tbuckley/cabot-search huggingface dataset:
Nelmastobart (hSTC810) combined with capecitabine therapy in metastatic colorectal cancer with resistance or intolerance to oxaliplatin and irinotecan-based chemotherapy: A phase 1b clinical trial.
Authors: Soohyeon Lee, Jiwon Lee, Jwa Hoon Kim, Jong Min Sim, Boyeon Kim, Bong-Ki Hong, Hyunjin Jung, Stephen S. Yoo
Journal: Journal of Clinical Oncology (2025)

162 Background: Treatment options for patients with metastatic colorectal cancer (mCRC) who experienced disease progression after receiving oxaliplatin and irinotecan-based chemotherapy are limited. Nelmastobart (hSTC810), a humanized anti-BTN1A1 (butyrophilin subfamily 1 member A1) monoclonal antibody of the IgG4 isotype, showed acceptable safety profile and the disease control rate was 39.3% in the first-in-human study, suggesting its potential efficacy. This phase Ib study was designed to evaluate the safety and explore synergistic anti-tumor activity of nelmastobart in combination capecitabine. The study aims to determine the maximal tolerated dose (MTD) and recommended phase ll dose (RP2D) of this combination therapy in patients with mCRC who are refractory to standard therapy. Methods: Dose escalation phases were conducted in patients with mCRC who were administered orally twice daily capecitabine (850mg, 1000mg, 1250mg orally, days 1-14) and nelmastobart (400mg, 800mg intravenously every 3 weeks). Standard "3 + 3" dose escalation was used to define the MTD. In this phase 1b, 12 participants enrolled between February 5 2024 and June 11 2024 were 18 years of age or older with mCRC previously treated oxaliplatin and irinotecan in the metastatic setting. Results: The first 3 patients at the dose level 0 (nelmastobart 400mg, capecitabine 1,000 mg/m 2 twice daily) and level 1 (nelmastobart increased to 800 mg, capecitabine 1,000mg/m 2 twice daily) had no dose-limiting toxicities (DLTs). In dose level 2 (nelmastobart 400mg, capecitabine 1,250mg/m 2 twice daily), 2 of 3 had DLTs (grade 3 hand-foot syndrome), which were attributed to capecitabine. When dose level 2 was expanded to 3 additional patients, 2 more patients experienced DLTs (grade 3 mucositis and hand-foot syndrome). Consequently, the combination of nelmastobart 800 mg once every three weeks and capecitabine 1,000 mg/m² twice daily (2 weeks on 1 week off) was established as the MTD/RP2D in patients with mCRC. The most common AEs were hand-foot syndrome (n=4), nausea (n=3) and stomatitis (n=2) which were related with capecitabine. Four patients experienced grade 1 fatigue, which was considered to be related to nelmastobart. Two patients (16.7%) out of 12 showed partial response and 8 patients have maintained stable disease for more than 4 months among 9 patients who had a median follow-up of more than 4 months (as of August 30). Conclusions: The combination of hSTC810 and capecitabine is well tolerated at the MTD, without unexpected AEs and shows promising antitumor activity in patients with heavily treated mCRC. The phase 2 study is currently in progress. Clinical trial information: NCT0599054 .
A method for classifying colorectal cancer and gastric/esophageal cancer using blood-based testing.
Authors: Elmira Forouzmand, Rachel Gittelman, Alan Selewa, Meromit Singer, Theresa Hoang, Yupeng He, Darya Chudova, AmirAli Talasaz
Journal: Journal of Clinical Oncology (2025)

52 Background: Identifying the cancer signal of origin is of great value in the clinical use of blood-based cancer testing, especially in those tests that have potential to assess for more than one cancer type. Thus, an approach that can accurately identify cancer signal of origin in order to guide subsequent diagnostic workup is impactful to the adoption of this new technology. Here, we report feasibility data using the DNA methylation signature of plasma cell-free DNA to differentiate between colorectal cancer (CRC) and gastric/esophageal cancer (GEC) types. Methods: We developed an algorithm to distinguish between CRC and GEC based on the DNA methylation signature of plasma cell-free DNA molecules from more than 3,000 differentially methylated regions. First, a regression model (a multi-cancer classifier) was trained to identify the samples with sufficient tumor derived methylation signal using 6,822 cancer samples of 24 cancer types and the samples from 4,423 cancer-free individuals. A second regression model (a CRC/GEC classifier) was trained to distinguish CRC from GEC cases on the samples with positive calls from the multi-cancer classifier. The second model was trained on methylation signals from advanced stage CRC samples, advanced stage GEC samples (including esophageal, gastroesophageal, and gastric cancers), and samples from cancer-free individuals. Results: The multi-cancer classifier identified 92% (2,954/3,204) of CRC and GEC samples as positive at 90% target specificity, including 93% (2,086/2,253) of CRC samples and 91% (868/951) of gastric/esophageal cancer samples. The performance of the CRC/GEC classifier is evaluated through 10-fold cross validation on these 3,204 cancer samples, where in each fold, an additional 6,298 samples from cancer-free individuals were also used in training. Among the 2,954 CRC and GEC samples detected by the multi-cancer classifier, 2,698 (91%) were accurately classified by the CRC/GEC classifier. Among the detected CRC samples, 91% (1,907/2,086) were correctly classified as CRC. Similarly, 91% (791/868) of the detected GEC samples were correctly classified. The precision of the CRC/GE prediction was also assessed and 91% (2,698/2,954) of the detected cancer samples were correctly classified. Of the 1,984 detected cancer samples predicted as CRC, 96% (1,907/1,984) were true CRC samples. Of the 970 detected cancer samples classified as GEC, 82% (791/970) were correct. Conclusions: This assay with high sensitivity and accurate CRC/GEC classification can effectively guide subsequent diagnostic workups following a positive result, maximizing potential clinical utility. Ongoing work will continue further refinements.
Clinical validation of plasma circulating-tumor DNA assay using highly sensitive Safe-SeqS technology for detecting <i>RAS</i> and <i>BRAF</i> V600E in metastatic colorectal cancer.
Authors: Yu Miyashita, Hideaki Bando, Jun Watanabe, Yusuke Suwa, Yoshinori Kagawa, Takeshi Kato, Hiroko Hasegawa, Yoshito Komatsu, Satoshi Yuki, Masako Asayama, Tomohiro Nishina, Akira Inoue, Eiji Oki, Hiroya Taniguchi, Takashi Ohta, Daisuke Kotani, Hiromichi Nakajima, Koji Yamamoto, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2025)

50 Background: We developed a circulating-tumor DNA (ctDNA) test assay for RAS/BRAF mutations using next-generation sequencing-based Safe-SeqS technology. The clinical performance of detecting RAS and BRAF mutations were evaluated versus approved liquid biopsy and tissue testing, respectively. Methods: Metastatic colorectal cancer (mCRC) patients (pts) were enrolled. The concordance of the RAS mutational status in ctDNA between Safe-SeqS assay and OncoBEAM RAS CRC kit, which is approved as a companion diagnostic in Japan, was evaluated using archival plasma samples. The primary endpoints were positive percent agreement (PPA) and negative percent agreement (NPA). The concordance of the BRAF V600E mutational status between plasma-Safe-SeqS assay and tissue-based testing using MEBGEN RASKET-B kit, which is approved as a companion diagnostic in Japan, was prospectively evaluated. The primary endpoints were sensitivity and specificity of Safe-SeqS assay compared to tissue-based testing. Multivariate analysis using LASSO regression model was performed to evaluate the discordance of BRAF V600E mutational status between Safe-SeqS assay and tissue-based testing. Results: In 125 eligible plasma samples, the PPA and NPA for RAS mutational status in ctDNA were 87.1% (95% confidence interval [CI]: 76.1–94.3) and 95.2% (95% CI: 86.7–99.0), respectively. On the other hand, in 103 eligible pts, the sensitivity and specificity of Safe-SeqS assay for BRAF V600E mutational status were 69.2% (95% CI: 48.2–85.7) and 98.7% (95% CI: 93.0–100.0), respectively. Multivariate analysis revealed the baseline longest diameter and the number of lesions in pts with peritoneal and/or lung metastasis were factors associated with discordance. The sensitivity for BRAF V600E mutations increased to 81.0% (95% CI: 58.1–94.6, fisher’s exact test p =0.02) when the 5 pts with lower tumor burden (peritoneal metastasis with the longest diameter &lt;20 mm, and lung metastasis with the longest diameter &lt;20 mm and &lt;10 lesions, according to the previous report [1] ) were excluded. Conclusions: The clinical validity of the ctDNA assay for detecting RAS/BRAF V600E mutations using Safe-SeqS technology was confirmed in pts with mCRC. Careful attention should be paid for mCRC pts with only peritoneal and/or lung metastases having fewer metastases or smaller diameter lesions. 1. Kagawa Y, et al. Clin Cancer Res 2021.
Lenvatinib plus hepatic arterial infusion chemotherapy of oxaliplatin, fluorouracil, and leucovorin versus lenvatinib alone for advanced hepatocellular carcinoma.
Authors: Feng Shi, Zhenwei Peng, Dongdong Xia, Qicong Mai, Meng Wang, Jie Mei, Ming Kuang, Xiaoming Chen
Journal: Journal of Clinical Oncology (2025)

580 Background: Lenvatinib stands out as a first-line therapy for individuals with advanced hepatocellular carcinoma (HCC). Concurrently, hepatic arterial infusion chemotherapy comprising oxaliplatin, fluorouracil, and leucovorin (FOLFOX-HAIC) has emerged as a potential option for those with advanced HCC. It is necessary to investigate the efficacy and safety of lenvatinib plus FOLFOX-HAIC (lenvaHAIC) for advanced HCC in real-world situations. Methods: In this retrospective analysis, 127 consecutive patients underwent lenvaHAIC, while 184 patients received lenvatinib alone as first-line treatment at six Chinese academic centers between January 2019 and June 2022. Following 1:1 propensity-score matching, we established paired cohorts (113 patients in each group) for evaluating survival. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) evaluated by RECIST 1.1 and mRECIST criteria, and safety profiles were compared between the two groups. Results: The lenvaHAIC group exhibited significantly prolonged median PFS and OS than the lenvatinib group (PFS: 12.3 vs. 6.2 months; OS: 25.6 vs. 12.3 months; P &lt; .001 for each). In the propensity-score matched cohorts (113 pairs), both PFS and OS were notably extended in the lenvaHAIC group compared with those in the lenvatinib group (P &lt; .001). Multivariate analysis identified lenvaHAIC treatment as an independent factor for improved PFS (hazard ratio [HR] 0.45; P &lt; .001) and OS (HR 0.38; P &lt; .001). Grade 3-4 adverse events, including nausea, vomiting, diarrhea, thrombocytopenia, and neutropenia, were more prevalent in the lenvaHAIC group. Conclusions: LenvaHAIC may be a promising treatment in patients with advanced hepatocellular carcinoma, demonstrating enhanced OS, PFS, and ORR and an acceptable safety profile.
CD8 <sup>+</sup> T cell proximity analysis of the tumor microenvironment (TME) in patients with pancreatic ductal adenocarcinoma (PDAC) and associated clinical outcomes.
Authors: Matthew Ebia, Anser Ali Abbas, Suzanne Dotson, Omer H.M. Elmadbouh, John Davelaar, Andrew Eugene Hendifar, Arsen Osipov
Journal: Journal of Clinical Oncology (2025)

754 Background: Immunosuppressive cells (cancer-associated fibroblasts [CAFs], tumor associated neutrophils [TANs], M2/M1 macrophages) can influence CD8 + T cell infiltration in the PDAC TME. The spatial proximity of these cells to CD8 + T cells and association with clinical outcomes is not well known. We hypothesize the cell distances between CD8 + T cells and these phenotypes: CXC chemokine receptor 4 (CXCR4) + TANs, CAFs, focal adhesion kinase (FAK) + tumor cells, FAK + M2 and M1 macrophages will correlate with survival outcomes. Methods: Twenty-two stage I/II PDAC patients who consented for tissue collection were stratified into two groups: standard responders (n=11) with overall survival (OS) &gt;2 years and poor responders (n=11) with OS ≤ 2 years. Multiplex IHC was performed on specimens using multiple biomarkers (CD8, CXCR4, CD66b, FAK, FAP, CD68, CSF1R, CD163, EPCAM) to identify cell phenotypes. Comprehensive spatial analysis with HALO software was used to measure mean cell distance between CD8 + T cells and other cells. The mean cell-to-cell distance among evaluable specimens was determined by phenotype. Patients were divided into two groups with average cell distance below or above the mean by phenotype. OS of each subgroup was compared using Kaplan-Meier method. Results: Median OS for standard and poor responders was 47.6 months vs 13.1 months (p&lt;.0001), respectively. There was a higher % of CD8 + T cells closer (&lt;50 µm) to CXCR4 + TANs in standard responders (56% vs 28%, p&lt;.0001). There were no significant differences in CD8 + T cell distance to other phenotypes. Longer survival was seen with average cell distance below the mean when comparing CD8 + T cells to FAK + tumor cells (1274 d vs 742 d, p=.306), to CXCR4 + TANs (854 d vs 442 d, p=.947) and to FAP + FAK + CAFs (890.5 d vs 672 d, p=.662). In contrast, longer survival was seen with a distance above the mean comparing CD8 + T cells to M2 (622 d vs 1274 d, p=.732) and to M1 (613 d vs 1397 d, p=.517) macrophages. Conclusions: Our study shows clinical outcomes may be correlated with spatial distance among TME immune cells in PDAC. Longer survival was seen when CD8 + T cells were closer to FAK + tumor cells, CXCR4 + TANs, and CAFs and further away from M2 and M1 macrophages. Larger cohort analyses may better elucidate the prognostic and biological significance of cell distance among TME phenotypes, which may have potential implications for response to immunotherapy.
Impact of pancreatic tumour biomechanics on diagnosis and post-operative complications.
Authors: Aidan O'Dowling, Michelle Fox, Micheal Hanly, Brian Rodriguez, Dermot O'Toole, Fergal Donnellan, Niall Swan, Stephen Thorpe, Tom Gallagher
Journal: Journal of Clinical Oncology (2025)

756 Background: Around 600 people are diagnosed with pancreatic cancer in Ireland each year, with 90% of these having pancreatic ductal adenocarcinoma (PDAC). Five-year survival for PDAC is around 10%. PDAC upregulates stromal collagen formation which contributes to tissue stiffness. Stiffer pancreatic tumours have worse oncological outcomes due to faster progression and increased chemoresistance. Softer pancreata, conversely, are more likely to develop post-operative pancreatic fistulae (POPF), a significant post-pancreatectomy complication. While incorporated in risk scores, softness is currently determined by subjective intra-operative observation. Methods: Atomic force microscopy (AFM) is the gold standard technique used to measure biomechanics at a cellular length scale. We obtained fine needle biopsies (FNBs) of pancreatic tumours during diagnostic endoscopic ultrasound. This is the first time tissue biomechanics have been measured from pancreatic biopsies. Separately, we applied this technique to pancreatic tumours and adjacent normal tissue following resection. We also assessed collagen organisation in these pancreatic tumours to understand its contribution to the observed mechanical properties. Results: Of the patients with PDAC who underwent FNB, those presenting with metastatic disease had significantly stiffer tumours than those without, 1,490 Pa (SD 2,048.03 Pa) vs 250 Pa (SD 555.06 Pa) (p&lt;0.0001). Neuroendocrine tumours exhibited larger variance compared to PDAC (p &lt; 0.0001), SD 5,885.97 Pa vs SD 1,797.23 Pa. Regarding tumours which have undergone curative resection, tumour stroma is significantly stiffer than both cancer and benign epithelium. The collagen strands in this stroma are straighter, more numerous, and more packed than epithelial tissues. Pancreata which develop post-operative pancreatic fistulae (POPF) are softer than those which do not 96.42 Pa (SD 691.14 Pa) vs 343.99 Pa (SD 1,678.37 Pa). Conclusions: We describe a novel technique to measure the biomechanical properties of pancreatic biopsies. Using this technique, we now have the opportunity to measure these properties for the first time on all pancreatic tumours, including those presenting with unresectable disease. It is possible to distinguish between different types of tumour based on the biomechanical profile of biopsies. Previous ex vivo studies have linked stiffer tumours to a higher metastatic potential, and our results are the first to suggest that this may be true in a human population. In resected tumours, we confirm the anecdotal belief that softer pancreata are associated with POPF. Overall, this research demonstrates that tissue biomechanics has potential diagnostic and prognostic applications in pancreatic cancer.
Real-world safety of trastuzumab deruxtecan with gastric cancer: All-patient post-marketing surveillance study in Japan.
Authors: Hisato Kawakami, Kazuhiro Uchino, Wataru Hashimoto, Kei Muro
Journal: Journal of Clinical Oncology (2025)

399 Background: Interstitial lung disease and pneumonitis (ILD/p) is an important identified risk in the Japanese risk management plan of trastuzumab deruxtecan (T-DXd). In Japan, an all-patient post-marketing surveillance (PMS) study was conducted to investigate the incidence of ILD/p and factors associated with its development among patients with gastric cancer treated with T-DXd in the real-world setting. Methods: This is an observational, multicenter, PMS study (jRCT2001200001) with an observation period of 12 months that enrolled all patients who initiated T-DXd treatment for HER2-positive unresectable advanced or recurrent gastric cancer between Sep 2020 and Dec 2021. All suspected ILD/p events reported by physicians were adjudicated by an independent ILD adjudication committee; events adjudicated as drug-related ILD/p were summarized. The factors associated with the development of adjudicated drug-related ILD/p were investigated using a Cox proportional hazards model. Effectiveness endpoints included best overall response rate according to the RECIST 1.1 and overall survival, which was estimated using the Kaplan–Meier method. Results: The safety analysis set included 1070 patients (77.4% male, 89.9% ECOG performance status ≤1) with median age of 70 years (range: 23-100). Median initial dose and treatment duration of T-DXd were 6.4 mg/kg (range: 3.1-6.4) and 3.9 months (range: 0.7-12.0), respectively.The incidence of any grade, grade ≥3, and grade 5 adjudicated drug-related ILD/p were 9.6% (n=103), 2.8% (n=30) and 1.2% (n=13), respectively. Within 24 weeks from onset, 73.8% of adjudicated drug-related ILD/p had resolved, were resolving, or resolved with sequelae.A multivariate analysis identified that medical history and/or comorbidity of ILD/p [hazard ratio (HR) = 3.372, 95% confidence interval (95% CI): 1.431, 7.840], radiation pneumonitis (HR = 8.523, 95% CI: 2.006, 36.215), COPD or emphysema (HR = 1.962, 95% CI: 1.032, 3.731) and age ≥75 years (HR = 1.648, 95% CI: 1.058, 2.567) were factors of interest associated with the development of ILD/p in patients with gastric cancer. The overall response rate at 12 months post-treatment initiation of T-DXd was 34.2%. Overall survival after 364 days post-treatment initiation of T-DXd was 43.8% (median survival time: 303.0 days). Conclusions: The results suggest that the risk of ILD/p in this PMS study does not differ from that in the Destiny Gastric-01 study, and no new safety concerns were identified. Medical history and/or comorbidity of ILD/p, radiation pneumonitis, COPD or emphysema and age ≥75 years were identified as factors of interest associated with the development of ILD/p in patients with gastric cancer. Further investigation into the identified factors of interest may offer insights into the development of ILD/p among T-DXd treated gastric cancer patients in Japan. Clinical trial information: jRCT2001200001.
Potential effect of the gut microbiome on tumour response to anti-cancer treatment in patients diagnosed with pancreatic ductal adenocarcinoma.
Authors: Andrew Peter Dean, Olivia Rose Comito, Ian Yusoff, Samarth Rao, Mikael Johansson, Suresh Navadgi, Laurence Webber, Yuki Watanabe
Journal: Journal of Clinical Oncology (2025)

757 Background: Chemotherapy is the standard of care for pancreatic ductal adenocarcinoma (PDAC), however, recent research has identified bacteria in the human gut microbiome that may influence patient response to chemotherapy. These bacteria are also present in faeces, and are thought to be representative of the bacteria in the pancreatic ductal system. Preliminary studies have suggested that patients with more advanced PDAC demonstrate lower levels of Firmicutes, and higher levels of Proteobacteria. Additionally, research has shown bacteria in the Firmicutes phylum possess several anti-cancer properties, which may improve patient treatment response, meanwhile, Gammaproteobacteria (Proteobacteria phylum), have been shown to attenuate gemcitabine efficacy and worsen treatment response. Methods: This prospective study involved 14 participants with locally advanced PDAC. Participants received combinations of Gemcitabine, Nab-Paclitaxel, and durvalumab (immunotherapy). Participant tumours were assessed every 8 weeks using radiological imaging according to RECIST v1.1, and serum CA19-9 levels were analysed monthly. Gut microbial profiling was completed on stool samples taken pre-treatment using PacBio HiFi full-length 16S rRNA sequencing. Results: 16S rRNA sequencing identified that of the 4 patients that died due to disease progression, 3 patients had a low Firmicutes abundance, and a high Proteobacteria abundance. The rother patient demonstrated low levels of Actinobacteriota and Bacteroidota, and a low bacterial diversity. One participant showed a significant increase in CA19-9 (1066.7%), and exhibited a low abundance of Actinobacteriota and Bacteroidota, a high abundance of Proteobacteria, and a low diversity. 5 participants demonstrated a significant treatment response (according to CA19-9 and RECIST analysis), with 4 patients showing a high Firmicutes abundance, high levels of Actinobacteriota or Bacteroidota, and low levels of Proteobacteria. The remaining patient demonstrated a low abundance of Firmicutes and Proteobacteria, yet, displayed the highest abundance of Actinobacteriota and Bacteroidota. Conclusions: This exploratory study suggests an association between microbial composition and treatment response, with Firmicutes potentially being associated with an improved treatment response, and Proteobacteria with a worsened response. We believe this study to be one of the first to explore correlation of microbiome with clinical treatment response in PDAC.