bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-human, phase I study of CBP-1008, a first-in-class bispecific ligand drug conjugate (Bi-XDC), in patients with advanced solid tumors.
Authors: Li Ning , Gong Jifang , Zhang Jian , Liu Dan , Chen Yaqing , Zhang Youzhong , Huang Yi , Wang Jing , Tang Jie , Li Guiling , Wang Ying , Wu Junyan , Luo Suxia , Lou Ge , Duan Wei , Huang Robert , Xu Mo , Hu Xichun , Wu Lingying , Shen Lin 
Published: June 2024

5556 Background: Folate receptor α (FRα) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are potential promising therapeutic targets due to their high expression level in many solid tumors including ovarian cancer. CBP-1008 is a first-in-class bi-specific ligand drug conjugate targeting FRα and TRPV6 carrying monomethyl auristatin E (MMAE) as payload and is administered by intravenous infusion Q2W. Methods: This phase 1 study includes the dose-escalation of Ia and the dose-expansion of Ib. The phase Ia started with accelerated titration (0.015, 0.03mg/kg) and then switched to 3+3 design (0.12, 0.15, 0.17, 0.18, 0.20mg/kg). Phase Ib dose-expansion study includes 4 cohorts, platinum-resistant high-grade serous ovarian cancer (HGSOC), other sub-types of ovarian cancer such as clear cell ovarian cancer (OCCC) and low-grade serous ovarian cancer, metastatic triple negative breast cancer (TNBC) and other solid tumors. The primary objective is to assess the safety and preliminary efficacy. Results: As of December 8, 2023, 240 patients (phase Ia: n=40; phase Ib: n=200) have been enrolled including 136 HGSOC,17 OCCC, 24 TNBC and 63 other tumor types. Majority of adverse events were mild to moderate. Common (≥50%) treatment-related AEs (TRAEs) were neutropenia, WBC decreased, AST increased, pyrexia, ALT increased and nausea. Grade 3/4 TRAEs (≥5%) were neutropenia (49%), WBC decreased (26.8%), AST increased (5.9%), ALT increased (5.9%), anaemia (5.4%). 41 HGSOC patients at dose of 0.15mg/kg with ≤3 prior treatment regimens, regardless of FRα expression levels were evaluable for efficacy assessment. 13 patients achieved partial response (PR) and 29 patients achieved stable disease (SD). The objective response rate (ORR) and the disease control rate (DCR) were 31.7% and 70.7%, respectively. For 19 patients with FRα expression level 0 to 49%, 6 patients achieved PR and ORR was 31.6%. The longest treatment duration exceeds 13 months. Conclusions: The current result showed that CBP-1008 demonstrated manageable safety profile. Promising antitumor activity was observed in ovarian cancer patients at dose of 0.15mg/kg, especially in platinum-resistant HGSOC patients with ≤3 prior treatment regimens. CBP-1008 has the potential to provide a better treatment option for ovarian cancer patients regardless of FRα expression levels. Clinical trial information: NCT04740398 .
Association of physical activity with self-reported quality of life after primary chemotherapy for ovarian cancer.
Authors: Meyer Larissa Alejandra , Schneider Amy K. , Aghajani Haleh , Basabe Maria del Sol , Martinez Leidy Huie , Estrada Gladys M , Iniesta-Donate Maria , Liao Yue , Sun Charlotte C. 
Published: June 2024

5574 Background: Patients (pts) with advanced stage ovarian cancer may proceed to maintenance therapy or routine surveillance following primary treatment. As part of a larger research study to assess real world experiences of pts, we explored whether physical activity was associated with self-reported quality of life (QOL). Methods: Pts were asked to wear a wrist health tracker and complete the FACT-Ovarian (FACT-O) survey at baseline and every 3 months for up to 24 months. Total FACT-O score, including well-being subscales for physical (PWB), social (SWB), emotional (EWB), functional (FWB), and ovarian cancer-specific QOL were calculated. Health tracker data corresponding to each FACT-O 7-day recall period were analyzed. Multilevel linear regression analysis examined the relationship between FACT-O and 7-day health tracker data. The potential moderating effect by age (<60 vs. ≥ 60 yrs) was examined. Results: Data were analyzed for 77 pts with 250 total observations. Median age was 59 yrs (range 31, 82); 69% were White (6/53 pts self-identified as Hispanic), 4% Black, 9% Asian, 17% Other (13/14 pts self-identified as Hispanic). Of the 77 pts, 73% were married/partnered; median BMI 25.5; the majority had some college education. Pts completed a mean of 3 FACT-O surveys beyond baseline. Younger pts had better PWB (p<.01) and FWB (p<.01) than older pts, while older pts had better SWB (p<.01). Compared to older pts, younger pts had more daily activity minutes (19.9 vs 10.2, p<.01) and higher step counts (7035 vs 4689.8, p<.01). Apart from SWB and FWB with activity minutes, activity minutes and step counts were positively associated with FACT-O overall and subscale scores (Table). Older pts had stronger positive associations between physical activity minutes and PWB (p<.001), step counts and PWB (p<.001); step counts and FWB (p=.004), while younger pts had stronger positive associations between step counts and ovarian cancer-specific QOL (p=.03). Positive associations between physical activity minutes and SWB (p<.001) and EWB (p=.03), and ovarian cancer-specific QOL with activity minutes (p<.001) were observed only in younger patients. Conclusions: We observed positive associations between health tracker physical activity data and pt-reported QOL. Stronger associations were observed in younger pts. Interventions aimed at increasing physical activity may have broader quality of life benefits for individuals with ovarian cancer. [Table: see text]
Characterization of ESR1 mutations in endometrial and ovarian cancers.
Authors: Gaillard Stephanie , Bayable Asnakech , Deshmukh Sachin Kumar , Nayar Utthara , Xiu Joanne , Ingram Lishann , Hubbard Gretchen , Sledge George W. , Herzog Thomas J. , Thaker Premal H. , Wu Sharon 
Published: June 2024

5598 Background: Low-grade ovarian (OC) and endometrial (EC) cancers frequently express estrogen receptor (ERα, encoded by ESR1), and are considered hormonally responsive tumors. The use of endocrine therapy in the advanced and recurrent disease setting is common. In breast cancer, ESR1 mutations ( ESR1mt) convey resistance to endocrine therapy. Mechanisms for endocrine failure in gynecologic cancers are not well understood. In this study, we aim to evaluate the prevalence of ESR1mt, and associated characteristics, in EC and OC. Methods: 17,666 EC and 21,879 OC samples were analyzed by NGS of DNA (NextSeq, 592 genes and NovaSeq, WES) and RNA (NovaSeq, WTS) (Caris Life Sciences, Phx, AZ). Tumor mutational burden (TMB) totaled all somatic mutations (mt) per tumor (TMB-H: > 10 mt/MB). Statistical significance determined using chi-square and Mann-Whitney U test and adjusted for multiple comparisons (q<0.05). Real-world overall survival (rwOS) and time on treat (ToT) obtained from insurance claims data and calculated from first treatment to last contact or last of treatment, respectively. Results: L536, Y537, and D538 were the most common ESR1 hotspot mutations. ESR1mt (EC: 2.38%, OC: 0.22%) were more prevalent in endometrioid EC tumors (4.2%) compared to other EC histologies (1.7%)(p<0.05). Compared to high-grade serous (HGS) OC tumors (0.07%), ESR1mtmore prevalent in in low-grade serous (1.08%) and endometrioid (1.48%) (p<0.05). ESR1mt was associated with higher ESR1 RNA expression (EC: 1.19-fc, OC: 1-.28-fc), ER+ (EC: 94.1% vs 63%, OC: 80.9% vs 49.3%), and PR+ (EC: 90.8% vs 46.7%, OC: 36% vs 24.5%) (q<0.05). ESR1mt were associated with decreased TP53 mt (EC: 10.7% vs 50.9%, OC: 16.7% vs 78.3%), but increased PI3K pathway alterations (EC: PTEN mt: 70.4% vs 40%, PIK3R1 mt: 34.1% vs 19.6%, PIK3CA mt: 47.9% vs 36.6%, AKT1 mt: 11% vs 2.8%; OC: PTEN mt: 36.2% vs 4.%, PIK3CA mt: 32.7% vs 8.97%, AKT1 mt: 8.33% vs 0.62%), CTNNB1 mt (EC: 52.5% vs 13.9%; OC: 39.6% vs 3.09%), ARID1A mt (EC: 56% vs 32.2%; OC:28.6% vs 8.04%) and TGFBR1 mt (EC: 55.6% vs 9.16%) (q<0.05). ESR1mt was associated with TMB high (30.7% vs 21.6%) and high median IFN score (EC: -0.42 vs -0.35, OC: -0.48 vs -0.27) (q<0.05). ESR1mt enriched in patients with prior AI treatment (EC: 6.38% vs 2.65%, q=0.02; OC: 1.26% vs 0.18%), especially in EOC (14.7% vs 3.37%) (q<0.05). Conclusions: ESR1mt were more common in EC and were enriched in the endometrioid subtype, and in general associated with increased molecular alterations but a more cold immune microenvironment. Hotspot mutations known to confer endocrine resistance were most common and enrichment was observed in cases previously exposed to AIs, suggesting this may be a mechanism of resistance to endocrine therapy for some gynecologic malignancies.
Efficacy of olaparib combined to metronomic cyclophosphamide and metformin in patients with recurrent advanced/metastatic endometrial by molecular subtypes: ENDOLA phase I/II trial.
Authors: You Benoit , Leary Alexandra , Follana Philippe , Abdeddaim Cyril , Joly Florence , Bin Sylvie , Villeneuve Laurent , Alexandre Marine , Bonjour Maxime , Schwiertz Vérane , Boulai Anais , Rodrigues Manuel , Piffoux Max , Freyer Gilles , Callens Celine 
Published: June 2024

5605 Background: In patients with recurrent advanced endometrial carcinomas (EC), innovative treatments are needed after platinum chemotherapy and immunotherapy. EC are characterized by frequent defective DNA repair, along with alterations of PI3K-AKT-mTor, and IGF1R pathways. ENDOLA trial was meant to assess the safety and efficacy of the triplet olaparib (PARP 1-3 inhibitor) + metronomic cyclophosphamide + metformin in patients with advanced recurrent EC. We assessed the outcomes by the 4 molecular EC subtypes (POLE; dMMR/MSI-high; NSMP; P53mutated). Methods: ENDOLA trial (NCT02755844) was an academic French prospective multicenter phase I/II open-label dose-escalation study conducted in 6 French centers. The RP2D was defined as olaparib 300 mg BID combined to metformin 1500 mg/day and metronomic cyclophosphamide 50 mg/day (You et al. Proc AACR 2022). Alterations of POLE, MMR and p53 were assessed using local in-house assays. BRCA & HRD status were centrally defined using shallow Whole Genome Sequencing (sWGS) (HRP/HRD status defined as large genomic alteration (LGA) ≤ 7/≥8). Results: From Sept 2016to Nov 2019, 35 patients enrolled, and 31 were assessable for ITT (median age: 69, IQR: 62-72; endometrioid: n=18 (51.4%); serous: n=11 (35.5%); carcinosarcoma: n=2 (6.5%)). 2 patients (6.5%) were previously treated with immunotherapy. In the whole population, the non-progression rate at 10 weeks (NP10w, primary endpoint) was 61.5%, and median PFS (mPFS) was 5.1 months. The molecular subtype could be defined for 20 patients (64.5%): MSI-high, n=3 (15.0%); NSMP, n= 4 (20.0%); P53mutated, n= 13 (65.0%). The NP10w (& mPFS) were 18.2% (5.1 months), 27.3% (9.0 months), and 54.5% (5.1 months), respectively. The rates of patients with LGA ≤7 (non-HRD)/≥8 (HRD) were 15(48.3%)/8(25.8%). 100% patients with P53wild-type had low LGA≤ 7. No clear impact of LGA score alone was found (LGA≤ 7: NP10w 63.6%, and mPFS 5.1 month; LGA /≥8: NP10w 36.4% and mPFS 5.1 months). By combining LGA and P53, the worse mPFS was for patients with P53mutated & LGA≤ 7 (n=5, 3.1 months), and the best for patients with P53mutated & LGA≥8 (n=10, 8.5 months). Conclusions: In this heavily pre-treated population of patients with advanced EC (55% patients treated with ≥ 4 previous lines; and 50% were > 69 years old), the combination of olaparib + metronomic cyclophosphamide and metformin was highly effective, especially in those with NSMP or with P53mutated & HRD (LGA≥8) subtypes, with mPFS ~8 months. It might a promising therapeutic alternative in recurrent setting. Clinical trial information: NCT02755844 .
Prognostic assessment of simple hysterectomy versus radical/modified radical hysterectomy in clinically apparent stage II endometrial cancer: A multi-center cohort study.
Authors: Chen Yuliang , Liu Penglin , Bu Hualei , Song Kun , Kong Beihua 
Published: June 2024

5611 Background: The extent of hysterectomy for endometrial cancer (EC) patients with suspected or gross cervical involvement remains controversial. This study aimed to compare the effect of simple hysterectomy (SH) and radical or modified radical hysterectomy (RH/mRH) on the prognosis in clinically apparent stage II endometrial cancer, stratified by aggressive and non-aggressive histological types. Methods: This multi-center retrospective study enrolled patients with clinically apparent stage II (macroscopically cervical involvement without pelvic extension based on the preoperative imaging examination and intraoperative exploration) from the largest endometrial cancer database in China between 2000 and 2019. The primary and secondary outcomes were cancer-specific survival (CSS) and disease-free survival (DFS), respectively. The prognostic difference was assessed using Kaplan-Meier analysis and Cox regression analysis, in total cohort and stratified by aggressive and non-aggressive histological subtypes. Propensity score matching (PSM) algorithm were applied. Results: A total of eligible 725 participants were enrolled, including 245 patients with aggressive histological types and 480 with non-aggressive subtypes. The Kaplan-Meier showed better CSS and DFS in the RH/mRH group than the SH group both in the before ( P=0.0014 and P=0.0038, respectively) and after PSM cohorts ( P=0.042 and P=0.046, respectively) among patients with aggressive histological types. Nevertheless, no significant difference was found (P>0.05) among the patients with the non-aggressive subtypes. Similarly, the multivariate COX analysis revealed that hysterectomy type was an independent prognostic factor for CSS (hazard ratio [HR] RH/mRH vs SH: 0.36, 95% confidence interval [CI] 0.14–0.95, P=0.039) and DFS (HR RH/mRH vs SH: 0.47, 95% CI 0.24–0.93, P=0.030) in patients with aggressive histological types. Conclusions: Compared to SH, RH/mRH were associated with better CSS and DFS in patients with aggressive histological types, but not in the non-aggressive histological types. Despite guidelines recommend SH as first-line treatment for patients with suspected or gross cervical involvement, RH/mRH might be a more reasonable and individualized choice for those with aggressive histological subtypes.
Real world effectiveness and safety of low dose nivolumab with metronomic chemotherapy in patients with advanced platinum-resistant head and neck cancer: An Indian institutional experience.
Authors: Kate Shruti , Sharma Richa , Nagarkar Rajnish Vasant , Shirsath Ankita Dadabhai , Choudhary Mukesh , Patil Roshan 
Published: June 2024

6050 Background: Triple Metronomic chemotherapy (TMC) regimen of low-dose methotrexate, erlotinib, and celecoxib has been proven to improve overall survival (OS) of advanced platinum-resistant head and neck cancer (HNC) patients. The addition of low-dose nivolumab to metronomic chemotherapy is an alternative standard of care for those patients, who cannot access full-dose checkpoint inhibitors. In the present study, we aimed to assess the real world effectiveness and safety of low-dose nivolumab along with TMC. Methods: We performed a prospective analysis of advanced platinum-resistant HNC patients treated at our institute from June 2021 to June 2023 with TMC and low-dose immunotherapy consisting of capsule celecoxib (200 mg twice daily), tablet methotrexate (9 mg/m2/week), and erlotinib (150 mg once daily), along with intravenous nivolumab 20 mg (once every 2 weeks). Data was analysed descriptively and the Kaplan-Meier method was used to estimate OS, progression-free survival (PFS), and duration of response (DOR). Results: Overall, 85 patients of advanced platinum-resistant HNC were enrolled in this study. The median age of the patients was 54 years with male predominance. The most common primary sites were buccal mucosa (54%) and tongue (32%). The median follow-up was 6.5 months with 5 months of DOR to therapy. Median number of nivolumab doses received were 8 (IQR 2–48). The termination of therapy in the majority of patients was due to disease progression (55%). Most common adverse events reported were acneiform rash (62%), mucositis (52%), and fatigue (34%). Dose reduction for triple metronomic chemotherapy was required in 42% of patients for grade 3 and above adverse events. No grade 3/4 immune-related adverse events were reported throughout the study period. The median PFS and OS of the study population were observed to be 4.3 months and 8.8 months, respectively. Overall, 8 of 85 patients survived for ≥30 months and 20 (24%) patients were on treatment at the time of data analysis. Conclusions: Low-dose immunotherapy along with triple metronomic chemotherapy is a safe treatment option in real world advanced platinum-resistant HNC patients with acceptable outcomes.
Genomic characteristics of exceptional responders to treatment with PD-1 inhibitors in refractory/metastatic head and neck squamous cell carcinoma.
Authors: Chang Mark , Song Alexander , Deyo Logan James , Stamos Daniel , Bloomer Chance H. , Khoury Lara M. , Porosnicu Mercedes 
Published: June 2024

6062 Background: With the emergence of immune checkpoint inhibitors (ICIs), there are patients with advanced cancers experiencing exceptional treatment response with overall low treatment-associated toxicities. Despite success in refractory/metastatic head and neck squamous cell carcinoma (HNSCC), only a portion of patients experience benefit from the treatment with ICIs. Critical information on predictors of patient’s response to treatment is limited. At our institution we analyzed the genomic profiles of 36 patients with advanced HNSCC who demonstrated an exceptional response to treatment with PD-1 inhibitors. Methods: We reviewed patients with histologically confirmed HNSCC that had been treated with PD-1 inhibitors at Atrium Health Wake Forest Baptist Health. Treatment regimen included pembrolizumab 200mg every 3 weeks or nivolumab 240mg every 2 weeks. Response to therapy and duration of remission were monitored via CT scans and/or MRI scans at 3-month intervals, using RECIST 1.1 criteria. Exceptional responders were defined as achieving complete response (CR) or partial response (PR) for greater than six months, or stable disease (SD) for greater than one year. Progression free survival (PFS) and overall survival (OS) were measured from the date of PD-1 inhibitor initiation. PD-L1 level was measured via FoundationOne immunohistochemistry staining and reported as combined positive score (CPS). Additionally, next generation sequencing was performed on tumor (30/36 patients) and blood (33/36 patients) specimens via FoundationOne and Guardant360 testing platforms. Results: Out of 155 HNSCC patients treated with a PD-1 inhibitor, 36 patients demonstrated an exceptional response as defined above. 20 with CR, 9 with PR and 7 with SD. With an average follow up of 32 mo (95% CI, 26 mo-ongoing), the average OS was 33 mo (95% CI, 28 mo–ongoing) and the average PFS was 25 mo (95% CI, 20 mo-ongoing). These patients underwent an average of 27 treatments (range, 10-64 treatments to date). PD-L1 average score at 36 (95% CI, 22-49) and average TMB at 19 mut/mb (range, 0-90 mut/mb). Of 290 detected gene mutations, the most frequently mutated genes were TP53 (75%), PIK3CA (42%), CDKN2A (36%), EGFR (33%), TERT (25%), BRCA2 (22%), ERBB2 (22%), HNF1A (22%), MLL2 (22%), NOTCH1 (22%), and RAD21 (22%). Conclusions: There is limited data reporting the genomic profile of exceptional responders to PD-1 inhibitors in refractory/metastatic HNSCC. Higher TMB and single gene mutations such as TP53, PIK3CA, CDKN2A, EGFR, and TERT are frequently detected in exceptional responders and may provide future direction into the investigation of predictors of response to ICIs.
A novel and selective oral PI3Kα/δ inhibitor, TQ-B3525, in patients with relapsed and/or refractory follicular lymphoma: A phase II, single-arm, open-label study.
Authors: Wang Huaqing , Liang Aibin , Feng Jifeng , LIU YANYAN , Qian Zhengzi , Gao Da , Ran Xuehong , Zhou Hui , Liu Lihong , Wang Binghua , Fang Meiyun , Zhou Hebing , Huang Zhenqian , Tao Shi , Chen Zhuowen , Su Liping , Su Hang , Yang Yu , Xie Xiaobao , Li Zhiming 
Published: June 2024

7057 Background: TQ-B3525 is a novel and selective oral PI3K α/δ inhibitor. In an earlier Phase I trial, TQ-B3525 achieved outstanding efficacy in subjects with refractory/relapsed follicular lymphoma (R/R FL) (2020 ASCO Abstract #8058). Here, we report the result from a single-arm, open-label, phase II registration study evaluating the safety and efficacy of TQ-B3525 in R/R FL patients. Methods: This phase II study included exploratory stage 1 and confirmatory stage 2. Patients with R/R FL after ≥2 lines therapies received oral 20 mg TQ-B3525 once daily in a 28-day cycle until disease progression or intolerable toxicity. Primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR). Secondary endpoints were ORR by investigator assessment; the IRC- and investigator-assessed disease control rate (DCR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: Based on results (ORR, 88.0%; DOR, 11.8 months; PFS, 12.0 months) in 25 patients at stage 1, second stage study was initiated and included 82 patients for efficacy/safety analysis.Patients received a median of 3 prior lines, with 56.1% refractory to previous therapies; 73.2% experienced POD24 at baseline. At stage 2, ORR was 86.6% (71/82; 95% CI, 77.3%-93.1%), with 28 (34.2%) complete responses. Seven (8.5%) had stable disease for DCR of 95.1%. Median TTR was 1.8 months. Among 71 responders, median DOR was not reached; 18-month DOR rate was 51.6%. At median follow-up of 13.3 months, median PFS was 18.5 (95% CI, 10.2-not estimable) months; estimated 24-month OS rate was 86.1%. Response rates and survival data were consistent across all subgroups. Grade 3 or higher treatment-related adverse events occurred in 63 (76.8%) patients, with neutrophil count decreased (22.0%), hyperglycemia (19.5%), and diarrhea (13.4%) being common. Conclusions: TQ-B3525 exhibited favorable efficacy and manageable safety profiles, supporting its potential as a valuable treatment modality for heavily pretreated Chinese R/R/ FL patients. Clinical trial information: NCT04324879 . [Table: see text]