aged ≥18 y) with mCRPC who were tested with Guardant360 (G360) next-generation sequencing and diagnosed/treated at a clinical site in the US with a first-line (1L) treatment were included. Matched rwOS was assessed in 2 subpopulations: patients with any missense mutation in AR LBD, excluding those with AR L702H alone ( AR LBD group), and patients with AR T878 and/or H875 without L702H ( AR 878/875 group) and compared with patients without any AR LBD missense mutations (control group). Patients were matched (1:5) on key prognostic variables, including age, Elixhauser Comorbidity Index weighted score, smoking status, prior novel hormonal agent (NHA) use, and 1L treatment year. Mutation prevalence, patient demographics, frequency and timing of G360 tests, and treatment patterns were assessed in patients treated from 2018 to 2022 to reflect more recent trends. Results: In the matched rwOS analysis, patients in the AR LBD group (n=275) had statistically significantly shorter 1L median rwOS compared with the control group (n=1375): 27.3 vs 47.8 months; P<0.0001. Similarly, patients in the AR 878/875 group (n=154) had shortened median rwOS compared with the control group (n=770): 28.9 vs 44.4 months; P=0.0004. Of 4833 patients treated for mCRPC from 2018 to 2022, 20% had AR LBD mutations, 4% had AR 878/875 with L702H, and 6% had AR 878/875 without L702H. Most patients (59%) were first tested at some point after 1L therapy, with only 15% of patients receiving >1 G360 test. Mutation prevalence was higher in patients tested in fourth-line (4L) compared with 1L, particularly for AR L702H mutations (17% vs 10%) and all AR LBD mutations (27% vs 20%). Use of NHAs was lower in 4L compared with 1L (20% vs 33%), whereas use of taxanes was higher (31% vs 22%). Conclusions: Patients with AR LBD–mutated mCRPC had notably shorter rwOS than those whose tumors did not harbor AR LBD mutations, indicating an unmet need for this population. The prevalence of AR LBD mutations was higher in later lines of therapy, but repeat testing rates were low, suggesting that AR LBD mutations may go undetected.
Real-world experience on tolerability and safety of relugolix combined with androgen signaling inhibitors in patients with advanced prostate cancer.
Authors: Guan Jian , Adroja Shubham , Ajmal Zainub , Gao Yuan , Spetsieris Nicholas , Hu Siqi , Satkunasivam Raj , Brooks Michael A , Farach Andrew M. , Butler E. Brian , Miles Brian , Efstathiou Eleni
Published: January 2024

85

Background: Relugolix is the first oral GNRH antagonist approved by the FDA in 2021 for the treatment of advanced prostate cancer (PCa). Approval was based on HERO study, which showed a rapid and sustained testosterone suppression superior to that of Leuprolide coupled with a significantly shorter time to eugonad state after discontinuation. Relugolix was associated with a 54% lower risk of major adverse cardiovascular events as compared with Leuprolide. There is very little data available regarding the tolerability safety of Relugolix in combination Enhanced Androgen Signaling Inhibitors (ASI). Here we provide real world experience on the combination of Relugolix and ASIs in patients(pts) with advanced PCa, focusing on safety, tolerability and pharmacodynamic outcome measures. Methods: Houston Methodist Genitourinary Oncology records were reviewed for identification of pts treated with combination Relugolix plus ASI for at least 1 month, from 09/21 to 07/23. Data collected included pts’ baseline and tumor characteristics, cardiovascular and metabolic comorbidities concomitant medication. We recorded Adverse Events, potential Drug Drug Interaction (DDI) and Testosterone (T) and PSA decline. Results: We report 152 advanced hormone-naive PCa pts with median age of 71 (range 48-96). 81% were White or/and Hispanic, 17 % black, 2 % Asian. Majority (90%) had at least 1 cardiovascular risk factor; hypertension (72%), hyperlipidemia (52%), obesity (41 %), diabetes mellitus (26%), coronary artery disease (30%) and atrial fibrillation (13%). ASIs combined with Relugolix included: Darolutamide (78%), Abiraterone (14%), Apalutamide (7%) and Enzalutamide (1%). All but one pt were compliant (99%). Median treatment exposure is 8 months (range 1 -21). All pts had baseline Testosterone >150ng/dL. All pts reached castrate T levels and 90% of patients achieved a T < 20 ng/dL. 55% pts reached PSA <0.1 at median of 4ms, 75% PSA decline > 90% and 91% PSA decline ≥50%. 7% pts discontinued Relugolix due to adverse events. Three pts (2%) had a major adverse cardiovascular event, including one sudden death, one with congestive heart failure, and one with myocardial infarction. Two pts (1%) reported grade 3 fatigue. G3 LFT elevations recorded in 2 pts (1%). No clinical signals of DDI reported. Conclusions: This is the first large original report of the combination of Relugolix with ASIs in real world practice. The combination has a favorable safety and tolerability profile with no new safety concerns. No new DDI concerns were raised. These findings in combination with pharmacodynamic outcome measures of T / PSA support the use of Relugolix in combination with ASIs as standard of care in advanced PCa.
SECuRE: A dose escalation/expansion study to assess the anti-tumor efficacy of 67Cu-SAR-bisPSMA in patients with metastatic castrate-resistant prostate cancer.
Authors: Johnson Geoffrey , Lengyelova Eva , Nordquist Luke T. , Prasad Vikas , Anderson Monique , Gervasio Othon , Parker Michelle , Miller Robert M. , Sartor A. Oliver , Tagawa Scott T.
Published: January 2024

TPS246

Background: Prostate cancer (PC) is common and despite recent advances in treatment options, patients with metastatic disease still have poor outcomes, warranting the development of new effective therapies in this setting. Prostate-specific membrane antigen (PSMA) is expressed in benign and malignant prostate tissues and luminal surface of salivary/lacrimal glands, small intestine and renal tubules. The double PSMA binding moiety of SAR-bisPSMA in 64Cu-SAR-bisPSMA (imaging) and 67Cu-SAR-bisPSMA (therapy) may offer advantages compared to currently used single-target PSMA agents. Clinical evidence demonstrated 2-3 times higher uptake of 64Cu-SAR-bisPSMA compared to the single-target PSMA agent, 68Ga-PSMA-11. Pre-clinical efficacy data of 67Cu-SAR-bisPSMA in mice showed statistically significant tumor growth inhibition compared to the control group as well as a dose-dependent delay in eventual tumor regression in a PC xenograft study. These results led to the development of this clinical study, which aims to assess safety and anti-tumor efficacy of 67Cu-SAR-bisPSMA in patients with metastatic castrate resistant PC (mCRPC). Methods: SECuRE is a phase I/IIa multi-center, open-label, non-randomized, dose-escalation and cohort expansion study of 64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA. mCRPC patients with progression, prior exposure to at least one androgen receptor pathway inhibitor, and positive 64Cu-SAR-bisPSMA PET may be treated with 67Cu-SAR-bisPSMA. This study is being conducted in 3 phases: a 64Cu-SAR-bisPSMA Dosimetry Phase (n=6), a 67Cu-SAR-bisPSMA Dose Escalation Phase (n=up to 24), and a 67Cu-SAR-bisPSMA Cohort Expansion Phase (n=14). The primary and key secondary objectives include assessment of 64Cu- and 67Cu-SAR-bisPSMA safety and dosimetry, determining the maximum tolerated dose (MTD) or maximum feasible dose (MFD) and anti-tumor efficacy of 67Cu-SAR-bisPSMA. The 67Cu-SAR-bisPSMA dose levels investigated in the escalation phase include: 4 GBq (cohort 1, single dose), 8 GBq (cohort 2, single dose), 12 GBq (cohort 3, single dose) and up to 24 GBq across two doses (cohort 4, two doses at MTD or MFD). The Dose Expansion Phase of the study will allow the administration of up to 4 doses of 67Cu-SAR-bisPSMA at the MTD/MFD. Response measurements include reduction in PSA levels, radiological progression-free survival, duration of response and overall survival. Radiological response will be assessed by RECIST 1 V1.1 and PCWG3. At the time of submission of this abstract, cohort 3 is open for recruitment and no dose limiting toxicities have been observed to date. Clinical trial information: NCT04868604 .
SWOG S2200 (PAPMET2): A phase II randomized trial of cabozantinib with or without atezolizumab in patients with advanced papillary renal cell carcinoma (PRCC).
Authors: Maughan Benjamin L. , Plets Melissa , Pal Sumanta Kumar , Ged Yasser , Tangen Catherine , Vaishampayan Ulka N. , Lerner Seth P. , Thompson Ian M.
Published: January 2024

TPS493

Background: The role of immune therapy is not established in PRCC. The S1500 (PAPMET) clinical trial established single agent cabozantinib as the standard of care for PRCC (PMID 33592176) with a median progression free survival (PFS) of 9.0 months compared to 5.6 months with sunitinib. Trials have shown activity of PD-(L)1 antagonists as monotherapy (PMID 33529058) or in combination with targeted therapy (PMID 34491815). In a single arm study of cabozantinib/nivolumab the median PFS was 12.5 months (PMID 35298296). There are no prior randomized studies of immune therapy in PRCC. Single arm trials often overestimate the true effect size (PMID 31218346), highlighting the unmet clinical need for a randomized clinical trial in PRCC. We hypothesize that the combination will have higher clinical activity than single agent cabozantinib. Methods: This is a prospective randomized phase II clinical trial conducted through the NCTN and led by SWOG. The primary endpoint is a comparison of PFS between cabozantinib and cabozantinib/atezolizumab. Secondary endpoints include comparison of objective response rate, overall survival and safety. Patients are treated with cabozantinib 60mg/day versus cabozantinib 60mg/day + atezolizumab 1200 mg q3 weeks. 200 patients will be enrolled and randomized 1:1. Key inclusion criteria include a pathologic confirmation of PRCC; presence of metastasis; 0-1 prior systemic lines of therapy for metastatic disease; and measurable disease as defined by RECIST 1.1 criteria. Prior treatment with adjuvant pembrolizumab is allowed if completed greater than 6 months before enrollment. Key exclusion criteria include clinically significant autoimmune disease; ongoing use of strong CYP3A4 inhibitors, strong CYP3A4 inducers. Planned correlatives include stool microbiome testing and genomic/transcriptomic analysis from blood and baseline tissue assays. Clinical trial information: NCT05411081 .
PRECISION 1: A phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2.
Authors: Iyer Gopa , Kwiatkowski David J. , Ding Li , Schmid Anita N. , Navarro Willis H. , Rodon Ahnert Jordi
Published: January 2024

TPS526

Background: According to SEER data, patients in the USA with advanced genitourinary (GU) cancers such as bladder and kidney cancers have low 5-year survival rates of 8.3% and 17.8%, respectively. This underscores the need for more efficacious treatments. Tumor growth and disease progression may be facilitated by aberrant activation of the mTOR pathway in some GU cancers. The tumor suppressor genes TSC1 and TSC2 are critical negative regulators of the mTOR pathway, and their inactivation may result in tumor growth. Inactivating TSC1 and TSC2 alterations have been observed in GU cancers with combined frequencies of up to 9.6% in bladder, 5.8% in kidney, and 0.7% in prostate cancers. nab-Sirolimus, approved in the USA for patients with advanced malignant perivascular epithelioid cell tumor (PEComa), is an albumin-bound mTOR inhibitor (mTORi) that inhibits the mTOR pathway via suppression of the mTORC1 complex. Clinically, in an exploratory analysis of AMPECT (NCT02494570), a pivotal trial of nab-sirolimus in advanced malignant PEComa, 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC2 and TSC1, respectively, had a confirmed response. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with mTORi-class adverse events. Based on the clinical observations from AMPECT and the underlying mechanism of action of nab-sirolimus, the PRECISION 1 trial was designed to assess the safety and efficacy of nab-sirolimus in a tumor-agnostic study of patients with advanced cancers harboring TSC1 or TSC2 inactivating alterations. Enrollment is open to patients with bladder, kidney, and prostate cancers with TSC1 or TSC2 inactivating alterations. Methods: In PRECISION 1 (NCT05103358), eligible patients are ≥12 years old and mTORi-naïve, have advanced malignant solid tumors with TSC1 or TSC2 inactivating alterations identified using next-generation sequencing (NGS) in tumor tissue or liquid biopsy (confirmed by central review of NGS reports), and they have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 will be given intravenously over 30 min on days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began in March 2022. Collaboration with leading NGS vendors will expedite the identification of patients with qualifying TSC1 and TSC2 alterations; ongoing study access is facilitated through a just-in-time approach to trial location activation. Clinical trial information: NCT05103358 .
Black Imaginaries and Nahua Rhetoric in Colonial Mexico: Diario de Don Domingo de San Antón Muñón Chimalpahin Quauhtlehuanitzin
Authors: Cuellar Manuel R.
Published: January 2024

In 1612, Chalca historian Don Domingo de San Antón Muñón Chimalpahin Quauhtlehuanitzin, Mexico’s most prolific Indigenous writer, documented the execution of thirty-five Black and mulatto people. The group of twenty-eight men and seven women was accused of scheming against the Spanish colonial government, threatening to riot, and plotting to “blacken” the population of New Spain by killing Spaniards and forcing racial mixing. Attending to the semantic and morpho-syntactic structure of Nahuatl, this article proposes a linguistic analysis to recontextualize Chimalpahin’s retelling of the alleged plot and the fears of a Black uprising in colonial Mexico from an Indigenous perspective. At stake is how the plurivocal structure of the Nahua archive allows for the inscription of Blackness and racialized subjectivities in colonial Mexico while challenging the claims to an absolute truth imposed by the Spanish.
The Politics of Kinship
Authors: Rifkin Mark
Published: January 2024

What if we understood the idea of family as central to representing alternative forms of governance as expressions of racial deviance? In The Politics of Kinship, Mark Rifkin shows how ideologies of family, including notions of kinship, recast Indigenous and other forms of collective self-organization and self-determination as disruptive racial tendencies in need of state containment and intervention. Centering work in Indigenous studies, Rifkin illustrates how conceptions of family and race work together as part of ongoing efforts to regulate, assault, and efface other political orders. The book examines the history of anthropology and its resonances in contemporary queer scholarship, contemporary Indian policy from the 1970s onward, the legal history of family formation and privacy in the United States, and the association of blackness with criminality across US history. In this way, Rifkin seeks to open new possibilities for envisioning what kinds of relations, networks, and formations can and should be seen as governance on lands claimed by the United States.
The ACE inhibitor captopril inhibits ACN-1 to control dauer formation and aging
Authors: Egan Brian M. , Pohl Franziska , Anderson Xavier , Williams Shoshana C. , Gregory Adodo Imienreluefe , Hunt Patrick , Wang Zuoxu , Chiu Chen-Hao , Scharf Andrea , Mosley Matthew , Kumar Sandeep , Schneider Daniel L. , Fujiwara Hideji , Hsu Fong-Fu , Kornfeld Kerry
Published: January 2024

The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in Caenorhabditis elegans, Drosophila and rodents, but its mechanism is not well defined. Here, we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril-hypersensitive mutants. We identified a missense mutation that causes a partial loss of function of the daf-2 receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in C. elegans by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of acn-1 via captopril or RNA interference promoted dauer larvae formation, suggesting that acn-1 is a daf gene. Captopril-mediated lifespan extension was abrogated by daf-16(lf) and daf-12(lf) mutations. Our results indicate that captopril and acn-1 influence lifespan by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control.
Polarisation vision in the dark: green-sensitive photoreceptors in the nocturnal ball-rolling dung beetle Escarabaeus satyrus
Authors: Yilmaz Ayse , Belušič Gregor , J. Foster James , Tocco Claudia , Khaldy Lana , Dacke Marie
Published: January 2024

Many insects utilise the polarisation pattern of the sky to adjust their travelling directions. The extraction of directional information from this sky-wide cue is mediated by specialised photoreceptors located in the dorsal rim area (DRA). While this part of the eye is known to be sensitive to the ultraviolet, blue or green component of skylight, the latter has only been observed in insects active in dim light. To address the functional significance of green polarisation sensitivity, we define the spectral and morphological adaptations of the DRA in a nocturnal ball-rolling dung beetle–the only family of insects demonstrated to orient to the dim polarisation pattern in the night sky.

Intracellular recordings revealed polarisation-sensitive green photoreceptors in the DRA of Escarabaeus satyrus. Behavioural experiments verified the navigational relevance of this finding. To quantify the adaptive value of green sensitivity for celestial orientation at night, we also obtained the polarisation properties of the night sky in the natural habitat of the beetle. Calculations of relative photon catch revealed that under a moonlit sky the green-sensitive DRA photoreceptors can be expected to catch an order of magnitude more photons compared with the UV-sensitive photoreceptors in the main retina. The green-sensitive photoreceptors – which also show a range of morphological adaptations for enhanced sensitivity – provide E. satyrus with a highly sensitive system for the extraction of directional information from the night sky.