bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes and immune response after peptide vaccination targeting human cytomegalovirus antigen pp65 in children and young adults with recurrent high-grade glioma and medulloblastoma.
Authors: Thompson Eric , Ashley David M. , Ayasoufi Kathy , Norberg Pamela , Archer Gerald E. , Buckley Evan , HERNDON JAMES E , Walter Ashley , Archambault Bridget , Flahiff Charlene , Jaggers Denise , Gorski Laura , Reap Elizabeth A. , Schroeder Kristin , Desjardins Annick , Johnson Margaret O , Peters Katherine B. , Khasraw Mustafa , Sampson John H. , Landi Daniel B
Published: June 2024

2039

Background: The human cytomegalovirus (CMV) antigen pp65 is ubiquitously expressed in high-grade glioma (HGG) and medulloblastoma but not in adjacent brain. The primary objective of this first-in-human phase I trial (NCT03299309) was to assess the safety and feasibility of a novel peptide vaccine targeting pp65 (PEP-CMV) in children/young adults with recurrent medulloblastoma and HGG. Methods: The vaccine is comprised of a synthetic long peptide of 26 amino acids and is administered as an emulsion in Montanide ISA 51. Patients receive a single 5-day course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning to promote dendritic cell migration, then PEP-CMV administered intradermally in the groin every two weeks for 3 doses, then monthly. Results: Forty-two patients were enrolled. Diagnoses include medulloblastoma (n=2), glioblastoma (n=21), anaplastic oligodendroglioma (n=3), anaplastic astrocytoma (n=11), and malignant glioma NOS (n=5). The median time from initial diagnosis to treatment was 24 months (range 4-35) and the median number of prior chemotherapy regimens was 4 (range 0-15). The mean age was 23.2 ± 9.3 years. 55% of patients were male. The median KPS was 80. Of the 38 patients who received PEP-CMV, the maximum grade adverse event (AE) possibly, probably, or definitely related to PEP-CMV was as follows: 17 (45%) had Grade 1 adverse events (AE), 16 (42%) had Grade 2 AEs, 2 (5%) had Grade 3 AEs (encephalopathy and pyramidal tract syndrome), and one (3%) had a Grade 4 AE (cerebral edema). One patient developed symptoms and had elevated inflammatory cytokines consistent with cytokine release syndrome (Grade 2). The median progression-free survival was 2.5 months (95% CI:2.2,3.2) and median overall survival was 6.4 months (95% CI:3.4,7.9). The 12-month OS was 26.6% (95% CI:14,41.1%). Of the 22 patients with evaluable immune monitoring data, T cell reactivity on IFNγ pp65 ELISpot was increased after PEP-CMV delivery (median spot pretreatment vs. prior to vaccine #4: 1 vs 30, P=0.004, Table). Lower percentage of pretreatment regulatory T cells and higher percentage of terminally differentiated effector T cells at vaccine #4 were associated with longer subsequent survival. Conclusions: PEP-CMV is well-tolerated and elicits an antigen-specific immune response in heavily pretreated, multiply recurrent patients with a 12-month OS of 26.6%. A multi-institutional Phase II trial (NCT05096481) of PEP-CMV is opening imminently. Clinical trial information: NCT03299309 . [Table: see text]
Phase I clinical trial of 64Cu-ATSM for malignant brain tumors.
Authors: Kurihara Hiroaki , Narita Yoshitaka , Ito Kimiteru , Sato Hidemitsu , Miyakita Yasuji , Takahashi Masamichi , Yanagisawa Shunsuke , Okita Natsuko Tsuda , Sadachi Ryo , Tateishi Kensuke , Yoshii Yukie , Waki Atsuo , Hashimoto Hiroki , Suzuki Hisashi , Zhang Ming-Rong , Kawamura Kazunori , Honda Natsuki , Yoshimoto Mitsuyoshi , Matsumoto Hiroki
Published: June 2024

2052

Background: Malignant brain tumors such as glioblastoma have poor prognosis. Current standard therapies such as surgery, radiotherapy, and chemotherapy were frequently insufficient. Hypoxic tissue microenvironments induced by rapid cellular growth within tumor lesions lead to treatment resistance. Methods: Eligible patients had a histological diagnosis of grade III/IV glioma, primary central nervous system malignant lymphoma (PCNSL), or grade II/III malignant meningioma based on the most recent pathological diagnosis prior to enrollment, or metastatic brain tumor based on clinical course or imaging. Diacetyl-bis( N4-methylthiosemicarbazone) radiolabeled with Cu-64 (64Cu-ATSM) was synthesized as described elsewhere. 64Cu-ATSM was administered intravenously once a week for 4 weeks. Adverse events were assessed using the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0). The trial had a traditional single arm open-label 3 + 3 design with four 64Cu-ATSM dose cohorts: 30, 60, 99, and 150 MBq/kg. The primary objective was to assess dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) of 64Cu-ATSM. Overall survival (OS), progression-free survival (PFS), pharmacokinetics, and 64Cu-ATSM effective radiation dose were evaluated as secondary endpoints. Results: In total, 20 patients were registered at National Cancer Center Hospital or Kanagawa Cancer Center. Eighteen patients who received 64Cu-ATSM were included in the primary analysis. None of the 3 patients at 30 MBq/kg, 1 of 6 patients at 60 MBq/kg, and 1 of 6 patients at 99 MBq/kg developed DLT (grade 3 lymphocytopenia). Two of 3 patients at 150 MBq/kg developed DLT (grade 4 lymphocytopenia). Therefore, additional patient recruitment was terminated. The MTD was considered to be 99 MBq/kg. No serious adverse events caused by 64Cu-ATSM administration were not reported. Median OS was 29.4 months and 1-year OS was 76.6%. Median PFS was 3.8 months and 1-year PFS was 19.0%. 64Cu-ATSM was rapidly distributed to body organs after intravenous administration and subsequently disappeared gradually. The liver (0.23 mSv/MBq) received relatively high doses, with an estimated effective dose of 0.037 mSv/MBq. Conclusions: Intravenous administration of 64Cu-ATSM was feasible and well tolerated in patients with malignant brain tumors. The recommended dose for future trials is 99 MBq/kg. The initial efficacy outcomes obtained in this study warrant more clinical evaluation of this new treatment approach for brain tumors with no currently available treatment options. Clinical trial information: jRCT2091220362 .
Cost-effectiveness of dabrafenib plus trametinib in BRAFV600E-mutant pediatric low-grade glioma: A microsimulation study.
Authors: Gascon Bryan , Yang Alan , Gauvreau Cindy , Bennett Julie , Nobre Liana , Tabori Uri , Hawkins Cynthia , Pechlivanoglou Petros , Denburg Avram
Published: June 2024

2055

Background: BRAFV600E mutations, detected in 15-20% of pediatric low-grade gliomas (PLGGs), have emerged as a key therapeutic target for patients with unresectable, progressive, or recurrent PLGG. In a recent phase II clinical trial (NCT02684058), dabrafenib, a selective inhibitor targeting BRAFV600E, plus trametinib outperformed standard chemotherapy as first-line therapy, demonstrating significantly longer progression-free survival and improved safety in BRAFV600E-mutant PLGG. The aim of this study was to estimate the cost-effectiveness of dabrafenib+trametinib (Dab-Tram) versus standard chemotherapy as first-line therapy for patients with BRAFV600E-mutant PLGG. Methods: We constructed a microsimulation model, simulating a cohort of 10,000 patients with BRAFV600E PLGG. We populated the model using progression-free and overall survival estimates derived from the NCT02684058 trial, a hospital-based PLGG registry and treatment- and PLGG-related adverse events from published literature. The simulated cohort was assigned to either targeted therapy or chemotherapy as first-line therapy. Key parameters included treatment cost, dosage, inpatient and outpatient costs, and health-related quality of life. We assumed a lifetime duration of targeted therapy, a healthcare system perspective, lifetime horizon, and discount rate of 1.5%. Outcomes included life years, quality-adjusted life years (QALYs), lifetime costs (2022 CAD), and incremental cost-effectiveness ratios (ICERs).Sensitivity analysis included the use of alternative data sources, including those derived from independent assessment of NCT02684058 trial outcomes and real-world data from The Hospital for Sick Children (SickKids) in Toronto, Canada. Results: Modeled life years with Dab-Tram and chemotherapy were 34.91 and 32.68 years, respectively. Dab-Tram was associated with a 1.77 QALY increase at an incremental cost of $2,701,409 compared to standard chemotherapy. The resulting ICER was $1,526,265 per QALY gained. At a willingness-to-pay (WTP) threshold of $150,000 per QALY, a price reduction of approximately 80% is required to render it cost-effective. Scenario analysis varying effectiveness of targeted therapy using independent assessment of NCT02684058 trial outcomes and real-world data from SickKids demonstrated comparable clinical benefits and ICERs. Results were sensitive to changes in survival distributions. Conclusions: While clinical outcomes using Dab-Tram as first line therapy for BRAFV600E PLGG are promising, our model-based analysis demonstrates that at the present price, Dab-Tram is not cost-effective, and would require a considerable price reduction to enable equitable access and affordability. This work also provides an exemplar for economic evaluation of precision therapies based on emergent trial and real-world data for rare diseases.
Claudin18.2-targeted chimeric antigen receptor T cell-therapy for patients with gastrointestinal cancers: Final results of CT041-CG4006 phase 1 trial.
Authors: QI Changsong , Liu Chang , Gong Jifang , Li Jian , Liu Dan , Wang Xicheng , Zhang Panpan , Qin Yanru , Zhang Miao , Peng Zhi , Zhou Jun , Zhang Xiaotian , Peng Xiaohui , Wang Yumeng , Zhang Zijing , Yuan Daijing , Liu Zhen , Baffa Raffaele , Li Zonghai , Shen Lin
Published: June 2024

2501

Background: Autologous anti-claudin18.2 (CLDN18.2) CAR T cell, satricabtagene autoleucel (satri-cel)/CT041, was investigated in gastrointestinal cancers in clinical trials. The interim results of CT041-CG4006 trial (NCT03874897) were published in June 2022 [1]. Herein, we present the final results of this trial. Methods: This single-arm, open-label, phase 1 trial evaluated the safety and efficacy of CT041 in patients (pts) with CLDN18.2-positive advanced gastrointestinal (GI) cancers. The trial consisted of a dose-escalation (250×106, 375×106, 500×106 or 1000×106cells) using modified ‘3+3’ design and dose expansion of CT041 in 4 cohorts (Cohort 1: CT041 in pretreated pts with advanced GI cancers, Cohort 2: CT041 plus anti-PD-1 therapy in pretreated pts with advanced GI cancers, Cohort 3: CT041 sequential treatment following first-line therapy in gastric cancer (GC) and Cohort 4: CT041 in pts with prior failure to anti-CLDN18.2 antibody). The primary endpoint was safety; secondary endpoints were efficacy using RECIST v1.1, pharmacokinetics, and immunogenicity. Results: From 26 March 2019 to 26 January 2024, a total of 98 pts received CT041 infusion, including GC (n=73), pancreatic cancer (n=10), biliary tract cancer (n=4), intestinal cancer (n=8) and other tumors (n=3). A total of 89 pts were dosed with 250×106, 6 pts with 375×106, and 3 pts with 500×106 cells, with a median follow-up of 29.7 (range: 1.2, 35.5) months. 250×106 was selected for the dose-expansion stage based on the dose-escalation results. The most commonly reported treatment-emergent adverse events of grade 3 or higher were hematologic toxicity related to lymphodepletion. No dose-limiting toxicities, treatment-related deaths, or immune effector cell-associated neurotoxicity syndrome were reported. Cytokine release syndrome occurred in 96.9% of pts, all classified as grade 1-2. Gastric mucosal injuries were identified in 8 (8.2%) pts, including 7 cases of grade 1-2 and 1 case of grade 3 gastritis erosive which recovered. For all pts (N=98), the ORR and DCR reached 37.8% and 75.5%, respectively. The median PFS and median OS were 4.4 (95% CI: 4.0, 6.0) months and 8.4 (95% CI: 7.0, 10.0) months for all pts. Among efficacy evaluable GC pts who received CT041 monotherapy, the ORR and DCR in those with measurable disease (n=47) reached 57.4% and 83.0%, respectively, and the median PFS and median OS in all efficacy evaluable GC pts (n=55) were 5.8 (95% CI: 4.2, 8.4) months and 9.7 (95% CI: 7.1, 14.4) months, respectively. Conclusions: Satri-cel/CT041 demonstrated a promising safety profile and highly encouraging efficacy in heavily pretreated patients with CLDN18.2-positive advanced GI cancers. Clinical trial information: NCT03874897 .
BGB-A317-212: A multicenter, open-label, phase II study to evaluate the efficacy and safety of tislelizumab in combination with lenvatinib in patients with selected solid tumors.
Authors: Liu Yufei , He Zhisong , Zhang Mingjun , Jiang Shusuan , Zhang Dahong , Feng Miao , Qu Shenhong , Ju Wutong , Wang Ke , Abdrashitov Ramil , Feng Jifeng
Published: June 2024

2610

Background: Tislelizumab, an anti-programmed cell death protein 1 (PD-1) monoclonal antibody, has demonstrated promising efficacy in several advanced solid tumors. However, some patients (pts) do not respond or develop resistance to tislelizumab monotherapy. Lenvatinib, a receptor tyrosine kinase inhibitor targeting VEGFR 1-3, FGFR 1-4, PDGFR alpha, KIT, and RET, has shown a potential synergistic effect with anti-PD-1 therapy. Here, we report the primary results of a phase II study evaluating the combination of tislelizumab plus lenvatinib in pts with solid tumors (NCT05014828). Methods: Pts with histologically/cytologically confirmed selected solid tumors, naïve to lenvatinib and anti-programmed death-ligand 1 (PD-L1)/PD-1 therapies were enrolled. Part 1 (safety run-in) determined the recommended phase II dose (RP2D) of lenvatinib in combination with tislelizumab 400 mg IV every 6 weeks. In Part 2 (expansion), pts received lenvatinib at the RP2D from Part 1 (20 mg orally/day) plus tislelizumab per the Part 1 regimen until disease progression, withdrawal, or death. The primary endpoints were safety and RP2D determination (Part 1) and overall response rate (ORR; Part 2). Results: At data cutoff (Oct 20, 2023; median follow-up 12.1 months [mo; renal cell carcinoma, RCC]; 10.8 mo [head and neck squamous cell carcinoma, HNSCC]; 14.8 mo [gastric cancer, GC], and 22.0 mo [non-small cell lung cancer, NSCLC]), 58 pts were treated in Part 2 (RCC, n=23; HNSCC, n=27; GC, n=3; NSCLC, n=5), 6 of whom were also included in Part 1. The ORR was 66.7% in pts with RCC, 33.3% (HNSCC), 33.3% (GC), and 20.0% (NSCLC). Median duration of response (mDoR) was 18.5 mo and 9.6 mo in pts with NSCLC and HNSCC, respectively; not estimable (NE) for RCC and GC (Table). No new safety signals were identified; grade ≥3 treatment-related adverse events were reported in 78.3%, 59.3%, 33.3% and 60.0%, of pts with RCC, HNSCC, GC, and NSCLC, respectively (Table). Conclusions: Tislelizumab plus lenvatinib had a manageable safety profile and showed preliminary antitumor activity in pts with selected tumor types. Longer follow-up is needed to further investigate the potential of this combination to benefit pts with advanced solid tumors. Clinical trial information: NCT05014828 .[Table: see text]
Phase 2 trial of brentuximab vedotin (BV) with pembrolizumab (pembro) in patients with previously treated metastatic non-small cell lung cancer (NSCLC) or cutaneous melanoma (SGN35-033): Overall survival.
Authors: Zakharia Yousef , Lee Sylvia , Jotte Robert M. , Gillespie-Twardy Amanda Lynn , Mehmi Inderjit , Chandra Sunandana , Hamid Omid , Watson Graham Thomas , Ward Patrick J. , Chaney Marya F. , Lu Hailing , Berndt Jason , Rathi Kapil , Gupta Anumeha (Anu) , Cowey Charles Lance
Published: June 2024

2617

Background: BV, a CD30 directed antibody-drug conjugate, may selectively deplete a subset of regulatory T-cells (Tregs) that express CD30 and re-sensitize tumors to anti-PD-1 therapy. This ongoing, multi-cohort, multicenter, open-label trial evaluating the efficacy and safety of BV+pembro in patients (pts) with anti-PD-1 refractory solid tumors previously reported an ORR (8-22%), DCR (67-80%), and CD8+T cell infiltration in on-treatment biopsies of responders (Lee, SITC 2023). Here we report OS and biomarker analyses. Methods: Pts with primary refractory (progression without response or SD for < 6 months) or secondary refractory (progression after response for ≥3 months or SD for ≥6 months) NSCLC or melanoma who progressed on anti-PD-1 therapy were included. Pts received BV (1.8 mg/kg) and pembro (200 mg) every 21 days. The primary endpoint was confirmed ORR. Exploratory endpoints included OS and biomarker analyses of blood and tumor samples. Results: 55 pts with NSCLC and 58 pts with melanoma were dosed (86% white, 63% male; 57% ≥ age 65 yrs). Pts received 3 median prior lines of therapy (as previously reported). Investigator-assessed response was measured according to RECIST v1.1. At a median follow up of 17.2 months, median OS (mOS) was 13.9 months (NSCLC) and 12.9 months (melanoma) (Table 1). The estimated probability of survival (Kaplan-Meier) at 12 months was 54.0% (95% CI 43.69, 63.22) for the study population. Immune mediated AEs were reported in 25% of pts, Grade ≥3 TEAEs in 56%, TESAEs in 42%, and TE peripheral neuropathy (SMQ) in 48% of pts. 17% of pts discontinued treatment due to TEAEs. No new safety signals were identified and no deaths due to treatment-related AEs were reported. Paired tumor biopsies from 19 pts showed increased CD8+T cell infiltration in 11 pts. Conclusions: These data support the immunomodulatory capacity of BV with pembro. This combination shows encouraging OS data in pts with solid tumors who have progressed on anti-PD-1 therapy. The safety profile is comparable to previously reported data. The study remains ongoing. Clinical trial information: NCT04609566 . [Table: see text]
Clinical impact of molecular profiling in the national prospective cohort Solving Unknown Primary Cancer (SUPER) study.
Authors: Sivakumaran Tharani , White Matthew , Prall Owen , Mitchell Catherine , Dijkstra Christine , Rebello Richard , Xu Huiling , Vissers Joseph , Grimmond Sean , Wong Hui-Li , DeFazio Anna , Gao Bo , Singh Madhu Sudan , Collins Ian M. , Steer Christopher B. , Warren Mark Andrew , Karanth Narayan Vaderahobali , Bowtell David , Tothill Richard W , Mileshkin Linda R.
Published: June 2024

3056

Background: Cancer of unknown primary (CUP) is a common cause of cancer death, with a median survival < 12 months. SUPER is a prospective cohort study designed to create a national information and biobank of patients (pts) with no confirmed primary site following diagnostic work-up. We aimed to determine the impact of tumour molecular profiling on treatment decisions. Methods: 449 pts were recruited (2013-2021) over 3 phases from 12 Australian sites. Clinical information collected over 12 months included: demographics, treatments, investigations and clinico-pathological characteristics. Molecular tests were centrally performed and included comprehensive panel (CCP) sequencing and gene-expression tissue of origin (TOO) assays in Phase 1&2 and CCP and whole genome sequencing (WGS) in Phase 3. The number of genes reported on increased over the 3 phases. Molecular results were discussed in a molecular tumour board. Clinicians completed clinical management questionnaires before and after receiving molecular results. A combined retrospective evaluation of therapeutic actionability was applied to all DNA sequencing data using the TOPOGRAPH database. Results: Median age 63 years [19-86], with 81% ECOG 0-1 and 87% classified as unfavourable CUP subtype. Reporting timelines and rates of successful sequencing improved over time (Table). Clinically actionable genomic abnormalities were detected in 95/331 (29%) pts. Moderate or high match results on TOO assay were consistent with a suspected or later confirmed TOO as reported by clinicians in 81/195 (42%) pts in phase 1 + 2. Germline pathogenic mutations were detected in 34/331 (10%) pts. Molecular tests confirmed clinician’s treatment (started while awaiting results) was consistent with the most likely TOO in 170/331 (51%) pts. Clinicians reported that molecular tests resulted in a change in management in 11/118 pts (9%) in phase 1 and 40/213 (19%) pts in phases 2+3, with 17/51 (33%) pts changed treatment based on potential TOO determination. 11/51 (22%) pts could access treatment via standard pathways given a more specific tumour-type diagnosis and 15/51 (29%) pts were potentially eligible for clinical trials; however, only 7 pts were well enough for referral. Conclusions: The clinical impact of molecular testing in CUP improved over time as testing became more sophisticated and turnaround times improved. Clinicians suspected TOO pre-profiling was consistent with molecular results in half of the pts. Routine access to novel therapies in CUP remains a challenge. [Table: see text]
Development of a serum miRNA panel for detection of early stage non-small cell lung cancer.
Authors: Zhang Echo Xinyu , Su Chang , Cai Songhua , Qu Jiahao , Guo Xiaotong , Cao Yuan , Cao Mengjing
Published: June 2024

3058

Background: Lung cancer remains the leading cause of cancer deaths, largely due to late-stage diagnosis. Early detection significantly improves survival rates, but current methods like chest X-rays and low-dose CT (LDCT) scans face limitations in sensitivity and specificity. MicroRNAs (miRNAs) are small non-coding RNAs whose dysregulation has been widely observed in different stages of cancer. Evidence suggests that circulating miRNAs could be promising biomarkers for early diagnosis of lung cancer. In this study, we developed and validated a 15-miRNA panel as a blood-based minimally invasive test for early detection of non-small cell lung cancer (NSCLC) using the proprietary multiplex quantitative real-time PCR (qPCR). Methods: 332 serum samples (182 Stage I&II NSCLC, 150 healthy controls) were divided into training (n=266) and validation (n=66) cohorts. Differentially expressed serum miRNAs were screened with Miseq sequencing followed by qPCR validation. The multi-miR panel was developed with a logistic regression model and validated using an independent cohort. Receiver operating characteristic curves were constructed to evaluate the diagnostic accuracy of the panel. A stem-loop quadruplex qPCR assay was invented for concurrent detection of 4 miRs in a single reaction. Results: 15 differentially expressed miRNAs were selected for logistic model construction based on their Ct values (Ct<35) and high diagnostic accuracy of stage I&II NSCLC (AUC>0.7). The 15-miRNA panel model achieved 88.4% sensitivity, 81.7% specificity (AUC = 0.912) in the training cohort (Table), and was validated with 94.4% sensitivity, 73.3% specificity (AUC = 0.892) in the validation cohort. Quantification of 15 miRs and 1 internal control was performed in 4 reactions tubes via quadruplex qPCR assay. Conclusions: The serum 15-miR panel developed and validated in this retrospective study exhibited robust performance for detection of early stage NSCLC. The panel demonstrates potential diagnostic applications and clinical utility to be implemented together with LDCT in current lung cancer screening program as a blood biomarker to reduce false positive results. In addition, the proposed stem-loop quadruplex qPCR system offers an efficient and promising approach for miRNA profiling in future clinical applications. [Table: see text]
A highly sensitive, low input, and automated assay for molecular residual disease detection (MRD) using whole-genome sequencing (WGS).
Authors: Liu Li , Tsai Jeff , Luong Khai , Bilke Sven , Davila Michael , Ding Yuan , Do Manh Vu , Gibson Jacob , Movsesyan Artem , Roessler Kyria , Song Fan , Talia Heather , Taylor Pete , Truong Jacquelyn , Wu Weixin , Zhu Yunjiao , Han James , Pawlowski Traci L.
Published: June 2024

3060

Background: Molecular residual disease (MRD) detection using cell-free DNA (cfDNA) for solid tumors requires a highly sensitive and specific assay that can overcome the limitation of low abundance circulating-tumor DNA (ctDNA) in a standard blood draw with fast sample-to-answer turn-around time (TAT). Here we describe the development and analytical performance of Illumina’s TruSight Oncology MRD WGS assay (TSO MRD, for research use only), for detecting MRD using tumor-informed whole-genome sequencing (WGS) of cfDNA extracted from plasma samples across multiple cancer types. Methods: The TSO MRD assay was built using Illumina’s best-in-class WGS library preparation, informatics and sequencing technologies. The assay is composed of two major steps, fingerprinting and ctDNA detection. At the fingerprinting step, the DNA from tumor tissue and matched normal samples is analyzed through WGS to generate a sample specific somatic variant list. At the ctDNA detection step, the cfDNA extracted from plasma is analyzed through shallow WGS and the presence of ctDNA is detected using the tumor specific fingerprint as an input in the MRD analysis pipeline. The plasma extraction and WGS library preparation workflows are fully automated for high-throughput sample processing with minimum hands-on time and touch points. Results: Testing of commercial MRD reference materials and ctDNA-positive samples serially diluted into normal cfDNA background demonstrated a limit of detection of down to 0.001% VAF or 10 parts per million (PPM) in multiple cancer types. Testing of a panel of normal plasma samples from healthy individuals assessed against 20 sets of fingerprints from multiple cancer types demonstrated an analytical specificity of 99.7%. Testing of ctDNA samples with multiple operators, instruments and library prep start days demonstrated high reproducibility in MRD detection. The ctDNA testing works at an optimal input amount of 5 ng and a minimum input amount down to 2 ng, which yields a high sample success rate from one standard 10 ml of blood draw. The TAT of the fingerprinting and the ctDNA detection steps is 5-7 days, respectively. Conclusions: The TSO MRD assay demonstrated high analytical sensitivity and specificity in detecting the presence of ctDNA from low input plasma samples with automated workflow and fast TAT. This assay enables a single streamlined solid tumor MRD platform for multiple cancer types.
RNA-based fusion testing in gastrointestinal (GI) carcinomas: A single-institution experience.
Authors: Caughey Bennett Adam , Wang Charlotte , Iafrate A. John , Corcoran Ryan Bruce
Published: June 2024

3061

Background: Molecular profiling with next-generation sequencing is critical to provide appropriate clinical care in most GI cancers. However, outside of biliary tract cancers (BTCs), the utility of routine comprehensive fusion testing in GI carcinomas is not well established. We evaluated fusion testing of GI carcinomas in routine clinical care at Massachusetts General Hospital Cancer Center (MGHCC). Methods: Patients with confirmed GI carcinomas who underwent RNA-based tissue fusion testing at MGHCC between Jan 2016 and April 2023 were included. Samples with tumor cellularity <20% or not meeting quality controls were excluded. Fusions of known clinical relevance were evaluated for molecular and histopathologic associations. Results: 2300 GI cancers with at least 1 fusion assay were included (see Table). As expected, BTCs had the highest incidence of fusions (13.7%), 80% of which were FGFR2. Fusions were detected in 3.9-7.7% of colorectal (CRC), pancreatic ductal (PDAC), esophagogastric (EGC), and small bowel (SBC) carcinomas. Fusions of BRAF, FGFR1-3, NTRK1/3, RSPO2/3, and NRG1 were rare (excepting FGFR2 in BTCs) but observed in 3 or more cancer types. Consistent with prior studies, the 3 NTRK1 fusions observed in CRC were associated with MLH1 loss and 15 of 21 (71%) PDAC tumors with fusions were KRAS wild-type (WT). RSPO2/3fusions were the second most frequent after FGFR1-3. RSPO3fusions were predominantly seen in CRC and SBC and were associated with poorly differentiated histology (43%), microsatellite stability (100%), APC WT (92.6%), and KRAS (44.4%), BRAF V600E (40%), and BRCA1/2 mutations (29.6%). Of 5 RSPO2fusions, 4 were in EGC and 100% had poorly differentiated histology and TP53 mutations. No fusions were detected in 47 GI neuroendocrine tumors. Conclusions: Although individually rare, in aggregate RNA-based testing identifies clinically relevant fusions in a small but significant fraction of BTC, CRC, PDAC, EGC, and SBC. Molecular selection may identify subpopulations in which fusion testing is higher yield. CRC and SBC harboring RSPO3 fusions have a distinct molecular and pathologic phenotype, including a potentially novel association with BRCA1/2 mutations. Several detected fusions had novel partners that were nonetheless predicted actionable, highlighting the utility of partner-agnostic fusion testing in this population. [Table: see text]
Dabrafenib and trametinib in patients with tumors with BRAF V600E/k mutations: Updated results from NCI-MATCH arm H.
Authors: Salama April K.S. , Wang Victoria , Macrae Erin Renee , Park Jong-In , Chen Helen X. , Gray Robert James , McShane Lisa , Rubinstein Lawrence , Williams P. Mickey , Hamilton Stanley R. , Armstrong Deborah Kay , Tricoli James V. , Conley Barbara A. , Arteaga Carlos L. , Harris Lyndsay , O'Dwyer Peter J. , Chen Alice P. , Flaherty Keith
Published: June 2024

3110

Background: The NCI-MATCH precision medicine trial assigns patients (pts) with solid tumors, lymphomas or multiple myeloma to a targeted therapy based on genetic alterations identified in pretreatment biopsies. Arm H (EAY131-H) evaluated the combination of the BRAF inhibitor (inh) dabrafenib (DAB), and the MEK inh, trametinib (TRM), in pts with BRAF V600E/K mutations. Thirty-five pts in the primary cohort (PC) were enrolled from Jan 2016-Feb 2018, with 30 patients included in the primary efficacy analysis (1). The trial reactivated for an expansion cohort (EC) in October 2020. Methods: Pts could enroll based on molecular results from approved local CLIA labs; central confirmation was required to be included in primary efficacy analyses. Pts with melanoma, thyroid, or colorectal cancer were excluded. Pts with NSCLC were excluded after the US Food and Drug Administration (FDA) approved DAB/TRM in 2017. Pts received DAB 150 mg po BID and TRM 2 mg PO daily on 28-day cycles until disease progression or intolerable toxicity, with restaging every 2 cycles. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), 6-month (mo) PFS, and overall survival (OS). Results: An additional 9 pts were accrued to the EC; 6 pts were eligible, started treatment and molecularly confirmed. One pt never started therapy and 2 pts had inadequate tissue for central molecular confirmation, resulting in a combined cohort (CC) population of 36 pts. The trial closed to accrual in Jan 2023. In the CC, 17 different histologies were represented. In the EC, 38% of pts were female, with a median age of 60; > 50% had received at least 3 lines of prior therapy. In the 6 pts with central assay results, 1 pt with a pilocytic astrocytoma had a CR, with a PFS >18 mo and 1 pt with GBM had a PR, with a PFS of >12 mo. The 2 pts without central assay results had PRs, both were alive and free of progression for >7 mo. Median OS in the EC is 19.8 mo. For the CC, the confirmed ORR is 36.1% (90% CI 22.9-51.2%); the estimated 6 mo PFS is 67.6% (90% CI 54.5-80.8%). Median OS for the CC is 28.6 mo. At the time of data cutoff (Nov 2023) 2 pts in the PC and 1 pt in the EC are still on therapy. Adverse events were comparable to previously reported profiles of DAB/TRM. Conclusions: In this pretreated cohort of BRAFV600 mutated solid tumors, the combination of DAB/TRM showed clinically meaningful activity with durable responses seen in pts across multiple histologies, further supporting the disease agnostic approval by the FDA for this regimen. 1. J Clin Oncol. 2020;38[33]. Clinical trial information: NCT04439292 .
Meta-analysis of the efficacy and safety of anlotinib combined with chemotherapy in the treatment of small cell lung cancer.
Authors: Gao Ting , Zhao Peiwen , Li Juanzhi , Li Yingjie , Li Xinxin , He Xiaopeng
Published: June 2024

e20101

Background: Immunotherapy combined with chemotherapy(CT) has become the standard treatment for SCLC. For patients who are not eligible for immune checkpoint inhibitors, CT alone has limited efficacy. Anlotinib (AL3818), an oral, small-molecular TKI, has displayed significant anti-angiogenesis and anti-tumor growth effects through the inactivation of the VEGFR, PDGFR, FGFR and c-Kit. Several study indicated that anlotinib could prolong PFS in patients with SCLC. A meta-analysis investigating the efficacy and safety of anlotinib in combination with CT for patients with SCLC is needed. SCLC is urgently demanding novel and effective strategies. Herein, this study was to evaluate the safety and efficacy of anlotinib plus CT for SCLC. This investigation of the efficacy and safety of anlotinib in combination with CT may provide a reference for the treatment selection and management of SCLC. Methods: The studies were searched through PubMed, Embase, Cochrane Library, Web of Science up to July 28, 2023, and China National Knowledge Internet (CNKI), Wanfang, and VIP databases up to July 4, 2023. The outcomes include ORR, DCR, mPFS, OS, VEGF, and AE. Subgroup analysis was performed regarding chemotherapy drug types and the number of previous treatment cycles. Results: A total of 16 studies with 1083 patients were included in the study. Anlotinib plus chemotherapy showed significantly better efficacy in improving ORR, DCR, and mPFS compared with anlotinib therapy alone or CT alone and better PFS, 1-year and 2-year OS, and lower VEGF compared with chemotherapy alone (all P <0.05). The combination of anlotinib with CT had a significantly higher risk of leukopenia (RR: 1.41, 95% CI: 1.09 to 1.82, P =0.008). Based on the subgroup analyses, the anlotinib plus etoposide group and anlotinib plus irinotecan were superior to the etoposide and the irinotecan groups, respectively, in terms of ORR outcome and DCR outcome. The risk of thrombocytopenia and myelosuppression was higher in the anlotinib plus etoposide group than in the etoposide group. For patients receiving one or NA cycle of therapy before, anlotinib plus CT was superior to CT for DCR outcome, and in patients receiving more than 2 cycles of treatment before, there was a higher risk of myelosuppression outcomes in the anlotinib plus CT group than in the anlotinib group. After more than 2 cycles of treatment, a higher risk of gastrointestinal reaction outcomes in the anlotinib plus CT group than anlotinib group. Conclusions: The findings in the present study suggest that the combination of anlotinib with CT could provide improved PFS, ORR, DCR, and OS in patients with SCLC. This meta-analysis may innovate new prospects in the therapy for SCLC.
Real-world burden and treatments of chemotherapy-induced myelosuppression among patients with extensive-stage small-cell lung cancer: A retrospective real-world study in China.
Authors: Fei Kailun , Zhang Yundi , Dong Yiting , Liman Liman , Li Yiqi , Yang Wenjing , Wang Jie , Wang Zhijie
Published: June 2024

e20102

Background: Chemotherapy-induced myelosuppression (CIM) is the major dose-limiting and severe complication for chemotherapy, particularly etoposide plus platinum-based therapy (EP), in patients with extensive-stage small-cell lung cancer (ES-SCLC). CIM adversely affects patient quality of life and imposes substantial economic burden. In China, there’s a scarcity of related studies, especially in large cohort. This study aims to summarize the burden and treatments of CIM in ES-SCLC patients using a nationally representative real-world database. Methods: Data were derived from 53 hospitals across 28 provinces, as part of the National Cancer Center (NCC) database. ES-SCLC patients receiving EP between 2018.1.1 and 2022.12.31 were included. CIM events, namely chemotherapy induced neutropenia (CIN), thrombocytopenia (CIT), and anemia (CRA) were identified based on laboratory tests and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5. Incidence, treatments and impact on hospitalization cost of CIM were described. Results: 7,505 patients were included, with an average age of 61.2 years (SD = 9.02) and an average of 5.0 chemotherapy cycles (SD = 2.01). The overall incidence of CIM was 91.95%, with grade 3-4 CIM occurring in 25.09% patients. Incidence of CIN, CIT, and CRA, were 44.74%, 39.20%, and 86.48%, respectively, with febrile neutropenia at 0.72%. Among patients with CIN, 90.89% patients used granulocyte colony stimulating factor (G-CSF), and 90.56% used it prophylactically. Among patients with CIT, 17.47% used recombinant human thrombopoietin (rhTPO) and 25.49% used recombinant human interleukin-11 (rhIL-11). Among patients with CRA, 10.26% used erythropoiesis-stimulating agent (ESA). Occurrence of grade 1-2 CIM and grade 3-4 CIM may increase 9.37% and 32.36% hospitalization cost per chemotherapy cycle, respectively (¥23,316.3 vs ¥21,318.2, ¥28,217.0 vs ¥21,318.2), compared to patients without any CIM. Conclusions: Incidence of CIM is notably high among ES-SCLC patients receiving EP, and treatments like G-CSF, rhTPO, rhIL-11 and ESA are widely used. Occurrence of CIM critically escalates hospitalization cost. Innovations to protect bone marrow from chemotherapy-induced damage are promising to alleviate the burden and benefit quality of life for ES-SCLC patients.[Table: see text]
Lurbinectedin versus platinum rechallenge in relapsed extensive stage small cell lung cancer: A retrospective cohort study.
Authors: Libre Michael , Lu Matthew , Lessans Spencer , Wu Jenny , Bhatia Shreya , Iams Wade Thomas
Published: June 2024

e20110

Background: Outcomes in small cell lung cancer (SCLC) remain exceptionally poor. Although patients typically have an excellent initial response to platinum doublet chemotherapy, relapse occurs quickly. Despite multiple available therapeutic options for patients with relapse after first-line treatment, there remains limited evidence indicating a preferred second-line therapy. We present findings from a retrospective cohort study comparing lurbinectedin with platinum rechallenge in a real-world setting. Methods: Patient records were identified from Vanderbilt Ingram Cancer Center between 2000 and 2023. The study cohort included extensive-stage (ES) SCLC patients treated with second-linelurbinectedin or platinum rechallenge following initial platinum-based chemotherapy.Primary outcomes included overall survival (OS) and progression-free survival (PFS). Secondary outcomes were drug-related adverse events including hospitalization, neutropenic fever, and laboratory abnormalities by CTCAE definitions. Analysis was done in R using Kaplan-Meier estimates and Cox proportional hazards models. Results: 57 patients met inclusion criteria, with 21 receiving lurbinectedin and 36 receiving platinum rechallenge. Cohorts were similar for sex, race, comorbidities, and performance status. The platinum rechallenge group skewed younger with longer chemotherapy-free interval (CTFI) (median 9.71 months vs. 2.59 months for lurbinectedin). Median PFS was 4.37 (1.53, 5.94) vs. 2.63 months (1.68, 4.40) (p = 0.030) and median OS was 8.61 (4.91, 14.26) vs. 4.70 months (2.63, 6.73) (p = 0.001) for platinum rechallenge and lurbinectedin, respectively. In a Cox proportional hazard analysis, OS and PFS hazard ratios for lurbinectedin compared to platinum rechallenge were 4.43 (1.89-10.4, p < 0.001) and 2.03 (0.87-4.8) (p = 0.102) after adjusting for age, sex, race, comorbidities, and CTFI. Notably, the OS and PFS hazard ratios for CTFI alone were 0.96 (0.9-1.0) and 0.99 (0.98-1.0). There was no statistically significant difference in hospitalizations, neutropenic fever, anemia, or transaminitis between groups, although 7 (29%) of platinum rechallenge patients discontinued due to tolerability compared to 0 (0%) with lurbinectedin. Conclusions: This retrospective cohort study suggests that second-line platinum rechallenge in patients with relapsed ES-SCLC may be associated with improved OS and PFS compared to lurbinectedin. While time since last platinum was notably different between cohorts, CTFI alone did not appear to explain the observed difference in outcomes. Drug-related safety events were similar, although tolerability led to greater discontinuation with platinum chemotherapy. Although a small, single-center retrospective study, these results support further research to identify an optimal therapeutic strategy in second-line treatment of ES-SCLC.
Treatment of relapsed small cell lung cancer in the real-world: A comparison of platinum-etoposide rechallenge and cyclophosphamide-doxorubicin-vincristine (CAV) chemotherapy.
Authors: Chowdhury Deepro , McKinnon Mathieu , Wheatley-Price Paul , Moore Sara
Published: June 2024

e20123

Background: Small-cell lung cancer (SCLC) is an aggressive malignancy, representing 15% of all diagnosed lung cancers. Initial therapy involves platinum-based chemotherapy, with recent evidence supporting the addition of immunotherapy. Despite excellent initial response to treatment, relapses are common and there is little prospective evidence available to guide second-line therapy. Depending on response to the previous regimen, second-line treatment can involve platinum-etoposide (PE) re-challenge or other therapies including CAV (cyclophosphamide-doxorubicin-vincristine), topotecan, taxanes, or immunotherapy. Methods: We reviewed all patients diagnosed with SCLC at the Ottawa Hospital from January 2014 – December 2021, and identified those treated with second-line systemic therapy. Baseline demographics, diagnostic, and treatment information were collected. The primary outcome was overall survival compared between platinum-etoposide re-challenge and CAV. Results: During the study period, 680 patients were diagnosed with SCLC, 521(76%) received first-line systemic therapy, and 161/521 (31%) went on to receive second-line systemic therapy. Baseline characteristics at initial diagnosis of this second-line cohort: median age 64, 93 (58%) female, 156 (97%) former/current smoking history, 156 (97%) extensive-stage. First-line treatment was almost exclusively platinum-based (n = 154, 96%). At the time of second-line therapy: 105 (69%) had ECOG performance status (PS) 0-1, and 103 (64%) had chemosensitive disease with a treatment-free interval (TFI) > 90 days. Second-line regimens included platinum-etoposide (n =64, 43%), CAV (n =67, 41%), platinum-irinotecan (n =3, 2%), docetaxel (n =10, 6%), and other (n =12, 7%). Median overall survival from the start of second line chemotherapy was 5.7 months (95% CI 5.0-6.4). Comparing patients who received PE-re-challenge versus CAV, there were no significant differences in age, sex, smoking history, or stage at diagnosis. Patients receiving CAV were more likely to have a lower performance status (ECOG >2: 40% versus 23%, p = 0.04) have a TFI < 180 days (81% vs 62%, p = 0.002). PE chemotherapy led to higher physician-assessed clinical benefit (83% vs 55%, p < 0.001) and median overall survival (7.3 (95% CI 5.7 – 8.8) versus 4.1 (95% CI 2.8 – 5.4 months), p < 0.001) compared to those receiving CAV. In a sensitivity analysis for patients with TFI < 180 days, PE-re-challenge had a higher mOS than CAV (6.2 (95% CI 5.1-7.2) versus 4.1 (95% CI 3.0 - 5.2), p < 0.003). Conclusions: Patients who receive second-line systemic therapy for relapsed SCLC represent a small subset of the overall SCLC patient population. In this real-world study, platinum-etoposide re-challenge appeared to offer benefit over CAV, even in patients with PFI < 180 days.
Tislelizumab combined with chemotherapy in advanced thymic tumors.
Authors: Li Shuke , Zhang Lantian , He Jing , Gao Wen
Published: June 2024

e20139

Background: Thymic tumors refer to tumors derived from thymic epithelial cells, including thymoma and thymic carcinoma. Most cases in advanced stages when detected, and treatment is still controversial. Since 2018, immunotherapy has gradually been used for a variety of solid tumors and the curative efficacy has been notable. The efficacy of immunotherapy is increasingly improved with the increased expression of programmed death-ligand 1 (PD-L1) by tumor cells. The thymus is an immune-rich organ. PD-L1 expression ranges from 23% to 92% in thymoma, and from 36% to 100% in thymic carcinoma. Thus, immunotherapy has been implicated as having broad prospects in the treatment of thymic tumors. Tislelizumab is an inhibitor of PD-1, which has shown preliminary anti-tumor effects in various solid tumors. The combination of immunotherapy and chemotherapy has produced excellent anti-tumor activity for various types of tumors. However, there is a lack of clinical trial data to support the application of tislelizumab for the treatment of advanced thymic tumors. In this article, the efficacy and safety of tislelizumab combined with chemotherapy were analyzed in eight patients with advanced thymic tumors to provide data for the use of this monoclonal antibody as first-line treatment of advanced thymic tumors. Methods: Here, after obtaining fully informed consent, we report cases involving eight patients with advanced thymic tumors treated with tislelizumab combined with chemotherapy. The clinical characteristics, lesion changes, treatment process, drugs used, drug efficacy, complications or adverse reactions were recorded and followed up to evaluate the efficacy and safety of tislelizumab combined with chemotherapy in the treatment of advanced thymic tumors. Results: This article reports eight cases of advanced thymic tumor treated with tislelizumab combined with chemotherapy. Two patients received tislelizumab combined with chemotherapy as first-line treatment, and the remaining six patients were treated with tislelizumab after poor response to chemotherapy. Five patients achieved a partial response to the combined treatment. Of these, the partial response was retained in three patients after switching to tislelizumab monotherapy. The remaining three patients displayed stable disease after the combined treatment. There were no serious immune-related adverse events during treatment. The side effects of tislelizumab combined with chemotherapy were well tolerated. Conclusions: No clinical study of immunotherapy combined with standard chemotherapy as first-line treatment for advanced unresectable or metastatic thymic epithelial tumors has been described. This article provides strong evidence for the early application or even first-line use of tislelizumab combined with chemotherapy for advanced thymic epithelial tumors. More clinical studies are needed to evaluate the efficacy and safety of tislelizumab in thymic tumors.