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MOF‐derived Carbon‐Based Materials for Energy‐Related Applications
Abstract New carbon‐based materials (CMs) are recommended as attractively active materials due to their diverse nanostructures and unique electron transport pathways, demonstrating great potential for highly efficient energy storage applications, electrocatalysis, and beyond. Among these newly reported CMs, metal–organic framework (MOF)‐derived CMs have achieved impressive development momentum based on their high specific surface areas, tunable porosity, and flexible structural‐functional integration. However, obstacles regarding the integrity of porous structures, the complexity of preparation processes, and the precise control of active components hinder the regulation of precise interface engineering in CMs. In this context, this review systematically summarizes the latest advances in tailored types, processing strategies, and energy‐related applications of MOF‐derived CMs and focuses on the structure‐activity relationship of metal‐free carbon, metal‐doped carbon, and metallide‐doped carbon. Particularly, the intrinsic correlation and evolutionary behavior between the synergistic interaction of micro/nanostructures and active species with electrochemical performances are emphasized. Finally, unique insights and perspectives on the latest relevant research are presented, and the future development prospects and challenges of MOF‐derived CMs are discussed, providing valuable guidance to boost high‐performance electrochemical electrodes for a broader range of application fields.
Survival benefits of adjuvant chemotherapy after surgical resection of para-aortic lymph node metastasis from colorectal cancer: A multicenter retrospective study.
140 Background: Surgical removal of metastasized paraaortic lymph nodes (PALNs) can prolong the survival of certain patients with colorectal cancer (CRC). However, the role of postoperative chemotherapy in such patients remains unknown. Methods: This multi-center retrospective study examined97 patients with PALN metastasis from CRC who underwent surgical resection at 36 centers in Japan between 2010 and 2015. Based on adjuvant chemotherapy (AC) after the lymphadenectomy, the patients were classified into Non-AC and AC groups (27 and 70 patients, respectively). After the exclusion of patients receiving irinotecan, the latter group was further categorized into 5-fluorouracil (5-FU) and oxaliplatin (L-OHP) subgroups (14 and 52 patients, respectively) according to the use of L-OHP. Background characteristics and postoperative survival were compared among the groups. Results: Marked differences were not seen in background characteristics, except for neoadjuvant treatment, between the Non-AC and AC groups. The AC group exhibited better recurrence-free survival (RFS, p = 0.009) and overall survival (OS, p = 0.040) than the Non-AC group. However, RFS and OS of the 5-FU group did not differ from those of the L-OHP group (p = 0.73 and p = 0.92, respectively). Conclusions: AC contributed to the improved prognosis of patients after the removal of PALN metastasis from CRC, but L-OHP did not offer additional survival benefits. Prospective studies comparing Non-AC with 5-FU- and L-OHP-based AC are needed to confirm these findings.
Correlation of tumoral collagen width with overall survival and tumoral collagen straightness with distant recurrence-free survival in patients with pancreatic ductal adenocarcinoma.
779 Background: Quantitative measurements of fibrillar collagen characteristics has been shown to correlate with survival in several types of malignancy. The aim of this study was to determine whether these characteristics correlate with survival in pancreatic ductal adenocarcinoma. Methods: Patients who underwent pancreatic resection for pancreatic ductal adenocarcinoma at an Allegheny Health Network hospital between 1/1/2019 and 12/31/2023, and for whom archived formalin-fixed paraffin-embedded tumor tissue was available, were included in the study. Clinical and pathologic characteristics were collected from the patient's electronic medical record. Survival data included overall survival (OS), local recurrence-free survival (RFS), and distant RFS. One section of tumor per patient was stained with Picrosirius Red and a representative digital image was obtained with a camera attached to a microscope at 100x magnification. Each image was analyzed with CT-FIRE software to determine averages of collagen fiber width, length, straightness, and angle. Descriptive statistics were initially computed. Log-rank tests were also conducted to compare the OS rate and RFS rate between four different groups (width, length, straightness, angle). Each group was divided into high and low groups, using the mean as cutoff. In the end, multivariate Cox regression was conducted by controlling the confounders including sex, perineural invasion, lymphovascular invasion, and presence of lymph node metastasis to examine the hazard ratios of OS, local RFS, and distant RFS for the four collagen fiber metrics. All statistical analyses were performed via SAS 9.4 under alpha level .05. Results: One hundred three patients met the inclusion criteria. Based on the results of log-rank test, OS was significantly different between high and low collagen width groups, p = .0251. The lower width group had higher survival rate than the upper width group. Also, distant recurrence-free survival was significantly different between high and low collagen straightness groups, p = .0053. The lower straightness group had higher distant RFS rate than upper group. The results of multivariate Cox regression were consistent with the Kaplan-Meier curves. Compared to the high collagen width group, the low collagen width group had a 57% lower chance of dying, hazard ratio = 0.43, 95% CI [0.23, 0.78], p = .0056. The low collagen straightness group had a 60% lower chance of distant recurrence than the high collagen straightness group, hazard ratio = 0.40, 95% CI [0.19, 0.85], p =.0163. Conclusions: Quantitative collagen fiber metrics could help identify patients with resected pancreatic adenocarcinoma who are at risk of earlier death and distant recurrence.
The crossover of the bevacizumab and panitumumab survival curves in the PARADIGM study: A clue to time-related effects of bevacizumab on the risk of tumor progression.
159 Background: The PARADIGM study in CRC patients demonstrated a cross over of the bevacizumab survival curve below the panitumumab survival curve at 28 months, followed by a steady decrease of the bevacizumab survival curve below the panitumumab survival curve up to 11% by 5 years. Similar differences were seen in the FIRE3, CALGB-80405 and PEAK trials starting at 20 months, suggesting an unsuspected time-related effect of bevacizumab on patient’s survival starting at about 2 years after its 1st administration. Methods: Review of time related effects of bevacizumab in 1st and 2nd line trials conducted in CRC, breast, ovary and renal cancer showed a significant PFS but no OS survival benefit, with a detrimental effect on survival in the adjuvant setting (AVANT, NSABP-08 studies). Preclinical data on tumor biology, intratumor-heterogeneity, clonal evolution and the cross talk between bevacizumab and the diverse tumor microenvironments, was correlated to the clinical data, in an attempt to explain the time-related effects of the biological. Results: In the NSABP-08 trial, bevacizumab reduced relapse for 6 months, effect diminished and lost at 12 months. At 24 months after bevacizumab's 1st administration, the relapse of the bevacizumab treated population increased steadily over the control. Identical kinetics were shown in AVANT study and metastatic ovarian patients suggesting that these time-related effects of bevacizumab are universal. The biologic explanation of the clinical data is that short-term treatment with bevacizumab (plus chemotherapy) induces initial tumor stasis and shrinkage, followed by selection and emergence of more aggressive and resistant tumor clones, characterized by an accelerated growth, invasiveness and metastasis shifting the overall tumor growth kinetics to a steeper angle. Bevacizumab appears to be effective for the time of its administration, followed by a slow rebound after its discontinuation. The initial survival benefit will be lost at about 20-24 months after its first administration, as clearly demonstrated in the PARADIGM, FIRE-3, CALGB 80405 and the PEAK studies. Conclusions: As bevacizumab benefit persist for about 2 years after its 1 st administration, it explains the "survival benefit" obtained in studies with with median survival of 20 months but not in studies with survivals >30 mo. (PARADIGM, FIRE-3, CALGB 80405 and the PEAK). This phenomenon also explains the crossover of the survival curves in PARADIGM study and the benefits of bevacizumab obtained preferentially in patients with short survival (rt. sided tumors), high tumor burden, and 2 nd and 3 rd line CRC.
Additives‐Modified Electrodeposition for Synthesis of Hydrophobic Cu/Cu <sub>2</sub> O with Ag Single Atoms to Drive CO <sub>2</sub> Electroreduction
Abstract Copper‐based electrocatalysts are recognized as crucial catalysts for CO 2 electroreduction into multi‐carbon products. However, achieving copper‐based electrocatalysts with adjustable valences via one‐step facile synthesis remains a challenge. In this study, Cu/Cu 2 O heterostructure is constructed by adjusting the anion species of the Cu ions‐containing electrolyte during electrodeposition synthesis. Then, Cu/Cu 2 O with tuned nanoarchitectures ranging from dendrites to polyhedrons is achieved by introducing transition metal ions as additives, leading to an adjustable interfacial microenvironment for CO 2 /H 2 O adsorption on the Cu/Cu 2 O electrodes. Additionally, the polyhedral Cu/Cu 2 O catalysts are used as templates for depositing Ag single atoms (Ag SA ), which are known as synergistic active sites for promoting * CO to * COH toward C 2+ products. The prepared Ag SA ‐Cu/Cu 2 O catalyst is evaluated in a flow cell and exhibited a FE C2+ of 90.2% and a partial current density (jc 2+ ) of 426.6 mA cm −2 for CO 2 electroreduction. As revealed by in situ Raman spectra and density functional theory calculations, the introduction of Ag single atoms slows down the reduction of Cu + during CO 2 electroreduction, especially at a high current density. This work provides a promising paradigm for diverse control of the compositions and hydrophobicity of Cu‐based catalysts for selective CO 2 electroreduction to C 2+ products.
A multicenter, prospective phase II trial of second-line aflibercept plus FOLFIRI in patients with metastatic colorectal cancer refractory to anti-EGFR agents (HGCSG1801): Updated analyses.
147 Background: The HGCSG1801 trial evaluated the treatment outcomes of aflibercept (AFL) plus FOLFIRI for patients(pts) with metastatic colorectal cancer (mCRC) refractory to an oxaliplatin-based regimen combined with an anti-EGFR agent. Here we report results of the updated efficacy, safety, and a biomarker analysis. Methods: This was a prospective open-label phase II trial. AFL (4 mg/kg iv) followed by FOLFIRI (irinotecan 180 mg/m 2 , leucovorin 200 mg/m 2 iv, bolus 5-fluorouracil [5-FU] 400 mg/m 2 , and infusional 5-FU 2400 mg/m 2 /46 h) was given every 2 weeks until progression or unacceptable toxicities. The primary endpoint was 6-month progression-free survival (PFS) rate, and the secondary endpoints included overall survival (OS), PFS, overall response rate (ORR), disease control rate (DCR), and adverse events. Angiogenic factors were analyzed in plasma sample using a Luminex multiplex assay using the Cox proportional hazards model. This study was sponsored by the Non-Profit Organization Hokkaido Gastrointestinal Cancer Study Group and supported by a grant from Sanofi. Results: Forty-three pts were enrolled between November 2019 and October 2022. The data cut-off date was April 30, 2024. The 6-month PFS rate was 59.0% (90% confidence interval [CI], 45.8–72.1%). Median PFS and OS were 7.3 months (95% CI, 5.5–11.0 months) and 18.8 months (95% CI, 12.9–26.6 months), respectively. The ORR was 20.9% (95% CI, 10.0–36.0%) and DCR was 88.4% (95% CI, 74.9–96.1%). No deaths and no new safety signals with a causal relation to the study treatment were observed. A biomarker analysis using pretreatment plasma samples showed a trend toward better PFS in pts with low VEGF-A (hazard ratio [HR] 0.40 [95% CI, 0.18-0.91]), TSP-2 (HR 0.40 [95% CI, 0.18-0.88]) or IL-8 levels (HR 0.43 [95% CI, 0.20-0.93]). There was also a trend toward better OS in pts with low levels of TSP-2 (HR 0.30 [95% CI, 0.11-0.81]) or TIMP-1 (HR 0.20 [95% CI, 0.06-0.69]). Conclusions: These updated data further support the activity and manageable safety profile of AFL plus FOLFIRI for pts with mCRC who failed an oxaliplatin-based regimen combined with an anti-EGFR agent. It was suggested the association between some angiogenic factors in plasma samples and the activity of AFL plus FOLFIRI in mCRC. Clinical trial information: jRCTs011190006 .
Utilizing an automated, high-throughput platform to generate comprehensive clinical & molecular datasets to enable a real-world evidence approach for improving care of patients with gastrointestinal malignancies.
816 Background: More than 44,000 patients are seen at MD Anderson Cancer Center annually. However, using the diverse, mostly unstructured, data from these patient encounters has been challenging and required manual chart reviews. In 2018, MD Anderson and Palantir Technologies (Denver, CO) began developing a unified, cloud-based, graphical user interface clinical informatics platform to extract, structure, and integrate data from the different data sources that comprise the electronic health record (EHR). Here, we describe our experience using this novel platform to apply a real-world evidence (RWE) approach to study patients with gastrointestinal (GI) malignancies. Methods: Institutional Review Board approval for retrospective chart review of patients with GI malignancies was previously obtained. The Foundry platform was used to incorporate more than 150 datasets, including structured data elements like lab values, unstructured data as the full text of clinical notes, and natural language processing (NLP) derived datasets. The datasets include unique patient identifiers to allow the merging of demographic, clinical, molecular, and outcomes information. The platform allows processing of the note text through NLP to extract non-discrete data elements into a discrete form. In addition, it continuously updates new data on daily bases, allowing the inclusion of new patients' information in an automated fashion. Results: From 2,013,048 patients with date of diagnosis ranging from 1944 to 2024, we have created datasets for colorectal adenocarcinoma (CRC, >50,000 patients, >8,000 with molecular data), pancreatic adenocarcinoma (PDAC, >13,000 patients), and appendiceal adenocarcinoma (AA, >3,000 patients). More than 50 variables have been integrated, including demographic information, stage, grade, overall survival, and molecular information. Focused manual validation of the automated extraction across the cohorts consistently demonstrated an accuracy of over 94%. Work is underway to extract additional features including DFS and PFS, sites of metastasis, and to build out additional cohorts for biliary tract, upper GI, and neuroendocrine tumors. Initial discovery efforts have already led to multiple publications including discovery of molecular causes of racial and ethnic disparities in CRC, survival impact of KRAS and co-mutations in PDAC, and prognostic utility of serum tumor markers in AA. Conclusions: Utilizing an automated, highly dynamic platform allowed integration of comprehensive datasets for multiparameter oncology data in patients with GI malignancies. This resulted in dramatic acceleration of cohort identification, outcomes analysis, and enabled utilizing a data-driven approach to guide decision making in an effort to enhance and optimize outcomes.
Histopathological growth patterns of gastric cancer liver metastasis and their association with patient prognosis.
484 Background: The histopathological growth patterns (HGPs) of liver metastasis reflect the complicated and varied interactions between tumor cells and the host microenvironment. We studied HGPs of gastric cancer liver metastasis (GCLM) and sought to predict them using radiomic and clinical variables. Methods: Hepatectomy was performed in 62 patients with GCLM at our university hospital between 2011 and 2021. HGPs were evaluated according to international consensus guidelines, and were classified as either desmoplastic HGP (dHGP) or non-dHGP. CD4, CD8, VEGF and CD31 were analyzed by immunohistochemistry. Eight hundred and fifty-one radiomics features were extracted from CT portal venous phase images and the optimal radiomics signature was determined by univariate analysis and LASSO regression. Multivariable regression analyses and ROC curves were used to assess the predictive performance of HGPs with a radiomic and clinical combined model. Results: Among 62 patients, 14 were categorized as dHGP, and 48 as non-dHGP. Non-dHGP vs. d-HGP was associated with higher tumor N stage and CEA level, and with decreased CD8 + T cells, and lower VEGF and CD31 expression. HGP status was independently associated with patient cancer-specific survival (CSS) (P＜0.05) multivariately.Analysis of percent relative contribution revealed that HGP ranked first for CSS (35.9%), ahead of T (28.9%) and N (28.9%) stage. A model with combined radiomic and clinical features demonstrated robust performance with area under the curve (AUC) values of 0.993 and 0.933 in the training and validation sets, respectively. Conclusions: Non-invasive determination of radiomic and clinical features was shown to predict HGPs types. Compared to dHGP, GCLM with non-dHGP exhibited significantly lower immune cell infiltration and decreased angiogenesis. Among features examined in GCLM, HGP was the most robust for prognostication. Univariate and multivariate analysis of prognostic factors for cancer-specific survival. Characteristics Univariate analysis Multivariate rergression analysis HR (95%CI) P HR (95%CI) P Gender ( Women vs Men ) 1.13(0.61-2.09) 0.71 Age ( >60years vs ≤60years) 1.08(0.60-1.70) 0.98 HGP ( non-desmoplastic HGP vs desmoplastic HGP ) 3.63(1.78-7.41) 0.00 3.48(1.37-8.88) 0.01 T stage ( T3-T4 vs T1-T2 ) 2.03(1.08-3.80) 0.03 2.29(1.15-4.58) 0.02 N stage ( N1-N3 vs N0 ) 3.46(1.66-7.23) 0.00 2.54(1.17-5.56) 0.02 CEA ( >5ng/ml vs ≤5ng/ml ) 2.37(1.25-4.48) 0.01 1.56(0.70-3.48) 0.27
Valence Electron: A Descriptor of Spinel Sulfides for Sulfur Reduction Catalysis
Abstract Catalysts are essential for achieving high‐performance lithium–sulfur batteries. The precise design and regulation of catalytic sites to strengthen their efficiency and robustness remains challenging. In this study, spinel sulfides and catalyst design principles through element doping are investigated. This research highlights the distinct role of lattice sulfur sites in lithium polysulfide conversion and emphasizes the differences in catalytic activity between metal and anion sites. The valence electron model as a descriptor can characterize catalytic performance, guiding the design of a (FeCo) 3 (PS) 4 catalyst co‐doped with cation and anion. The (FeCo) 3 (PS) 4 exhibits the highest catalytic performance among spinel catalysts to data, particularly under high sulfur loading conditions. It achieves an initial specific capacity of 1205.9 mAh g −1 (6.1 mAh cm −2 ) at a sulfur loading of 5 mg cm −2 and 1192.7 mAh g −1 (11.9 mAh cm −2 ) at 10 mg cm −2 , demonstrating excellent electrocatalytic performance.
Use of immune repertoire sequencing analysis to detect differences in treatment responses for advanced esophageal squamous cell carcinoma treated with camrelizumab and platinum-based chemotherapy.
488 Background: The study evaluated the efficacy and safety of camrelizumab combined with platinum-based chemotherapy (platinum plus paclitaxel [TP] or fluorouracil [FP] agents) as first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC), and explored potential biomarkers for treatment response using immune repertoire (IR) sequencing. Methods: In this multi-center, prospective cohort study, advanced ESCC patients were treated with camrelizumab and TP or FP chemotherapy. Primary outcome was 1-year progression free survival (PFS). Secondary outcomes included 1-year overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Patients were categorized based on their treatment responses into the non-ORR and ORR groups. IR sequencing was exploratorily performed on the peripheral blood mononuclear cells from 15 patients in each group. Results: From June 2020 to April 2023, 88 out of 98 screened patients were enrolled, with a median follow-up of 15.9 months. The 1-year PFS was 56.8%, OS was 68.2%, ORR was 64.8%, and DCR was 91.1%. Most treatment-related adverse events were grade 1-2, though 12.5% experienced grade ≥3 toxicities. The FP regimen's efficacy was comparable to the TP regimen. The analysis of the complementarity-determining region 3 polypeptide sequences revealed significant differences in amino acid composition between the non-ORR and ORR groups in T-cell receptor beta-chain (TRB) and immunoglobulin heavy chain (IGH) repertoire. Furthermore, the ORR group exhibited a more concentrated distribution of clones within TRB. Two V genes (TRBV29-1 and TRBV4-1) and one J gene (TRBJ1-3) in the TRB region, along with six V genes (IGHV1-45, IGHV3-20, IGHV3-48, IGHV3-49, IGHV4-4, and IGHV5-51) in the IGH region, were differentially expressed between the two groups. Conclusions: Camrelizumab with platinum-based chemotherapy is effective and well-tolerated as first-line treatment in advanced ESCC. IR sequencing may provide insights into the underlying mechanisms influencing treatment response. Clinical trial information: ChiCTR2000037942. Objective response and disease response. Efficacy evaluation Total (N=88) Camrelizumab plus T（n=69） Camrelizumab plus FP (n=19) p 1-year PFS rate 50/88 (56.8%) 39/69 (56.5%) 11/19 (57.9%) 1.000 1-year OS rate 60/88 (68.2%) 47/69 (68.1%) 13/19 (68.4%) 1.000 ORR 57/88 (64.8%) 43/69 (62.3%) 11/19 (57.9%) 0.793 DCR 81/88 (91.1%) 63/69 (91.3%) 15/19 (79.0%) 0.213 ORR group, n (%) 54/88 (61.4%) 43/69 (62.3%) 11/19 (57.89%) 0.793 Non-ORR Group, n (%) 34/88 (38.6%) 26/69 (37.7%) 8/19 (42.1%) 1.000 2-year PFS rate 38/88 (43.2%) 30/69 (43.5%) 8/19 (42.1%) 1.000 2-year OS rate 42/88 (47.7%) 33/69 (47.8%) 9/19 (47.4%) 1.000 *p<0.05, a statistically difference.
The role of stereotactic radiotherapy in brain metastases from gastrointestinal cancer.
181 Background: The incidence of brain metastases from Gastrointestinal primary tumors (GI-BMs) is approximately of 6%. Appropriate management of these patients, who often presents at advanced disease stage, is poorly defined. Stereotactic Radiotherapy (SRT) could be proposed to improve symptoms and extend disease control. The aim of this study is to assess the impact of SRT in this population. Methods: Data from consecutive patients treated for GI-BMs with SRT from March 2015 to March 2024 were retrospectively collected. Dose was expressed as Equivalent Dose in 2Gy Fractions (EQD2). lntra-Cranial Control (IC) and Overall Survival (OS) were calculated from date of SRT to event (intracranial relapse and death respectively) or last follow-up. Results: Fifty-four patients (median age 68 years, range 46-84) accounting for 98 GI-BMs were included. Primary tumors were colorectal and gastro-oesophageal adenocarcinoma in 37 (68.5%) and 17 (31.5%) patients respectively. Eighteen (33%) patients presented with a single GI-BM. Extra-cranial disease was present in 41 (76%) patients, including unresected/relapsing primary tumor in 9 (17%) cases. Detection of BMs occurred at diagnosis in 8 (15%) patients, as first site of relapse in 27 (50%) or as progression of known metastatic disease in 19 (35%) patients. Before SRT, surgery and/or WBRT were performed in 10 (19%) and 5 (9%) patients respectively. For each SRT course a median of 1 (range 1-5) GI-BMs was treated. Dose regimens consisted of 12-30 Gy in 1-5 fractions, to a median EQD2 of 50 Gy 10 (range 22-68). A second SRT course for out-of-field intracranial progression was performed in 7 patients (13%). First- and further chemotherapy lines were administered in 39 (72%) and 15 (28%) patients respectively. IC rate was 88% at 6 months and 70% at 1 year. At univariate analysis (UVA) no variables were correlated with IC. Median OS was 11 months (IC 95% 9-16), 6-months and 1-year OS rate was respectively 76% and 48%. Only systemic treatment beyond first line was correlated with OS at UVA (4 versus 15 months, p=0.02). Two (4%) patients developed mild symptomatic radionecrosis. Conclusions: Onset of GI-BMs can occur at any stage of disease. Despite poor overall outcome, selected patients may benefit from SRT to improve IC, particularly in association with first-line systemic treatment. Multiple SRT courses can be delivered in case of further intracranial recurrence. Symptomatic radionecrosis may occur in less than 5% of cases.
Fruquintinib plus camrelizumab combined with paclitaxel liposome and nedaplatin as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, phase II clinical trial.
445 Background: Camrelizumab in combination with chemotherapy has become a standard of care for the first-line treatment of advanced ESCC. Previous studies have indicated synergistic effect of fruquintinib in combination with chemotherapy or immunotherapy. Hence, we conducted a phase II trial to evaluate the efficacy and safety of fruquintinib plus camrelizumab, paclitaxel liposome, and nedaplatin as a first-line therapy for advanced ESCC. Methods: This is a single-arm, phase II study consisting of a dose-finding and a dose-expansion phase. A total of 33~36 patients aged 18~80 years with previously untreated advanced ESCC and an ECOG PS of 0-2 were planned to be enrolled. The dose-finding phase followed a 3+3 approach in order to determine the recommended phase II dose (RP2D) of fruquintinib for dose expansion. Patients received fruquintinib (3 mg, 4 mg, and 5 mg once daily on days 1-14, starting at 4 mg) orally, plus intravenous camrelizumab 200 mg d1, paclitaxel liposome 135 mg/m 2 d1, and nedaplatin 70 mg/m 2 d1, 21 days as one cycle. A maximum of 6 cycles was conducted, followed by maintenance therapy with fruquintinib in combination with camrelizumab. The primary endpoint was objective response rate (ORR, RECIST 1.1). Secondary endpoints included RP2D, disease control rate (DCR), progression-free survival (PFS), and adverse events (AEs). Results: As of August 24, 2024, 11 patients (9 males) were enrolled with a median age of 66 years (range 50-76). All patients had distant metastases, and the median number of sites of metastasis was 2 (range 1-5). In the dose-finding phase, 3 patients were treated with 4 mg of fruquintinib, and 6 patients were treated with 5 mg of fruquintinib. No dose-limiting toxicities (DLTs) were observed. Thus, the RP2D of fruquintinib was established as 5 mg once daily on days 1-14, 21 days as one cycle. Of the 7 evaluable patients, 6 achieved partial response, and 1 had stable disease. The ORR was 85.7% (95% CI 42.1%-99.6%), and the DCR was 100.0% (95% CI: 59.0%-100.0%). The median PFS was not reached. The most common treatment-related adverse events (TRAEs) were anemia (7/11), hypercholesterolemia (6/11), hypoalbuminemia (5/11), oral mucositis (5/11), hematuria (4/11), hypertension (4/11), fatigue (4/11), constipation (3/11), and neutropenia (3/11). Grade 3 TRAEs were identified in 2 patients, including oral mucositis (2/11), and anemia (1/11). No treatment-related serious adverse events (SAEs) or deaths occurred. Conclusions: The combination of fruquintinib, camrelizumab, paclitaxel liposome, and nedaplatin demonstrated significant efficacy and manageable toxicity profiles as a first-line treatment for advanced ESCC, suggesting a potential new treatment strategy. Clinical trial information: NCT06010212 .
Updated results of the PATH study: Adjuvant therapy with donafenib plus a PD-1 inhibitor for patients with hepatocellular carcinoma at high risk of recurrence after resection.
571 Background: There is no universally accepted standard treatment option or strategy for post-surgery adjuvant therapy in hepatocellular carcinoma (HCC). Among BCLC A/B patients (pts) with MVI, adjuvant transarterial chemoembolization has been reported to provide a 1-year recurrence-free survival (RFS) rate of around 60-70%. We conducted a pilot study to explore the utility of donafenib combined with a PD-1 inhibitor as adjuvant therapy for pts at high risk of recurrence. Herein, we present the updated results with a median follow-up of 11.6 months. Methods: It was planned to enroll 30 HCC pts who had undergone radical surgery and presented with at least one of the following risk factors: a) Presence of microvascular invasion (MVI); b) Presence of satellite nodule(s); c) More than three tumor nodules; d) Portal vein tumor thrombus. Pts with invasion of the main portal venous system were excluded. Donafenib combined with a PD-1 inhibitor (i.e., toripalimab) was initiated at 4 to 8 weeks post-resection and was to be continued for up to six months, unless recurrence occurred or there was an intolerable adverse reaction. No other adjuvant therapies were permitted before enrollment and during the study, except for anti-virus treatment. The primary endpoint was the cumulative 1-year RFS rate. The secondary endpoints included overall survival, quality of life (QoL) measured with the FACT- Hepatobiliary questionnaire, and safety. Results: From June 2020 to November 2023, a total of 30 pts were recruited. 27 pts were included in the efficacy analysis. The median time from surgery to enrollment was 1.4 months. MVI was the most common risk factor (n=25, 92.6%). The majority of the pts had only one risk factor (n=23, 85.2%). As of the data cutoff on August 13, 2024, relapse had occurred in four pts and the median RFS was not reached. The 1-year RFS rate was 81.6% (90% CI, 67.8%-95.4%) in all evaluable pts. QoL showed a mild increase from baseline while on adjuvant therapy. No deaths were observed. In the 30 pts who had received at least one dose, the incidence of any grade and grade 3 treatment-related adverse events (TRAEs) were 90.0% (27/30) and 40.0% (12/30), respectively. No grade 4 or 5 TRAEs were reported. The grade 3 TRAEs occurring in at least two pts were palmar-plantar erythrodysesthesia syndrome (13.3%), rash (13.3%), increased alanine aminotransferase (10.0%), and increased aspartate aminotransferase (6.7%). Conclusions: The study's duration exceeded expectations due to slow recruitment. Nonetheless, it showed a promising outcome with a regimen of 6 months of adjuvant therapy with donafenib plus toripalimab in BCLC A/B pts at high risk of recurrence. An improvement in QoL was observed among patients during the adjuvant therapy. No new safety issues were identified. Clinical trial information: NCT04418401 .
Genetic mutations and cytotoxic chemotherapy response for advanced solid tumors: A detailed analysis using the C-CAT database in Japan.
130 Background: Chemotherapy regimens are selected based on information about the primary organ or its histological type and are administered based on the results of previous clinical trials. Even now, as cancer genomic research has progressed and precision medicine, which optimizes therapeutic interventions based on tumor genome profiling using next-generation sequencing(NGS), has become standard treatment, cytotoxic anticancer drugs still remain key drugs. We examined the real-world database of genomic and clinical information established by the national central datacenter, the Center for Cancer Genomics and Advanced Therapy (C-CAT) to systematically analyze the effects of mutations across multiple cancers and therapies. Methods: This study delineated the association between genetic mutations and the therapeutic efficacy of cytotoxic chemotherapy in advanced solid tumors in a real-world Japanese clinical context. We incorporated data from 15,474 patients enrolled in the C-CAT database between June 2019 and June 2022. We analyzed the overall response and time to next treatment (TNT) for genetic alterations and five categories of cytotoxic anticancer drugs in gastrointestinal cancers. Results: In the C-CAT data, gastrointestinal cancers were frequently registered, with colorectal cancer being the most common, followed by pancreatic cancer, esophageal/gastric cancer, and biliary tract cancer. For platinum-based drugs, in colorectal cancer, the presence of gene X was associated with not only a higher response rate but also a longer TNT (hazard ratio 0.82, p<0.001). In the case of colorectal cancer and pancreatic cancer with KRAS gene mutations, the ORR was low, and the TNT was also short in the case of pancreatic cancer (hazard ratio 1.33, p<0.001). Interestingly, when BRCA2 genes are mutant, TNT tended to be longer in many organs, suggesting that platinum-based drugs are effective across organs in carcinomas with BRCA2 mutations. Additionally, gene X showed differences in efficacy not only for platinum but also for antimetabolites and topoisomerase inhibitors. Moreover, KRAS mutation was observed in almost all pancreatic cancers and was a treatment-resistant mechanism for all platinum drugs and antimetabolites. Conclusions: This study demonstrated that the effects of cytotoxic anticancer drugs differ depending on genetic mutations. When determining chemotherapy regimens, considering not only the organ but also genetic mutations may enable more efficient drug selection.
Preliminary results of benmelstobart plus anlotinib combined with SOX in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma with low PD-L1 expression: A single-arm, multicenter phase II clinical trial.
444 Background: First-line chemotherapy for advanced HER2-negative gastric/gastroesophageal (G/GEJ) adenocarcinoma has limited efficacy. PD-1 inhibitors plus chemotherapy show promise but need improvement, especially for patients (pts) with low PD-L1 expression. Anlotinib, a multi-targeted TKI for tumor angiogenesis/proliferation, is approved in China. This study aims to evaluate the efficacy and safety of benmelstobart a PD-L1 blockade) in combination with anlotinib and SOX (S-1 plus oxaliplatin) as a first-line regimen for advanced G/GEJ adenocarcinoma in patients with low PD-L1 expression, Preliminary findings will be reported promptly. Methods: Pts with HER2-negative, unresectable, locally advanced, or metastatic G/GEJ adenocarcinomas and a PD-L1 Combined Positive Score (CPS) < 5, who had not received prior systemic therapy were included. They received benmelstobart (1200mg, iv, d1, q3w) combined with anlotinib (10mg, po, d1~14, q3w), oxaliplatin (130mg/m 2 , d1, iv, q3w) and S-1 (40mg, po, bid, d1~14, q3w) for 6 cycles as initial therapy. Maintenance therapy with benmelstobart (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) followed for non-progressive diseaseuntil PD or unacceptable toxicity occurred. Tumor responses were evaluated by RECIST 1.1 criteria. The target sample size was 37, with ORR as the primary endpoint, and safety, DCR, DoR, PFS, and 1-year OS rate as secondary endpoints. Results: From Jun 2023 to Sep 2024, 28 pts were enrolled and 27 were available for efficacy and safety evaluation. The patients’ characteristics were as follows; median age (range): 59 (38-77) years, Male/Female: 19 (70%)/8 (30%), ECOG PS 0/1: 2 (7%)/25 (93%), Surgical history yes/no: 6 (22%)/21 (78%), CPS: ＜1/ ≥1: 4 (15%)/23 (85%), respectively. In the response assessment, 19 PR (70.4%), 6 SD (22.2%), and 2 NE (7.4%) were observed, yielding an ORR of 70.4% (95% CI: 49.8-86.2) and DCR of 92.6% (95% CI: 75.7-99.1). As of September 17, 2024, 6 of 27 patients discontinued (3 due to PD, 3 voluntary), leaving 21 ongoing. The longest DoT was 15.08 months, and the median PFS was not reached. Common TEAEs ≥10% included thrombocytopenia (37%), anemia (33%), leukopenia (22%), HFS (19%), fatigue (15%), liver function abnormalities (15%), and appetite loss (11%). Grade ≥3 TEAEs were thrombocytopenia (4%) and anemia (4%). Conclusions: Preliminary findings indicate that the combination of benmelstobart and anlotinib with the SOX regimen as a first-line treatment for advanced G/GEJ adenocarcinoma with low PD-L1 expression demonstrates promising therapeutic efficacy and tolerable adverse events. Further validation of these results in a larger, consecutive patient population is warranted. Clinical trial information: ChiCTR2400085396.
The efficacy of anti-EGFR therapy across different lines of treatment in <i>RAS</i> wild-type left-sided metastatic colorectal cancer.
86 Background: Anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs) are recommended as a first-line treatment in RAS wild-type (RASwt ) left-sided metastatic colorectal cancer (mCRC). However, the efficacy of these therapies across different treatment lines remains unclear. This study aims to evaluate the efficacy of anti-EGFR mAb across first, second, third, and later-line treatments. Methods: We conducted a retrospective analysis of patients diagnosed with RASwt mCRC who received anti-EGFR mAb in all treatment lines at Siriraj Hospital between 2008 and 2023. The impact of anti-EGFR mAb treatment line on progression-free survival (PFS) and overall survival (OS) was determined using the Kaplan-Meier method and compared with the log-rank test. Results: Of the 350 patients with RASwt mCRC receiving anti-EGFR mAb, 33% (115 of 350) were treated in the first-line, while 16%, 45% and 6% were treated in the second-, third- and later-line settings, respectively. Eighty-six percent of patients had left-sided tumors, and anti-vascular growth factors were used in 34% of patients. The median follow-up time was 30.4 months (mo). Among patients with left-sided tumors, those receiving first-line anti-EGFR mAb treatment exhibited a significantly longer mPFS (11.9 mo, 95% CI 7.4-16.3, p<0.001). The mPFS in the second-, third- and later-line settings were 6.1 mo (95% CI 4.6-7.5), 4.9 mo (95% CI 3.8-6.0), and 5.1 mo (95% CI 2.3-7.9), respectively. There were no significant differences in terms of OS across treatment lines (p=0.27). Conclusions: Although first-line treatment with anti-EGFR mAb had the longest mPFS in left-sided mCRC, OS did not significantly differ among treatment lines. Therefore, anti-EGFR mAb can be incorporated as a part of therapy at any line of treatment.
Neoadjuvant therapy in borderline resectable and resectable pancreatic cancer.
735 Background: To improve clinical outcomes in borderline resectable and resectable pancreatic cancer patients, preoperative chemotherapy with or without radiation can be administered. According to NCCN, there is limited evidence to recommend a specific neoadjuvant chemotherapy regimen. The Dutch randomized phase III PREOPANC trial showed that preoperative chemoradiotherapy led to improved disease free survival. We compared overall survival (OS) between two chemotherapy regimens; mFOLFIRINOX (mFOL) and Gemcitabine/nabPaclitaxel (Gem/nabP). Methods: We performed a retrospective analysis of biopsy-proven pancreatic cancer patients from 1/1/2019 to 2/1/2024. We included borderline resectable and resectable pancreatic cancer patients who received neoadjuvant chemotherapy and then underwent pancreatic resection. We divided them into two cohorts: those receiving mFOL and those receiving Gem/nabP. Kaplan-Meier and multivariate Cox regression analyses were performed to analyze OS and rates of R 0 resection amongst the two groups. A p-value < 0.05 was deemed statistically significant. Results: From January 2019 to January 2024, 85 pancreatic cancer patients received preoperative chemotherapy prior to pancreatic resection. 50 patients received mFOL and 35 patients received Gem/nabP. The mean overall survival (OS) for the mFOL group was 1,137 days, while for the Gem/nabP group it was 876 days. The hazard ratio was estimated as 1.692 (confidence interval 0.901- 3.177, p-value 0.10). After matching for pathological stage and grade, preoperative radiation, postoperative chemotherapy, and presence of perineural and lymphovascular invasion, the hazard ratio was 1.981 (p-value 0.065). The R 0 resection rate was 92.1% for mFOL and 82.2% for Gem/nabP. The odds ratio for having negative margins with mFOL compared to Gem/nabP was 2.005 with a p-value of 0.37. Conclusions: Preoperative chemotherapy with mFOL did not demonstrate improved OS compared to Gem/nabP. The probability of achieving negative margins was also similar amongst the two groups. The SWOG S1505 which is a randomized phase II trial comparing perioperative chemotherapy with mFOL versus Gem/nabP in resectable pancreatic cancer patients has also shown similar OS and progression free survival in both groups.
Management trends and outcomes of appendiceal cancers: A National Cancer Database study.
810 Background: Appendiceal tumors encompass a variety of histological types that exhibit different behaviors. The current study aimed to investigate and compare overall survival, predictive factors for overall survival, and management of histological variations of appendiceal tumors. Methods: The National Cancer Data Bank (NCDB) database (2004–2020) was evaluated to include patients with appendiceal tumors histologies including goblet cell adenocarcinoma (GCA), neuroendocrine neoplasm (NEN), non-mucinous adenocarcinoma (NMA), and mucinous adenocarcinoma (MA). Univariate and multivariable analyses were conducted. Results: The GCA, MA, NEN, and NMA groups consist of 6,111, 16,471, 19,199, and 11,065 patients, respectively. The NMA and NEN groups had significantly lowest and higher overall survival compared to other types (p<0.001 for both) (GCC: 143.27 (140.23-146.30), MA: 111.91 (109.996-113.832), NEN: 170.88 (168.56-173.20), and NMA: 101.399 (99.132-103.666) months). The independent predicting factors of worse overall survival were age (HR: 1.03 (1.03-1.04)), black race (HR: 1.24 (1.08-1.43), ref: white race), fourth median income (HR: 0.84 (0.74-0.96), ref: first median), Charleson index comorbidity score (HR: 1.3 (1.22-1.38)), lymphovascular invasion (HR: 1.28 (1.15-1.42)), pathologic stage 2 (HR: 1.32 (1.12-1.57)), stage 3 (HR: 1.99 (1.66-2.40)), stage 4 (HR: 4.20 (3.47-5.07)), ref: stage 1, intraoperative systemic therapy (HR: 0.52 (0.39-0.70)), positive surgical margin (1.55 (1.39-1.73)), number of positive lymph nodes (HR:1.06 (1.05-1.07)), moderately differentiated tumors (HR:1.43 (1.25-1.63)), poorly differentiated (HR: 1.94 (1.69-2.24)), undifferentiated (HR: 1.48 (1.14-1.91)), ref: well differentiated, and NMA type (HR:1.30 (1.10-1.55)). Furthermore, in terms of type of surgery, significantly higher patients of GCA (54.6%) and NMA (55.2%) groups underwent subtotal colectomy compared to other groups. Regarding systemic therapy, significantly higher patients of MA group received intraoperative, and both neoadjuvant and adjuvant therapy compared to other groups. Also, NEN group had significantly higher patients who underwent surgery with laparoscopic approach compared to others. Conclusions: This study reveals that different types of appendiceal tumors have distinct characteristics in regard to overall survival outcomes and treatment approaches. NENs showed the highest survival rates, while NMAs had the lowest. These results underscore the need for personalized treatment strategies for each tumor type to improve patient outcomes.
Impact of tislelizumab + chemotherapy versus placebo + chemotherapy on patient-reported symptoms and overall survival (OS) by programmed death-ligand 1 (PD-L1) expression in advanced or metastatic esophageal squamous cell carcinoma (ESCC): A post hoc analysis of the RATIONALE-306 trial.
366 Background: While improved survival has been previously demonstrated, the impact of immunotherapy on HRQoL in ESCC has not been well examined. Traditional PRO-based analyses in oncology trials, such as time to deterioration (TTD) and mixed models for repeated measures (MMRMs), are limited by discounting recurrent PRO events. Thus, we applied a 3-component joint model (JM) framework to define more clinically interpretable associations between patient-reported symptoms, treatment effects, and OS among subgroups of patients with ESCC from RATIONALE-306, which met its primary endpoint, with PD-L1 expression of ≥1%, ≥5%, and ≥10%. Methods: The final analytic sample included 226 patients in the tislelizumab + chemotherapy arm (T+C), 242 in the placebo + chemotherapy arm (P+C) for PD-L1 ≥1%, 113 in the T+C arm and 103 in the P+C arm for PD-L1 ≥5%, and 168 in the T+C arm and 178 in the P+C arm for PD-L1 ≥10%.From EORTC QLQ-C30 and OES18, 7 keysymptom domains were modeled (GHS, physical functioning, fatigue, dysphagia, pain, reflux, dietary restrictions). PRO data were collected at baseline and at every treatment cycle (up to 6 cycles), then every other cycle, and at safety follow-up, and change from baseline (CFBL) was analyzed. The joint model comprised three components: 1) linear mixed model predicting CFBL symptom scores; 2) Cox proportional hazard model (CPH) for time to OS; and 3) frailty (random effects for recurrent deterioration events [RDEs]) CPH model for time to PRO-based RDEs. Osoba (1998) 10-point threshold was used to define RDEs. Results: Adjusted completion rates were >90% in the ITT population for both arms. Significant T+C treatment effects wereobserved for physical functioning in PD-L1 ≥5% ( P =0.0476), and pain in PD-L1 ≥1% ( P =0.0028) and PD-L1 ≥5% ( P =0.0149) subgroups, but not in PD-L1 ≥10%. For other 5 symptoms (ie, GHS, fatigue, reflux, dysphagia, dietary restrictions), there were no statistically significant differences between treatment arms. However, T+C was associated with significant reductions in the risk of death across all 7 key symptoms and PD-L1 subgroups. As one example, with respect to interaction between pain and OS, T+C was associated with a 22% (HR, 0.78 [95% CI, 0.652-0.931]), 33% (HR, 0.67 [95% CI, 0.515-0.860]), and 47% (HR, 0.50 [95% CI, 0.344-0.720]) reduction in the risk of death in PD-L1 ≥1%, ≥5%, and ≥10%, respectively compared with P+C. Conclusions: In this analysis, the addition of tislelizumab to chemotherapy was associated with significantly less deterioration in multiple PRO symptoms including physical functioning and pain, alongside a lower risk of death, after adjusting for recurring deterioration events using a frailty model across multiple PD-L1 expression subgroups.
A global comparative study on real-world clinical and genomic differences in advanced biliary tract cancer.
628 Background: Biliary tract cancers (BTC) are aggressive malignancies with poor survival outcomes and limited treatment options. This study compared the epidemiological and molecular differences of advanced BTC patients through a global collaboration involving the Mayo Clinic and National Cancer Center Hospital East. Methods: We included patients with advanced BTC who underwent comprehensive tumor molecular profiling who received at least 30 days of systemic therapy. Patients were grouped based on specific alterations. Overall survival (OS) was calculated from the start of first-line therapy until death and compared among subgroups using Cox regression models. Results: 332 (36%) out of 932 patients had at least one actionable mutation : somatic BRCA1/2 mutations N=106, FGFR2 fusions N=61, HER2 amplifications N=65, KRAS G12C/D mutations N=46, IDH1 mutations N=38, and TMB >10 mut/Mb N=16. BRCA1/2 -mutated BTC were more commonly found in older Asian males with intrahepatic tumors and often presented with peritoneal and liver metastases upon initial diagnosis. FGFR2 fusions were more prevalent in younger White females with intrahepatic tumors, while HER2 amplifications were mainly seen in Asian females with gallbladder tumors. KRAS mutations were primarily observed in Asian males, and IDH1 mutations were common in White males with intrahepatic tumors, frequently presenting with liver metastasis. Survival outcomes varied significantly based on the alteration type: patients with FGFR2 fusions had the longest median OS (mOS) at 23.3 months (mo) (95%CI 18.4-34.9), followed by those with IDH1 mutations (19.3 mo; 95% CI 17.4-NE) and TMB >10 mut/Mb (17.8 mo; 95% CI 13.6-NE). BRCA mutations had a mOS of 16 mo (95% CI 14.6-19.8), while HER2 amplifications and KRAS mutations had mOS of 15.5 (95% CI 11.9-20.2) and 11.6 mo (95% CI 10.0-20.9), respectively. Conclusions: These findings underscore the heterogeneity in clinical and genomic characteristics among BTC patients, highlighting the importance of tailored therapeutic approaches. Baseline patient characteristics stratified by mutation status. KRAS G12C/D (N=46) BRCA 1/2 (N=106) IDH1 (N=38) HER2 amplification(N=65) FGFR2 fusion(N=61) TMB>10 mut/Mb(N=16) P-value Median Age, year 67 68 64 66 52 73 <0.001 Female, n (%) 19 (41) 34 (32) 18(47) 34 (52) 45(74) 6 (38) <0.001 Race, n (%) <0.001 Asian 31 (67) 97 (92) 13 (34) 51 (79) 10 (16) 6 (38) White 14 (30) 8 (8) 24 (63) 13 (20) 48 (79) 10 (63) Primary tumor location, n (%) <0.001 Intrahepatic 28 (68) 45 (45) 33 (100) 19 (31) 54(95) 10 (67) Extrahepatic 9 (22) 27(27) 0 (0) 10 (16) 2 (4) 4 (27) Gallbladder 4 (10) 28 (28) 0 (0) 32 (53) 1 (2) 1 (7) Sites of Metastasis at diagnosis, n (%) Abdominal Wall / Peritoneal 9 (24) 15 (19) 4(13) 7 (12) 6 (10) 4 (27) 0.309 Bone 33 (92) 70 (90) 26 (87) 2 (3) 9(15) 0 (0) 0.212 Liver 20 (49) 52 (61) 28 (82) 45 (73) 45 (76) 6 (38) 0.001 Lung 26 (70) 65 (82) 22 (69) 36 (58) 27(45) 11 (69) 0.006