tbuckley/cabot-search huggingface dataset:
First-line regorafenib with nivolumab and FOLFOX or CapeOX in patients with advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: A single-arm, phase Ib/II trial (REGONIVOCTx, EPOC2104).
Authors: Akihito Kawazoe, Tadayoshi Hashimoto, Kota Itahashi, Takuma Irie, Hiromi Ono, Hitomi Tamura, Kyoko Hongo, Takashi Ikeno, Masashi Wakabayashi, Akihiro Sato, Yoshiaki Nakamura, Takao Fujisawa, Izuma Nakayama, Shohei Koyama, Takayuki Yoshino, Hiroyoshi Nishikawa, Kohei Shitara
Journal: Journal of Clinical Oncology (2024)

4052 Background: We previously reported anti-tumor activity of regorafenib plus nivolumab for advanced gastric cancer (AGC) patients at a third or later line (1). Recently, first-line regorafenib with nivolumab and FOLFOX in AGC showed promising results in a phase 2 in the United States. CapeOX requires less frequent outpatient visits than FOLFOX and is preferred in Asian countries. We investigated the safety and efficacy of regorafenib with nivolumab and chemotherapy including CapeOX for AGC in the first-line treatment. Methods: Enrolled patients received regorafenib with nivolumab and CapeOX (Cohort A) or FOLFOX (Cohort B) in the phase Ib part (safety lead-in) to determine the recommended dose. Additional patients were enrolled in the phase II part. Regorafenib of 90 mg was administered once daily for 21 days on/7 days off with nivolumab 360 mg every 3 weeks (Cohort A) or 240 mg every 2 weeks (Cohort B) and chemotherapy. The primary end point was dose-limiting toxicity (DLT) during the first 4 weeks in the phase Ib part and objective response rate (threshold 60%, expected 80%, α = 0.1, β = 0.2) in patients with the recommended dose in the phase Ib/II part. The primary endpoint would be met if at least 22 of 30 patients showed objective tumor response. We also conducted biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: A total of 30 patients (14 in Cohort A and 16 in Cohort B) were enrolled from June 2022 to April 2023. All patients had MSS/pMMR tumors. No DLTs were observed in both cohorts. Objective tumor response was observed in 22 of 30 (73%; 80%CI 60.3-83.8) patients, thus the primary endpoint was achieved. Disease control rate was 97%. Six-month progression-free survival was 66.7% (95%CI 46.9-80.5). The most common grade 3 or worse treatment-related adverse events included neutropenia (33%), AST/ALT increased (13%), hypertension (13%), and leucopenia (7%) without unexpected safety signals. Conclusions: First-line regorafenib with nivolumab and chemotherapy including CapeOX showed anti-tumor activity with acceptable safety profiles in AGC patients. The results of biomarker analysis will be presented. A randomized, phase III trial is planned. 1. Fukuoka S, J Clin Oncol 2020. Clinical trial information: NCT05394740 .
Comparative outcomes of esophageal stent placement in patients with esophageal cancer: A prospective study of 183 cases.
Authors: Dilichukwu Chudy-Onwugaje, Ahmed Elsayed Salem, Bani Roland
Journal: Journal of Clinical Oncology (2024)

4061 Background: Esophageal stent placement is vital for alleviating dysphagia, enabling immediate relief and smoother food passage. This minimally invasive procedure reduces hospital stays, enhancing quality of life and offering a safer option for high-risk patients. Effective in both malignant and benign cases, stents are cost-efficient and require skilled professionals for optimal outcomes. This study examines outcomes of various stent types in 183 esophageal cancer patients, evaluating efficacy, safety, and impact on quality of life. Methods: Between January 2022 and December 2022, 183 patients with esophageal cancer were enrolled from three tertiary health care facilities and divided into three groups based on the type of esophageal stent used: self-expanding metallic stents (SEMS, n = 84), self-expanding plastic stents (SEPS, n = 61), and fully covered self-expanding metallic stents (FCSEMS, n = 38). Stent placement was performed under endoscopic guidance. Follow-up with endoscopic assessments were conducted at 1 week, 1 month, 3 months, and 6 months post-stent placement to evaluate stent patency, dysphagia relief, and complications. Results: The technical success rates for stent placement were high across all groups, with SEMS at 96.4%, SEPS at 95.1%, and FCSEMS at 97.4%. Immediate dysphagia relief was achieved in 87.4% of patients across the three stent types. FCSEMS demonstrated a significantly longer median stent patency duration (8.0 months) compared to SEMS (6.3 months) and SEPS (5.6 months). The SEPS group experienced a higher incidence of stent migration (13.1%) compared to SEMS (8.3%) and FCSEMS (6.5%) groups. Post-interventional complications were documented in 18.0% of patients, with tissue overgrowth (8.7%) and stent migration (6.0%) being the most common. Overall survival rates at 6 months were comparable across the three groups. Notably, FCSEMS displayed superior patency (p &lt; 0.05), suggesting its potential preference in specific cases. The study confirms the effectiveness of stent placement in enhancing patient comfort and quality of life. Conclusions: This study underscores the efficacy of esophageal stent placement as a crucial palliative intervention for dysphagia in esophageal cancer patients. Fully covered self-expanding metallic stents (FCSEMS) exhibited notable advantages, demonstrating prolonged stent patency compared to other types. However, careful consideration is warranted for patients in the self-expanding plastic stents (SEPS) group due to a higher incidence of stent migration. The high technical success rates and immediate dysphagia relief affirm the proficiency and immediate positive impact of this procedure. Overall, this research highlights the importance of tailored stent selection and ongoing investigation to optimize outcomes for esophageal cancer patients.
Perioperative chemotherapy for patients with gastric cancer with microsatellite instability or deficient mismatch repair: A systematic review and meta-analysis.
Authors: Baike Liu, Zhaolun Cai, Yuan Yin, Jingjing Wang, Chaoyong Shen, Xiaonan Yin, Tianxiang Jiang, Yihui Han, Bo Zhang
Journal: Journal of Clinical Oncology (2024)

4039 Background: Currently, the efficacy of perioperative chemotherapy for gastric cancer (GC) patients with deficient mismatch repair or microsatellite instability-high (dMMR/MSI-H) remains controversial. It is still inconclusive whether chemotherapy can be spared for dMMR/MSI-H GC patients. Meanwhile, in the different therapeutic settings (e.g. neoadjuvant, adjuvant, or both), the efficacy of chemotherapy remains to be clarified. Therefore, a systematic review and meta-analysis in this regard was conducted. Methods: Studies comparing perioperative chemotherapy with surgery alone in resectable dMMR/MSI-H GCs (up to December 1, 2023) were included. The hazard ratio (HR) and its 95% confidence interval (CI) of survival outcomes were extracted from the original research or recalculated using Kaplan-Meier curves if the number of patients at risk was provided. In the pooled analysis, a random-effects model was employed. Subgroup analyses (perioperative chemotherapy in stage II and stage III diseases) and sensitivity analysis including studies reporting the results from multivariable analyses were conducted. This study was previously registered on PROSPERO platform (CRD42023494276). Results: Nineteen studies, encompassing over 1500 dMMR/MSI-H GC patients, were included in this study. The results revealed that perioperative chemotherapy (including neoadjuvant and adjuvant chemotherapy) did not significantly improve the overall survival (OS) (HR 0.86, 95% CI 0.57–1.31) and disease-free survival (DFS) (HR 0.70, 95% CI 0.46–1.05) in dMMR/MSI-H GCs. Furthermore, adjuvant chemotherapy did not confer a significant survival advantage for dMMR/MSI-H GCs (OS, HR 0.83, 95% CI 0.50–1.37) and (DFS, HR 0.67, 95% CI 0.41–1.07). Similar results were observed for neoadjuvant chemotherapy (OS, HR 1.09, 95% CI 0.55–2.15). In addition, stage stratification analysis demonstrated no significant survival benefit of adjuvant chemotherapy for stage II (OS, HR 0.77, 95% CI 0.31–1.90) or stage III (OS, HR 0.72, 95% CI 0.36–1.46) dMMR/MSI-H GCs. In the sensitivity analysis, the results remained consistent. Conclusions: Perioperative (including adjuvant and/or neoadjuvant) chemotherapy does not significantly improve survival in resectable dMMR/MSI-H GC patients. Immunotherapy may be better suitable for these patients in the future.
NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Updated overall survival analysis with 29-month follow-up of NAPOLI 3.
Authors: Maen A. Hussein, Gazala Khan, Sreenivasa R Chandana, Roberto A. Pazo Cid, Igor Kiss, Javier Gallego, Teresa Macarulla, Christelle De La Fouchardiere, Thorsten Goetze, Andrew Peter Dean, Eileen M. O'Reilly, Zev A. Wainberg, Woo Jin Lee, Eric Van Cutsem, Richard Hubner, Andrew Scott Paulson, Tanios S. Bekaii-Saab, Shubham Pant, Fiona Maxwell, Davide Melisi
Journal: Journal of Clinical Oncology (2024)

4136 Background: NAPOLI 3 (NCT04083235, N = 770), a global, randomized, open-label phase 3 study, demonstrated that NALIRIFOX significantly improved overall survival (OS, primary endpoint) and progression-free survival compared with nab-paclitaxel and gemcitabine in patients with untreated mPDAC. Here, we report an updated analysis of OS. Methods: Eligible patients with histopathologically/cytologically confirmed untreated mPDAC were randomized (1:1) to receive liposomal irinotecan 50 mg/m 2 + oxaliplatin 60 mg/m 2 + leucovorin 400 mg/m 2 + 5-fluorouracil 2400 mg/m 2 (NALIRIFOX, n = 383) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m 2 and gemcitabine 1000 mg/m 2 (Gem+NabP, n = 387) on days 1, 8 and 15 of a 28-day cycle. Randomization was stratified by ECOG performance status, geographic region and presence/absence of liver metastases. An updated OS analysis (data cutoff: 3 October 2023) was conducted. Kaplan–Meier methods were used to estimate median (95% confidence interval [CI]) OS and hazard ratios (HRs [95% CI]) were estimated using stratified Cox proportional hazard models. The difference between groups was tested using a stratified log-rank test. Results: The median follow-up for OS was 28.7 months in the NALIRIFOX arm and 29.7 months in the Gem+NabP arm. At data cutoff, 11 patients were still receiving study treatment, all of whom were in the NALIRIFOX arm. With a total of 673 OS events (NALIRIFOX, n = 328; Gem+NabP, n = 345), median OS was 11.1 months (95% CI 10.0–12.1) in the NALIRIFOX arm compared with 9.2 months (8.3–10.6) in the Gem+NabP arm (HR 0.84 [95% CI 0.72–0.98]; nominal p = 0.026). At 12 months and 18 months, survival rates were 45.6% (95% CI 40.5–50.5) and 26.6% (22.2–31.1), respectively, in the NALIRIFOX arm and 39.6% (34.7–44.5) and 20.0% (16.1–24.1), respectively, in the Gem+NabP arm. Conclusions: In this 29-month follow-up of NAPOLI 3, NALIRIFOX continued to demonstrate improved OS compared with Gem+NabP, with 11 patients still receiving the NALIRIFOX regimen. These data confirm NALIRIFOX as a new possible standard of care and reference regimen for the first-line treatment of patients with mPDAC. Clinical trial information: NCT04083235 .
Neoadjuvant therapy using PD-1 inhibitor plus chemotherapy with different intervals between chemotherapy cycles for locally advanced gastric or gastroesophageal junction cancer: A randomized phase 2 study.
Authors: Quanli Gao, Lingdi Zhao, Weijie Zhao, Zibing Wang, Peng Qin, Zhiqiang Jiang, Jinxi Huang, Bin Zhang, Zhimeng Li, Qiang Fu, Yuzhou Zhao, Yingkun Ren, Chuang Shang, Xiangbin Wan, Yang Gao, Yongchao Xu, Long Yuan, Chaomin Lu, Zhi Li
Journal: Journal of Clinical Oncology (2024)

4064 Background: To explore the influence of reducing dose-intensity of chemotherapeutic agents by prolonging the interval of chemotherapeutic cycles on clinical efficacy, especially when combined with immune checkpoint inhibitors, we conducted a single-center, prospective, randomized, phase II exploratory study in patients with locally advanced gastric or gastroesophageal junction (G/GEJ) cancer. Methods: Patients were randomly assigned to receive either toripalimab plus FLOT regimen for four biweekly cycles or three triweekly cycles before the operation. The primary endpoint was pathological complete response (pCR) rate, the secondary endpoints were major pathological response (MPR) rate, event-free survival (EFS), and safety. Results: 70 patients were enrolled; of these, 69 were eligible for inclusion. The overall pCR rate was 26.1% and the MPR rate was 55.1%. There were no statistical differences in pCR rates and MPR rates between the two groups. Although no statistical differences were found among the subgroups, the pCR rate for patients with PD-L1 CPS ≥1 was 42.1% (8/19) while 6.7% (1/15) for PD-L1 CPS&lt;1 in the triweekly group ( P=0.047). Analysis of lymphocyte subsets in peripheral blood showed that CD3+CD8+PD-1+Ki-67+ T lymphocyte absolute counts were elevated in triweekly group and reduced in biweekly group before the second and third cycle of therapy. The incidence rates of pyrexia and myelosuppression in the biweekly group were higher than those in the triweekly group. Conclusions: These data support the idea that the efficacy of toripalimab plus FLOT, given triweekly for three cycles, was not inferior to its administration biweekly for four cycles in locally advanced G/GEJ cancer. The finding is particularly significant for those with PD-L1 CPS ≥1 and warrants further validation. Clinical trial information: NCT04891016 .
Neoadjuvant dual checkpoint inhibition followed by immune-chemoradiation in patients with resectable gastric adenocarcinoma.
Authors: Cindy M. Pabon, Lianchun Xiao, Brian D. Badgwell, Paul F. Mansfield, Naruhiko Ikoma, Matheus Sewastjanow-Silva, Jeffrey H. Lee, Manoop S. Bhutani, Brian Weston, Emmanuel Coronel, Grace L. Smith, Emma Holliday, Jessie Tian, Prajnan Das, Bruce D. Minsky, Rebecca E Waters, Jeannelyn Estrella, Jenny Jing Li, Jaffer A. Ajani, Mariela A. Blum Murphy
Journal: Journal of Clinical Oncology (2024)

4067 Background: Localized gastric cancer is a potentially curable condition and long-term outcomes depend on YP staging. Currently, preferred adjunctive therapy depends on geographic location. Preliminary data from NCT01928394 have shown promising clinical activity of immunotherapy (IO) agents nivolumab (nivo) +/- ipilimumab (ipi) in the metastatic setting. We conducted a single-arm study using IO + chemotherapy followed by immune-chemoradiation prior to surgery, followed by adjuvant IO, in patients with localized gastric adenocarcinoma. Our primary objective was to determine safety and toxicity with this approach. Secondary objectives included efficacy by YP staging and R0 resection rate. Methods: Patients with localized gastric adenocarcinoma were enrolled into NCT03776487 (n=30). Participants received the following: (1) biweekly chemotherapy with 4 doses of 5-Fluorouracil (5-FU)/Oxaliplatin, (2) nivo 240mg q2weeks (x3) and ipi 1mg/kg q6weeks (x1), (3) immune-chemoradiation (biweekly nivo + 5FU Mon-Fri concurrently with a total of 45 Gy given in 25 fractions), and (4) surgical resection. Those with residual disease received adjuvant nivolumab monthly for 6 doses. Correlative studies are planned. To assess preliminary efficacy, the clinical and pathologic complete response rates (pCR) were estimated along with the corresponding exact 95% confidence interval. Adverse events and toxicities were summarized using descriptive statistics. Results: Median follow-up was 27.4 months at the time of data cutoff. Of 30 enrolled, 23 patients completed surgery and seven did not due to progression of disease(n=5) and worsening co-morbidities(n=2). The side effect profile was similar to prior IO studies, with no grade 5 events observed. Three patients (10%) experienced grade 4 events (acute kidney injury, myocarditis, and neutropenia). The most frequent grade 3 toxicity was nausea and vomiting (10%). From the 23 participants that underwent resection, 22 had pathologic data at the time of analysis, with 9 achieving ypT0ypN0 (40.9%, 95% CI: 20.7%, 63.7%). There was an 86% R0 resection rate. Conclusions: Our results are encouraging and support further development of this strategy for localized gastric adenocarcinomas. The regimen is safe and potentially generalizable. Clinical trial information: NCT03776487 .
Neoadjuvant immunotherapy (PD-1) combined with chemotherapy for locally advanced thoracic esophageal carcinoma (EC): A single-arm, open-label, phase II study.
Authors: Qi Wang, Siyou Deng, Qian Shen, Ni Zhang, Li Zhang
Journal: Journal of Clinical Oncology (2024)

4075 Background: This study aimed to evaluate the efficacy and safety of PD-1 combined with chemotherapy as neoadjuvant therapy in patients with locally advanced EC and sought to explore biomarkers related to treatment prognosis and efficacy prediction for screening patients who would benefit most from this therapy. Methods: In this phase 2 study, patients (pts) with histopathologically confirmed ESCC, diagnosed as clinical stage cT 1-3 N 1-3 M0 and ECOG PS 0-1 were enrolled to receive two cycles of neoadjuvant chemoimmunotherapy with PD-1 blockade (Pembrolizumab/Tislelizumab on d1) plus nab-paclitaxel (260mg/m 2 in total on d1 and d8) and cisplatin (60mg/m 2 in total on d1-3) of each 21-day cycle, followed by esophagectomy. Biopsied pretreatment tumor tissues along with surgical tumor specimens were collected for RNA sequencing. The primary endpoint was complete pathologic response (pCR) rate. The secondary endpoints were overall response rate (ORR), event-free survival (EFS), overall survival (OS) and safety. Biomarkers associated with clinical prognosis were assessed as exploratory objectives. Results: From Jan 11, 2021 to, Apr 25 2022, 56 pts were enrolled and 42 pts received neoadjuvant therapy and operation. Among them, 66.7% (28/42) had clinical complete response, 50% (21/42) had partial response, and ORR was 78.6% (33/42). 42 pts underwent surgical resection, achieving a 100% (42/42) R0 resection rate and a pCR rate of 33.3% (14/42), tumor regression grade (TRG, Mandard system) 1, 2 and 3 were 14.3% (6/42), 14.3% (6/42) and 71.4% (30/42) respectively. With a median follow-up of 24.4 months (range 14.3-33.4), 12(28.6%) patients had disease recurrence. Within 24 months, 14.3% (2/14) pts who achieved pCR experienced recurrence. 2-year EFS rate was 54.8% (95%CI,43.4, 66.3% ), 2-year OS rate was 81.5% (95%CI,69.4, 90.2% ). Overall, grade ≥3 AEs included leukopenia (11.9% [5/42]), thrombocytopenia (4.8% [2/42]), and no deaths were due to TRAEs. With 34 patients of RNA sequenced, we divided the patients into two groups based on whether they had recurred within 24 months as favorable prognosis and poor prognosis respectively, to analyze gene expression in different treatment effect. The poor outcome patients had significant molecular differences were seen in PI3K−Akt pathway gene expression, markers of immune activation, and genes involved in ECM−receptor interaction and focal adhesion in baseline samples, and the pathway enriched by differential genes expression in samples after treatment validated this result. Conclusions: Combining PD-1 blockade with nab-paclitaxel and cisplatin is feasible and effective in patients with locally advanced resectable ESCC, and might be a promising approach for neoadjuvant treatment. Clinical trial information: NCT05028231 .
Fragmentomics of cell-free DNA as a sensitive biomarker for early detection of pancreatic cancer.
Authors: Lingdi Yin, Cheng Cao, Jianzhen Lin, Kai Zhang, Yunpeng Peng, Cheng Xu, Ruowei Yang, Dongqin Zhu, Fufeng Wang, Shuang Chang, Hua Bao, Feng Guo, Min Tu, Jianmin Chen, Jishu Wei, Junli Wu, Wentao Gao, Yi Miao, Zipeng Lu, Kuirong Jiang
Journal: Journal of Clinical Oncology (2024)

4173 Background: Pancreatic ductal adenocarcinoma (PDAC) is one for the most lethal types of cancer. Nearly 80% of the PDAC patients are diagnosed at advanced unresectable stages. Therefore, an accurate early diagnosis assay is urgently needed for reducing PDAC related mortalities. In this study, we aim to utilize cfDNA fragmentomics and machine learning techniques for sensitively detecting PDAC patients. Methods: Total647 cases were prospectively enrolled in this study. Plasma samples were collected from each participant for shallow WGS (~5X). After quality control process, 166 PDAC patients and 167 healthy controls were enrolled as a training cohort. Additional 112 PDAC patients and 111 healthy controls were included as an independent validation cohort. Additional 67 cases with pancreatic benign cystic tumors were also enrolled for model validation including IPMN (Intraductal papillary mucinous neoplasms), MCN (Mucinous cystic neoplasms) and SCN (Serous cystic neoplasms). Four fragmentomics profiles, including copy number variation, fragment size, mutation signatures, and FRAGmentomics-based Methylation Analysis (FRAGMA) were utilized by a machine learning algorithm for developing a predictive model. Results: The predictive model showed an exceptional performance to distinguish PDAC patients from healthy controls, yielding Area Under the Curve (AUC) of 0.993 in the training cohort (5-fold cross validation) and 0.990 in the validation cohort. In the training cohort, our model was capable of detecting PDAC patients at sensitivity of 95.8% and specificity of 95.2% while using 0.49 as cutoff. The validation cohort achieved 99.1% sensitivity at 91.0% specificity while applying the same cutoff. Conclusions: Our model was able to accurately detect PDAC at early stages, by incorporating fragmentomics features through machine learning. It can potentially be used for PDAC early screening, and therefore reducing PDAC related mortalities.