bluuebunny/crossref_metadata_2025 huggingface dataset:
Intratumoral Ral-binding protein 1 (RalBP1) expression as a potential predictor of bevacizumab treatment efficacy in patients with ovarian cancer.
Authors: Kraus Fabian Bernhard Thaddäus , Schramm Christina , Mayr Doris , Chelariu-Raicu Anca , Reichenbach Juliane , Topalov Nicole Elisabeth , Tauber Christina Viktoria , Burges Alexander , Kessler Mirjana , Mahner Sven , Trillsch Fabian , Czogalla Bastian
Published: June 2024

5576

Background: The anti-VEGF antibody bevacizumab (Bev) has become part of the first-line treatment of patients with advanced ovarian cancer (OC) due to its significant impact on progression-free survival (PFS). However, a significant effect on overall survival (OS) was not demonstrated. In this context, we hypothesized that the stress-responsive multidrug transporter and modulator of neovascularization Ral-binding protein 1 (RalBP1) might be prognostic for patient survival and stratify patients according to their predicted Bev response. Methods: Tissue samples from 554 patients with epithelial OC were obtained during first-line cytoreductive surgery at the Department of Obstetrics and Gynecology, University Hospital, LMU Munich, between 2003 and 2021. RalBP1 immunohistochemical staining was quantified using a mean staining intensity score (MSIS, 1-3) and a cut-off was defined as 2.5. Correlationbetween MSIS and clinicopathologic data was assessed using two-sample t-tests. Additional correlation measures included Spearman’s correlation, Chi2-test and ANOVA. PFS and OS were visualized by Kaplan-Meier curves and significant differences determined by Wilcoxon. Cox regression models were used for multivariate analysis. Results: RalBP1 was present in the cytosol of almost all OC cells (RalBP1-low: n= 385, RalBP1-high: n= 169) and independent of histopathologic subtype or grading. Patients with elevated intratumoral RalBP1 expression showed significantly improved median PFS (73.5 vs. 35.8 months, HR=0.62, p=0.033) and median OS (120.1 vs. 71.7 months, HR=0.56, p=0.007) after complete tumor debulking and platin-based adjuvant chemotherapy (n=155). In a comprehensive multivariate analysis, RalBP1 expression levels emerged as an independent prognostic marker for both OS (HR=0.67, p=0.031) and PFS (HR=0.72, p=0.033). Interestingly, in the subgroup of all patients that received an adjuvant platinum-based chemotherapy (n=351), the RalBP1–low patient status was shown to be a predictive factor for response to Bev therapy for both PFS (median 26.4 vs. 18.1 months, HR=0.94, p=0.036) and OS (median 63.4 vs. 49.3 months, HR=0.72, p=0.041). Conclusions: RALBP1 may serve as a prognostic biomarker for OC patients, helping to identify those who are likely to benefit not only in PFS but also in OS following Bev therapy. Its tumor biological role remains a matter of current investigations.
Molecular profiling of plasma from matched NCI-MATCH gynecological cancers.
Authors: Peach Amanda , Le Bao , Rahul Kannan Vishnuprabha , Greenbank Eric , Pauly Rini , Chen Li , Chang Ting-Chia , LoCoco Jennifer S. , Harris Lyndsay , Chen Alice P. , Takebe Naoko , Pawlowski Traci L. , McShane Lisa , O'Dwyer Peter J. , Doroshow James H. , Williams P. Mickey , Das Biswajit , Karlovich Chris Alan
Published: June 2024

5579

Background: During the screening phase of the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH; NCT02465060) trial, 5954 patients with advanced cancer, approximately 60% of whom had rare or less common cancers, underwent next-generation sequencing of their tumor tissue to determine study eligibility. The majority of the patients could not be assigned to a treatment arm because they did not have a study mutation of interest (MOI). The plasma collected from these patients may provide insight into the genomic landscape of circulating tumor DNA (ctDNA) and inform the potential utility of ctDNA testing for the identification of clinically relevant mutations in these rare histologies. Here we report the molecular profiles of ctDNA from a subset of the NCI-MATCH screened patients with gynecologic cancers. Methods: Cell-free DNA (cfDNA) was extracted and quantitated from plasma collected in Streck blood tubes at study enrollment. Libraries were constructed using the NCI ctDNA v2 assay with a minimum input of 10 ng and were sequenced on the Illumina NovaSeq 6000 with S4 flow cells. Results: Among 200 samples sequenced, four different histologies were represented: uterine endometrioid adenocarcinoma (UEC, n=51), serous endometrial adenocarcinoma (USC, n=35), uterine leiomyosarcoma (ULMS, n=40), and ovarian epithelial (OVT, n=74). Two samples failed, one ULMS due to sequencing error and one OVT due to contamination. The positive percent agreement (PPA) values calculated from clinically relevant MOI derived from OncoKb as both PPAref_tumor and PPAref_ctDNA, were 88.6% and 44.1% respectively. The most commonly mutated genes were TP53, KRAS, CTNNB1, and PIK3CA. Additionally, the ctDNA detected mutations not identified in the tumor, including 8 patients (4%) with a PIK3CA mutation. By employing predefined cutoffs of tumor fractions, ctDNA identified 21 out of 25 expected copy number amplifications demonstrating an 84% concordance. Microsatellite instability (MSI) using ctDNA was highest in the UEC (17.6% of patients) followed by USC at 8.6%, OVT at 6.8%, and ULMS at 2.6%. Among the patients with mismatch repair deficiency (MMRd) identified by tumor immunohistochemistry, 50% were identified as MSI-High in plasma. Conclusions: In this cohort of patients with advanced gynecological cancers from the NCI-MATCH trial, clinically relevant mutations detected by ctDNA were 88.6% concordant with data derived from tumor biopsy. In addition, some mutations were identified only in ctDNA, which may be due to tumor heterogenity. The data suggest that liquid biopsy is valuable as a complement to tumor biopsy data and when tissue is unavailable.
Post hoc analysis of progression-free survival (PFS) and overall survival (OS) by mechanism of mismatch repair (MMR) protein loss in patients with endometrial cancer (EC) treated with dostarlimab plus chemotherapy in the RUBY trial.
Authors: Mirza Mansoor Raza , Sharma Sudarshan , Roed Henrik , Landrum Lisa M. , Gilbert Lucy , Gold Michael A. , Novák Zoltán , Edelson Mitchell , Meirovitz Mihai , Diaz John Paul , Huygh Greet , Buscema Joseph , Pothuri Bhavana , Eshed Helen Dinkelspiel , Coleman Robert L. , Slomovitz Brian M. , Kostadinov Rumen , Stevens Shadi , Ronzino Graziana , Powell Matthew A.
Published: June 2024

5606

Background: MMR deficiency (dMMR) is caused by aberrant expression of MMR proteins that mediate DNA repair. The loss can be explained by epigenetic regulation (epi-dMMR; MLH1 promoter hypermethylation preventing MLH-1 expression) or mutation (mut-dMMR; MMR proteins lost through deleterious mutations) accounting for 70%–75% and 25%–30% of dMMR/microsatellite instability–high (MSI-H) EC, respectively. The GARNET trial showed that mechanism of MMR loss did not influence response of EC to monotherapy with dostarlimab (DOST), an anti-PD-1. No data exist examining OS by mechanism of MMR loss in patients (pts) with EC receiving immunotherapy. Here, we report analyses of PFS and OS in pts with primary advanced or recurrent EC (pA/rEC) in Part 1 of the RUBY trial (NCT03981796) by mechanism of MMR protein loss. Methods: Pts with pA/rEC were randomized 1:1 to receive DOST or placebo (PBO), plus carboplatin-paclitaxel (CP), followed by DOST or PBO monotherapy for up to 3 years. MMR protein status was assessed by immunohistochemistry. MMR loss of function gene mutations were determined by Personalis ImmunoID NeXT whole-exome sequencing assay. MMR protein loss without mutations in MMR genes was a surrogate indicator for epi-dMMR. Post hoc PFS and OS analyses utilized data from the data cut at which each endpoint was met (PFS at Sep 28, 2022; OS at Sep 22, 2023). Results: Part 1 of the RUBY trial included 118 pts with dMMR/MSI-H pA/rEC (DOST+CP = 53; PBO+CP = 65); 39 pts (73.6%) in the DOST+CP arm and 52 pts (80.0%) in the PBO+CP arm had MMR gene mutation data available. Substantial PFS and OS benefits were observed with DOST+CP vs PBO+CP in pts with mut-dMMR or epi-dMMR (Table). No significant differences were seen in PFS or OS in pts with mut-dMMR vs pts with epi-dMMR. Conclusions: DOST+CP led to substantial PFS and OS benefits compared with PBO+CP indMMR/MSI-H pA/rEC, regardless of mechanism of MMR protein loss. A limited number of pts with mut-dMMR treated with DOST+CP were available for analysis; however, the results support that mechanism of MMR loss does not appear to be a significant predictor of clinical benefit for dostarlimab treatment in pts with dMMR pA/rEC in Part 1 of the RUBY trial. Clinical trial information: NCT03981796 . [Table: see text]
Time course of adverse events in primary advanced or recurrent endometrial cancer treated with dostarlimab plus chemotherapy in the ENGOT-EN-6-NSGO/GOG-3031/RUBY trial.
Authors: Lokich Elizabeth , Jørgensen Trine Lembrecht , Black Destin , Cibula David , Gilbert Lucy , Savarese Antonella , Powell Matthew A. , Herbertson Rebecca , Gill Sarah , Monk Bradley J. , Nevadunsky Nicole , Ring Kari L. , Cloven Noelle , Podzielinski Iwona , Myers Tashanna K. N. , Dabrowski Christine , Stevens Shadi , Willmott Lyndsay , Mirza Mansoor Raza
Published: June 2024

5607

Background: Dostarlimab (DOST)+carboplatin-paclitaxel (CP) significantly improved PFS and OS vs CP alone in patients (pts) with primary advanced or recurrent endometrial cancer (pA/rEC) in the phase 3RUBY trial (NCT03981796). Safety has been reported for immunotherapy+chemotherapy combinations in EC, though timing of adverse events (AEs) and the longer-term AE profile is not yet clear. This analysis examines the time course of AEs related to any study treatment (TRAEs) during the RUBY trial. Methods: Pts with pA/rEC were randomized 1:1 to DOST+CP or placebo (PBO)+CP Q3W (6 cycles), followed by DOST or PBO monotherapy Q6W for up to 3 years. AEs were assessed according to CTCAE v4.03 and summarized by quarter. Results: The safety population included 487 pts who received ≥1 dose of treatment (241 DOST+CP; 246 PBO+CP). TRAEs were experienced by 97.9% of pts in the DOST+CP arm and 98.8% of pts in the PBO+CP arm. In both arms, the majority of the most common TRAEs (≥30%) and grade ≥3 TRAEs (≥10%) occurred within the first 3 to 6 months of treatment (Table). The timing of immune-related AEs (irAEs) was generally consistent with this finding. Conclusions: The majority of TRAEs seen in the RUBY trial occurred within the first 3 to 6 months, with limited differences between arms. This timing is consistent with the pts’ receipt of chemotherapy. Few pts experienced an onset of new TRAEs in the DOST+CP arm after 12 months. These safety data further support a favorable long-term benefit-risk profile of dostarlimab+CP in pts with primary advanced or recurrent EC. Clinical trial information: NCT03981796 . [Table: see text]
Fruquintinib plus sintilimab in treated advanced endometrial cancer (EMC) patients (pts) with PMMR status: Results from a multicenter, single-arm phase 2 study.
Authors: Wu Xiaohua , Wang Jing , Wang Danbo , Li Guiling , Zhang Jieqing , Chen Hongmin , Yang Hongying , Zhou Qi , Wang Ke , Wu Yumei , Yi Tienan , Liu Jihong , Huang Yi , Bai Yuxian , Wang Keming , Jiang Kui , Lou Hanmei , An Ruifang , Li Xiumin , Su Weiguo
Published: June 2024

5619

Background: Antiangiogenic therapy plus immunotherapy significantly improved PFS and OS as compared to chemotherapy among pts with previously treated advanced EMC per KEYNOTE-775 study. However, no combination immunotherapies are currently approved for EMC in China. Fruquintinib (F, a highly selective VEGFR inhibitor) plus sintilimab (S, an anti-PD-1 monoclonal antibody) showed encouraging antitumor activity in multiple solid tumors. Here, we reported the results of F plus S in treated EMC with pMMR status from an open-label, single-arm registrational phase 2 study (NCT03903705). Methods: Eligible pts had histologically confirmed, previously treated advanced EMC with pMMR status confirmed by central lab. They received F (5 mg QD, 2 weeks on/1 week off, orally) plus S (200 mg, IV, Q3W) in 21-day cycles until disease progression or unacceptable toxicity. The primary endpoint was IRC-assessed ORR per RECIST v1.1. Secondary endpoints included DCR, DoR PFS, and OS. Results: As of data cutoff date (November 15, 2023), a total of 98 pts with pMMR status were enrolled and received the combination treatment. All pts had previously received at least first-line platinum-containing systemic therapy, and 22.4% pts had received bevacizumab therapy. Detailed disease histories are summarized in the table. With the median (95% CI) follow-up time of 15.7m (14.6, 17.7), 87/98 pts had at least one post-baseline tumor assessment result (efficacy evaluable pts), among them, IRC-assessed ORR and DCR was 35.6% (CR: 2/87 and PR: 29/87) and 88.5% respectively; DoR was not reached and the 9m-DoR rate was 80.7%. Among 98 pts, the median (95% CI) PFS and OS was 9.5m (5.6, -) and 21.3m (17.3, -) respectively. Based on prior bevacizumab therapy (Yes vs No), ORR was 40.9% vs 30.3%, and median (95%CI) PFS was 13.8m (4.1, -) vs 9.5m (5.5, -). All pts experienced TEAEs, and the most common ≥Grade 3 TEAEs included hypertension (18.4%), hypertriglyceridaemia (11.2%), and palmar-plantar erythrodysaesthesia syndrome (11.2%). Conclusions: F plus S showed meaningful efficacy improvements in advanced EMC pts with pMMR status, regardless of prior bevacizumab treatment. The combination therapy had a manageable toxicity profile. F plus S could offer a new potential treatment option for this patient population. Clinical trial information: NCT03903705 . [Table: see text]
Neoadjuvant versus adjuvant chemotherapy in muscle-invasive bladder cancer: The RealBLADDER study—Results on behalf of the GOIRC.
Authors: Gambale Elisabetta , Giorgione Roberta , De Gennaro Aquino Irene , Scolari Federico , Roviello Giandomenico , Catalano Martina , Mela Marinella Micol , Doni Laura , Modesti Mikol , Vascotto Ismaela Anna , Rossi Virginia , Galli Luca , Atzori Francesco , Scagliarini Sarah , Baldazzi Valentina , Pillozzi Serena , Masini Cristina , Basso Umberto , Fornarini Giuseppe , Antonuzzo Lorenzo
Published: June 2024

e16503

Background: In regard to resectable muscle-invasive bladder cancer (MIBC) patients, treatment with radical cystectomy (RC) and perioperative platinum-based chemotherapy (CT) (neoadjuvant or adjuvant) represents the standard of care. Perioperative treatment can improve overall survival (OS), and the most robust evidence are in favor of neoadjuvant CT. RealBLADDER is an observational study aiming to describe the use and the impact on survival of perioperative CT for patients with MIBC in an Italian real-world setting. Methods: RealBLADDER is a multicentric, observational, retrospective and prospective study, which enrolled patients with MIBC treated with perioperative CT from June 2018 up to June 2023. The primary endpoint was the rate of pathological complete response (pCR)(<pT1), defined as the absence of residual tumor cells in bladder and nodes at the pathological examination after neoadjuvant CT. Secondary endpoints were disease-free survival (DFS), OS and surgical outcomes (morbidity and mortality rates). DFS and OS by setting of chemotherapy were determined. Results: 172 eligible patients were identified. One hundred and thirty-six patients (79.1%) received neoadjuvant and 36 (20.9%) received adjuvant CT. The rate of pCR was 43.3%. The rate of surgical morbidity and mortality were 20.9% and 0%, respectively. Compared to adjuvant chemotherapy, 12-months DFS was improved in patients treated with neoadjuvant CT (p=0.042). Notably, patients treated with neoadjuvant CT had 12-months OS longer in than those treated with adjuvant CT (p=0.043). Conclusions: This real-world analysis of Italian patients with MIBC confirmed that neoadjuvant chemotherapy is associated with a high rate of pCR and low rate of surgical morbidity and mortality supporting the use of neoadjuvant CT in MIBC prior to RC.
Real-world outcomes among patients with advanced/metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKls) monotherapy or TKI-IO combination therapy.
Authors: Dong Pei , Huang Tingxuan , Peng Yulu , Wei Wensu , Jiang Lijuan , Zhong Xi , Zhang Zhiling , Han Hui , Zhou Fangjian
Published: June 2024

e16514

Background: Tyrosine kinase inhibitors (TKI) monotherapy or TKI in combination with immunotherapeutic agents (IO) are standard of care fist-line treatment for advanced or metastatic renal cell carcinoma (RCC). TKI monotherapy is extremely frequently in China because of the medicine Indications and health care policy. We examined the outcomes of patient treated with TKI in monotherapy and in combination with immunotherapy (TKI-IO) in Chinese patients. Methods: We performed a retrospective analysis of clinical outcomes in patients with RCC treated with TKI (cohort 1) or TKI-IO (cohort 2) in Sun Yat-sen Cancer Center between Dec 1,2015 and Nov 30,2022. Median follow-up was 26.1m (range from 0 to 87.6). Real-world progression free survival (1L-rwPFS), 2L-rwPFS and PFS2 (1L-rwPFS+2L-rwPFS),which means progression free survival from first-line treatment to second-line progression were calculated by Kaplan-Meier analysis and compared by the log-rank test. Cox proportional-hazard models were used to obtain hazard ratios (HRs) with 95%. Results: In total,325 patients were included. The median age was 55 (16-83), Male 75% (244), Female 25% (81). In cohort 1, 264 patients received 1L TKI and in cohort 2, 61 patients received 1L TKI-IO treatment. Median 1L-rwPFS in cohort1 was 7.7m VS 17.2m in cohort2 (HR 0.43 [0.32; 0.56]; p<0.00001), amongst all patients, the TKI monotherapy most frequently prescribed was sunitinib, for TKI-IO, the most prescribed was axitinib plus Tislelizumab Injection. Median PFS2 was longer in TKI-IO (32.6m vs 24.8m) (HR 0.42 [0.27;0.66], p<0.00001). In cohort 1, 37 patients progression with prior TKI monotherapy received 2L TKI therapy, while 211 patients received TKI-IO, median 2L-rwPFS was longer in 2L TKI-IO (14.2m vs 7.5m) (HR 0.52 [0.33;0.83], p=0.00043), PFS2 also had similar trend 20.3m VS 27m (HR 0.62 [0.40;0.96], p=0.0095). In 211 patients 2L TKI-IO cohort, the most prescribed was axitinib+IO (182/211), median 2L-rwPFS was 15.2m in axitinib+IO VS 8.2m in IO+other TKI (HR 0.41 [0.23;0.72], p<0.00001).Data is contained in the table. Conclusions: Our retrospective cohort study suggests that TKI-IO provides a significant progression-free survival advantage over TKI monotherapy, whether used in the first-line or the subsequent line of therapy. Axitinib may be one of the best companions for immunotherapy. [Table: see text]
Clinical and pathological outcomes of nephrectomy/metastasectomy in patients with metastatic renal cell carcinoma after prior immune checkpoint inhibitor exposure.
Authors: Amaral Paulo Siqueira , Beckermann Katy , Hillis Mikala , Schaffer Kerry Roe , Ancell Kristin Kathleen , Lambrecht Morgan , Kaiser Elizabeth , Rini Brian I.
Published: June 2024

e16515

Background: The landscape of metastatic renal cell carcinoma (mRCC) treatment has changed with the emergence of immune checkpoint blockade (ICB) which leads to enhanced responses and prolonged survival compared to tyrosine kinase inhibitors (TKI). The higher objective response rates and durable disease control has resulted in consideration of consolidative surgery in a subset of patients. Methods: A single-center retrospective analysis of mRCC patients who had cytoreductive nephrectomy or metastasectomy between October 2017 and January 2024 after prior ICB exposure was conducted. Clinical and pathological characteristics, response to ICB, and safety outcomes were evaluated. We also assessed the time off systemic therapy after surgery. Results: Seventeen patients were identified. The median age was 59 years, and the median follow-up was 24.8 months after starting ICB. 76.5% received combination regimens (six with dual ICB and seven with ICB plus TKI), while the remaining four patients had anti-PD1 monotherapy. Fourteen patients initiated ICB as first- line treatment while the remaining three patients had ICB in the second line. Median ICB exposure time before surgery was 10.9 months (range, 0.8 - 41.5). 70.6% were International mRCC Database Consortium (IMDC) intermediate risk and 29.4% were poor risk. Fifteen patients had radical nephrectomy, and one had a renal bed resection. The best overall response before surgery included 6% complete response, 35.2% partial response, 41.1% stable disease, 17.6% disease progression (PD of primary tumor only). Pathological findings revealed 76.5% clear cell, 11.8% unclassified and 11.8% papillary RCC. 58.8% showed Fuhrman grade 3 or 4 and 11.8% had a sarcomatoid component. Notably, three (17%) patients had a complete pathological response in the primary tumor and 88.2% displayed necrosis. One patient (6%) had a 30-day post-operative complication of deep vein thrombosis. Fourteen (82.4%) patients had residual disease after surgery, but ten patients (58.8%) discontinued systemic treatment. Among the seventeen patients, nine resumed systemic therapy after a median time of 8.3 months off therapy (range, 2.8 -15.5). Conclusions: Surgical consolidation after ICB is safe and may allow patients time off systemic therapy. ICB is active in primary renal tumors, with complete pathological responses and necrosis observed.
The prognostic significance of venous tumor thrombus grading for patients with renal cell carcinoma.
Authors: Ge Silun , Qu Le , Wang Linhui , Ge Jingping
Published: June 2024

e16520

Background: Venous tumor thrombus (VTT) is observed in 4−10% of newly diagnosed RCC patients, and a successful radical nephrectomy and thrombectomy provides considerable palliation to a proportion of nonmetastatic RCC patients with VTT. However, the reported postsurgical survival varies significantly with the 5‐year overall survival (OS) rate ranging from 37.0 to 71.0%. Hence, accurate risk factors are critically needed for these patients. Here we evaluate the prognostic significance of VTT grading for these patients. Methods: The final evaluable dataset enrolled 706 consecutively nonmetastatic ccRCC patients who underwent radical nephrectomy and thrombectomy, including 304 in the Training cohort from the Eastern China Renal Cancer Collaborative Group, 320 in the China‐Validation cohort and 82 in the Poland‐Validation cohort. All pathological specimens were centrally reviewed by three genitourinary pathologists blinded to clinical information. Univariable and multivariable Cox regression analyses were performed to identify independent predictors associated with survival outcomes. Results: To comprehensively evaluate the potential of VTT in risk assessment, multiple characteristics of VTT were incorporated, including VTT height, consistency and the pathological nuclear grading of VTT (VTT grading), which has not been studied yet. Although higher pathological grading of primary tumor (PT) and VTT were both significantly correlated with dismal prognosis, only VTT grading remained as an independent predictive factor for OS and DFS after multivariable Cox regression. Furthermore, VTT grading showed superiority in risk assessment compared with PT grading and other variables by c‐index analysis (OS: 0.663 vs. 0.501–0.610, 0.667 vs. 0.544–0.651, and 0.719 vs. 0.511–0.700 for Training, China‐Validation, and Poland‐Validation cohorts, respectively; DFS: 0.664 vs. 0.501–0.606, and 0.672 vs. 0.530–0.640 for Training, and China‐Validation cohorts, respectively), which was confirmed by the receiver operating characteristic (ROC) analysis (OS: area under the curve [AUC] 0.764 vs. 0.650–0.664, 0.684 vs. 0.650–0.667, and 0.814 vs. 0.641–0.711 for Training, China‐Validation, and Poland‐Validation cohorts, respectively; DFS: AUC 0.753 vs. 0.648–0.651, and 0.704 vs. 0.601–0.665 for Training, and China‐Validation cohorts, respectively). Conclusions: VTT grading displayed superior accuracy and discriminatory ability in predicting survival risk for nonmetastatic ccRCC patients with VTT. Assessing VTT grading in routine pathology reports may provide further information for stratification of patient risk.
A phase 1 study of BAT8007, an anti-nectin-4 monoclonal antibody-exatecan conjugate, in patients with advanced solid tumors.
Authors: Jiang Lijuan , Song Zhengbo , Gong Yi , Jin Jianan , Ding Yao , Tang Long , Deng Xia , Li Xiangdong , Li Su , Cheng Xiangdong , Zhou Fangjian , Zhou Xiaoyan , Fu Ziyi , Yu Jin-Chen
Published: June 2024

e16567

Background: BAT8007 is an antibody-drug conjugate targeting Nectin-4. In this phase 1 study, the authors investigated BAT8007 in subjects with advanced solid tumors. Methods: Subjects with advance solid tumor received BAT8007 on day 1 of a 21-day cycle until subject intolerance or disease progression. The study objectives were tolerability, safety, pharmacokinetic characteristics, immunogenicity, and preliminary efficacy. Results: As of January 30, 2024, 16 Chinese subjects with urothelial carcinoma (UC), non-small cell lung cancer (NSCLC), prostatic cancer, esophageal squamous cancer, hepatocellular carcinoma, ovarian cancer were allocated into five cohorts of 0.8, 1.6, 2.4, 3.0, 3.6mg/kg dose levels. The Nectin-4 expression on tumor tissue was not a requirement for eligibility. There was no dose-limiting toxicity observed, the dose escalation beyond 3.6mg/kg is continuing to be explored. The maximum tolerated dose has not yet been reached. In 16 subjects who have received at least one dose of BAT8007, at least one treatment-emergent adverse events (TEAEs) were reported in 13/16 (81.25%) subjects. The most common TEAEs (≥20%) of any grade were anemia, neutropenia, leukopenia, nausea, vomiting, hypoalbuminemia, hypertriglyceridemia and fatigue. The majority of the treatment-emergent adverse events were Grade 1 or 2; 18.75% subjects experienced Grade 3 or greater AEs, including thrombocytopenia 1/16 (6.25%), worsening anemia 1/16 (6.25%), neutropenia 1/16 (6.25%). The gastrointestinal toxicity was mild. There were no subjects terminated the study treatment due to TEAE. No skin, ocular toxicity and interstitial lung disease were reported. Six subjects with UC were recruited and distributed in 0.8mg/kg(n=1), 1.6mg/kg(n=1) and 3.0mg/kg(n=4) cohort. All of them had undergone prior 3-5 lines of systemic treatments including PD-1 antibodies and platinum-based regimens. Four subjects with UC were enrolled, and 2 of them performed one tumor assessment as data cut off. Both of them showed stable disease with target lesion reductions of -14% and -16.3%, respectively. Both of these two UC subjects had been treated with RC48 (disitamab vedotin, an anti-HER2 ADC) treatment prior to this assessment. Additionally, 1 subject with NSCLC achieved a confirmed partial response (target lesion reduction of -61.0%) in 2.4 mg/kg cohort, and is still benefiting from BAT8007. Conclusions: BAT8007 was well-tolerated with manageable toxicity and demonstrated preliminary antitumor activity in urothelial carcinoma and NSCLC. Clinical trial information: NCT05879627 .
Maintenance therapy with avelumab as the first-line treatment in patients with metastatic urothelial carcinoma: A real-world, ambispective RAVE-Bladder study.
Authors: Gridneva Yana , Sultanbaev Alexander , Anzhiganova Yulia , Gluzman Mark , Mochalova Anastasia , Shkurat Alexey , Parsadanova Elvira , Israelyan Edgar , Murzina Yulia , Kalpinsky Aleksey , Stativko Olesia , Karabina Elena , Kеln Artyom , Petkau Vladislav , Tovbik Natalya , Turganova Maria , Safina Sufiia , Kopyltsov Evgeny , Volkova Maria , Tsimafeyeu Ilya
Published: June 2024

e16569

Background: The RAVE-Bladder study was designed to assess the efficacy and safety of avelumab maintenance in patients with metastatic urothelial carcinoma in a real-world population. Methods: In this non-interventional, ambispective study, eligible patients had metastatic urothelial carcinoma and measurable disease that had not progressed with first-line platinum-based chemotherapy. Patients received maintenance avelumab according to a standard regimen (800 mg, administered every 2 weeks). Tumor imaging was performed at baseline and then every 12 weeks. The primary endpoint was overall survival (OS) at the initiation of avelumab treatment, while secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Results: At data cutoff (February 02, 2024), 110 patients (81% male, 19% female) were recruited from 21 sites and median follow-up was 9.71 months. Median age was 65 (range, 36-84) years. All patients had confirmed urothelial carcinoma (high grade, 62.8%). Primary tumor site was upper urinary tract in 26 (23.6%) and bladder in 84 (76.4%) cases. Forty-five (40.9%) patients had radical surgery; 68 (61.8%) had metastatic disease at time of diagnosis; 44 (40%) had 2 and more metastatic sites. First-line chemotherapy included gemcitabine + cisplatin, gemcitabine + carboplatin, cisplatin only, carboplatin only, and MVAC in 51 (46.4%), 32 (29%), 19 (17.3%), 7 (6.4%), and 1 (0.9%) patients, respectively. Median number of chemotherapy cycles was 4 (range, 3-9) and median number of avelumab infusions was 16 (range, 2-43). ORR to chemotherapy was 48.2%. An additional 38 patients (34.6%) responded to avelumab therapy (16 CR, 22 PR). Median OS was not reached and 1-year OS rate was 78.7%. Median PFS was 9.5 months (95% CI 7.8 – 11.2 months). Thirteen (11.8%) patients experienced grade 3 adverse events during avelumab therapy. Conclusions: The findings illustrate the favorable tolerability of maintenance therapy with avelumab, a remarkable progression-free interval subsequent to standard platinum-containing chemotherapy and prominent additional response rate among patients with metastatic urothelial carcinoma. Ongoing follow-up continues to provide additional insights. Clinical trial information: KCRB01012022 .
Noninvasive early detection and recurrence monitoring for non-muscle-invasive bladder cancer via urine tumor DNA.
Authors: Wu Junlong , Cheng Huanqing , Wang Huina , Chen Libin , Liu Lei , Cao Shanbo , Lou Feng , Ye Ding-Wei
Published: June 2024

e16586

Background: Traditional methods for the detection and surveillance of non-muscle-invasive bladder cancer (NMIBC) were generally invasive, costly, and not effective for early-stage, low-grade, and minimal residual disease (MRD) tumors. Whether urine tumor DNA could be used to early detect urothelial carcinoma and monitor MRD with high sensitivity should be explored. Methods: We conducted a perspective study to determine the performance of utLIFE-UC (our previously reported urine tumor DNA multidimensional bioinformatic predictor) in early detection and recurrence monitoring of NMIBC (Trial No. ChiCTR2300072635). We prospectively recruited 49 patients initially diagnosed with NMIBC. Urine samples were collected prior to transurethral resection of bladder tumor (TURBT) and repeat TURBT (Re-TURBT) if needed. Postsurgical samples were collected every 3-6 months when patients underwent routine cystoscopy. The utLIFE-UC score > 60 indicates a positive clinical significance. Results: Overall, utLIFE-UC could discriminate NMIBC with high sensitivities of 91.8% (45/49), both in different T stages (Ta, 84.0%; T1, 100%; P = 0.110) and grades (low-grade, 88.2%; high-grade, 93.3%; P = 0.613). Twenty patients underwent Re-TURBT, of whom 8 cases had residual tumor. The utLIFE-UC correctly diagnosed 8 of 8 (100%) patients with residual tumor. In addition, the assay showed a high NPV of 100%, implying that it may aid in avoiding Re-TURBT in patients predicted to have no residual tumor. Notably, utLIFE-UC score before Re-TURBT in patients with multiple tumors (MT) was markedly increased than that of patients with single tumor (ST) (P = 0.028). MRD-positive rate in MT patients was 100%, whereas 50% of ST patients were MRD-negative. During follow-up, recurrence status of 27 patients was collected, and 18.5% (5/27) of them recurred. The median follow-up time was 211 days (range 39 to 326 days). For patients receiving Re-TURBT, all the tumors with MRD-negative results before Re-TURBT, had no recurrence, further supporting the possible unnecessity of Re-TURBT in this population. The prognostic value of postsurgical utLIFE-UC results in NMIBC was explored. MRD-positive patients showed a worse recurrence-free survival than MRD-negative ones (median 200 days vs unreached; P = 0.001). However, it was not observed the correlation between prognosis and clinical features, including age, sex, tumor number, T stage, and grade. Compared to clinical confirmed recurrence, utLIFE-UC could predict recurrence with a median lead time of 100 days (range 17 to 140 days; P = 0.056). Conclusions: TheutLIFE-UC assay for early diagnosis, MRD detection and surveillance in NMIBC is a noninvasive and effective approach, which may contribute to reducing the burden of cystoscopy and invasive examination. Clinical trial information: ChiCTR2300072635 .
Effectiveness of adjuvant immunotherapy in muscle-invasive urothelial cancer: A systematic review and meta-analysis of randomized controlled trials.
Authors: Silva Isadora Mamede Mendes da , Silva Caroliny , Alves Ana Caroline Fonseca , Oliveira João Pedro , Maia Melissa , de Liz Caio Dabbous , Oliveira Audrey Cabral Ferreira de
Published: June 2024

e16599

Background: Neoadjuvant platinum-based chemotherapy followed by radical surgery is the established treatment for muscle-invasive urothelial cancer (MIUC). However, over 50% of patients face lethal metastatic recurrence, and adjuvant chemotherapy's efficacy lacks consensus for high-risk cases, with others encountering eligibility issues. Recent breakthroughs highlight adjuvant pembrolizumab's significant enhancement of disease-free survival. In response, a meta-analysis was conducted to assess immunotherapy's effectiveness in managing high-risk MIUC. Methods: A systematic search across PubMed, Embase, Cochrane, ClinicalTrials.gov, and ASCO GU abstracts identified randomized controlled trials (RCTs) comparing adjuvant PD-1 and PD-L1 inhibitors against control (placebo or observation) for MIUC. Key outcomes included disease-free survival (DFS), grade 3 or higher adverse events (AE), and overall survival (OS). Heterogeneity was assessed using I2 statistics, employing a random-effects model for analysis. Statistical analyses utilized R software version 4.3.2. Results: In a cohort of 2,220 patients from three RCTs, 1,113 (50.14%) received immunotherapy. Immunotherapy significantly improved DFS (HR 0.73; 95% CI 0.59-0.90; p < 0.01), particularly in lower tract tumors (HR 0.71; 95% CI 0.56-0.91; p < 0.01). No significant DFS improvement was observed in the upper tract subgroup (HR 1.21; 95% CI 0.87-1.68; p = 0.25) (p-interaction = 0.01). Further analyses showed no significant subgroup differences in PDL1+/- (p-interaction = 0.85) and previous neoadjuvant chemotherapy use (p-interaction = 0.12). However, immunotherapy exhibited a higher incidence of grade ≥ 3 AE (RR 1.47; 95% CI 1.13-1.91; p < 0.01). No differences in OS were found (HR 0.94; 95% CI 0.80-1.11; p = 0.46). Conclusions: Adjuvant PD-1 and PD-L1 inhibitors significantly enhance MIUC disease-free survival, irrespective of PD-L1 status. However, this benefit comes with an increased risk of grade 3 or higher adverse events. These results offer compelling evidence supporting immunotherapy as a valuable adjuvant treatment option for high-risk MIUC patients.
Efficacy of first line (1L) poly ADP-ribose polymerase inhibitors (PARPi) in combination with androgen pathway inhibitors (API) by homologous recombination repair (HRR) genes in metastatic castration-resistant prostate cancer (mCRPC): A living meta-analysis.
Authors: Bibi Arifa , Naqvi Syed Arsalan Ahmed , Khan Muhammad Ali , Raina Ammad , Khakwani Kaneez Zahra Rubab , Orme Jacob , Childs Daniel S , Kase Adam McLain , Baca Sylvan C. , Sartor Oliver , Singh Parminder , Bryce Alan Haruo , Riaz Irbaz Bin
Published: June 2024

e17059

Background: It is unclear if patients with different HRR gene-mutated mCRPC derive consistent benefit from treatment with PARPi and API combination. Approval labels for PARPi+API are inconsistent across regulatory bodies in the US (Food and Drug Administration, FDA) and Europe (European Medical Agency, EMA), adding to confusion among practicing clinicians. Therefore, we aimed to assess the differential efficacy of PARP+API therapy by different genes using up-to-date trial evidence. Methods: We maintain a living meta-analysis on mCRPC treatments that is updated when new data becomes available. Here, we report data from phase III randomized control trials (RCTs) assessing PARPi+API in 1L mCRPC. The outcomes of interest included radiographic progression-free survival (rPFS) and overall survival (OS). Hazard ratios (HR) for rPFS and OS by different genes were summarized using random effects meta-analysis via inverse variance approach. Results: We have screened 27376 references since the inception of this living review. Here, we report data from three trials (15 references) with a total of 1618 patients. Frequently reported HRR gene mutations in the included trials were BRCA2 (35%), ATM (21%), CDK12 (12.2%), CHEK2 (12.2%), BRCA1 (4.6%), and PALB2 (3.4%). In terms of rPFS, statistical benefit was observed in BRCA (0.28; 95% CI: 0.13-0.59) and CDK12 (0.58; 95% CI: 0.35-0.95) subgroups, whereas no statistically significant benefit was seen in PALB2 (0.53; 95% CI: 0.21-1.32), ATM (0.93; 95% CI, 0.57-1.53), and CHEK2 (0.92; 95% CI: 0.53-1.61) subgroups. For OS, benefit was observed in BRCA (0.47; 95%CI: 0.31-0.71) subgroup. While not statistically significant, a signal of meaningful OS benefit was observed in PALB2 (0.33; 95%CI: 0.10-1.16) but no OS benefit was observed in ATM (0.97; 95% CI: 0.57-1.67), CDK12 (0.80; 95% CI: 0.36-1.78), and CHEK2 (0.81; 95% CI: 0.37-1.75) subgroups. Conclusions: Current results show that mCRPC patients with BRCA and CDK12 alterations had delayed disease progression with PARPi+API as 1L therapy. BRCA mutations are also associated with improved OS, while patients with CHEK2 and ATM derived no significant benefit with PARPi+API combination. [Table: see text]
Exploring the prognostic value of the TRAQinform Profile applied to end-of-treatment PSMA PET/CT in patients with mCRPC and treated with 177Lu-PSMA radioligand therapy: A retrospective, single-center analysis.
Authors: Murthy Vishnu , Lokre Ojaswita , Perk Timothy G. , Thin Pan , Nguyen Kathleen , Chen Lucia , Gafita Andrei , Czernin Johannes , Calais Jeremie
Published: June 2024

e17060

Background: To explore the prognostic value of the TRAQinform Profile trained on mid-treatment prostate-specific membrane antigen (PSMA) PET/CT (PSMA-PET) when applied to end-of-treatment PSMA-PET (ePET) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA Radioligand Therapy (PSMA-RLT). Methods: This was a single-center retrospective study. mCRPC patients who underwent PSMA-RLT with available baseline PSMA-PET (bPET) and ePET within 6 mo of the last PSMA-RLT cycle were eligible. Overall survival (OS) from ePET was collected. TRAQinform IQ technology (AIQ Solutions, Madison, WI) was used to conduct lesion region of interest (ROI)-based analyses at bPET and ePET, and changes in SUVmax, SUVmean, volume (cm3), and SUVtotal (SUVmean x volume) across all lesion ROI from bPET to ePET were extracted. Lesion ROI were matched across time points and categorized into new, increasing, stable, decreasing, and disappeared based on changes in SUVtotal. Associations between % new, % increasing, % stable, % decreasing, and % disappeared lesions and OS were evaluated using univariate Cox regression models. This study applied TRAQinform Profile (a random forest model), trained on 185 external PSMA-PET, to generate TRAQinform Profile scores for early identification of optimal vs. suboptimal responders to PSMA-RLT. Associations between TRAQinform Profile scores and OS were evaluated by Kaplan-Meier analysis. Results: Twenty mCRPC patients were included. Thirteen of 20 patients (65%) had died at the last follow-up. The median survival time from ePET was 14.5 mo (IQR, 10.2–44.3). The median number of lesion ROI identified on bPET and ePET were 13.5 (IQR: 5.8-59.5) and 33 (IQR: 2.8-86.3) respectively. The median % changes in SUVmax, SUVmean, volume, and SUVtotal from bPET to ePET were -33.9%, -20.7%, 4.3%, and -13.9% respectively. An increase in percent new and percent new or increasing lesions was associated with a higher risk of death (HR = 1.03; p = 0.002, HR = 1.03; p = 0.003 respectively), while an increase in percent disappeared or decreasing lesions was associated with a lower risk of death (HR = 0.97; p = 0.006). The median TRAQinform Profile score was 0.27, and patients with a TRAQinform Profile score above the median had shorter OS compared with patients with a TRAQinform Profile score below the median (median OS, 10.9 mo [IQR, 5.0-13.3] vs. median OS, 44.3 mo [IQR, 14.5-44.3]; p = 0.02). Conclusions: In this retrospective study of 20 mCRPC patients treated with PSMA-RLT, the TRAQinform Profile score was prognostic for OS. Percent new, percent new or increasing, and percent disappeared or decreasing lesions were significantly associated with OS. Validation in larger, prospective multicentric clinical trials is warranted.
Characteristics and treatment (Tx) patterns (TxP) of high-risk biochemically recurrent (HR-BCR) non-metastatic castration-sensitive prostate cancer in the real-world by race, age, and prostate-specific antigen (PSA) doubling time (PSADT).
Authors: Morgans Alicia K. , Mucha Lisa , El-Chaar Nader N. , Elsouda Dina , Ramaswamy Krishnan , Schuler Tammy , Feinberg Bruce A. , Pathak Prathamesh , Asgarisabet Parisa , Gentile Danielle , Freedland Stephen J.
Published: June 2024

e17071

Background: The optimal approach to manage HR-BCR is undefined. Recent trials examined early intensified androgen-deprivation therapy (ADT), but its alignment with current practice is unclear. We describe real-world characteristics and TxP in patients (pts) with HR-BCR, and how age, race, and PSADT impact them. Methods: This physician-abstracted chart review used de-identified data from the Cardinal Health’s Urology and Oncology Provider Extended Network 2018-2022 in the US. HR-BCR was defined as in EMBARK: PSADT ≤9 months (m) and PSA ≥1 ng/mL for pts with prior radical prostatectomy (RP) or ≥2 ng/mL above nadir PSA for pts with radiotherapy (RT) without prior RP. Data were collected from index date (PSADT ≤9 m observed) until disease progression/last follow-up/death. PSADT was reported by physician (rwPSADT) or calculated (cPSADT) retrospectively. First-line (1L) Tx was that received ≤60 days post-index; no Tx received was defined as observation. Pt characteristics and TxP were analyzed descriptively in the overall cohort and by age ( < 65 or ≥65 years [yrs]), race (White [W]/Black [B]), and PSADT (≤3 m, > 3─9 m). Results: Of 284 pts with HR-BCR (mean [SD] age, 67 [7.5] yrs), most had Gleason ≥8. While one-third received 1L Tx (mainly systemic Tx ± RT [Table]), during a median follow-up of 1193 days, 75% of pts on 1L observation received systemic Tx (median time to Tx, 162 days), mostly ADT alone. Observation was used as 1L more often in the < 65 yrs, W, and PSADT ≤3 m groups, but few pts in these groups, especially in PSADT ≤3 m and < 65 yrs, had rwPSADT. At follow-up, over 70% pts received systemic Tx in all subgroups. Conclusions: During a short follow-up period, most pts with HR-BCR received systemic Tx suggesting that current practice includes Tx with systemic therapy rather than surveillance alone. Notably, pts < 65 yrs and PSADT ≤3 m, those who perhaps stand the most to benefit, had lower rates of 1L systemic Tx, likely because many lacked rwPSADT (i.e., physician didn`t know PSADT). Our data support that lack of knowing PSADT in real-time may be associated with delayed Tx, which may warrant further research. [Table: see text]
Experience with de-intensification of intensified treatment in metastatic castration-sensitive prostate cancer in Venezuela: A pilot study.
Authors: Sucre Carlos Eduardo , Sucre Oscar , Cavaniel Rudy , Sucre Santiago , Borga Guillermo
Published: June 2024

e17080

Background: Novel therapeutic approaches in recent years have changed the management of metastatic castration-sensitive prostate cancer (mCSPC). Traditionally, an antiandrogenic agent was used for androgen deprivation (AD); currently, the approach is to do treatment intensification with AD plus an additional medication (such as abiraterone, enzalutamide, docetaxel, among others). Historically, intermittent versus sustained AD have been considered as equally effective therapeutic measures. In developing countries, treatment adherence has been limited by access to some of these medications, as well as financial toxicity. Recently a new therapeutic approach has been proposed, one which entails treatment de-intensification in patients with a negative PSA after 1 year of treatment, aiming to decrease adverse events and improve treatment adherence. Methods: We included patients with mCSPC that received treatment intensification with AD plus either abiraterone or enzalutamide. Concurrent use of docetaxel was allowed. After at least twelve months of treatment and with a PSA level under 0.2 ng/mL, we proceeded to suspend intensified therapy, maintaining AD alone (de-intensification). These patients were followed up every 12 weeks, with a clinical evaluation plus PSA measurement. Patients that were deemed to have biochemical progression were excluded from the study, and underwent full imaging evaluation as well as a change in their current therapy on a case-by-case basis. Results: A total of 28 patients with mCSPC are included, with a mean age of 71.71 years. Thirteen patients have synchronic disease (46.42%), and fifteen patients have metachronic disease (53.58%). Of the original 28 patients, 16 patients have low volume disease (57.14%) and 12 have high volume (42.85%). Concurrently, 26 out of the 28 included patients had a negative PSA after six months of follow up (92.85%). To this date, 18 patients have completed twelve months of follow up, out of which 15 patients have maintained a negative PSA (83.3% of total sample). Out of the other 3 that developed biochemical progression, 2 of them had high volume disease and all 3 had a Gleason 8 score. Conclusions: Treatment de-intensification appears to be an acceptable therapeutic approach. This strategy could prove most beneficial in developing countries, where access to some medications is limited, and could improve treatment adherence in the long run. Adverse events associated to medications is also minimized with this approach. It’s also possible that this new therapeutic approach is most beneficial in lower risk patients (Gleason score < 8, low volume metastatic disease). In order to make these results more robust, a larger population sample and longer follow up is required.