tbuckley/cabot-search huggingface dataset:
Seven year update on SOC-1702: A phase 2 study using trabectedin (T) in combination with ipilimumab (I), nivolumab (N) and trabectedin (T) in previously untreated patients with advanced soft tissue sarcoma.
Authors: Erlinda Maria Gordon, Sant P. Chawla, Nadezhda Omelchenko, Samantha Jeffrey, Anmol Dia Agarwal, Vaishali Kumar, Neal Shiv Chawla, Victoria Chua, Doris V. Quon, Ania Moradkhani, Noah Federman
Journal: Journal of Clinical Oncology (2024)

11577 Background: Advanced soft tissue sarcoma is most often associated with a fatal outcome. This report is an update on the results of the SOC-1702 Phase 2 study for previously untreated STS. Methods: Objectives, Primary: Evaluate best response rate by RECIST v1.1; Secondary: Assess progression-free survival (PFS) at 6 months and overall survival. Patients and Methods: Eligible patients for this Phase 2 study are males or females ≥ 18 years of age with locally advanced unresectable or metastatic soft tissue sarcoma, previously untreated, with measurable disease by RECIST v1.1. Treatment protocol: (I) 1 mg/kg i.v. q 12 wks, (N) 3 mg/kg i.v. q 2 wks, (T) 1.2 mg/m2 CIV q 3 wks. Results: Efficacy: Ninety-one patients were evaluated for efficacy. These subjects completed at least two treatment cycles and had at least one follow-up CT scan. The best responses were 9CR, 14PR, 54SD and 14PD with 25% ORR, 85% DCR. PFS rate at 6 months was 56%; Median PFS was 7.4 (95% CI: 5.6-9.2) months; Median OS was 32.0 (95% CI: 19.8-44.2) months. The best responders (CR and PR) were patients with LMS, UPS, LPS, synovial sarcoma, myxofibrosarcoma, endometrial stromal sarcoma, clear cell sarcoma, DSRCT, and chondrosarcoma. Notably, out of the 91 patients who participated in the study between 2017 and 2022, 23 (25%) patients are still alive as of January 1, 2024, the data cut-off date. Safety: Grade 3/4 TRAEs related to Trabectedin include both hematologic and non-hematologic toxicities: fatigue, nausea, vomiting, fever, exhaustion, dehydration, asthenia, cellulitis of port, anemia, neutropenia, thrombocytopenia, transaminitis, elevated CK. There were no hematologic toxicities related to Nivolumab or Ipilimumab. Grade 3/4 TRAEs include decreased TSH, increased T4, increased TSH, transaminitis, hyponatremia, dehydration, pruritus, and psoriasis. Conclusions: Taken together we have confirmed that (1) Trabectedin in combination with Ipilimumab and Nivolumab is a safe and effective regimen for previously untreated advanced STS, and (2) Randomized studies are needed to confirm whether this regimen is superior to standard first line therapy for advanced soft tissue sarcoma. Clinical trial information: NCT03138161 .
AlphaMissense performance as a classifier of germline and somatic variants of unknown significance in high-grade sarcoma.
Authors: Andrew Bassim Bassim Hassan, Rachael Wilkinson, Stuart Brown, Richard Wallbank, Mirvat Surakhy, Sofia Alves-Vasconcelos, Paul Metz, Qinan Qian, Hannah Mallon, Tanya Ren, Isabel Karia, Harriet Branford-White
Journal: Journal of Clinical Oncology (2024)

11538 Background: Missense variants associated with high frequency, clinical context, splicing, penetrance and biochemical function are scored as pathogenic by ClinVar/ACMG (scores &gt;99%/&gt;90%). Pathogenic scores that range from this cut-point to 10% (benign) are referred to as variants of unknown significance (VUS). Alphafold2 is a deep neural network algorithm for protein structure trained on known molecular structures. It has informed AlphaMissense (AM) where the impact of every possible single missense variant in the human genome is assessed. The AM continuous pathogenicity score (roughly 0-0.35 benign, 0.36-0.55 ambiguous, 0.56-1.0 pathogenic) are claimed to have 90% accuracy based on ClinVar (based on 1,263 pathogenic and 1,263 benign variants). Methods: Here, we identified VUSs from the Oxford Sarcoma Precision Oncology real world cohort. This included the identification of somatic variants from FoundationOne Heme Sarcoma analysis of Formalin-Fixed Paraffin Embedded (FFPE) tumour samples. Germline variants were identified from whole exome sequencing (WES) (97 genes) from patient blood samples followed by analysis using GATK guidelines. All VUS identified were further analysed using AM. Results: AM reclassified the identified &gt;1000 VUSs from 60 high grade sarcoma gene panels predominantly into benign or pathogenic, with only ~1% remaining as ambiguous. Variants reclassified as pathogenic were assessed for likelihood of pathogenicity based on scientific rationale. This involved evaluating current literature on the variant, determining evolutionary consensus of the residue, structural analysis to assess the potential function of the residue and enrichment of the variant within sarcoma patients compared to known frequencies across the population. Conclusions: In conclusion, the AM classifier dichotomises VUS to either benign or pathogenic, but this is not based on either structural or functional predictions directly. We conclude that it should not be currently used in the analysis of clinical samples seeking actionable variants but could instead stratify potential pathogenic variants for functional investigation.
Comparison of machine learning algorithms for the radiomic classification of gastric subepithelial tumors.
Authors: Woo Kyoung Jeong, Jeong Hyun Lee
Journal: Journal of Clinical Oncology (2024)

11536 Background: Diagnostic challenges arise in classifying gastric subepithelial tumors (SETs) due to the absence of specific imaging findings and limitations in endoscopic biopsy, particularly for deep-seated tumors. Differentiating SETs that require surgical intervention from those suitable for diagnostic imaging follow-up is crucial. Gastrointestinal stromal tumors (GIST), with malignant potential, necessitate prompt resection, while leiomyoma and schwannoma are benign and can be followed up if asymptomatic. Many radiomic approaches using machine learning (ML) were tried to classify gastric SET. Nevertheless, a comprehensive exploration of current ML algorithms still needs to be explored. Methods: The patients who underwent the surgery for gastric SET in our hospital were considered eligible subjects. All cases were confirmed by pathologic evaluation, and the cases of GIST and leiomyoma were chosen for this study. Manual segmentation and radiologist validation were performed, followed by image resampling to 1 x 1 x 1 mm resolution. Radiomics features were extracted using PyRadiomics 3.0.1, focusing on 32 first-order and shape features for interpretability and robustness. Various models, including K-nearest neighbors (KNN), support vector machines (SVM), logistic regression (LR), lightGBM, random forest (RF), and TabPFN (by Hollman N et al.), underwent evaluation. Nested cross-validation with 10 folds and 10 repetitions ensured fair comparison, and Bayesian hyperparameter optimization was conducted in a 5-fold inner CV, excluding TabPFN. Comparative evaluation included area under the receiver operating characteristics (AUROC), accuracy, balanced accuracy, and Matthew Correlation Coefficient (MCC). Results: Among the 359 eligible patients, resulting in 241 GISTs and 27 leiomyomas post-exclusion. We used 26 pre-isolated cases as a test set of the model. The model test results for various ML models in classifying gastric SETs are presented (Table). Notably, LR exhibited the highest accuracy (0.899), F1 score (0.950), and AUROC (0.653) compared to other models without statistical significance. Conclusions: Our study highlights that LR improves the accuracy of diagnosing gastric SETs. These findings contribute to refining diagnostic approaches and may optimize patient management strategies for gastric SETs.[Table: see text]
Phase 1 results of the WEE1 inhibitor, azenosertib, in combination with gemcitabine (gem) in adult and pediatric patients (pts) with relapsed or refractory (R/R) osteosarcoma.
Authors: Viswatej Avutu, J. Andrew Livingston, Noah Federman, Lee D. Cranmer, Nathalie Gaspar, Maud Toulmonde, Joseph Gerald Pressey, Mehdi Brahmi, Andrew Stewart Poklepovic, Qing Shi, Nathan Jameson, Adrian Michael Jubb, Chrystal Ursula Louis, Sant P. Chawla, William D. Tap
Journal: Journal of Clinical Oncology (2024)

11525 Background: Patients with R/R osteosarcoma have poor outcomes with a historical 16-week event-free survival (EFS) of ~12% after treatment with salvage therapy (Lagmay et al, 2016). Azenosertib is a highly selective WEE1 inhibitor that induces cancer cells to accelerate through the G1/S and G2/M checkpoints without repairing damaged DNA, causing mitotic catastrophe and cell death. Azenosertib has demonstrated significant synergy with gem in non-clinical models. The purpose of this study was to evaluate the safety and tolerability, determine the maximum tolerated dose (MTD), and assess for anti-tumor activity in pts with R/R osteosarcoma receiving C and gem. Methods: This dose-finding study (NCT04833582) assessed azenosertib + gem in pts ≥12 years of age using a standard 3+3 design. The MTD was defined as the dose level with prespecified adverse events (dose-limiting toxicities [DLTs]) occurring at a rate &lt;33%. The primary endpoint was the incidence and severity of DLTs in cycle 1. Secondary endpoints included the incidence and severity of adverse events and EFS at 18-weeks per RECIST v1.1 (time from treatment initiation until disease progression or death due to any cause). Pts were treated across 5 dose-finding cohorts, receiving azenosertib (starting dose 200 mg QD PO on a continuous schedule) and gem (starting dose 1000 mg/m 2 IV on D1 and D8 of a 21D cycle) until disease progression or unacceptable toxicity. Results: As of Nov 30, 2023, 31 pts had been treated. The median age was 27y (range 12-76); 21 (68%) pts were ≤39y. Pts received a median of 3 (1-9) prior therapies. At tolerated doses, the most frequent grade ≥3 adverse events (≥20%) included thrombocytopenia and lymphopenia (33% each); there were no grade 4 thrombocytopenia events or instances of febrile neutropenia. DLTs included thrombocytopenia and gastrointestinal toxicity. The MTD was determined to be azenosertib 150 mg daily on a 5:2 schedule (5 days on, 2 days off) + gem 800 mg/m 2 . None of the pts treated at the MTD (n=6) required dose reductions of azenosertib due to AEs and only 1 required a dose interruption. The 18-week EFS was 39% (11/28) across all dose levels. Conclusions: Azenosertib + gem was well tolerated at the MTD and provided a greater EFS than historical control cohorts of salvage therapy in pts with R/R osteosarcoma. The MTD of the combination was well tolerated and these data support further investigation of azenosertib with gem in pts with R/R osteosarcoma in an upcoming Investigator-Initiated Phase 2 trial. Clinical trial information: NCT04833582 .
Prospective evaluation of pre-treatment ctDNA burden in localized osteosarcoma to identify patients with inferior outcomes: A report from the LEOPARD study.
Authors: David Stephen Shulman, Kelly S. Klega, Nan Chen, Elliot Gohn, Donovan Henry, Edwin Choy, Thomas Cash, Kris Ann Pinekenstein Schultz, Leo Mascarenhas, Rochelle Bagatell, Brian Turpin, Bhuvana Setty, Bradley DeNardo, Douglas S. Hawkins, Michael W. Bishop, Avanthi T Shah, Luke Devon Maese, Wendy B London, Steven G. DuBois, Brian D. Crompton
Journal: Journal of Clinical Oncology (2024)

11510 Background: Prior retrospective analyses demonstrated that elevated pre-treatment ctDNA was associated with poor outcomes in newly diagnosed localized osteosarcoma. The primary objective of the LEOPARD study (Liquid biopsy in Ewing sarcoma and osteosarcoma as a prognostic and response diagnostic) was to determine whether patients with detectable pre-treatment ctDNA have an inferior event-free survival (EFS) compared to patients with undetectable ctDNA. Methods: The LEOPARD study is a prospective multicenter ctDNA study for patients with bone sarcomas. Patients enrolled through 12 primary study sites, or provided samples after enrolling on the Children’s Oncology Group Project EveryChild (ABTR18B1-Q). Eligible patients were 1-50 years of age at enrollment, had unresected, high-grade, localized, non-pelvic osteosarcoma and were to receive standard chemotherapy (primary centers only). We utilized a validated ctDNA assay, ultra-low pass whole genome sequencing (ULP-WGS), for ctDNA quantification based on tumor aneuploidy (limit of detection 3%). We compared EFS according to baseline ctDNA burden using two pre-specified cut points (detectable/undetectable [≥3%] and ~median [≥5%]. We planned 113 patients for 80% power to detect a difference in 2-year EFS of ~20% or greater for patients with detectable baseline ctDNA (2-year EFS: 68%) vs undetectable ctDNA (2-year EFS: 87%; one-sided log-rank test; ⍺ =0.05). Results: From 10/1/17 to 3/3/23, 138 patients with osteosarcoma met eligibility and enrolled (67 - primary study centers; 71 - ABTR18B1-Q). 133 patients had an evaluable pre-treatment ctDNA measurement. Median age was 14.2 years (range: 4.2-30.3) and 50% of patients were male. At diagnosis, 63% had detectable ctDNA [median: 5.3% (range: 0-43.1)]. Age, sex, race, ethnicity, and tumor size were not associated with a difference in ctDNA burden. Baseline detectable ctDNA burden (≥3%) was associated with an increased risk of EFS-event (relapse/progression, second malignant neoplasm, death) compared to undetectable ctDNA (2-year EFS: 56% [95% CI 45-68%] vs. 88% [95% CI 78-98%]; P&lt; 0.0001; Table). A similar pattern was seen using a cut point of ≥5% (53% [95% CI 41-67%] vs. 83% [95% CI 74-94%], P&lt; 0.0001). Conclusions: These findings validate prior data associating baseline ctDNA detection with inferior EFS in patients with localized osteosarcoma and identify the first prospectively validated molecular biomarker in this disease. Baseline ctDNA burden is now positioned for implementation into upcoming therapeutic trials of risk-stratified therapy in localized osteosarcoma. [Table: see text]
Personalized tumor-informed circulating tumor DNA analysis in monitoring recurrence following resection of high-risk stage II-III gastrointestinal stromal tumor.
Authors: Zhidong Gao, Baosen Cheng, Yudi Bao, Peng Cui, Haiwei Du, Xuning Fan, Di Peng, Shuya Yang, Xin Wu, Dongbing Zhao, Zhaodong Xing, Feng Cao, Wei Zhang, Bing Li, Chengcheng Li, Yuzi Zhang, Guoqiang Wang, Shangli Cai, Yingjiang Ye
Journal: Journal of Clinical Oncology (2024)

11534 Background: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Radical resection is the standard treatment of localized GIST, yet the 5-year recurrence rate for high-risk GIST is more than 50%. It remains unclear whether detecting post-surgery molecular residual disease (MRD) via circulating tumor DNA (ctDNA) can predict the recurrence of high-risk locally advanced GIST. Methods: Patients with high-risk stage II-III GIST who underwent R0 surgery and following adjuvant imatinib/avapritinib were enrolled prospectively. Surgical tissue samples were collected. Blood samples were drawn pre-surgically, and at 7 days, 1 month, and every 3–6 months post-surgically. Tumor-derived variants were identified by whole-exon sequencing of the surgical tissues. Up to 50 highly ranked variants with a variant allele frequency 3.0% were selected for the personalized panel design, which was subsequently used to assess MRD status. Results: A total of 36 patients with a median age of 65 years were included in the current analysis (data cutoff on January 16, 2024). Most tumors (17/36, 47%) were located at the stomach or gastroesophageal junction, and 94.4% of patients (34/36) did not receive neoadjuvant treatment. The mean maximum diameter of tumors was 7.87 ± 2.87 cm. At present, 36 tissue samples, 34 pre- and 161 post-surgical blood samples were collected and analyzed. Tissue sample-based sequencing identified variants in KIT and PDGFRA in 31 (86%) and 4 (11%) patients, respectively. 98.4% (1003/1019) of tumor variants included in personalized panels were patient-specific. ctDNA was detected in 64.7% (22/34) of pre-surgical plasma samples. The ctDNA-positive rate at baseline was associated with tumor mutation burden (p &lt; 0.05), rather than tumor size (p = 0.6). Landmark analysis at 1 week post-surgery showed that 12.1% of patients were positive for ctDNA. Up to now, 4 patients were identified with tumor recurrence based on imaging results. Among these patients, 3 patients (3/4) exhibited ctDNA positivity preceding radiological recurrence. Notably, a 71-year-old patient was ctDNA-positive at 1 week post-surgery. Longitudinal analysis revealed that his ctDNA became negative after adjuvant treatment but turned positive at 9 months post-surgery, with a lead time of 2 months prior to his radiological recurrence. Additionally, a patient tested positive for ctDNA at 3 months post-surgery but had negative imaging results. Follow-up visits are ongoing for this patient. Conclusions: The present study suggests that personalized tumor-informed ctDNA has the potential to inform recurrence in high-risk stage II-III GIST patients. Clinical enrollment is still ongoing.
Anti-angiogenic TKIs in patients with advanced Ewing sarcoma: A systematic review and single-arm meta-analysis.
Authors: Caio Castro, Ana Paula Belluco, Isabella Michelon, Maria Inez Dacoregio, Jonathan N. Priantti, Maysa Vilbert, Erica C. Koch Hein, Ludimila Cavalcante
Journal: Journal of Clinical Oncology (2024)

11531 Background: The treatment of patients with localized Ewing Sarcoma (ES) is well established; however, strategies for relapsed disease remain uncertain. Encouraging outcomes have surfaced from early-phase trials assessing tyrosine kinase inhibitors (TKIs) with anti-angiogenic properties in this population. Hence, we conducted a systematic review and meta-analysis to synthesize current data on efficacy and safety of TKIs in patients with ES. Methods: We comprehensively searched PubMed, Embase, and Cochrane databases for clinical trials and cohort studies assessing anti-angiogenic TKIs in the treatment of advanced ES patients who had received at least one previous line of therapy. Main outcomes were objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS), and safety. Heterogeneity was assessed using I 2 statistics. All analyses were conducted using R software (v.4.2.2), employing random effects models. Results: We included 10 studies: four phase II clinical trials and six retrospective cohort studies, comprising 191 patients. The following TKIs were evaluated: cabozantinib, regorafenib, apatinib, anlotinib and sorafenib. Median age in each study varied from 15 to 33 years, and 48.6% of patients had received ≥2 previous lines of therapy. In a pooled analysis of all ES patients treated with TKIs, the ORR was 30.1% (95%IC 16.3-43.8; I 2 =83.14%) and DCR was 66.8% (95%IC 59.4-73.5; I 2 =3.97%). In a comparative analysis stratified by drug, anlotinib was associated with an increased ORR (p&lt;0.01) and no difference was seen in DCR among TKIs assessed (p=0.26). Seven studies evaluated TKIs in monotherapy, while the others included patients treated with TKIs + chemotherapy (CT); TKI+CT displayed higher ORR (p=0.04) and DCR (p=0.05), in a subgroup analysis by treatment strategies. The median PFS varied from 3.5 to 16.0 between drugs, and the overall median PFS was 4.4 months (95%CI 3.4-10). Dose reduction and interruption of treatment due to toxicity were reported in 39.6% and 6% of patients, respectively. Most common grade 3 or 4 adverse events were leukopenia (24.5%), anemia (8.8%), hypertension (5.6%), and diarrhea (4.3%). Conclusions: Anti-angiogenic TKIs are well tolerated and have shown anti-tumoral activity and clinical benefit in the treatment of patients with advanced Ewing sarcoma. Prospective randomized trials with adequate control groups are warranted to further evaluate the benefits of these agents. [Table: see text]
ImmunoSarc II master trial (phase II of sunitinib and nivolumab): Results from the dedifferentiated chondrosarcoma (DDCS) cohort—A GEIS, ISG and UCL study.
Authors: Sandra J. Strauss, Nadia Hindi, Emanuela Palmerini, Javier Martínez-Trufero, Antonio Lopez-Pousa, Irene Carrasco-Garcia, Enrique Gonzalez-Billalabeitia, David Silva Moura, Rafael Ramos, Roberto Tirabosco, Antonio Gutierrez, Javier Martin Broto
Journal: Journal of Clinical Oncology (2024)

11506 Background: Dedifferentiated chondrosarcoma (DDCS) is a rare aggressive CS subtype with a dismal prognosis and no standard of care systemic therapy. For those with advanced, metastatic disease, retrospective chemotherapy studies demonstrate short-term median progression-free survival (PFS) of around 3 to 5.5 months. Benefit from checkpoint and tyrosine kinase inhibitors has been reported, however clinical trial data is scarce, and endpoints are not well defined, thus benchmarking outcomes is challenging. The IMMUNOSARC I master-trial exploring sunitinib plus nivolumab in multiple sarcoma subtypes, detected potential activity in DDCS leading to a specific cohort within the phase II trial IMMUNOSARC II (NCT03277924). Methods: Patients (pts) with ECOG 0-1, centrally confirmed and progressive, measurable DDCS were eligible and treated with sunitinib 37.5 mg/d for 14 days (induction phase), followed by 25 mg/d, in combination with nivolumab 240 mg every 2 weeks until progressive disease (PD) or intolerance. Imaging assessments were performed every 8 weeks. Main endpoint was 6-m PFSR with one-arm survival design (type I error α 0.05, power 0.90, H0 40%, H1 70%) and a Brookmeyer-Crowley like test was assumed with at least 14 of 23 pts required without progression at 6 months. Results: Between December 2019 and October 2023, 24 pts with a median age of 60 years (38-76) were enrolled in 7 centres. Sixteen pts (66%), were male. Pts had received a median of 1 (0-2) prior lines of therapy. In total, 23 pts were evaluable with a median follow-up of 20.1 months (95%CI: 11.6-28.6). Median PFS, according to local site assessment, was 5.6 months (95%CI: 4.5-6.7); the 6m-PFSR was 10 of 23 pts (46%); (95%CI: 23-66) and median overall survival 10.3 months (95%CI: 6.7-13.9). In 19 pts with RECIST measurable response, 5 pts (26.3%) achieved a partial response; 10 (52.6%) stable disease and 4 (21.1%) PD. End-of-treatment reasons were PD in 21 pts (87%), toxicity 1 pt (4.2%) with two pts (8.4%) ongoing. For safety population, the most relevant study drug-related G3-4 toxicities were neutropenia (20.9%), anemia (16.7%), and increased ALT (12.5%). Conclusions: Sunitinib and nivolumab demonstrated encouraging activity in advanced DDCS that did not meet the primary endpoint, but compares favourably with previous analyses of cytotoxic and targeted therapy. The combination is worthy of further exploration in conjunction with reaching a consensus on clinically meaningful endpoints in this challenging population. Translational studies to identify potential predictive biomarkers are ongoing. Clinical trial information: NCT03277924 .