bluuebunny/crossref_metadata_2025 huggingface dataset:
Cadonilimab safety and efficacy in recurrent or metastatic cervical cancer: First real-world experience from a Chinese multicenter study.
Authors: Sun Yang , Chen Jian , Yu Haijuan , Fan RenLiang , Liu Li , Xiao Weixiong , Lin Rong , Chen DeZhao , Weng Xiaoying , Shen Fengfang , Wang Shaoyu , Tian Qihua , Zeng Wei , Lian Rong
Published: July 2024

e17510

Background: Cadonilimab, a bi-specific antibody that simultaneously targets PD-1 and CTLA-4, was approved on 29 June 2022 in China for the treatment of recurrent or metastatic cervical cancer (R/M CC) in patients who have progressed following platinum-based chemotherapy. The COMPASSION-03 trial recently demonstrated promising tumor response rates with cadonilimab in R/M CC patients. This study aims to assess the efficacy and safety of cadonilimab in a real-world clinical setting in China. Methods: This multicenter retrospective study enrolled 102 patients with R/M CC, who received at least one cycle of cadonilimab at seven medical centers from July 2022 to October 2023. Among these, 94 patients were administered 10 mg/kg of cadonilimab once every 3 weeks on day 1, while 8 patients received 6 mg/kg every 2 weeks on day 1. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and the disease control rate (DCR) of the overall patients, as well as toxicity, were evaluated. Results: The study included patients with squamous cell carcinoma (73 patients), adenocarcinoma (20), adenosquamous carcinoma (5), and small cell neuroendocrine carcinoma (4). The median age was 54 years, ranging from 28 to 83. Initially, most patients presented with advanced disease: stage IIIB (8 patients), stage IIIC (24), and stage IV (43). The Eastern Cooperative Oncology Group (ECOG) performance status was 0, 1, 2, and 3 for 150, 12, 6, and 3 patients, respectively. Cadonilimab was administered as first, second, and third line or beyond in 35 (34.3%), 31 (30.4%), and 36 (35.3%) patients, respectively. Treatment regimens included cadonilimab monotherapy (13.7%), combined with chemotherapy (33.3%), chemoradiotherapy (19.6%), anti-angiogenesis therapy (11.8%), chemotherapy and anti-angiogenesis therapy (7.8%), chemoradiotherapy and anti-angiogenesis therapy (10.8%), and surgery plus chemoradiotherapy (2.9%). After a median follow-up of 10.2 months, median PFS and OS were not reached. Among the 93 patients (88.2%) with evaluable efficacy, 8 were CR, 32 were PR, 32 were SD, and 22 were PD. The ORR reached 43.0% and the DCR reached 77.4%. Adverse events were reported by 88.2% of patients, with 31 (30.4%) experiencing grade 3-4 immunotherapy-related adverse effects, mainly decreased white blood cell count(21 patients, 20.6%),, anaemia (6, 5.9%), infection (4, 3.9%), and increased alanine aminotransferase (3, 2.9%). Treatment discontinuation or reduction due to toxicity occurred in 17 patients (16.7%). There were no treatment-related deaths. Conclusions: Cadonilimab demonstrates efficacy and safety for patients with recurrent/metastatic cervical cancer in a real-world setting.
Prognostic analysis of PD-1/CTLA-4 bispecific antibody combined with chemotherapy first-line treatment for recurrent or metastatic cervical cancer: A multicenter real-world study.
Authors: Li Jiwei , Wu Tao , Deng Yuping , Xu Chao , Jiang Yupeng , Zou Wen , Feng Yeqian , Wu Lin , Wang Jingjing
Published: July 2024

e17520

Background: PD-1/CTLA-4 bispecific antibody, cadonilimab, has shown excellent efficacy in advanced cervical cancer patients who have previously received platinum containing chemotherapy. However, its effectiveness in first-line treatment remains unclear yet. This study aims to evaluate the efficacy, safety, and prognostic biomarker of cadonilimab combined with chemotherapy for the first line treatment of recurrent or metastatic cervical cancer. Methods: Information on patients with recurrent or metastatic cervical cancer who received chemotherapy combined with cadonilimab as first-line treatment at three cancer centers from July 2022 to September 2023 were collected. Patients have not received systemic chemotherapy previously and are not suitable for curative local treatment, received cadonilimab 10mg/kg Q3W for up to 17 cycles + chemotherapy for up to 6 cycles (paclitaxel 135-175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5), ± bevacizumab 10-15 mg/kg. Clinical outcomes were analyzed using the Kaplan–Meier method with log-rank test. RNA-seq was used to analyze differential expressed genes (DEGs) between PR+CR group and PD+SD group. Results: There are 52 patients enrolled, median age 56.5 years (39–87 years). The median follow-up time was 12 months (5–23 months). There were 29 cases of lung metastasis, 7 cases of liver metastasis, 11 cases of bone metastasis, 12 cases of pelvic metastasis, and 11 cases of lymph node metastasis. The median number of cycles of cadonilimab and chemotherapy were 8 and 5, respectively. The 1-year overall survival (OS) and progression-free survival (PFS) rates were 91% and 72.5%, respectively. The objective response rate (ORR) was 75%.The expression of PD-L1 and bevacizumab had no effect on prognosis. The most common treatment-related adverse events (TRAEs) were neutropenia (78.2%), anemia (82.7%), thrombocytopenia (51.9%), thyroid dysfunction (50%), nausea and vomiting (88.5%), fatigue (71.2%). Grade 3 or 4 adverse events (AE) were reported in 36.5% patients, mainly hematological toxicity. The most significant differential pathways between PR+CR group and PD+SD group were adhesion, Hippo signaling pathway, NOD like receptor signaling pathway, programmed cell death, and secretory granules. Conclusions: Cadonilimab combined with chemotherapy ± bevacizumab as first-line treatment for recurrent or metastatic cervical cancer was effective and well-tolerant.
Phase II study of tislelizumab combined with concurrent chemoradiotherapy for locally advanced cervical cancer.
Authors: Ma Shanshan , Zhang Yong , Wu Fang , Jiang Li , Zhang Tingting
Published: July 2024

e17523

Background: Concurrent chemoradiotherapy (CRT) is the standard treatment for locally advanced cervical cancer (LACC). However, local recurrence and distant metastasis are the main modes of treatment failure in LACC, especially for patients with stage IIIA ~IVA as well as patients with large masses (>4cm) and regional lymph node metastasis. This study aimed to evaluate the efficacy and safety of tislelizumab (anti-PD-1 antibody) combined with concurrent chemoradiotherapy for locally advanced cervical cancer. Methods: Eligible patients were age 18-75 years, ECOG performance status of 0-1 and untreated cervical cancer (2018 FIGO stage IIIA, IIIB, IVA, or cervical tumor diameter > 4cm with regional lymph node metastasis, or paracervical invasion with regional lymph node metastasis). All patients received CRT plus tislelizumab 200mg Q3W for 1 year or disease progression or intolerable toxicity. The CRT includes at least 4 cycles of cisplatin 40mg/m2 QW + EBRT 45~50Gy/25f then BT 28~30Gy/4~5f. The primary endpoint was tumor regression ratio before brachytherapy. Secondary endpoints were 3-month and 6-month objective response rate (ORR), 1-year and 3-year OS and PFS, safety. Results: From August 24, 2022 to February 4, 2024, 30 patients were enrolled. 25 patients completed CRT and were available for evaluation. The median age was 59 years (range 40-75). The tumor regression ratio before brachytherapy was 90.6%. The ORR at 3 and 6 months were 100%, The OS and PFS rate at 1 year were 100%. The main adverse effect was neutropenia (36% for grade 3-4 and 20% for grade 1-2). Radiation enteritis incidence was 64% and were grade 1-2. Other adverse effect such as nausea, vomiting, and dizziness occurred during CRT and could be alleviated after symptomatic treatment. No immune-related adverse events were observed. Conclusions: Our results suggest that Tislelizumab combined with concurrent chemoradiotherapy showed valuable antitumor activity and controllable safety in LACC. We will keep strictly implementing our study protocol for further PFS and OS. Clinical trial information: NCT05588219 .
Deciphering the correlation between Chr3q26.2 amplification through homologous recombination deficiency and improved survival in ovarian cancer under platinum-based adjuvant therapy.
Authors: Ding Ning , Wu Yaqin , Zhao Xiaotian , Zhu Minyi , Ou Qiuxiang , Pang Jiaohui , Ruan Luxi , Zhang Ying , Sun Wei , Chen Xiaoxiang
Published: July 2024

e17537

Background: Discriminant copy number alterations (CNAs) have been linked to aberrant DNA repair mechanisms. This study aimed to identify CNA-based biomarkers, alongside homologous recombination deficiency (HRD) scores for ovarian cancer patients receiving platinum (Pt)-based chemotherapy, especially in BRCA1/2 wild-type or HRD-low patients. Methods: Fourteen most prevalent and significant focal CNA regions (seven amplification and seven deletion) were examined to investigate their correlations with HRD scores via SHAP values of an XGBoost model and the effectiveness of Pt-based adjuvant chemotherapy in a cohort of high-grade serous ovarian cancer (HGSC) patients (TCGA cohort, N=576), and the results were validated in a separate Chinese ovarian cancer cohort (test cohort, N=457). An in-house developed next-generation sequencing HRD pipeline (GeneseeqPrime HRD) was used to determine HRD scores. Histological subtypes, molecular features, and potential molecular mechanisms associated with the identified biomarkers were further explored. Results: Of 14 high-level CNA regions identified by GISTIC in the TCGA cohort, Chromosome 3q26.2 amplification [ Chr3(q26.2) Amp, a prevalence of 30.7%] was associated with increased HRD scores in both BRCA1/2-altered ( p=0.01) and wild-type HGSCs ( p=0.03). Consistently, in the test cohort, higher HRD scores ( p<0.01) and elevated chromosome instability scores ( p<0.01) were observed in Chr3(q26.2) amplified samples. Among 406 patients administrated with Pt-based adjuvant chemotherapy in the TCGA cohort, those with Chr3(q26.2) Amp exhibited a relatively high sensitivity rate ( p=0.09) and significantly superior disease-free survival after adjusting for HRD score, patient age, tumor stage, and residual disease [hazard ratio (HR): 0.65, 95% confidence interval (CI): 0.48–0.88] when compared to those without, representing Chr3(q26.2) Amp as an independent predictive biomarker. Similar results were obtained in 78 patients using Pt-based adjuvant chemotherapy in the test cohort (HR: 0.68, 95% CI: 0.40–1.15). Moreover, Chr3(q26.2) Amp was more prevalent in HGSCs harboring BRCA1/2 or TP53 aberrations than other histological subtypes driven by PIK3CA, PTEN or KRAS mutations ( p<0.01). In comparison to HGSCs without Chr3(q26.2) Amp, Chr3(q26.2) amplified HGSCs exhibited higher Ragnum hypoxia scores ( p<0.01) and a total of four overexpressed proteins, including p62 ( p<0.01), PIK3CA ( p<0.01), CCNB1 ( p<0.01) and TSC1 ( p<0.01), indicative of suppressed homologous recombination repair pathway and cycle cell arrest. Conclusions: Chr3(q26.2) Amp emerges as a promising biomarker for Pt-based adjuvant chemotherapy in ovarian cancer, potentially reflecting a hypoxia-induced etiology through suppressed homologous recombination repair pathway.
A phase I/II study of maplirpacept in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer (OC): Phase 1 results.
Authors: Street Daron G. , Kuttschreuter Luke , Starks David , Mahdi Haider , Linn Carlos , Pavlov Dmitri , Peguero Julio Antonio , Chawla Sant P. , Bruns Ingmar , Waggoner Steven E.
Published: July 2024

e17546

Background: CD47, an overexpressed factor correlated with poor clinical characteristics and prognosis in OC, is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a signal to suppress macrophage phagocytosis. Maplirpacept (PF-07901801) is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4, enhancing phagocytosis by blocking CD47. Blockade of CD47, both alone and combined with doxorubicin, has shown anti-tumor activity in vitro and in vivo in xenograft animal models. PLD 40mg/m2 conveyed poor efficacy (PFS 4 months; ORR 8%), as did bevacizumab + PLD (PFS 5 months; ORR 14%) (AURELIA), highlighting the need for new treatments for platinum-resistant OC. C4971002 [NCT05261490] is an open label, multicenter dose-escalation and expansion study evaluating the safety, preliminary anti-tumor activity, pharmacokinetics and -dynamics of maplirpacept in combination with PLD in patients with platinum-resistant recurrent OC. Methods: The study included adults with platinum-resistant recurrent epithelial OC (PD ≤6 months after platinum-based therapy or unable/unwilling to receive platinum-based therapy). PLD while platinum-resistant or directly prior to study was not permitted. Patients received maplirpacept (12mg/kg Dose Level [DL] 1; 24mg/kg DL2; 48mg/kg DL3) weekly in Cycle 1 and every 2 weeks in Cycle 2+, and PLD (40mg/m2) on Day 1 of each 4-week cycle. Assessments of adverse events (AEs) were based on CTCAE v5.0. Response assessments (RECIST v1.1) were performed every 8 weeks. Results of the Phase I portion, aiming to evaluate the DLTs, the MTD and the RP2D, are presented as of 18 December 2023, after all patients completed the 28-day DLT assessment period. Results: 10 patients were treated (DL1 n=3; DL2 n=3; DL3 n=4) with a median (min, max) age of 69 (53, 77) years, 80% ECOG 1, 60% serous adenocarcinoma. Median (min, max) treatment duration was 14 (8, 32) weeks. Most common adverse events are shown in the table. No DLTs occurred in the assessment period. 1 serious AE (gait disturbance & muscle weakness) related to maplirpacept was reported (DL3). 2 deaths occurred >120 days after 1st dose, both due to disease. 5 (50%) patients had a best response of stable disease, 2 of which were treated into at least Cycle 6. Conclusions: Despite immature anti-tumor activity, maplirpacept + PLD was tolerable at all dose levels, not reaching the MTD. The encouragingly tolerable dose of 48mg/kg thus represents the RP2D which could support further development for this population. Clinical trial information: NCT05261490 . [Table: see text]
Overall survival and patterns of care for women with rare ovarian cancers: A prospective study from the Australian National Gynae-Oncology Registry (NGOR).
Authors: Naidoo Mahendra , Scott Clare L. , McNally Orla , Rome Rob , Perera Sharnel , Lee Yeh Chen , Whitely Aleesha , Burling Michael , Anderson Lyndal , Cohen Paul , Richardson Gary Edward , Friedlander Michael , Brand Alison , Hyde Simon , Bunting Michael , Jobling Tom , Zalcberg John Raymond
Published: July 2024

e17554

Background: Ovarian cancer (OC) is a heterogenous group of malignancies, most of which are rare. Data on patterns of care and survival of the most-rare sub-groups of OC (incidence rates < 6 per 100,000) in the real-world setting is limited. This study aims to describe patterns of care and overall survival (OS) for women with rare ovarian cancers in Australia. Methods: Clinical data were sourced from the NGOR and assessed for accuracy and completeness. High grade serous and endometrioid OC subtypes were excluded. Due to incompleteness of survival follow-up data, 3-year OS was only calculated for the state of Victoria. Results: Data on 2812 women with newly diagnosed OC from 2017-2023 within NGOR were collected and 716 women were subsequently identified with rare subtypes of OC. The 5 sub-types with the highest incidences were clear cell (n = 168, 23.4%), mucinous (n=151, 21.1%), adult granulosa cell (n=111, 15.5%), low grade serous (n=98, 13.7%) and carcinosarcoma (n=59, 8.2%). A further 23 additional rare subtypes included germ cell tumours and sex cord stromal tumours. The median follow-up time was 2.6 years and median age at diagnosis was 55 years. Most women had an ECOG 0-1 performance status (n=551, 77.0%). The primary treatment modality was surgery only (n=360, 50%), followed by surgery and systemic therapy (n = 317, 44.2%), systemic therapy only (n=28, 3.9%) and no treatment (n=11, 1.5%). Most women were discussed at a multi-disciplinary meeting (n=701, 97.9%). The diagnosis was confirmed on histology for all women. The 30-day post-operative adverse events (Clavien-Dindo >III severity) was 3.6 % (n=26), with the highest rate of post-operative events in the carcinosarcoma group of 12% (n=6). Using Fisher’s exact test across the 5 most common sub-types described above, there were significant differences in treatment modalities (p<0.001), rates of 30-day post-operative events (p=0.002), age adjusted charlson comorbidity index (p<0.001) and metropolitan versus remote regional status (p=0.007) between the sub-types. Survival at 3 years for these five sub-types of rare OC within the state of Victoria are summarised in the table. The highest 3-year OS was in adult granulosa and low grade serous sub-types. Conclusions: This is a large, real-world analysis of patterns of care and survival for women with rare sub-types of OC. Combining data with international sites will likely further enhance research on patterns of care and outcomes for women with rare OC. [Table: see text]
Association of homologous recombination repair mutation defined with a 15-gene panel with the prognosis of epithelial ovarian cancer: A Chinese multicenter retrospective study.
Authors: Liu Yi , Chen Xiaojun , Lu Huaiwu , Wu Xin , Liu Xuehan , Xu Fei , Ye Dongdong , Ding Bo , Lu Xiaoyan , Qiu Ling , Zhu Jing , Wang Yingying , Huang Xinya , Shen Zhen , Zhu Tao , Shen Yang , Zhou Ying
Published: July 2024

e17556

Background: There was no consensus regarding the optimal homologous recombination repair (HRR) gene panel to predict prognosis of epithelial ovarian cancer (EOC). Methods: The genetic testing results in a 15-gene panel from 308 EOC patients diagnosed between 2014 and 2022 from six centres were collected. The association of clinicopathologic characteristics, the use of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors and progression-free survival (PFS) with 15-gene panel mutation status was assessed. Results: 43.2% (133/308) of patients were determined to carry 144 deleterious HRR mutations (HRRm), among which 68.1% (98/144) were germline mutations and 32.8% (101/308) were BRCA1/2 gene lethal mutations. Patients who received PARP inhibitors (PARPis) were 29.1% (37/127) and 50.5% (46/91) in the HRR wild-type (HRRwt) group and HRRm group at IIIC-IV stages, respectively. A prognostic difference was observed only between the BRCA mutation group and the HRRwt group, not between the non-BRCA HRRm group and the HRRwt group. In univariate analysis, significant predictors of relapse included nonresidual status (HR, 0.62; 95% CI, 0.39-0.98; P = 0.0287), 15-gene panel mutation (HR, 0.42; 95% CI, 0.28-0.64; P = 0.0001), platinum sensitivity (HR, 0.07; 95% CI, 0.02-0.22; P < 0.001) and maintenance therapy (PARPi) (HR, 0.48; 95% CI, 0.31-0.74; P = 0.0028) (Figure 5). In multivariate Cox analysis, nonresidual (HR, 0.63; 95% CI, 0.40-0.99; P = 0.046), 15-gene panel mutation (HR, 0.49; 95% CI, 0.28-0.88; P = 0.016) and platinum sensitivity (HR, 0.02; 95% CI, 0.01-0.05; P < 0.001) remained independent prognostic factors. Conclusions: This study provides evidence that HRRm with a 15-gene panel can predict the prognosis of EOC, among which only BRCA1/2 mutations contribute to prognosis prediction. [Table: see text]
Autologous, oncolytic virus-activated killer (VAK) cell therapy to treat malignant pleural and peritoneal effusions.
Authors: Dong Shuang , Wang Yang , Li Yuanxiang , Cai Qian , Hu Sheng , Hu Han , Zhou Qin , Yang Weiju , Zhang Hong , Liu Lirong , Yue Yun , Zheng Haohuang , Alevizopoulos Nassos , Liu Binlei
Published: July 2024

e20549

Background: OH2 is an attenuated oncolytic Herpes Simplex-2 virus expressing GM-CSF. OH2 replicates only in cancer cells, causing their lysis, which reverses the immunosuppressive tumor microenvironment, leading to tumor regression. OH2 monotherapy is safe and efficacious in phase I-III trials of 300+ patients across several cancer indications. We previously showed that OH2 treated briefly with UV light (UV-OH2) is unable to form plaques yet still able to infect cancer cells and to potently activate human PBMCs, leading to increased antitumor activity in vitro and in animal models. Methods: Translating these findings in humans, 12 stage IV lung cancer patients with malignant pleural or peritoneal effusions were enrolled in an Investigator-Initiated Trial (NCT05565014). Lymphocytes from each patient’s effusions were isolated, incubated in vitro with UV-OH2 for 36-48h, and then re-infused into the patient's pleural or peritoneal cavity. Each patient received 2 cycles of 3 or up to 6 infusions of this Virus Activated Killer (VAK) Autologous Cell Therapy. Results: Effusion volume (EV) measurement and local and whole-body tumor assessments were performed at the beginning and 28 days post VAK treatment. On D28, EV remained stable in 3 patients (SD), whereas 4 of 12 patients recorded a reduction of EV (PR). Notably, subject S004’s PR was maintained for 210 days post-treatment. Evaluation of target lesions per RECIST revealed 4 subjects with PR and 7 with an SD in target lesions. There was no toxicity or treatment-related adverse events. The median patient OS was 384 days (12.8 months), which is up to 4 times the average published OS for stage IV lung cancer with malignant pleural effusions. RNA-Seq analysis indicated increased expression of many T and NK cell effectors and NK cell activating receptors. Importantly, average autologous CD8+ T lymphocytes rose from 53% to 74% in the effusions post VAK-treatment, thereby confirming activation of the patient’s immune system by UV-OH2 (preliminary clinical PoC). Conclusions: In sum, our VAK therapy offers a cost-effective, extremely safe, and patient-friendly autologous treatment that dramatically increases overall survival in patients with essentially no options. Larger scale studies are in the works. Clinical trial information: NCT05565014 .
Nivolumab combined with high dose multisite radiotherapy in previously untreated advanced melanoma (NIRVANA): A non-randomised, open-label, multicenter, phase 2 trial.
Authors: Montaudie Henri
Published: July 2024

e21505

Background: Outcome of advanced melanoma remains poor for the majority of patients (pts) and new treatment strategies are needed. Preclinical and clinical data suggest a potential increase of the immunotherapy efficacy when combined with hypofractionated multisite radiotherapy (HMR). Objective: To assess the impact of HMR combined with nivolumab in advanced melanoma. Methods: This is a non-randomised, open-label, multicentre phase 2 trial(NCT02799901). Pts must have locally advanced or metastatic melanoma (AJCC7), previously untreated. Pts with mucosal or uveal melanoma, those with brain metastasis and LDH ≥ 1.5 the upper limit were not included. Pts received (until progression or unacceptable toxicity) nivolumab (fixed dose 240 mg/15 days) plus radiotherapy (day 15) delivered 3 x 6 Gy every second day, at every metastatic organ, if feasible.At progression, second irradiation was authorized while pursuing nivolumab (rechallenging strategy).The primary endpoint was 1-year overall survival (OS) (hypothetic improvement of 1-year OS from 71%1). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Subgroups and multivariate analyses were performed. Results: A total of 64 pts were included, from 03/2017 to 07/2019. Median follow-up was 23.5 months [IQR 2.3-43.8]. Median age was 64 years [35-95], majority of pts were male (67%), had an ECOG-PS 0 (75%), a stage IV-M1C disease (47%) and were BRAF-wild-type (67%).] The 1-year OS and PFS rates were 79% and 56% respectively (p = 0.12 and p = 0.0.3 in comparison with the 1-year OS and PFS of 71% and 43% of Robert et al’study1). 39 pts were irradiated at 1 target, 25 at ≥2 targets (total of 92 tumor targets). The 2-years OS rates were 83% and 52% for pts who were irradiated on several sites and one site respectively (p = 0.03). The ORR in the whole cohort was 53% [95% CI, 40.23; 65.72], 33% [95% CI, 14.59; 56 .97] and 62% [95% CI, 45.64; 76.43] in BRAF mutated and BRAF-wild type respectively. Among BRAF status, gender, PS, stage, age, LDH level and number of irradiated sites (1 vs ≥ 1), the independent prognostic factors for OS in multivariate analysis were number of irradiated sites (HR = 0.26, p = 0.03) and ECOG-PS (HR = 6.2, p = 0.001). Rechallenging was performed in 11 pts, among them; 3 were progression-free at last follow-up, 10 were reirradiated once and 1 was reirradiated 3 times. ICI was stopped due to toxicities for 6 pts. Drug-related adverse events of grade 3-4 occurred in 8.3% of the patients (no grade 5). Conclusions: Combined nivolumab and HMR did not improve significantly OS compare to nivolumab alone but improve significantly PFS1. However, this strategy has an acceptable safety and could be a treatment option for some patients. Multisite irradation and rechallenging strategies deserve to be considered. 1 Robert et al, J Clin Oncol 2020. Clinical trial information: NCT02799901 .
Target trial emulation with real-world data to determine the population-level cost-effectiveness of multi-gene panel sequencing in advanced melanoma.
Authors: Krebs Emanuel , Weymann Deirdre , Ho Cheryl , Pollard Samantha , Regier Dean A
Published: July 2024

e21508

Background: Compared to single-gene BRAF testing to guide targeted treatment for advanced melanoma, multi-gene panels can identify additional gene mutations with known therapeutic or prognostic relevance. No randomized control trials of multi-gene panel sequencing have been completed in advanced melanoma. This study determined the population-level cost-effectiveness of multi-gene panel sequencing compared to single-gene BRAF testing for advanced melanoma. Methods: Our population-based retrospective study emulated a hypothetical pragmatic trial using comprehensive patient-level clinical and health administrative data between September 2016 and December 2018 from British Columbia, Canada. To emulate random treatment assignment, we 1:1 matched multi-gene panel patients to contemporaneous controls using a machine learning approach that maximized balance on 15 covariates. Following matching, we estimated mean three-year survival time and costs (2021 CAD), and calculated incremental net monetary benefit (INMB) for life-years gained (LYG) at $100,000/LYG using inverse probability of censoring weighted linear regression and nonparametric bootstrapping. Besides an intention-to-treat (ITT) effect, we also estimated the per-protocol (PP) effect of initiating treatment within 90 days of receiving test results additionally using inverse probability of treatment weights. We also estimated overall survival using Weibull regression and Kaplan-Meier (KM) survival analysis. Results: We matched 147 patients receiving multi-gene panel sequencing to controls, achieving good balance for all included covariates. ITT mean incremental costs were $19,541 (95%CI: -$18,939, $77,396) and mean incremental LYG were 0.22 (95%CI: -0.06, 0.50). We did not find statistically significant different differences in overall survival using the KM (P = 0.11) and Weibull regression (HR: 0.73 [95%CI: 0.51-1.03]) survival analysis in the ITT analysis. PP incremental costs were $36,367 (95%CI: -$6,653, $120,216) and incremental LYG were 0.56 (95%CI: 0.39, 1.24), with corresponding differences in overall survival using KM (P = 0.02) and Weibull regression (HR: 0.56 [95%CI: 0.36-0.87]) survival analysis. The probability of multi-gene panel sequencing being cost-effective at $100,000/LYG was 54.9% in the ITT analysis and 64.5% in the PP analysis. Conclusions: We found the cost-effectiveness of multi-gene panel sequencing to be evenly poised, with estimates favouring multi-gene panel sequencing with respect to overall survival and cost-effectiveness when accounting for probability of treatment initiation. This real-world evidence generated using randomized trial design principles can support jurisdictions’ deliberations on the reimbursement of precision oncology interventions.
Endoscopic surgery combined chemoradiotherapy and PD-1 blockade in patients with sinonasal mucosal melanoma.
Authors: Yan Li , Song Xiaole , Wang Xiaoshen , Yu Hongmeng
Published: July 2024

e21552

Background: Primary sinonasal mucosal melanoma (SNMM) is a rare and aggressive disease different from cutaneous melanoma. The best treatment modality including the role of immune checkpoint blockade in SNMM has not been defined. Methods: Between 2021 and 2023, patients with previously untreated sinonasal melanoma were enrolled by three single-center investigator-initiated phase II clinical trials (ChiCTR2100046498 / ChiCTR2100045797/ ChiCTR2100049031). Eligible patients in ChiCTR2100045797 trial received postoperative radical chemoradiotherapy combined with toripalimab (a PD-1 inhibitor) for a year or until the disease progressed. Eligible participants in ChiCTR2100046498 study received surgery combined with radiation without immunotherapy. And for patients in ChiCTR2100049031 study, preoperative radiation was carried out firstly. The locoregional control, distant metastasis-free survival (DMFS), and overall survival (OS) were the main efficacy goals. Results: Fifty-four patients were enrolled (mean age 62 years, 33 males [61.1%] and 21 women [38.9%]) with 2y-OS rate 62.3±7.9%, 2y-RFS rate 67.1±8.2%, and 2y-DMFS rate 63.9±8.1%. Patients with T3 (n = 23), T4a (n = 14), and T4b (n = 17) stages, including12 patients with node-positive disease, were included at baseline. During a median follow-up of 11 months, 19 patients ultimately died, 10 experienced relapses, and 17 developed metastases. Tumor T staging was demonstrated to be an independent prognostic predictor according to the Cox univariate analysis. The primary factor contributing to a poor prognosis and the primary cause of death for 73.7% of patients was distant metastases. Preoperative radiation had an improved long-term survival with 2y-OS rate of 85.7±13.2%, and it can considerably lower the risk of distant metastases (p≤0.05). The overall survival rate for patients receiving postoperative chemoradiotherapy combined with immunotherapy was higher than that for patients not receiving immunotherapy (2y-OS rate 74.1±11.4% vs. 39.3±15.8%), although the difference was not statistically significant due to a small number of patients (p = 0.16). No immune-related adverse effects grade≥3 was recorded. Conclusions: The primary cause of the poor prognostic performance of SNMM is distant metastasis. The risk of distant metastases might be considerably decreased by preoperative radiation treatment. Surgery combined with radiation and immunotherapy could bring promising survival benefit. The way forward may involve investigating the combination of immunotherapy and preoperative radiotherapy. Clinical trial information: NCT04879654 ; NCT05009446 .
Safety and efficacy of PEG-rhG-CSF as primary prophylaxis against neutropenia induced by combination chemotherapy regimens involving oral chemotherapy agents in gastrointestinal cancer patients: A prospective, exploratory, non-randomized controlled study.
Authors: Zhao Jun , Wang Hui , Zhang Gehong , Zhang Xiaoling , Du Yunyi , Ma Ning , Yang Wei , Yang Bo , Gao Yangjun , Wang Mei , Cai Linlin , Feng Tingting , Zhang Na , Yang Suxia , Guo Xiaobo , Wang Ouxiang
Published: July 2024

e24107

Background: The safety and efficacy of PEGylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for prevention of chemotherapy-induced neutropenia (CIN) in patients undergoing oral chemotherapy remain unclear. This study investigated the safety and efficacy of PEG-rhG-CSF as primary prophylaxis against CIN in gastrointestinal (GI) cancer patients receiving combination chemotherapy regimens involving oral chemotherapy agents. Methods: This is a prospective, single-center, open-label, exploratory, non-randomized controlled study. GI cancer patients receiving two consecutive cycles of IV oxaliplatin (150mg/m2 on day 1) combined with oral capecitabine 1000mg/m2 or tegafur gimeracil oteracil potassium capsule 40-60mg twice daily on days 1-14 every 3 weeks. PEG-rhG-CSF (6mg) was administered subcutaneously 24 hours post-oxaliplatin treatment in the PEG-rhG-CSF group, while the control group did not receive it. The primary endpoint was safety, and secondary endpoints included CIN incidence and neutropenic complications. The study was registered with the Chinese Clinical Trial Registry (registration number ChiCTR2100054854). Results: Between March 2022 and January 2023, a total of 49 patients was screened, and 43 patients completed the treatment (26 in PEG-rhG-CSF group and 17 in control group). The average age was 61.4 years, with 90.7% males and 83.7% having gastric cancer. Baseline characteristics were similar between the two groups. The overall adverse events (AE) did not differ statistically (88.5% vs. 88.2%, p = 1.000), with grade £2 fatigue and nausea being the most common AEs. Grade 3 platelet reduction showed no significant difference between the two groups (7.69% vs. 17.65%, p = 0.432). Four cases of bone pain (15.4%) and five cases of injection site reactions below grade 3 (19.2%) were observed in the PEG-rhG-CSF group. Grade ≥2 CIN was significantly lower in the PEG-rhG-CSF group (3.84% vs. 58.82%, p < 0.001). One case in the PEG-rhG-CSF group required antibiotic treatment due to febrile neutropenia. Regarding neutropenic complications, the PEG-rhG-CSF group exhibited lower proportion of chemotherapy delay (3.85% vs. 35.29%, p < 0.001) and dose reduction (1.92% vs. 23.53%, p = 0.002). Rescue treatment with rhG-CSF for grade 3/4 CIN was significantly less frequent in the PEG-rhG-CSF group (1.92% vs. 23.53%, p = 0.002). Conclusions: Primary prophylaxis with PEG-rhG-CSF in GI cancer patients undergoing oral capecitabine/tegafur gimeracil oteracil potassium may be safe, without an increased chemotherapy-related AEs, and is associated with a reduced grade ≥2 CIN. Clinical trial information: ChiCTR2100054854.
Understanding discordance in systematic reviews for treating chemotherapy-induced peripheral neuropathy: A focused umbrella review.
Authors: Ye Alice , Butt Ahmed , Geng Yimin , Abdi Salahadin
Published: July 2024

e24111

Background: Despite the abundance of publications on chemotherapy-induced peripheral neuropathy (CIPN), we are still lacking effective management options. CIPN-focused systematic reviews (SRs) are increasingly encountered but have not aided much in clarifying treatment guidance. Additionally, there is a rising concern that SRs are now over-saturating the clinical literature, leading to redundant and misleading publications. Umbrella reviews (URs) are an attempt to appraise SRs but do not yet have firm methodologic frameworks. The aims of our UR were to appraise the discordance in recently published CIPN SRs and use content analysis as a method for identifying risks of discordance. Methods: This is a focused UR as part of a larger study to characterize the number of efficacy trials for established CIPN. Following PRISMA guidelines, we conducted a systematic literature search of databases MEDLINE, Embase, and Cochrane Library for publications in English from 1/1/2023 to 11/21/2023. Inclusion criteria were published systematic reviews attempting a comprehensive effort to synthesize any treatment outcomes for established CIPN. The AMSTAR 2 framework was used to appraise results for bias. Measures of randomized controlled trial (RCT) overlap are presented using a novel measure of time-adjusted CA, which accounts for RCT publication dates and SR search dates. Grounded theory coding was used for content analysis on efficacy. Results: We identified 18 SRs containing CIPN treatment RCTs published in less than 1 year, resulting in 32 unique CIPN RCTs. Seven SRs assessed exercise interventions, covering 6 exercise RCTs (41% time-adjusted CA). Five SRs assessed acupuncture, with 9 RCTs (50% time-adjusted CA). One SR searched for all CIPN treatments for pain but missed 4 RCTs. One SR was concerning for spurious data. Bias was variable and imperfect across SRs. Contextual analysis identified the themes of SRs combining preventative and treatment RCTs, confusing comparative vs. controlled trials, and frequent use of p-value only reporting to conclude treatment efficacy as major risks of SR discordance. Conclusions: UR was useful in identifying 32 CIPN RCTs that were not comprehensively identified by SRs. We presented a time-adjusted CA measure to indicate concordance percentage. A higher percentage indicates more re-citation of the same RCTs across SRs, with likely better chances of more concordant conclusions. This measure showed that SRs for CIPN treatment are discordant across the topics of exercise and acupuncture interventions. Content analysis revealed multiple potential causes of discordance. However, SR redundancy was helpful for identifying more unique RCTs. CIPN SR content standards should be developed to minimize discordancy and improve clinical applicability. Clinicians should be cautious when applying CIPN SR recommendations given the high discordance.
Retrospective evaluation of drug to drug interactions with paclitaxel use in military health.
Authors: Kigelman Oskar , Luong Thu-Lan T. , Shou Karen J. , Reinhardt Brian J. , Greenfield Kimberly
Published: July 2024

e24118

Background: Paclitaxel is an antineoplastic agent used in the management of multiple metastatic and non-resectable tumor types approved for ovarian, breast, AIDS-related Kaposi sarcoma, non-small cell lung, pancreatic, cervical, endometrial, and thymoma or thymic carcinoma cancer by the US Food and Drug Administration. Cytochrome P450 (CYP) 3A4 or 2C8 inducers, inhibitors, or substrates may alter paclitaxel metabolism. Because DDIs can have an effect on clinical outcomes, we aimed to identify drugs that interact with paclitaxel and describe their clinical manifestations. Methods: A retrospective analysis was performed on the health records of patients in the US Department of Defense Cancer Registry (retrieved March 2022), Comprehensive Ambulatory/Professional Encounter Records, and Pharmacy Data Transaction Service database (both retrieved October 2022). Patients’ medical history, diagnoses, and demographics were extracted and analyzed for differences in adverse effects when these agents were used alone vs concomitantly with other prescription drugs. Patients’ diagnoses and prescription drug use were extracted to compare completed vs discontinued treatment groups, identify medications commonly co-administered with paclitaxel, and evaluate DDIs with antidepressants. Results: Of 702 patients using paclitaxel, 338 completed treatments. The P value for paclitaxel discontinuation when used alone vs concomitantly or 1 drug (alone or before or after) vs combination (2 to 4 drugs) was < .001. Patients who took paclitaxel concomitantly with a greater number of prescription drugs had a higher rate of treatment discontinuation than those who received fewer medications. Patients in the completed group received 9 to 56 prescription drugs, and those in the discontinued group were prescribed 6 to 70. Those who discontinued treatment had more diagnosed medical issues than those who completed treatment. Conclusions: This review cannot conclude that concomitant use with prescription drug(s) resulted in paclitaxel discontinuation. There were no significant DDIs determined between paclitaxel and antidepressants.[Table: see text]
Enhancing prostate cancer diagnosis communication: A multicenter study evaluating the impact of animated videos, CartDiag Prostate study.
Authors: Helissey Carole , Pautas Marie , Brureau Laurent , Cessot Anatole , Picchi Hugo , Le Roy Audrey , Audisio Marie-Anne , Barhli Aline , Vanquaethem Hélène , Schernberg Antoine
Published: July 2024

TPS12148

Background: Prostate cancer is the leading cancer among men. Advances in therapeutic techniques, personalized medicine, and the integration of targeted therapies have significantly improved patient outcomes, resulting in a 5-year overall survival of 93%. However, effective patient care requires a shared decision-making framework and clear communication between healthcare professionals and patients. The initial step in patient care involves disclosing the cancer diagnosis during a dedicated consultation, laying the foundation for the patient-physician trust relationship. Nowadays, less than 50% of patients declared that they understood the information provided during the announcement consultation. The main objective of our study is to assess the effect of the announcement system, reinforced by animated videos, on patients' overall understanding of their diagnosis and treatment. Methods: To enhance the disclosure process, animated videos were developed to outline the patient care journey. This multicenter, controlled before-and-after study aimed to evaluate the impact of the usual disclosure process enhanced by animated videos on patients' understanding of advanced or metastatic prostate cancer. Patients were sequentially assigned to two arms: the standard arm (first 45 patients) received usual written and oral information, while the intervention arm (next 45 patients) received written and oral information supplemented by animated videos. To evaluate the effect of the enhanced disclosure process on patients' overall understanding of their diagnosis and treatment using the EORTC QLQ-INFO25 questionnaire at baseline (Day 0) and after 1 month (Day 30), compared to the standard group without enhanced disclosure. This prospective study is the first to assess the impact of supplementing the standard disclosure process with animated videos positively impacts patients' comprehension of advanced or metastatic prostate cancer. The findings will support the potential value of integrating visual aids into the diagnostic disclosure consultation to enhance patient understanding and promote informed decision-making. Clinical trial information: NCT06117696 .
Randomized, placebo-controlled trial of atorvastatin to prevent hearing loss in patients with head and neck squamous cell carcinoma receiving cisplatin based chemoradiation (CRT).
Authors: Schmitt Nicole C. , Fernandez Katharine , Newlands Shawn , Allen Paul , Kaufman Adam , McMillan Garnett P. , Switchenko Jeffrey M. , Stokes William A. , Mehra Ranee , Mandawat Anant , Shamburek Robert , Saba Nabil F. , Cunningham Lisa L.
Published: July 2024

TPS12153

Background: Cisplatin chemotherapy is associated with several adverse effects, including a permanent, high-frequency, sensorineural hearing loss in about 50% of patients. Preclinical studies suggest that statin drugs can mitigate cisplatin ototoxicity (Fernandez et al., Hearing Research 2020). In our prior combined retrospective/prospective dataset of patients with head and neck squamous cell carcinoma (HNSCC) treated with cisplatin-based CRT, the incidence of CTCAE grade ≥ 2 hearing loss was 29.4% in statin non-users, versus 9.7% in atorvastatin users (Fernandez et al., J Clin Invest 2021). An adjusted odds ratio analysis indicated that atorvastatin users are significantly less likely to develop hearing loss versus statin non-users (odds ratio 0.47), providing the rationale for a randomized, controlled, prospective study. Methods: This multi-center, randomized, placebo-controlled study is enrolling patients with previously-untreated, locally advanced head and neck squamous cell carcinoma (HNSCC) for which cisplatin-based chemoradiation is indicated, either in the definitive or adjuvant setting. Patients who will be treated with cisplatin (at 75-100 mg/m2 bolus every three weeks or 40 mg/m2 weekly) are eligible. Patients currently taking a statin or those without measurable hearing in at least one ear are excluded. A baseline audiogram is performed, and patients are randomized to atorvastatin (40 mg/day) or placebo, which is started 2-7 days before CRT and taken daily until 3 months after completion of CRT. Post-treatment audiometry is repeated at 3 months and 2 years after CRT, along with collection of patient-reported outcomes on hearing, tinnitus, and peripheral neuropathy. Patients are monitored for liver and muscle toxicity, with dose de-escalation or cessation of atorvastatin as needed. The primary endpoint is the incidence of CTCAE grade ≥2 hearing loss at 3 months after CRT. Secondary endpoints include other treatment related grade 3-4 adverse events, overall survival, and disease-free survival. Up to 214 subjects will be enrolled at 4 U.S. sites (NIH Clinical Center, Emory University, University of Maryland, University of Rochester). Funding: NIH/NIDCD, U01 DC020452 and intramural project ZIA DC000079. Clinical trial information: NCT04915183 .
Acupuncture for preventing progression of taxane-induced peripheral neuropathy (ATP): A phase II randomized, placebo-controlled trial.
Authors: Zhi Iris , Han Katherine , Kim Danne , Piluson Lauren , Weitzman Matthew , Baser Raymond E , Li Qing Susan , Bao Ting , Mao Jun J.
Published: July 2024

TPS12154

Background: Chemotherapy-induced peripheral neuropathy (CIPN) from chemotherapy drugs such as taxanes can be detrimental to cancer survival, increasing the risk of falls and worsening physical functions. The current management of worsening and persistent CIPN during chemotherapy is dose reduction or discontinuation of chemotherapy. There is no effective treatment or preventative measure for CIPN. Methods: Trial design: The ATP trial is a two-arm, parallel, randomized controlled trial comparing weekly real acupuncture (RA) versus sham acupuncture (SA) during preplanned curative intent taxane containing regimens in patients with breast cancer. Eligibility criteria: English or Spanish-proficient; aged ≥18 years; histological diagnoses of invasive carcinoma of the breast; and plan to receive curative intent chemotherapy regimen containing paclitaxel or nab-paclitaxel weekly or biweekly as standard of care, developed CIPN grade ≥1 based on the NCI-CTCAE version 5.0, while receiving taxane; ≥ four weeks of paclitaxel or nab-paclitaxel weekly or biweekly planned, as standard of care and at treating physician’s discretion; willing to adhere to requirement that no new pain medication or dose changes be taken throughout the first 12 weeks of the study period; and willing to adhere to all study-related procedures. Specific aims: The primary aim is to evaluate the effectiveness of RA versus SA in preventing taxane-induced peripheral neuropathy progression as measured by Neuropathic Pain Scale (NPS) in patients with early-stage breast cancer who are receiving curative intent neurotoxic chemotherapy. The secondary aim is to evaluate the effectiveness of RA versus SA on chemotherapy relative dose intensity (RDI) and CIPN-related chemotherapy discontinuation. Statistical methods: We will randomize 80 patients, 40 to each arm. All randomized patients will be evaluable in the Intent to Treat (ITT) analyses because all will have completed the baseline assessment before randomization. We will use a linear mixed model (LMM) to compare the change in NPS between the arms from baseline to week 4. Based on our pilot data, a difference in CIPN grade from 1 to 2 corresponded to a difference in NPS from 12 to 22, a difference of ten points in 27 patients. The NPS standard deviation (SD) in patients with grade 1 CIPN was 17. With 80 patients we will have 80% power to detect a difference between arms as small as 10 points on the NPS, assuming a one-sided test, type I error of 5%, correlation between baseline and follow-up measurements of 0.5, SD of 17, and 15% attrition at week 4. Present accrual and target accrual: We accrued 43 participants in the intervention phase by the end of January 2024; the target accrual is 80 participants. Clinical trial information: NCT05458284 .