bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beacon: A phase II study of bevacizumab, atezolizumab, and cobimetinib in patients with recurrent, platinum resistant, high grade serous ovarian cancer.
Authors: Manoharan Sathya , Bressel Mathias , James Paige , Ko Yi-An , Hamilton Anne L. , Scott Clare L. , Mileshkin Linda R. , Grossi Marisa , Burdett Nikki , Ananda Sumitra , Desai Jayesh , Rischin Danny , Neeson Paul J. , Bowtell David , Au-Yeung George ,   on behalf of the imCORE Network
Published: June 2024

5565 Background: Platinum resistant high grade serous ovarian cancer (HGSC) is associated with a poor prognosis and limited treatment options. Immune checkpoint inhibitors have failed to show significant impact in treatment of HGSC to date. Bevacizumab (anti-VEGF) and atezolizumab (anti-PDL1) have shown synergy in multiple cancer types. Cobimetinib (MEK inhibitor) may also potentiate immune responses, particularly by altering the tumour microenvironment. We sought to evaluate the efficacy of cobimetinib, bevacizumab and atezolizumab in women with platinum resistant HGSC. Methods: BEACON is a Phase II single arm study of cobimetinib (60mg oral D1-21 q 28-days), bevacizumab (5mg/kg IV q2w) and atezolizumab (840mg IV q2w from Cycle 2) in patients with platinum-resistant recurrent HGSC. Patients continued therapy until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) according to RECIST 1.1 at 24 weeks. Secondary endpoints included best overall response (BOR), safety, progression free survival, and response duration. Correlative studies on paired tumor biopsy and blood samples will explore molecular characteristics/subtypes and potential biomarkers of response as exploratory objectives. This study has now completed accrual and we present the 24-week response data, with a data cut off 21st December 2023. Results: Twenty-nine patients were enrolled between September 2018 and June 2023. Median age was 62 years (range 37 - 79) and 97% had received ≥ 2 prior lines of chemotherapy. The median number of cycles received was 3 cycles of atezolizumab and cobimetinib, and 4 cycles of bevacizumab. The ORR at 24 weeks was 21% [95% CI: 8-40], and a further 28% had stable disease as assessed per RECIST. Five patients (17%) have remained on study treatment for ≥ 52 weeks to date, suggesting that in some patients there was durable disease control. In terms of safety, 22 patients (76%) required a dose reduction in cobimetinib, mainly due to gastrointestinal and skin toxicity. Seventeen patients (59%) experienced a ≥Grade 3 treatment related adverse event, most commonly hypertension (6 patients, 21%). Two patients (7%) discontinued all study treatments due to toxicity. Conclusions: Preliminary results from this study show promising efficacy with the combination of atezolizumab, bevacizumab and cobimetinib in platinum resistant HGSC. Duration of response, progression free survival data and translational data exploring molecular characteristics will be presented as data matures. Clinical trial information: NCT03363867 . [Table: see text]
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]