bluuebunny/crossref_metadata_2025_split huggingface dataset:
RC48-ADC for metastatic urothelial carcinoma with HER2-positive: Combined analysis of RC48-C005 and RC48-C009 trials.
Authors: Sheng Xinan , He Zhisong , Shi Yanxia , Luo Hong , Han Weiqing , Yao Xin , Shi Benkang , Liu Jiyan , Hu Changlu , Liu Ziling , Guo Hongqian , Yu Guohua , Ji Zhigang , Yu Shiying , Hu Yi , Guo Jianming , Ying Jianming , Fang Jianmin , Zhou Aiping , Guo Jun 
Published: June 2022

4520 Background: RC48-ADC (Disitamab Vedotin) is a novel humanized anti-HER2 antibody-drug conjugate (ADC). RC48-ADC demonstrated a promising efficacy with a manageable safety profile in HER2-positive locally advanced or metastatic UC patients who failed to platinum based chemotherapy in RC48-C005 and RC48-C009 trials. Here are the pooled results of the two studies with the supplementary efficacy, safety and updated OS data. Methods: Both of the two trials are single-arm, multi-center, phase II trials. Eligible patients were 18̃80 years old, with central-laboratory confirmed, histologically HER2-postive (IHC2+,3+), unresectable mUC. Patients had at least one line of systemic chemotherapy. The primary endpoint was objective response rate (ORR). Progress-free survival (PFS), overall survival (OS), and safety were also assessed. Results: RC48-C005 and RC48-C009 enrolled HER2-positive locally advanced or metastatic UC patients from Nov 2017 to Sep 2020. 107 mUC patients (80 males; median age 63 y [40-79]) were enrolled. 64.5% patients had received ≥ 2 lines systemic chemotherapy. 90.7% patients had visceral metastases. As of 04 Sep 2021 (data cutoff), The overall confirmed ORR as assessed by the BIRC was 50.5% (95% CI: 40.6%, 60.3%). Similar responses were observed in prespecified subgroups. cORR was 52.1% (25/48) for patients with liver metastasis and was 55.6% (15/27) in patients with previous PD-1/L1 treatment. The cORR was 62.2% (28/45) for HER2 IHC2+&FISH+ or IHC3+ patients, 55.6% (5/9) for HER2 IHC2+&FISH unknown patients, and 39.6% (21/53) for HER2 IHC2+&FISH- patients respectively. DCR was 82.2% (95% CI:73.7%, 89.0%). The mPFS was 5.9 (95% CI:4.2, 7.2) months. The mOS was 14.2 (95% CI:9.7, 18.8) months. The median OS follow up time was 19.1 months. Most common treatment-related AEs were hypoaesthesia (50.5%), Leukopenia (49.5%), aspartate aminotransferase increased (43.0%), neutropenia (42.1%), alopecia (40.2%), asthenia (39.3%), alanine aminotransferase increase (35.5%), decreased appetite (31.8%). The grade ≥3 TRAEs (≥5%) only included hypoaesthesia (15.0%), neutropenia (12.1%) and r-GT increased (5.6%). Conclusions: RC48-ADC showed continuously a promising efficacy with a manageable safety profile in HER2-postive mUC patients who had failed at least one line systemic chemotherapy. Clinical trial information: NCT03507166, NCT03809013.
Long-term outcomes in patients with advanced urothelial carcinoma (UC) who received avelumab first-line (1L) maintenance with or without second-line (2L) treatment: Exploratory analyses from JAVELIN Bladder 100.
Authors: Bellmunt Joaquim , Powles Thomas , Climent Duran Miguel Angel , Sridhar Srikala S. , Gurney Howard , Costa Nuno , Di Pietro Alessandra , Huang Bo , Gupta Shilpa , Grivas Petros 
Published: June 2022

4560 Background: Avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) vs BSC alone in patients (pts) with advanced UC that had not progressed with 1L platinum-based chemotherapy (median OS, 23.8 vs 15.0 months; HR, 0.76 [95% CI, 0.631-0.915]; 2-sided p = 0.0036). Avelumab 1L maintenance is now considered standard of care per international guidelines. However, data on outcomes in pts who receive 2L treatment after avelumab 1L maintenance are limited. We report a descriptive analysis of outcomes in pts enrolled in the avelumab + BSC arm of the JAVELIN Bladder 100 trial based on receipt of 2L treatment. Methods: In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), eligible pts had unresectable locally advanced or metastatic UC without progression with 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin. Pts were randomized 1:1 to receive avelumab + BSC or BSC alone. Exploratory analyses of time from randomization to end of 2L treatment and OS were performed in the avelumab + BSC arm in subgroups defined by 2L treatment administered by investigators after discontinuation of study treatment. Results: In the avelumab + BSC arm (n = 350), median follow-up at data cutoff (June 4, 2021) was 38.0 months. 185 pts (52.9%) had discontinued avelumab 1L maintenance treatment for any reason and received 2L treatment, whereas 122 (34.9%) had discontinued avelumab and did not receive 2L treatment. Median OS (95% CI) in subgroups is shown in the Table. In 43 pts (12.3%) who were still receiving avelumab, median treatment duration was 154.6 weeks (range, 106.7-216.0). Among pts who received 2L treatment, median time from end of avelumab 1L maintenance to start of 2L treatment was 1.35 months (range, 0.3-30.9) and median time from randomization to end of 2L treatment was 11.7 months (95% CI, 9.7-13.8). 2L treatment comprised rechallenge with platinum-based chemotherapy in 75 pts (21.4%) or other 2L treatment in 110 pts (31.4%), including 2L anti–PD-(L)1 therapy in 11 pts (3.1%). Additional data based on different types of 2L treatment will be presented. Conclusions: In this exploratory analysis from the JAVELIN Bladder 100 trial with extended follow-up, approximately 60% of pts (185/307 pts) who had discontinued avelumab received 2L treatment. Long-term OS was observed in pts who received avelumab 1L maintenance with or without 2L treatment. Clinical trial information: NCT02603432. [Table: see text]
Landscape of fibroblast growth factor receptor (FGFR) genomic alterations (GA) in urothelial bladder cancer (UBC).
Authors: Bou Zerdan Maroun , Bratslavsky Gennady , Jacob Joseph M , Huang Richard S.P. , Kravtsov Oleksandr , Parimi Vamsi , Lin Douglas I. , Graf Ryon , Danziger Natalie , Ross Jeffrey S. , Goldberg Hanan , Basnet Alina 
Published: June 2022

4568 Background: Urothelial bladder carcinomas (UBC) with genomic alterations (GA) in the Fibroblast Growth Factor Receptor ( FGFR) genes have been postulated to be less responsive to immune checkpoint inhibitors (ICI). Immune microenvironment of these tumors could be altered due to suppression of interferon signaling pathways. Here, we present comprehensive genomic profiling (CGP) of FGFR altered UBC to study the underlying immunogenomic mechanisms of response and resistance. Methods: 4,035 UBC underwent hybrid capture based CGP. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined using 114 loci. Programmed death ligand (PD-L1) expression in tumor cells was assessed by IHC (Dako 22C3). Results: 894 (22%) of UBC featured FGFR GA ( FGFR1 3.7%; FGFR2 1.1%; FGFR3 17.4%). Gender and age distribution was similar in all groups. FGFR3 cases had lower GA/tumor and 14.7% GA were fusions. ERBB2 amplification was significantly higher in FGFR1/2 altered UBC compared with FGFR3 altered UBC. MTOR pathway GA were highest in FGFR3 altered UBC. FGFR3 altered UBC featured significantly higher frequencies of biomarkers predicting resistance to ICI including lower TMB, lower PD-L1 expression and higher frequencies of GA in MDM2. FGFR3 driven UBC also features significantly higher frequencies of CDKN2A/B loss and MTAP loss which have also recently been linked to IO drug resistance. Conclusions: UBC harboring FGFR GA have increased frequency of alterations that have been linked to ICI resistance. Further evaluation of FGFR-based biomarkers in UBC clinical trials focused on the assessment of the patient response to ICI appears warranted. [Table: see text]
Outcomes of patients with advanced urothelial cancer who develop infection while on treatment with pembrolizumab.
Authors: Kieser Ryan Blair , Xu Jiaqiong , Burns Ethan , Muhsen Ibrahim , Shah Shivan M , Umoru Godsfavour , Mylavarapu Charisma , Sun Kai , Zhang Yuqi , Crenshaw Aubrey , Esmail Abdullah , Guerrero Carlo , Gong Zimu , Gee Kelly , Heyne Kirk , Singh Monisha , Zhang Jun , Efstathiou Eleni , Bernicker Eric , Abdelrahim Maen 
Published: June 2022

4573 Background: Over the past decade, studies have shown the benefit of immune checkpoint inhibitors (IO) in patients with advanced urothelial cancer. These agents work by reconditioning the adaptive anti-cancer immune response within the tumor microenvironment. Immune-related adverse events have been well documented, but there is limited data evaluating infections in patients treated with IO. We performed a retrospective analysis to assess the incidence of infection and its effect on morbidity and mortality in patients treated with pembrolizumab for advanced urothelial cancer. Methods: Data was collected from a network of 7 hospitals for patients who received pembrolizumab for advanced urothelial cancer from 1/1/2017-8/1/2021. Date of last follow up was 12/1/2021. Covariates compared among infected and non-infected cohorts included age, gender, race, comorbidities, ECOG, anti-infective therapy at IO initiation, and line of therapy (1L, 2L, > 2L). Univariable analysis with reported odds ratio (OR) and 95% confidence interval (CI) was used to assess risk factors for infection. Outcome measures included all-cause emergency department (ED) visits, inpatient and intensive care unit (ICU) admissions, median number of IO cycles, and overall survival (OS). OS was evaluated using the Kaplan-Meier model. All analyses were deemed statistically significant if the p-value was < 0.05. Results: A total of 51 patients were identified. Of these, 34 (66.7%) had at least one documented infection and 17 (33.3%) had no reported infections. Baseline characteristics were similar across cohorts. Compared to non-infected patients, infected patients received fewer cycles of IO (median 4 vs 8, p = 0.016). At last follow-up, 20 (58.8%) patients in the infected cohort and 4 (23.5%) in the non-infected cohort died (p = 0.017). Median OS was 7.4 months (95% CI: 3.4-24.9) among patients with infection while not reached in those without infection (p = 0.014). ED visits (p = 1.00), inpatient admissions (p = 0.21), and ICU admissions (p = 0.17) did not significantly differ between cohorts. Univariable analysis did not identify significant risks among covariates. Conclusions: The incidence of infection in patients treated with pembrolizumab for advanced urothelial cancer is high and associated with fewer cycles of IO therapy and shorter OS. Further study of infectious process prevention is of value to maximize immunotherapy benefit.
Phase II clinical study of tislelizumab combined with nab-paclitaxel (TRUCE-01) for muscle-invasive urothelial bladder carcinoma: Bladder preservation subgroup analysis.
Authors: Niu Yuanjie , Hu Hailong , Wang HaiTao , Tian Dawei , Zhao Gangjian , Shen Chong , Wu Zhouliang , Da La , Zhan Xuejian , Huang Shiwang 
Published: June 2022

4589 Background: The current strategy for bladder preservation is focused on trimodality treatment, including complete transurethral resection of bladder tumor (cTURBT), with concurrent chemotherapy and radiotherapy. Chemotherapy is usually a cisplatin-based regimen. However, many pts cannot tolerate cisplatin-based chemotherapy and radiation therapy. It fails to meet clinical needs. Meanwhile, the efficacy and safety of checkpoint inhibitors (ICIs) have now been demonstrated. We conduct a study to evaluate ICIs in combination with second-line chemotherapy agents for patients with MIBC. Methods: TRUCE-01 is a phase II trial (NCT04730219) of tislelizumab combined with nab-paclitaxel before cTURBT or radical cystectomy. Pts with pure or mixed urothelial bladder cancer (T2-4a Nx M0) received tislelizumab 200mg on days 1 plus paclitaxel 200mg on days 2 every 3 weeks (Q3W) x 3 cycles followed by cTURBT or radical cystectomy. Imaging evaluation is usually done before and after the drug administration using the same tests to assess the efficacy. Pts who choose to preserve bladder usually continue their medication after cTURBT. This abstract focuses on patients with bladder preservation. Results: Between July 2020 and November 2021, 47 pts completed at least 2 cycles of treatment, 22 (47%) pts received cTURBT, 16 (34%) pts received radical cystectomy and 9 (19%) pts refuse surgery. As for radiological response, 22 achieved complete response (CR), 16 achieved partial response (PR). In the bladder-preserving subgroup, 13 CR pts and 9 PR pts selected cTURBT, pathology showed 17 pT0, 1 pTa, 3 pT1 and 1 pTis. The median medication cycle is 9 (6-11). There were 3 pts experienced grade 3-4 adverse events (CTCAE), a grade 3 rash, a grade 3 gastric perforation and a grade 4 acute renal failure. In addition, The most common grade 1-2 adverse events include alopecia (86%), fatigue (77%), rash (41%), appetite decreases (41%), hyperglycemia (36%), fever (18%), and creatinine increased (14%). Median follow-up 357 (438-291) days with 3 recurrences and 1 death. The 1-year recurrence-free survival rate was 82%. Conclusions: The early efficacy data further support the role of tislelizumab combined with paclitaxel in bladder preservation setting with an acceptable adverse events. Patients with imaging CR or PR after neoadjuvant therapy are preferred for bladder preservation. Enrollment is ongoing. Clinical trial information: NCT04730219.
[177Lu]Lu-PSMA-617 in PSMA-positive metastatic castration-resistant prostate cancer: Prior and concomitant treatment subgroup analyses of the VISION trial.
Authors: Vaishampayan Nitin , Morris Michael J. , Krause Bernd J. , Vogelzang Nicholas J. , Kendi Ayse T. , Nordquist Luke T. , Calais Jeremie , Nagarajah James , Beer Tomasz M. , El-Haddad Ghassan , Brackman Marcia , Desilvio Michelle , Messmann Richard Adam , Sartor A. Oliver , Fizazi Karim 
Published: June 2022

5001 Background: In the phase 3 VISION trial, targeted radioligand therapy with lutetium (177Lu) vipivotide tetraxetan ([177Lu]Lu-PSMA-617; 177Lu-PSMA-617) significantly prolonged radiographic progression-free survival (rPFS) and overall survival (OS) when added to standard of care (SoC) in patients with advanced prostate-specific membrane antigen (PSMA) PET-positive metastatic castration-resistant prostate cancer. Benefits were consistent across most pre-specified subgroups. In this post hoc exploratory analysis, we examined rPFS and OS in the context of prior and concomitant cancer-directed treatments. Methods: In VISION, adult patients previously treated with at least 1 androgen receptor pathway inhibitor (ARPI) and 1–2 taxane regimens were randomized 2:1 to 177Lu-PSMA-617 (7.4 GBq Q6W, up to 6 cycles) + SoC or SoC alone. Protocol-permitted SoC excluded cytotoxic chemotherapy, systemic radioisotopes, immunotherapy, or other investigational drugs. Exploratory subgroup analyses of rPFS and OS were performed by: number of prior ARPIs; taxane regimens; non-taxane regimens and immunotherapies; prior treatment with bone-sparing agents; 223Ra and PARP inhibitors; and concomitant treatment with ARPIs, radiation therapy, and bone-sparing agents. Results: Prior and concomitant treatments were generally well balanced between study groups (Table). rPFS and OS benefits with 177Lu-PSMA-617 were consistent across all prior treatment subgroups. Notably, there were benefits in patients who had not received a second prior taxane. There were also consistent benefits regardless of concomitant systemic and radiation therapy as part of SoC. Conclusions: The clinical efficacy of 177Lu-PSMA-617 was observed regardless of prior treatment or SoC chosen, suggesting that disease biology rather than prior and concomitant treatment context drives outcomes. Small differences in outcomes between subgroups may warrant further study to understand better the predictors of improved clinical benefit. Clinical trial information: NCT03511664. [Table: see text]
Event-free survival by residual cancer burden after neoadjuvant pembrolizumab + chemotherapy versus placebo + chemotherapy for early TNBC: Exploratory analysis from KEYNOTE-522.
Authors: Pusztai Lajos , Denkert Carsten , O'Shaughnessy Joyce , Cortes Javier , Dent Rebecca Alexandra , McArthur Heather L. , Kuemmel Sherko , Bergh Jonas C. S. , Park Yeon Hee , Hui Rina , Harbeck Nadia , Takahashi Masato , Untch Michael , Fasching Peter A. , Cardoso Fatima , Zhu Yalin , Pan Wilbur , Tryfonidis Konstantinos , Schmid Peter 
Published: June 2022

503 Background: KEYNOTE-522 (NCT03036488) tested the benefit from adding pembrolizumab (pembro) to chemotherapy (chemo) in patients (pts) with early TNBC. The primary results showed statistically significant and clinically meaningful improvements in pCR and EFS with pembro.Prior studies have shown the prognostic value of the residual cancer burden (RCB) method to quantify the extent of residual disease after neoadjuvant chemo. In this exploratory analysis, we assessed EFS by RCB in KEYNOTE-522. Methods: 1174 pts with previously untreated, nonmetastatic, stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2:1 to pembro 200 mg Q3W or placebo (pbo) given with 4 cycles of paclitaxel + carboplatin, then 4 cycles of doxorubicin or epirubicin + cyclophosphamide. After definitive surgery, pts received pembro or pbo for 9 cycles or until recurrence or unacceptable toxicity. Dual primary endpoints are pCR and EFS. RCB was assessed by the local pathologist at the time of surgery. The association between RCB categories (RCB-0, -1, -2, -3, corresponding to increasingly larger residual cancer) and EFS was assessed based on a Cox regression model with treatment as a covariate. Results: Median follow-up was 39.1 months at data cutoff (23 MAR 2021). Pembro shifted RCB to lower categories across the entire spectrum (Table). The HRs (95% CI) for EFS were 0.70 (0.38 - 1.31) for RCB-0 (equivalent to pCR), 0.92 (0.39 - 2.20) for RCB-1, 0.52 (0.32 - 0.82) for RCB-2, and 1.24 (0.69 - 2.23) for RCB-3. The most common EFS event in both arms was distant recurrence, which occurred in fewer pts in the pembro arm in all RCB categories. Conclusions: Increased RCB score was associated with worse EFS. Pts with residual disease had lower RCB values in the pembro arm, including fewer pts with RCB-3. Pembro + chemo prolonged EFS vs chemo alone in the RCB-0, -1, and -2 categories; the small sample size limits interpretation in the RCB-3 category. The small subset of pts with extensive residual disease (RCB-3) in both arms, 5.1% and 6.7%, respectively, had a poor prognosis. These results highlight the importance of neoadjuvant treatment with pembro for improving survival in pts with early TNBC, and identified a subset of pts for whom additional therapies will be needed. Clinical trial information: NCT03036488. [Table: see text]
Characterization and impact of canonical Wnt Signaling Pathway (WSP) alterations on outcomes of metastatic prostate cancer.
Authors: McKay Rana R. , McGrath Julie , Pan Elizabeth , Farrell Alex , Beltran Himisha , Heath Elisabeth I. , Nabhan Chadi , Ryan Charles J. , Antonarakis Emmanuel S. 
Published: June 2022

5053 Background: Recurrent alterations in the WSP have been identified in patients with advanced prostate cancer. Aberrant Wnt signaling has been implicated in disease progression and hormonal resistance in prostate cancer. We utilized a multi-institutional real-world dataset to characterize molecular alterations in the canonical WSP in men with prostate cancer, and correlate that with overall survival (OS). Methods: Prostate cancer patients who underwent tissue-based DNA and RNA sequencing utilizing a commercially available CLIA-certified assay (Caris Life Sciences) were investigated. Next generation sequencing (NGS)/ whole exome (WES) and transcriptome sequencing (WTS) was performed on prostate cancer tissue derived from prostatic and/or metastatic sites. Patients with somatic activating mutations in CTNNB, pathogenic fusions in RSPO2, or inactivating mutations in APC or RNF43 were characterized as having aberrant canonical Wnt signaling (WSP-MT). A subset analysis was conducted in metastatic prostate cancer (mPCa) samples with microsatellite stable (MSS) tumors excluding RNF43 (G569fs*) mutations. Comparative analyses were done using Fisher-Exact or X2 tests, and significance was determined by adjusted p value using Benjamini-Hochberg correction (q < 0.05). OS was obtained from insurance claims data and calculated using Kaplan-Meier estimates. Enriched mRNA transcripts were identified as those with an adjusted p value < 0.001, logFC > 1.5, and (-)log10 FDR > 20. Results: Overall, 21.8% (n = 715/3283) of samples were classified as WSP-MT, of which 297 (41.5%) were from primary tumor samples and 418 (58.5%) were from metastatic sites. WSP-MT were highest in metastases to CNS (54.5%, n = 12/22), liver (43.8%, n = 91/208) and lung (42.3%, n = 91/208). Compared to WSP wild-type, WSP-MT tumors had a greater frequency of dMMR/MSI-H status (18% vs. 2%, q < 0.001). In the subset of mPCa, MSS tumors (WSP-MT excluding RNF43 (G569fs*) mutations, n = 318; WSP wild-type n = 951), WSP-MT were enriched for mutations in SPOP (14.3% vs. 6.9%, q = 0.004). In these tumors, WSP-MT samples were most enriched for mRNA expression of CST1, NKD1, AXIN2, and ZNRF3 (all known canonical WSP activators). OS was inferior in mPCa WSP-MT patients compared to WSP wild-type (HR 0.49, 95% CI 0.37-0.64, p < 0.0001). Relative to WSP wild-type cases, OS was shorter from time of enzalutamide/abiraterone/apalutamide start (HR 0.25, 95% CI 0.15-0.43, p = 0.0001), and from first-line taxane chemotherapy (HR 0.47, 95% CI 0.21-1.02, p = 0.052) in pts with WSP-MT. Conclusions: Canonical WSP alterations are enriched in metastatic tumors, with highest prevalence in visceral (CNS, liver, lung) metastases. Clinical outcomes in WSP-mutant cancers are inferior with both hormonal and chemotherapies, heralding an urgent need to develop novel therapeutic strategies for such patients.