Stable Disease Research Articles

Ruxolitinib for pediatric acute and chronic graft-versus-host disease: a single-center retrospective study of efficacy and safety

Abstract Graft-versus-host disease (GVHD) is a major concern for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Ruxolitinib has been proven effective in treating adult steroid-refractory GVHD; however, studies on pediatric patients are relatively scarce. Thus, this single-center study evaluated the efficacy and safety of ruxolitinib in pediatric patients with steroid-refractory GVHD. We retrospectively reviewed the data of patients aged < 18 years who underwent allogeneic HSCT and received ruxolitinib treatment for either acute GVHD (aGVHD) or chronic GVHD (cGVHD) between 2018 and 2023. Data on the clinical response, concomitant and subsequent medications, adverse events, and outcomes were obtained through medical chart review. Sixteen patients were analyzed in this study: seven with aGVHD and nine with cGVHD. The overall response rate for the 16 patients was 81% (aGVHD, 86%; cGVHD, 77%). The overall survival rate was 56%: (aGVHD, 57%; cGVHD, 55%). For 11 patients with at least stable disease, steroid dosage could be reduced by at least 75%; however, corticosteroids were successfully tapered off in only six patients at the last follow-up. Among four patients with documented lung cGVHD, none experienced lung cGVHD progression at 1-year follow-up. Further, 50% of the patients experienced grade 3 or 4 neutropenia and/or thrombocytopenia, and 56% had viral reactivation. Two patients discontinued ruxolitinib owing to adverse events. Ruxolitinib treatment for pediatric patients with aGVHD and cGVHD is associated with a high overall response rate, significant steroid-sparing effect, acceptable toxicity, and manageable adverse events. However, blood count and viral reactivation should be closely monitored during ruxolitinib use.

Potential radiotherapy-related reactivation of immune checkpoint inhibitor hepatitis.

This report details the reactivation of immune checkpoint inhibitor (ICI)-related autoimmune hepatitis triggered by stereotactic body radiation therapy (SBRT) in a55-year-old male with hilar cholangiocellular carcinoma. Initially diagnosed in December 2021, the patient underwent successful resection and subsequent adjuvant therapy. Despite stable disease following chemotherapy augmented with durvalumab, he developed grade3 acute hepatitis after seven cycles of durvalumab. Following abrief prednisolone regimen and normalization of liver tests, SBRT targeting para-aortic lymph nodes was initiated. Remarkably, severe hepatitis reoccurred 7days after starting SBRT, 88days following the last durvalumab infusion, necessitating resumed and escalated prednisolone treatment. Another course of SBRT for anewly diagnosed metastatic liver lesion was administered in September 2023, with ongoing prednisolone adjustment. By February 2024, liver tests normalized, but subsequent radiological assessments indicated tumor progression, leading to the reintroduction of chemotherapy. This case underscores the potential of SBRT for activating severe immune-mediated hepatotoxicity in patients treated with ICIs, highlighting the need for careful monitoring and management of such patients. Further, this report highlights the possible survival benefit of the strategic application of SBRT in addition to systematic treatment in recurrent and metastatic cholangiocellular carcinoma.

PIVKA-II as a surrogate biomarker for therapeutic response in Non-AFP-secreting hepatocellular carcinoma.

Alpha-fetoprotein (AFP) is a key biomarker for hepatocellular carcinoma (HCC), but 30-40% of cases are AFP-negative. Prothrombin induced by vitamin K absence II (PIVKA-II) is more sensitive for HCC detection, though its role in systemic therapy remains underexplored. This study aimed to evaluate PIVKA-II in non-AFP-secreting HCC treated with systemic therapy. Patients with unresectable HCC undergoing systemic therapy were enrolled. Baseline imaging and PIVKA-II levels were recorded. After 8-12 weeks of treatment, response was evaluated through imaging and repeat PIVKA-II measurements. A total of 116 treatment assessments from 61 cases were analyzed. Baseline PIVKA-II levels correlated with tumor size, but not tumor number or liver function. PIVKA-II regression (≥ 50% reduction) and progression (≥ 50% increase) were defined using ROC analysis. Imaging showed 71.0% objective response in the regression group, 50.0% stable disease in the stable group, and 83.7% progressive disease in the progression group (p < 0.001). This association held for targeted therapies, immune checkpoint inhibitors, and chemotherapy. Progression-free survival (PFS) for the regression, stable, and progression groups was non-reached, 6.7, and 3.2 months (p = 0.0002), and overall survival (OS) was non-reached, non-reached, and 18.5 months (p = 0.02). This study is the first to establish the "50-50 rule" for PIVKA-II response in non-AFP-secreting HCC treated with systemic therapy, highlighting its value as a surrogate marker for radiological outcomes and prognosis.

Electrochemotherapy in metastatic epidural spinal cord compression: a review and technical update.

This review aims to analyse the safety and clinical efficacy in terms of pain relief and local tumour control, in patients with metastatic epidural spinal cord compression undergoing electrochemotherapy (ECT). Moreover, a recommendation detailing optimal electrodes insertion is proposed with the intent of improving treatment planning. Clinical studies published between 2015 and 2023 were included since this time window is consistent with recent developments in the field of ECT of spinal metastases. In the whole, three articles were included. Results showed that percutaneous image-guided ECT provides effective pain relief with limited procedure-related morbidity, along with local tumour control (complete response 28.5%, 38% partial response, 24% stable disease) at 3- month follow-up in the largest published series so far. In conclusion, ECT should integrate the armamentarium of therapies that are currently being proposed to patients with painful metastatic epidural disease.

First-in-human trial of engineered NK cells in lung cancer refractory to immune checkpoint inhibitors.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality necessitating the exploration of alternate therapeutic approaches. Tumor reactive or activated-by-cytokine killers (TRACK) are PD-L1+ highly cytolytic natural killer (NK) cells derived from umbilical cord blood NK cells and engineered to express soluble IL15 (sIL15), showing promise in preclinical studies against NSCLC. We assessed safety, persistence, homing and cytotoxic activity in six patients with advanced, refractory, and progressing NSCLC who received a low dose of unmatched, allogeneic, off-the-shelf sIL15_TRACK NK cells. We evaluated NK cell presence and persistence with droplet digital (dd) PCR, flow cytometry, and immunofluorescent staining. sIL15_TRACK NK cells had peak measurements at one hour and became undetectable four hours after each in fusion. Cognate ligands to activating NK cell receptors were found in NSCLC. sIL15_TRACK NK cells were observed in a lung tumor biopsy seven days after the final infusion, confirming their sustainment and tumor-homing ability. They retained cytolytic function following isolation from the lung tumor. Three out of six patients achieved disease stabilization on repeat imaging, while the others progressed. Unmatched, allogeneic, cryopreserved, off-the-shelf sIL15_TRACK NK cells express activating receptors, home to tumor sites that express their cognate ligands, and retain cytolytic activity after infusion, underscoring their potential as a therapeutic approach in solid tumors. At low doses, the therapy was safely administered and showed preliminary evidence of activity in three of six patients with advanced and progressive NSCLC. Additional dose escalation cohorts and co-administration with atezolizumab are planned. gov NCT05334329FUNDING. Funding was provided by CytoImmune Therapeutics; CA266457; CA033572; CA210087.

Lichen planopilaris presenting with symmetrical patchy alopecia of the beard.

We present a case series of three male patients who developed symmetrical patches of alopecia dermoscopically and histopathologically consistent with lichen planopilaris (LPP) in the beard. One patient subsequently developed scarring hair loss along the frontotemporal hairline but the other two did not experience any scalp hair loss. Intralesional corticosteroid injections resulted in disease stabilisation in two patients, while the third patient was lost to follow-up. One patient had a small hair transplant within a patch of hair loss, with excellent graft survival at 18 months. Our study highlights LPP as a differential diagnosis for beard alopecia, even in the absence of scalp hair loss.

Sex Differences in Computed Tomography Coronary Stenosis Severity Versus Flow Impairment and Impact on Revascularization, Clinical Events and Health Care Costs: A FORECAST Substudy.

The impact of sex-related differences in coronary atheroma and flow impairment severity on clinical events and costs remains unclear. This is a secondary analysis of patients with stable coronary artery disease who underwent both coronary computed tomography angiography and fractional flow reserve derived from computed tomography as part of the FORECAST (Fractional Flow Reserve Derived From Computed Tomography Coronary Angiography in the Assessment and Management of Stable Chest Pain) trial, investigating (1) the relationship between coronary stenosis severity on coronary computed tomography angiography and fractional flow reserve derived from computed tomography FFRCTby sex and (2) the association with revascularization, resource usage, and adverse clinical events. A total of 212 patients (64 female participants [32.1%]) and 1245 vessels were included. There was no significant sex difference in the frequencies of significant coronary artery disease (38.2% of women versus 51.3% of men; P=0.073), but female participants had significantly less coronary flow impairment, according to the presence of at least 1 fractional flow reserve derived from computed tomography≤0.8 (47.0% versus 71.5%; P=0.008). Female subjects underwent fewer revascularization procedures (23.5% versus 42.3%; P=0.014), less coronary artery bypass graft surgery (2.9% versus 13.1%; P=0.025) and were less likely to be on statin treatment (72.0% versus 84.7%; P=0.022) by 9-month follow-up. This resulted in lower overall health care costs for female participants compared with male counterparts (median total cost, £1276 versus £2051; P=0.014). In multivariable Cox analysis the presence of significant coronary artery disease (hazard ratio [HR], 2.91; 95% CI, 1.30-6.51) and having a positive fractional flow reserve derived from computed tomography (HR, 4.11; 95% CI, 1.15-14.69) were independent predictors of major adverse cardiovascular events at 9 months, whereas sex was not statistically significant (p=0.13). There are significant sex differences in the anatomico-functional assessment of coronary artery disease leading to differences in clinical management, costs, and adverse events.

Short interval circulating tumor DNA (ctDNA) kinetics as a predictor of tumor response in patients with gastrointestinal (GI) cancer receiving immune checkpoint inhibitor (ICI)-based treatment.

836 Background: Circulating tumor DNA (ctDNA) has a short half-life (&lt;2 hours) which may permit real-time monitoring of tumor status. This single-institution study aimed to assess the feasibility of rapid treatment response evaluation through serial short-interval ctDNA testing. Methods: Patients with gastrointestinal (GI) cancer undergoing immune checkpoint inhibitor (ICI)-based therapy were included. A personalized, tumor-informed ctDNA assay (Signatera, Natera, Inc.) was used in this study. We collected samples to measure the baseline ctDNA levels on cycle 1, day 1 (C1D1) of treatment or within 14 days prior to C1D1. A second ctDNA sample was obtained after 14-21 days depending on the cycle length of the treatment regimen employed (on cycle 2, day 1 [C2D1]). Changes in ctDNA levels between baseline and C2D1 were recorded, as well as the tumor response at the first radiographic assessment. Patients achieving partial response (PR) or better, or stable disease (SD) with tumor shrinkage supporting continuation of same treatment were considered responders. Results: The study cohort consisted of 14 patients aged 36-89 years (median age 66); 5 patients were female. Tumor types included advanced colorectal (n=5) and gastroesophageal (n=9) cancers. Treatments consisted of pembrolizumab alone (n=5), ICI + chemotherapy combinations (n=8), and regorafenib plus nivolumab (n=1). Baseline ctDNA levels were obtained on C1D1 in 9 patients, with the remaining 5 patients having baseline measurements within 14 days before C1D1. All patients had the second ctDNA level drawn on C2D1. The median interval between C1D1 and the first radiographic response assessment was 61 days (range, 45-84). A reduction in ctDNA levels by 50% or more (range: 66-100%) was observed in 9 patients (64%) after one cycle of treatment. All 9 patients were classified as responders at the time of first radiographic assessment: 7 with PR and 2 with SD but significant tumor shrinkage leading to continuation of the same treatment. In 3 patients (21%), ctDNA levels increased (range: 20-500%), correlating with progressive disease (PD) on first assessment scan. Two patients showed increased ctDNA levels of 82% and 22% after one cycle of treatment but achieved PR and SD, respectively. In both patients, however, the 3rd ctDNA level drawn before the first assessment scan dropped by &gt;90%. Overall, short-interval ctDNA kinetics correlated with treatment response in 12 of 14 patients (86%), with a binomial test p = 0.0065. Conclusions: Short-interval ctDNA kinetics demonstrates a strong correlation with radiographic tumor response and clinical benefit in GI cancer patients receiving ICI-based treatments, providing early signal of tumor response. This approach has the potential to guide treatment decisions if validated in larger prospective studies.

An exploratory phase II trial of low-dose decitabine and sintilimab combined with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma.

390 Background: Combining epigenetic modulator with PD-1 inhibitor may enhance treatment outcomes in cancer patients. This study aimed to evaluate the efficacy and safety of epigenetic drug decitabine, sintilimab (a PD-1 inhibitor), and chemotherapy in gastric cancer. Methods: In this single-arm, exploratory phase II trial, patients with HER2-negative, locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma were enrolled between August 12, 2021, and October 22, 2022. Treatment included low-dose decitabine (10 mg/m² for 5 days), sintilimab (a PD1 inhibitor, 200 mg every 21 days), and XELOX. The primary endpoint was objective response rate (ORR) and second endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. The protocol was approved by the ethics committee of the Changzhi Medical College Affiliated Changzhi People's Hospital (No. 2021K002). All patients provided written informed consent form before study participation. The trial is registered with Chinese Clinical Trial, number ChiCTR2100043312. Results: Sixteen patients were initially enrolled, with a median follow-up of 14.8 months. Eleven patients exhibited a PD-L1 combined positive score (CPS) &lt; 5. In the per-protocol sets, 11 patients remained eligible for efficacy analysis. In the intention-to-treat analysis of all 16 patients, 9 achieved partial response and 2 had stable disease, resulting in an ORR of 69% and a DCR of 56%. As of the data cutoff on November 4, 2023, the median PFS was 11.1 months (95% CI, 5.1-not reached) and the median OS was 13.2 months (95% CI, 5.1-not reached). Treatment-related adverse events were generally well-tolerated, with most being grade 1-2. Three patients experienced severe AEs, including one fatal case of grade 4 immune-related pneumonia. Conclusions: The combination of low-dose decitabine, sintilimab, and chemotherapy appears promising strategy for locally advanced or metastatic G/GEJ adenocarcinoma, especially in patients with negative HER2 and low PD-L1 expression. These preliminary findings support further investigations to confirm the benefits and explore the underlying mechanisms. Clinical trial information: ChiCTR2100043312. Objective response and disease response. Full analysis set (n=16) Efficacy analysis set (n=11) Complete response 0 0 Partial response 9 9 Stable disease 2 2 Progressive disease 0 0 Non-evaluable* 5 NA Objective response 9 (56%) 9 (81.8%) Disease control 11 (69%) 11 (100%) NA=not applicable. *Included patients without any post-baseline response assessment.

Prognostic implications and therapeutic response in GNAS-mutated colorectal adenocarcinoma: A retrospective cohort analysis.

244 Background: GNAS, a key regulator of the G-protein signaling pathway, is frequently mutated in colorectal adenocarcinomas and other malignancies. Despite its role in tumorigenesis, GNAS mutations remain understudied, with no established targeted therapies. Exploring the impact of GNAS alterations on therapeutic response and outcomes in colorectal cancer (CRC) is crucial for developing effective treatment strategies. Methods: We reviewed 531 CRC cases from our institutional Molecular Tumor Board database, identifying 8 patients with GNAS mutations. The prevalence ofGNASmutations in our cohort was 1.5%, which aligns with reported rates of 2-5% in various CRC cohorts. Comprehensive clinicopathologic data, including tumor histology, staging, treatment outcomes, and response rates, were analyzed. A detailed evaluation was conducted on stage IV patients to assess their response, progression-free survival (PFS), and overall survival (OS) in comparison to historical stage IV CRC benchmarks. Results: The cohort included 8 patients with a median age of 61 years (range: 33-73 years), with balanced gender representation (50% male, 50% female). The racial distribution was 50% Black or African American, 25% White, and 12.5% Asian or Pacific Islander. The majority of patients (62.5%) were diagnosed at stage IV, with primary tumor sites predominantly in the sigmoid colon and cecum. Among the 5 stage IV patients, while no patients achieved a complete or partial response, 3 exhibited stable disease, resulting in a 60% disease control rate (including stable disease). The median progression-free survival (mPFS) was 9 months, reflecting the duration of disease control before progression, while the median overall survival (mOS) was 15 months. These outcomes are notably lower than historical benchmarks for stage IV CRC, where response rates typically range from 40-50% with mOS of 20-24 months, highlighting the potentially adverse prognostic impact of GNAS mutations. Conclusions: Patients with GNAS-mutated colorectal adenocarcinoma appear to represent a unique subset with poorer therapeutic outcomes, even when achieving stable disease. The observed disease control in the absence of objective responses underscores the complexity of treating GNAS-mutated tumors and highlights the urgent need for targeted therapies tailored to this molecular subtype. Further research into the biological mechanisms underlying GNAS mutations and their impact on CRC treatment resistance is warranted to improve patient outcomes.

Efficacy and Safety of Low-Dose Oral Etoposide Combined With Capecitabine for Patients With Postoperative Metastatic Breast Cancer Resistant to Anthracycline/Taxanes.

The purpose of this study is to determine the efficacy and safety of metronomic chemotherapy with all-oral combination of low-dose etoposide/capecitabine in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and/or taxanes. Metronomic chemotherapy, giving lower, more frequent doses of chemotherapy drugs over an extended period, often without long breaks between cycles. With oral low-dose etoposide + capecitabine was administered to patients who had postoperative MBC resistant to anthracycline/taxanes: etoposide 30 mg/m2/day, qd for 7 days + capecitabine 1400 mg/m2/day, administered in two equal dose for 14 days, with 21 days as a cycle. Patients received treatments if complete response, partial response, or stable disease was obtained until disease progressed or became intolerable. RECIST criteria were used for standard efficacy evaluation and NCI-CTC version 3.0 was used for evaluation of side effects. From June 2008 to May 2020, 85 patients received the aforesaid treatment; 67 of these patients were eligible for efficacy and side effects evaluation. After treatment, 6 (8.96%) patients obtained partial response, 41 (61.19%) patients had stable disease, and 20 (29.85%) patients had disease progression. The overall response rate (complete response + partial response) was 8.96%, and disease control rate (complete response + partial response + stable of disease) was 70.15%. Clinical benefits (complete response + partial response + stable of disease ≥ 24 weeks) were obtained for 50% of the patients. The median and mean treatment to progression time was 5 months and 6.06 months (95% CI: 3.43~8.70), respectively. The most common grade I/II side effects were leukopenia and fatigue (15.8%). For patients with postoperative MBC resistant to anthracycline/taxanes, oral low-dose etoposide + capecitabine was effective with tolerable safety. The patients did not need antiemetics or leukocytic drugs, and the treatment was cost-effective because the patients did not need to be hospitalized for intravenous infusion.

Phase II study of mFOLFIRINOX efficacy as first and subsequent lines of advanced gastrointestinal neuroendocrine tumors G3 and neuroendocrine carcinomas therapy.

659 Background: Gastrointestinal (GI) neuroendocrine carcinomas (NEC) are rare tumors and account for 3% of all NECs. Despite the differences in genetic characteristics, treatment principles of GI NECs are extrapolated from lung NECs. The standard first-line therapy is platinum and etoposide-containing regimens, which allow to achieve a median PFS of 5-6 months. A small retrospective study demonstrated the potential effectiveness of the mFOLFIRINOX regimen with a median PFS of 5.4 months, despite that the majority of patients (pts) received this regimen as second or subsequent lines. The aim of this study is to evaluate mFOLFIRINOX +/- somatostatin analogues (SA) efficacy in GI NEC subgroup. Methods: This prospective, single center phase II study used a two-stage Simon design. The primary endpoint is disease control rate (DCR) ≥ 6 months. Statistical hypothesis: investigated therapy improves DCR compared with historical control from 50 to 70%. Secondary endpoints are progression-free survival (PFS), overall survival (OS), objective response. At the first stage, enrollment of 16 pts was planned (α=0.05, power 80%). If a disease control ≥ 6 months was achieved in at least 9 of the 16 pts, it was planned to continue enrollment up to 39 pts. Here we present results of the first stage of this study. Inclusion criteria: pts ≥18 y.o. with histologically confirmed advanced GI NEC or neuroendocrine tumor (NET) G3 ki67≥55%; ECOG 0-2. Recruitment of pts was carried from 2019 to February 2024. Results: The study included 16 pts, 12 male and 4 female. The most common sites of primary tumor are stomach (N=8, 50%) and pancreas (N=5, 31.3%). 10 (62.5%) pts had large cell carcinoma, 1 – small cell carcinoma (6.3%), 5 (31.3%) – NET G3. The median ki-67 was 70% (40-95%). 15 pts (93.7%) had IV stage, 1 (6.3%) – III. The most common site of metastases is liver – 11 (68.8%), more than half of pts have isolated metastases in liver (N=9, 56.3%). ECOG status was evaluated as 0-1 in 15 (93.7%) cases. Majority of pts (N=14, 87.5%) received mFOLFIRINOX as first line therapy. 7 pts (46.7%) had positive expression of SSTR-2A or -5 and received concurrent treatment with SA. ORR was 62.5% (N=10/16), stable disease – 37.5% (N=6/16). DCR ≥ 6 months was 93.7% (N=15). With a median follow-up of 13.2 months, median PFS was 10.8 months (95% CI 7.57-14.1). One pts had serious adverse event - myocardial infarction, no grade 5 toxicity was observed. Conclusions: Chemotherapy with mFOLFIRINOX showed promising results in GI NECs or NETs G3 ki67≥55% treatment. Primary endpoint was met, enrollment of patients in the study continues.

Utilization of SDC2 gene in conjunction with SEPTIN9 gene methylation analysis for the diagnosis and efficacy assessment of colorectal cancer.

240 Background: SDC2 gene encodes the transmembrane proteoglycan molecule Syndecan-2. Syndecan-2 protein affects the proliferation, migration and invasion of colorectal cancer cells by participating in the regulation of cell adhesion, tissue differentiation and angiogenesis. Plasma methylated SEPTIN9 gene has been shown to be a sensitive and specific biomarker for the detection of CRC, which is involved in apoptosis, pseudopod projection, tumor cell migration and invasion. The aim of this study is to validate the value of SDC2 and S9 gene methylation detection in the diagnosis and efficacy evaluation of CRC. Methods: A total of 102 patients were enrolled in the study. The methylation levels of fecal SDC2 gene and blood SEPTIN9 gene were detected by fluorescence PCR. The clinical diagnostic accuracy of SDC2 kit was evaluated by patients with benign gastrointestinal lesions, gastrointestinal tumors and healthy subjects. Combined detection of SDC2 and S9 to improve the detection rate of CRC. SDC2m levels were analyzed in 26 patients with partial remission or stable disease after palliative treatment and 32 patients with complete remission after radical surgery. Results: The detection rate of SDC2 in patients was 0.0% for UC and CD, 66.7% for AA and 60.0% for NA, 25.0% for HOP. For 8 healthy subjects with negative colonoscopies, the true negative rate was 100%. The detection rates of GC and EC were 50.0% and 0.0%, respectively. Data from 72 patients with CRC were evaluated, with a sensitivity of 89.1% (41/46,95%CI 0.798-0.985) for patients with untreated CRC. The sensitivity of SDC2 was 46.2% (12/26,95%CI 0.256-0.667) in patients with partial response or stable disease after palliative treatment. The difference was statistically significant (P &lt; 0.001). The sensitivity of S9 for CRC detection was 88.2% (15/17, 95%CI 0.712-1.053). By two tests, 94.1%(16/17, 95%CI 0.816-1.066) of CRC cases could be detected.The sensitivity was 89.1% (41/46 95%CI 0.798-0.985) in untreated CRC and 46.2% (12/26 95%CI 0.256-0.667) in patients with PR and SD after chemotherapy/radiotherapy/targeted/immunotherapy. The difference rate of SDC2m between two groups was statistically significant (P &lt; 0.001). Among 46 untreated patients with CRC, 32 patients with positive SDC2m underwent radical surgery, of which 30 CR patients turned SDC2m test negative after surgery. We found reduced SDC2m in stool from patients with clinical benefit (CR+PR+SD). Conclusions: Detection of SDC2m in untreated CRC patients has high sensitivity and has the potential to become a non-invasive diagnostic tool for CRC. Combination of S9 and fecal SDC2 could improve the detection rate of SDC2 in non-dominant population. The methylation level of SDC2 may be helpful for postoperative follow-up of CRC after radical surgery, prediction of recurrence, and monitoring the efficacy of a series of palliative treatments for CRC.

Efficacy and safety of Shexiang Baoxin Pill (MUSKARDIA) in patients with stable coronary artery disease across different weight subgroups.

Shexiang Baoxin Pill (MUSKARDIA), a traditional Chinese patent medicine, plays a crucial role in both preventing and treating diverse cardiovascular diseases, including coronary heart disease, myocardial infarction (MI), and heart failure. Preclinical research has demonstrated that the cardioprotective effects of MUSKARDIA are achieved through multiple pathways, such as enhancing coronary artery dilation, fostering new blood vessel growth, reducing inflammation and oxidative stress, improving lipid metabolism, and protecting vascular endothelium. This subgroup analysis aimed to evaluate the efficacy and safety of Shexiang Baoxin Pill (MUSKARDIA) plus optimal medical therapy (OMT) across different weight categories in treating stable coronary artery disease (CAD). This investigation was a subgroup analysis of a multicenter, randomized, double-blind, placebo-controlled phase IV clinical study. Patients receiving OMT were randomly assigned to either MUSKARDIA or placebo group for a 24-month period. This analysis focused on body weight as a distinguishing factor, using 65kg as the cutoff. The primary efficacy endpoint was the composite of major adverse cardiovascular events (MACEs), including cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke. Secondary efficacy endpoint comprised a composite of all-cause mortality, non-fatal MI, non-fatal stroke, hospitalizations for unstable angina or heart failure, and coronary revascularization procedures. A total of 2646 patients were included in the analysis, with 916 patients weighing less than 65kg and 1730 patients weighing 65kg or more. The median ages were 68 (range: 35-90) years and 62 (range: 29-90) in these two subgroups, respectively. For patients weighing less than 65kg, the MUSKARDIA group exhibited a significantly lower incidence of the primary efficacy endpoint (0.65%) compared to the placebo group (2.64%) (P=0.018), with a reduced risk of MACEs (HR=0.241, 95%CI: 0.068-0.856; P=0.0168). Conversely, in patients weighing 65kg or more, no significant differences were observed in the incidence rates or risks of primary or secondary efficacy endpoints between the MUSKARDIA and placebo groups (All P>0.05). Adverse events were similar between two groups across both weight subgroups. MUSKARDIA plus OMT demonstrated promising efficacy and acceptable safety in CAD patients weighing less than 65kg, potentially reducing the risk of MACEs. For patients weighing 65kg or more, further investigation is needed to optimize dosing strategies.

A phase 2 basket study of talabostat, a small-molecule inhibitor of dipeptidyl peptidases, administered in combination with pembrolizumab in patients with advanced solid cancers.

Talabostat, an oral small molecule inhibitor of dipeptidyl peptidases (DPP4 and DPP8/9), has shown synergistic activity with immune checkpoint inhibitors in preclinical studies. This open label, phase 2 basket trial assessed the antitumor activity of combining talabostat and pembrolizumab (anti-programmed death-1 antibody) in advanced solid tumor patients. The primary objective was assessment of dose-limiting toxicity (DLT) rates in the first six patients (lead-in stage) and response rate (efficacy stage; included cohort A [checkpoint inhibitor (ICI) naive] and cohort B [ICI pretreated]) for the study treatment using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune RECIST (iRECIST). Efficacy was assessed using a Bayesian optimal phase 2 design. A total of 31 patients enrolled in this trial (14 in cohort A, 17 in cohort B). The median age was 61 years; 17 (55%) patients were male and 21 (68%) patients were White. Among 19 (61%) patients evaluable for response, the best response was stable disease in nine patients, unconfirmed progressive disease in seven patients, and clinical progressive disease in three patients based on iRECIST. Disease control rate was 47%. One patient with programmed death-ligand 1 negative, microsatellite stable endometrial cancer had unconfirmed partial response. Median progression-free survival was 2.7 months; median overall survival was 20.5 months. One patient (cohort A) experienced a grade 4 hypotension as a DLT and treatment discontinuation. The most common toxicities were hypotension (22.6%), fatigue (9.7%), diarrhea, rash, thrombocytopenia, vomiting, syncope, general disorders and administration site conditions-other, and skin and subcutaneous tissue disorders-other, each in 6.5% of patients. This study of the combination of talabostat and pembrolizumab in patients with advanced solid tumors demonstrated predictable adverse events and limited activity. The combination was shown to be safe. Efficacy data shows immune stable disease in nine of 19 evaluable patients, and an unconfirmed immune partial response in a patient with endometrial cancer.

Clinical outcome after complete response with immunotherapy in hepatocellular carcinoma.

573 Background: Immunotherapy has shown great efficacy in hepatocellular carcinoma (HCC). No clear consensus exists on when to stop the immune checkpoint inhibitor (ICI) after complete response (CR), and clinical course after stopping ICI remains unknown. Methods: We identified 138 HCC patients who received ICI at Cedars-Sinai Medical Center and Mayo Clinic Rochester from 2016-2023. Modified Response Evaluation Criteria In Solid Tumors (mRECIST) was used to assess treatment response. We further described the clinical course of patients who achieved CR after ICI discontinuation, including cancer recurrence, subsequent treatment, liver transplantation (LT) listing and outcomes. Results: The median age at ICI initiation was 68 years; 79% were male; 55.9% were white; 51.5% were BCLC stage C. 9.4% CRs, 25.4% partial responses, 39.9% stable diseases, and 25.4% progressive disease. Hepatitis C etiology was associated with higher likelihood of CR (P=0.005). Among 13 patients who achieved CR, 10 stopped ICI (60% for LT evaluation, 40% for toxicity). After stopping ICI, 40% had recurrence (Table). 3 patients underwent local therapy for recurrent HCC within Milan criteria and 1 patient restarted ICI for recurrence beyond Milan criteria. Among CR patients, 9 patients underwent LT evaluation after stopping ICI and 7 patients were waitlisted. After listing, 3 dropouts were observed, due to recurrent HCC beyond Milan criteria, sepsis leading to death, and personal preference. 4 patients underwent LT. 2 patients underwent local therapy before LT for recurrent HCC (Table). All transplanted patients had the last dose of ICI more than 1 year before LT (12, 21, 24, and 29 months). On explanted livers, 2 patients had no residual viable tumor and 2 patients had residual HCC within Milan criteria. 1 patient developed acute cellular rejection and was treated with immunosuppressants and maintained stable graft function. None had graft loss or evidence of HCC recurrence in the follow-up period at 8, 20, 28, and 51 months. Conclusions: Immunotherapy demonstrated excellent effects on a subset of HCC patients, including 9.4% who achieved CR. After stopping ICI, 40% had cancer recurrence but 3 out of 4 were within Milan criteria. 4 underwent successful LTs (2.9%) with excellent post LT outcome. Larger prospective data is needed to establish a protocol for ICI use, especially to determine the optimal timing for ICI discontinuation after CR. BCLC at ICI initiation ICI cycles before stopping, ICI Recurrence after last ICI (days) Within Milan at recurrence Treatment(s) received after recurrence and outcomes OS (days) Patient 1 B 7, Nivolumab 730 No Nivolumab. Died from GI bleeding 1065 Patient 2 B 64, Atezo/Bev 149 Yes TACE with CR, followed by LT without recurrence. 1203 Patient 3 A 8, Nivolumab 1393 Yes Y90 with CR. No recurrence. 1984 Patient 4 C NA, Pembrolizumab 407 Yes TACE and MWA with CR, followed by LT without recurrence. 1722

Postradiotherapy Response Assessment Using 18 F-FDG PET/CT in Salivary Gland Carcinoma-A Multicenter Study.

This multicenter study investigates the efficacy of 18 F-FDG PET/CT in postradiotherapy (post-RT) response evaluation in salivary gland carcinoma (SGC). We retrospectively reviewed 115 SGC patients who underwent definitive or adjuvant RT followed by 18 F-FDG PET/CT between 2004 and 2021. Most tumors were parotid gland malignancies (50%). The most common histological subtypes were adenoid cystic (29%) and mucoepidermoid carcinomas (18%). The median follow-up was 65 months. Post-RT anatomic images (CT/MRI) revealed complete response (CR) in 51 patients (44%). Among 53 patients with partial response or stable disease, only 17 (32%) patients experienced locoregional recurrence, with a 5-year locoregional control rate of 69%. Post-RT 18 F-FDG PET/CT documented metabolic CR in 81 patients (70%). Metabolic complete responders had significantly higher 5-year locoregional control (90% vs 43%), distant metastasis-free survival (80% vs 48%), progression-free survival (76% vs 24%), and overall survival rates (89% vs 42%) compared with non-complete responders (all P < 0.001), as confirmed in both univariate and multivariate analyses. It identified additional viable tumors in 18 cases (16%) and facilitated salvage local therapies in 7 patients (6%). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of post-RT 18 F-FDG PET/CT were 63%, 91%, 70%, 88%, and 84%, respectively, in predicting locoregional recurrence. 18 F-FDG PET/CT showed significantly higher sensitivity (88% vs 36%, P = 0.011) in tumors with pre-RT SUV max ≥7.39 compared with those with SUV max <7.39. Post-RT 18 F-FDG PET/CT demonstrates high negative predictive value and specificity, with metabolic CR predicting excellent outcomes. Additionally, it exhibits higher sensitivity for high-SUV max SGC, facilitating early detection of viable tumors.

Immunotherapy engagement in pancreatic adenocarcinoma: Provisional results of iLSTA study— Durvalumab, LSTA1 (certepetide), gemcitabine, and nab-paclitaxel for locally advanced pancreatic ductal adenocarcinoma.

746 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterised by a dense, extracellular matrix-rich stroma, which creates a physical barrier against drug penetration. Evidence suggests that the iRGD peptide, LSTA-1, can increase the penetration of anti-cancer drugs to tumours through selective targeting of tumour endothelial cell receptors. Additionally, LSTA-1 administration promotes CD8+ immune cell tumour infiltration, potentially enabling immunotherapy as a treatment modality. iLSTA examined safety, tolerability and effect of the combination. Methods: Participants diagnosed with locally advanced PDAC were divided into 3 cohorts in a 1:1:4 ratio. Cohort 1 (n=5) received gemcitabine (1000mg/m 2 ), nab-paclitaxel (125mg/m 2 ), placebo LSTA-1 (3.2mg/kg) and placebo durvalumab (750mg). Cohort 2 (n=5) received gemcitabine, nab-paclitaxel, active and placebo LSTA-1, and placebo durvalumab. Cohort 3 (n=20) received gemcitabine, nab-paclitaxel, LSTA-1 and durvalumab. Tissue biopsies via endoscopic ultrasound were obtained pre-treatment and between weeks 12 and 16 for analysis of tumour infiltrating lymphocytes (TILs). Patient tumour sizes were assessed every 8 weeks using radiological imaging according to RECIST v1.1, and serum CA19-9 levels were analysed monthly. Results: 6/17 patients showed significant RECIST partial response after 2 cycles of treatment (5 patients in cohort 3), with the remaining 11 patients exhibiting stable disease. After 4 cycles of treatment, 10/17 patients demonstrated partial response (9 patients in cohort 3). Of the remaining 7 patients, 6 demonstrated stable disease, and 1 patient (cohort 2) exhibited a RECIST complete response. 13/17 patients who completed 4 treatment cycles showed a decrease in CA19-9 levels. 6 patients demonstrated &gt;90% reduction in CA19-9 (5 in cohort 3), with the remaining 7 patients showing a &gt;50% reduction in CA19-9 levels (5 in cohort 3). 12 patients underwent repeat biopsies 12-16 weeks post-treatment to assess TILs. 10 patients showed immune cell infiltration (5% to 50% stroma infiltration), 2 had no tumour found (Cohort 3). The combination was safe with no unexpected toxicities. Conclusions: The preliminary results of this study suggest that the combination of gemcitabine and nab-paclitaxel with LSTA-1 and durvalumab is safe and potentially induces tumour infiltrating lymphocytes and RECIST response in locally advanced pancreatic adenocarcinomas. Clinical trial information: ACTRN12623000223639 .

Phase II study of trifluridine/tipiracil (TAS-102) plus irinotecan in combination with bevacizumab as a second‐line therapy for patients with metastatic colorectal cancer.

155 Background: Metastatic colorectal cancer (mCRC) patients have poor prognoses with limited response to second-line chemotherapy. Therefore, it is urgent to refine and design an optimal second-line treatment regimen to improve the response rate and prolong the survival of patients with mCRC. This study assessed the safety and efficacy of the trifluridine/tipiracil (TAS-102), irinotecan, and bevacizumab regimen in second-line settings for mCRC patients. Methods: This was a multicenter, single-arm, phase II trial. The mCRC patients who are refractory to standard first-line treatment, including fluoropyrimidine and oxaliplatin, are eligible. Based on the recommended phase II dose established in phase I, enrolled patients received TAS-102 (30 mg/m2 twice daily on days 1-5) and irinotecan (150 mg/m2 on day 1) combined with bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the objective response rate (ORR). Results: Between October 1, 2023, and August 31, 2024, 60 patients were enrolled, and all of them were evaluated for efficacy. As of August 31, 2024, efficacy was assessed in all 60 participants with an ORR of 18.3% (2 had complete response, CR; 9 had partial response, PR; 39 had stable disease, SD). Among the 39 patients with SD, 29 patients experienced tumor shrinkage. The disease control rate (DCR) was 83.3%. The median follow-up was 8.6 months (95% confidence interval [CI], 6.743-10.457). The six-month progression-free survival (PFS) was 59.6%. The median PFS was 6.9 months (95% CI 5.016-8.784), whereas the median overall survival (OS) was not reached. The 1-year OS rate was 92%. At the time of analysis, four patients have died, and 56 patients are still alive. All patients were evaluable for safety assessment. The most common treatment-related adverse events (TRAE) were nausea (100%), neutropenia (86.7%), and anemia (83.3%). The most frequent grade 3/4 TRAE were neutropenia (48.3%), febrile neutropenia (8.3%), nausea (3.3%), and anemia (3.3%). No treatment-related death occurred. Conclusions: The regimen of irinotecan, TAS-102, plus bevacizumab preliminarily demonstrated promising efficacy with tolerable toxicity for mCRC patients as second‐line treatment. This regimen warrants further exploration in refractory mCRC patients. Clinical trial information: NCT06202001 .

Trastuzumab emtansine as second-line therapy in HER2 positive advanced biliary tract cancers: Single arm prospective phase II clinical trial (TAB-3 trial).

584 Background: HER2 overexpression or amplification is a therapeutic target of interest in advanced BTC, especially gallbladder cancers (GBC). Limited studies evaluate the role of T-DM1 in these groups of cancers. Methods: This study was an investigator-initiated, open-label, single-arm, phase II trial in patients (pts) aged 18 years or older with HER2-positive (defined as IHC 3+ or IHC 2+, and FISH positive), advanced BTCs who had previously received systemic therapy (irrespective of prior additional HER2 targeted therapy). Pts received T-DM1 at 3.6mg/kg q 3 -weekly till disease progression (PD), unacceptable toxicities, or patient choice. The primary end-point of the study was an improvement in 3-month progression-free survival (PFS) from 50% (historical cohort) to 70% in the study arm. Secondary endpoints included overall response rates (ORR), disease control rate (DCR), overall survival (OS), and incidence of grade 3 and 4 treatment-related adverse events (TRAE). Results: From July 2023 to July 2024, ‘52’ pts with HER2-positive BTC were screened, and 40 enrolled in the study. A majority of patients had GBC (95%) and most commonly received combination chemotherapy with gemcitabine-cisplatin, with or without nab-Paclitaxel (78%). Six patients (15%) had previously received trastuzumab in combination with chemotherapy. A majority of patients (n=24; 60%) had rapid progression (within 3 months) on prior systemic therapy. With a median follow-up of 7.1 months [95% confidence interval (CI): 5.1-9.1] , 24 patients had disease progression with a 3-month PFS of 51.2% (95% CI: 33.4 - 69) and median PFS of 3.1 months (95% CI: 2.3-3.8); median OS was 7.1 months (95% CI: 5.1-9.1). Partial responses (PR) were seen in 5 patients (12.5 %) and 8 had stable disease (20 %) for a disease control rate of 32.5 %. Patients without rapid disease progression on prior therapy (n=16; 40%) had a 3-month PFS of 70% (95% CI: 44.8 - 95.2) and median PFS of 4.9 months (95% CI: 2.9-6.9). Grade 3 and grade 4 TRAE in the overall cohort were noted in 11 patients (28%), with the commonest being grade 2 fatigue in 6 patients and grade 3 thrombocytopenia in 2 patients. Conclusions: T-DM1 was well tolerated in pre-treated HER2 positive advanced BTCs, but did not statistically improve PFS in comparison to historical data. Patients who did not have rapid progression on prior systemic therapy appeared to have a more favorable survival in comparison to rapid progressors and the role of T-DM1 in such favorable cohorts can be explored in larger studies. Clinical trial information: CTRI/2023/07/055785.