Initial Treatment Research Articles

Association between ctDNA levels, timing of blood collection, and overall survival in metastatic colorectal cancer.

245 Background: While circulating tumor DNA (ctDNA) detection is influenced by various factors, the impact of blood collection timing remains understudied. This study investigated the relationship between ctDNA detection, and blood collection timing and prognosis in patients with metastatic colorectal cancer (mCRC) from the GOZILA study. Methods: GOZILA is a nationwide plasma genomic profiling study using Guardant360 CDx for advanced solid tumors. This study evaluated the association of ctDNA levels with blood collection timing and prognosis in patients with mCRC. ctDNA levels were determined by the maximum variant allele frequency. Blood collection timing was categorized into five groups: naive (before initiation of 1st line treatment), after treatment initiation (days 1-14 of treatment), during treatment (between “after treatment initiation” and “before progression disease [PD]”), before PD (from 28 days before PD to PD), and after PD (after disease progression but before the next line of treatment). Overall survival (OS) was compared across treatment lines using ctDNA level cutoff of 10. Results: We analyzed 2,398 blood samples from 1,994 patients with mCRC enrolled in the GOZILA between February 2018 and July 2023. ctDNA levels were significantly lower during treatment compared to the naive (median, 13.2 vs. 5.7, p < 0.001). No significant differences were observed between naive and other blood collection timing. Compared to blood collection before 1st line treatment, ctDNA levels significantly decreased before 2nd line (median, 13.5 vs. 8.3, p = 0.02) and 3rd line treatments (median, 13.5 vs. 7.6, p = 0.01). Patients with ctDNA levels<10 demonstrated significantly better OS across all treatment lines, including 1st line (median, NA vs. 23.9 months, HR 0.49, 95% CI, 0.34-0.72), 2nd line (median, 22.1 vs. 10.3 months, HR 0.42, 95% CI, 0.33-0.55), and later line treatments (FTD/TPI: median, 12.7 vs. 5.7 months, HR 0.51, 95% CI, 0.26-0.99; FTD/TPI+Bev: median, 9.3 vs. 6.5 months, HR 0.55, 95% CI, 0.37-0.82; Regorafenib: median, 13.5 vs. 7.4 months, HR 0.45, 95% CI, 0.26-0.80). Conclusions: In mCRC, blood collection during treatment is suboptimal due to decreased ctDNA levels. Patients with ctDNA levels <10 showed significantly better OS across all treatment lines. Optimal timing of blood collection can enhance ctDNA levels, enabling more accurate gene mutation assessment and stratifying outcomes.

Extracellular vesicles released by ALL patients contain HNE-adducted proteins: implications of collateral damage

Off-target neuronal injury is a serious side-effect observed in cancer survivors. It has previously been shown that pediatric acute lymphoblastic leukemia (ALL) survivors have a decline in neurocognition compared to healthy age-matched counterparts. Elevated oxidative stress has been documented to be a mediator in off-target tissue damage in cancer survivors. Early detection of oxidative stress markers may provide an opportunity to prevent off-target tissue damage. Extracellular vesicles (EVs) have surfaced as a potential diagnostic tool due to molecular cargo they contain. We investigated the potential for EVs to be a sensitive indicator of oxidative stress and off-target tissue damage by isolating EVs from pediatric ALL patients throughout their first 2 months of treatment. EVs were measured throughout the collection points for: 1) number of EV particles generated using nanoparticle tracking analysis (NTA); 2) markers of neurons (NeuN), astrocyte activation (GFAP), neuronal stability (BDNF), 3) markers of pre-B cell ALL (CD19 and CD22); and) 4-hydroxy-2-nonenal (HNE) adducted proteins. HNE protein adductions were measured in the patient sera and CSF. Pro-inflammatory cytokine levels were also measured in patient sera because of their contribution to oxidative stress and neuronal injury. Our results: 1) demonstrate EVs are a sensitive indicator of oxidative damage; 2) suggest EVs as a marker of a decline in neuronal stability; and 3) show the presence of leukemia has a greater contribution to pro-inflammatory cytokine production in the patient's serum than the cancer treatment. Specifically, we observed a significant decrease in cytokine levels (e.g., TNF-α, IL-1β, IL-6, and IL-8) following the initiation of treatment, highlighting the influence of leukemia burden on systemic inflammation. The results support the utilization of EVs as a sensitive marker of oxidative stress and off-target tissue damage.

Long-term outcomes and surgical conversion following immunotherapy in MSI-H biliary tract cancers.

592 Background: Deficient mismatch repair/microsatellite instability (MSI-H) in biliary tract cancers (BTC) is rare, estimated to be 1-5%. MSI-H across solid tumors has shown unprecedented durable response to immune checkpoint inhibitors (ICI) regardless of anatomic location. Here we describe the clinical outcomes of unresectable BTC patients with MSI-H treated with ICIs and their conversion to surgery. Methods: We conducted a multicenter, retrospective analysis of patients (pts) with advanced BTC who had been identified with MSI-H by molecular analysis performed between 2017 and 2024 at Mayo Clinic and University Hospitals Seidman Cancer Center. The outcomes of interest were overall survival (OS), defined as time from initiation of first-line systemic treatment to death; Time-to-treatment failure (TTF), defined as time from initiation of treatment to cessation due to any cause; and response. All analyses were done descriptively. Results: We identified 22 MSI-H pts with BTC, 19 with cholangiocarcinoma and 3 with gallbladder cancer. Median age at diagnosis was 61 (range 26-86), 20 (90.9%) were Caucasian, 9 (40.9%) were male gender, and 5 (22.7%) had etiology as Lynch syndrome. Twelve (54.5%) pts had metastatic disease at diagnosis. Twenty pts (90.9%) received first line systemic therapy, of whom 11 (55%) continued onto second line. Among the 20 pts that received first line therapy, median TTF was 7.6 months (95% CI: 4.8-14.3), objective response was observed in 7 (35%) pts, and disease control was observed in 15 pts (75%). Among the 11 pts that continued onto second line systemic treatment, objective response was observed in 4 pts (36%) and disease control was observed in 6 pts (55%). Among the 20 pts that received first line therapy, 19 (95%) ever received ICI +/- chemotherapy as a part of their treatment plan. Two-year OS for pts who ever received ICI was 63% (95% CI: 41%-96%). In total, 4 pts (20%) were restaged to resectable following treatment with an ICI, underwent resection, and currently have no evidence of disease. Conclusions: Administration of ICI during treatment plan in pts with MSI-H confirmed durable response and even downstage pts to resectable stage for curative intent. Testing for MSI-H should be performed upfront to guide treatment decision.

A phase two trial evaluating FOLFIRI plus aflibercept after failure of FOLFOXIRI plus bevacizumab in patients with unresectable metastatic colorectal cancer.

FOLFOXIRI plus bevacizumab (BEV) is an option for first-line treatment of metastatic colorectal cancer (mCRC). However, there is no consensus on the optimal treatment strategy when disease progresses. The EFFORT open-label, multicenter, single-arm phase II study investigated whether FOLFIRI plus aflibercept retains activity after progression of FOLFOXIRI plus BEV treatment. The patients with unresectable mCRC who failed first-line FOLFOXIRI plus BEV received FOLFIRI plus aflibercept. The primary endpoint was progression-free survival (PFS) in the full analysis set (FAS). Angiogenic biomarkers were measured before treatment initiation. From April 2019 to May 2021, 35 patients were enrolled and 34 were analysed in the FAS population (men, 18; median age, 63years [range: 32-78]). The primary tumor was left-sided in most cases (23/34), 23 patients were RAS mutant, 3 patients had BRAF V600E mutation and 27 patients had liver metastases. The primary end-point was met with a median PFS of 4.3months [80% confidence interval [CI] 3.7-5.1]. Median overall survival was 15.2months [95% CI 8.9-22.7]. Per RECIST, there were 1 complete response, 4 partial responses, 21 stable diseases and 8 disease progressions. Overall response rate was 14.7% [95% CI 5.0-31.1], and disease control rate was 76.5% [95% CI 58.8-89.3]. Responses were more common in patients with high VEGF-C, low VEGF-D and low PlGF levels before treatment. FOLFIRI plus aflibercept, administered after failure of FOLFOXIRI plus BEV, is effective and has a manageable safety profile. This regimen may be a useful second-line treatment option for these patients.

Chemotherapy selection for advanced or metastatic pancreatic cancer using machine learning models trained with multi-center datasets.

738 Background: Several factors must be considered when selecting the chemotherapeutic regimen for advanced or metastatic pancreatic cancer. The decision between FOLFIRINOX and Gemcitabine/Nab-paclitaxel (GnP) as the first-line therapy is challenging, as survival is influenced by the efficacy and toxicity profiles of these treatments, along with individual patient characteristics and therapeutic vulnerabilities. This study aims to facilitate the selection of an appropriate first-line regimen for advanced or metastatic pancreatic cancer by employing machine learning (ML) methods trained on multi-center datasets. Methods: Our study is based on a cohort of 191 patients who underwent systemic chemotherapy for advanced or metastatic pancreatic cancer at the Gangneung Asan Hospital and Asan Medical Center in South Korea between 2014 and 2023. The dataset consisted of 17 types of demographic and clinical characteristics, as well as time-course of response and survival outcomes. We divided the cohort into training and test groups (4:1) in a stratified manner. ML models predicting overall survival (OS) were trained on the former group using the CatBoost method. The models utilizing a minimal subset of variables were selected with respect to ROC-AUC during 5-fold cross validation. A patient was classified as having high risk to a therapy when the predicted probability of death following treatment initiation was above the threshold value as determined during training of the respective model. Results: The median age of the entire cohort was 62 years, with 64% being male. The ML models achieved ROC-AUCs of 0.81 and 0.82 when predicting early death within 12 months following the initial administration of FOLFIRINOX or GnP, respectively. The predictive accuracies of the models were 0.77 and 0.80 for the unseen datasets from the two treatment groups, respectively. The median OS of the high- versus low-risk groups of FOLFIRINOX predicted by the ML models were significantly different (9 vs 15 months, P <0.0001), with a hazard ratio (HR) of 2.8. Similarly, the median OS of the high- and low-risk groups of GnP were significantly different (9 vs 18 months, P <0.01, HR of 2.5). We observed that 27% of the patients predicted as high risk to FOLFIRINOX therapy were predicted as low risk to GnP and vice versa for 32% of the patients predicted as high risk to GnP therapy. Conclusions: We developed ML models to compute the probability of early death following FOLFIRINOX or GnP therapy from routinely collected data of the patients with advanced or metastatic pancreatic cancer. After confirming robust predictive performance with multi-center datasets, we believe that these models may assist clinicians in selecting a first-line regimens, potentially enhancing personalized treatment strategies for this challenging disease.

Effects of sacubitril/valsartan on cardiac remodeling in heart failure with reduced ejection fraction: An integrated study of molecular biomarkers and imaging techniques.

Treatment of heart failure and reduced ejection fraction (HFrEF) using angiotensin receptor-neprilysin inhibitor demonstrates beneficial effects on cardiac remodeling (CR). We assessed the impact of sacubitril/valsartan on the concentrations of HF biomarkers in relation to parameters of CR using imaging techniques in patients with HFrEF. In a prospective single-center open-label study, 68 patients with symptomatic HFrEF were treated with sacubitril/valsartan and followed-up every three months for 12 months. Soluble suppression of tumorigenicity 2 (sST2), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity cardiac troponin I (hs-cTnI) were measured in blood samples. Additionally, echocardiography and cardiac magnetic resonance imaging (cMRI) were performed to assess heart structural and functional changes. Following treatment initiation, follow-up visits revealed an improved NYHA functional class in these patients, alongside significant decreases in all circulating biomarkers, increases in left ventricular ejection fraction (LVEF), and reductions in volume- and diameter-related LV parameters. Sustained gradual decreases in sST2 concentrations over time correlated with NT-proBNP concentrations (rho=+0.26, P < 0.001). Both biomarkers were inversely correlated with LVEF, and positively correlated with volume- and diameter-related LV parameters from echocardiography and cMRI. However, NT-proBNP concentrations exhibited stronger correlations with these LV parameters and were associated with the number of LV segments showing fibrosis, unlike sST2. Sacubitril/valsartan treatment in HFrEF leads to reduced sST2 and NT-proBNP concentrations with distinct decreasing curves, which are linked to reverse CR through LV-related parameters. In contrast to sST2, NT-proBNP is also associated with fibrosis, suggesting that both biomarkers unveil distinct mechanisms during CR in patients treated with sacubitril/valsartan.

PD-L1 testing patterns in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the U.S.

Pembrolizumab with/without platinum+5-FU is approved for the first-line (1L) treatment of R/M HNSCC, and its monotherapy use requires PD-L1 Combined Positive Score (CPS)≥1. We aimed to understand PD-L1 testing patterns and associations with patient characteristics and treatment choice in R/M HNSCC. Adults with R/M HNSCC initiating 1L systemic therapy were included from a U.S. nationwide database primarily compromised of community practices (07/01/2019-12/31/2023). PD-L1 testing patterns, treatment sequence, and time gaps related to testing and treatment initiation were summarized. Logistic regression was used to test associations between patient characteristics and PD-L1 testing patterns, and between CPS scores and 1L pembrolizumab monotherapy use. Of 2,207 patients, 32.7% received PD-L1 testing before 1L therapy initiation, 17.4% after 1L therapy initiation, and 50.0% were never tested. Most patients (55.9%) who tested positive before 1L therapy received pembrolizumab monotherapy while those who tested negative received pembrolizumab+platinum+5-FU most commonly (31.6%). Among patients untested before 1L therapy, the most common 1L treatment was pembrolizumab monotherapy (24.3%). Patients with an ECOG≥2 had higher odds of being tested before 1L therapy (OR: 1.42, p<0.01). CPS scores were associated with higher odds of receiving 1L pembrolizumab monotherapy (OR: 4.11 and 4.96 for CPS 1-19 and≥20, respectively; both p<0.0001). This study revealed low utilization of PD-L1 testing to guide treatment choice and impactful gaps between specimen collection, the receipt of results, and 1L therapy initiation. There is a need to improve clinician awareness of the importance of PD-L1 testing and an opportunity for updated guidelines on testing.

Implementation of model-informed precision dosing for tamoxifen therapy in patients with breast cancer: A prospective intervention study.

Tamoxifen is an estrogen-receptor (ER) antagonist, used as adjuvant treatment of ER-positive breast cancer. It is converted by CYP2D6 into endoxifen, its most active metabolite. Patients with endoxifen plasma concentrations <16nM face a higher risk of recurrence. The use of a priori model-informed precision dosing (MIPD) may lead to faster target attainment and thus potentially improve patient outcomes. In total, 106 evaluable patients were prospectively included in this single-arm MIPD-intervention study. Patients received a model-predicted tamoxifen dose when starting tamoxifen-treatment (65.1% of patients received 20mg, 16.0% received 30mg and 18.9% received 40mg). Seventy-five percent of the 40mg group was predicted to be unable to reach the threshold of 16nM despite receiving the highest registered dose. After attaining steady-state, 84.0% of patients reached endoxifen levels ≥16nM, which was not significantly higher compared to a historical control cohort (77.9%, p=0.17). The model showed adequate performance and correctly identified patients requiring 40mg tamoxifen. Endoxifen samples that were acquired 4-6 weeks after treatment initiation, are informative of steady-state endoxifen levels and can be used to inform MIPD and adjust tamoxifen dosing prior to steady-state attainment. In this first MIPD implementation study for patients treated with tamoxifen, MIPD did lead to more patients achieving endoxifen levels ≥16nM as compared to the one-dose-fits-all strategy, albeit insignificant. This may partly be explained by a larger proportion of patients who were recommended to switch to an aromatase inhibitor (AI) in the intervention cohort. In conclusion, MIPD seems beneficial compared to one-size-fits-all-dosing, but TDM still remains an important addition.

Impact of next-generation sequencing in advanced gastrointestinal cancer.

814 Background: Next-generation sequencing (NGS) is a cutting-edge technology that allows for rapid DNA and RNA sequencing, identifying key mutations in cancer patients. It provides both diagnostic and predictive data for treatment decisions. Approximately 75.6% of US oncologists use NGS testing for patients with advanced solid tumors.This study retrospectively evaluates the impact of NGS testing on treatment outcomes for advanced GI cancer patients at a community-based cancer center in Florida. Methods: Between March 2019 and September 2023, 267 patients with stage 3 or 4 solid malignancies underwent NGS testing. Of these, 77 patients with advanced GI cancer were included in the study. Nearly half (48%) of the patients were diagnosed with advanced-stage colon cancer.NGS testing was performed using tissue samples (79.22%), blood samples (16.88%), or both (3.90%). Demographic and clinical outcomes, including time to diagnosis, treatment initiation, and survival, were collected and analyzed. Results: The median age of the study population was 70, with 88.31% of patients insured through Medicare. The cohort was composed of 61.04% males. Targetable mutations were identified in 59.74% of patients, leading to FDA-approved targeted therapies for 44.16%, and clinical trial eligibility for 79.22%. 52 patients were alive at the time of this analysis; those with biomarkers identified through NGS testing had a median treatment duration of 11 months regardless of whether testing impacted choice of therapy; whereas, patients without identified biomarkers had a median duration of 7.5 months. NGS testing impacted first-line therapy in only 6.49% of all patients; however, 80% of those patients were alive at the time of this analysis with a median duration of response of 5 months. Conclusions: NGS testing has become a cornerstone of oncologic care for advanced solid tumors; however, in this cohort of advanced GI malignancies, NGS results influenced first-line treatment decisions in only 6.49% of cases. Although the study included a small sample size, it reflects a real-world community setting where access to therapies and insurance coverage varies. For example, though patients may have targetable novel therapies available for their disease, the indications for such therapies may not be in the first line setting or covered by insurance. Advancements in NGS targeted therapies has greatly impacted the care of other solid malignancies such as non-small cell lung cancer; however, this study highlights that in the field of GI oncology, there is a large clinically unmet need of identifying newer biomarkers that are clinically relevant and impactful in earlier lines of oncologic care.

Excess cardiometabolic risk in children and adolescents initiating antipsychotic treatment compared to young adults: results from a nationwide cohort study.

Antipsychotic treatment is associated with cardiometabolic risks that may be especially detrimental to children and adolescents. In this Danish population-based cohort study, we included individuals with psychiatric diagnoses who initiated antipsychotics in 2000-2021 at age 6-31 years. We assessed the risk of cardiometabolic adverse events up to 10 years following incident exposure to antipsychotics, compared to age- and sex-matched unexposed individuals with psychiatric diagnoses. Cox regression models were used to calculate hazard ratios (HRs) after adjustment using high-dimensional propensity scores, including age, sex, calendar time, hospital diagnoses, and prescription drug use. HRs were compared between incident exposure in youths (6-17 years) and young adults (18-31 years), and between incident exposure in children (6-11 years) and adolescents (12-17 years). The total cohort consisted of 335,093 individuals, including 36,092 subjects exposed to antipsychotics (children and adolescents: 8,547, mean follow-up: 6.8±3.2 years; young adults: 27,545, mean follow-up: 6.5±3.4 years) and 299,001 age-, sex- and calendar-matched unexposed subjects. The incidence rate of cardiometabolic events was higher for young adults initiating antipsychotics than for children and adolescents (23.2 vs. 14.1 events/1,000 person-years). However, the adjusted excess risk of cardiometabolic events was significantly higher in exposed compared to unexposed children and adolescents (HR=1.87, 95% CI: 1.71-2.05) than in exposed compared to unexposed young adults (HR=1.46, 95% CI: 1.40-1.51) (p<0.001). The excess risk of cardiometabolic events was even higher when antipsychotic treatment was initiated before age 12 years (HR=2.44; 95% CI: 1.99-2.98) than at age 12-17 years (HR=1.69, 95% CI: 1.52-1.87) (p=0.012). Concerning specific cardiometabolic outcomes, there was an effect of age at antipsychotic initiation on the risks of metabolic syndrome (p=0.011) and obesity (p<0.001), that were higher among children and adolescents than young adults. Thus, initiation of antipsychotic treatment before age 18 years is associated with an excess risk of cardiometabolic events compared to age- and sex-matched youths with psychiatric disorders but unexposed to antipsychotics. The excess cardiometabolic risk is significantly higher than that of individuals who start antipsychotic treatment in early adulthood, and significantly higher for treatment onset in childhood compared to adolescence. On the basis of these findings, recommendations are provided about the use of antipsychotics in children and adolescents.

Changes in food preferences after oral semaglutide administration in Japanese patients with type 2 diabetes: KAMOGAWA-DM cohort.

This study aimed to investigate the effects of oral semaglutide on the changes in food preference of Japanese patients with type 2 diabetes. This retrospective multicenter study included 75 patients with type 2 diabetes who received oral semaglutide. The primary outcome was the change in the score of brief-type self-administered diet history questionnaire (BDHQ) score 3months after the initiation of oral semaglutide treatment. The secondary outcome was the change in the Control of Eating Questionnaire (CoEQ), HbA1c, and body mass index (BMI) after 3months. The median age, BMI, and HbA1c of the 23 participants were 64.0years, 26.9kg/m2, and 7.6% (59mmol/mol). The BDHQ results showed total energy was significantly reduced. Among the individual nutrients, carbohydrates most decreased. The CoEQ results particularly showed declines in cravings for something sweet, chocolate or chocolate flavored foods, and starchy foods, satisfaction at meals, frequency and intensity of food craving, difficulty of resisting the craving for food, and frequency of eating in response to cravings for food were significantly lower after 3months. The mean HbA1c and BMI significantly decreased. In Japanese patients with type 2 diabetes, oral semaglutide treatment decreased total energy intake and changed food preferences.

Perceptions of Obesity Among Healthcare Professionals and Policy Makers in 2023: Results of the Global OPEN Survey.

Obesity is a disease with severe health impacts on individuals and economic impacts on society, yet healthcare practitioners (HCPs) and policy makers often fail to address it. This survey was conducted to examine current global obesity care and perceptions influencing care delivery among HCPs and healthcare decision makers (HC DMs). A survey with a cross-sectional design was conducted among 1200 HCPs (primary care providers, endocrinologists, cardiologists, and nurses) and 414 HC DMs from eight countries across five continents. Respondents' perceptions of obesity, characteristics of patient populations, obesity management practices, and obesity-related healthcare policies were collected. Surveys were administered online from June-July 2023. All respondent data were anonymized. Among HCPs, 26.4% and 29.0% of HC DMs considered obesity a chronic disease, and 44.6% of HCPs reported that obesity was recorded as a chronic disease in patients' medical records. The pattern of responses was consistent across countries and professional roles. Obesity care approaches focused on lifestyle concerns. HCPs and HC DMs appeared to overestimate the provision of obesity-related medical care for affected patients. These results corroborate prior findings that many HCPs do not consider obesity a disease, which hinders initiation of appropriate treatment, and also highlight challenges in obesity management, including gaps in obesity guidelines and accessibility to healthcare. These findings may help guide education and outreach by health authorities as well as HCPs.

Prompt initiation of durvalumab and tremelimumab treatment for unresectable hepatocellular carcinoma in patients with chronic active hepatitis B.

568 Background: Chronic hepatitis B virus (HBV) infection is a common etiology of HCC, especially in East Asia. Clinical trials using immune checkpoint inhibitors (ICIs) usually exclude patients with chronic active hepatitis B (serum HBV viral load &gt; 2000 IU/mL) or require the HBV viral load to be below a certain level using anti-HBV medications. This study examines the safety and efficacy of concurrently administering the STRIDE regimen (durvalumab with a single dose of tremelimumab) or durvalumab alone with anti-HBV medications in this patient population. Methods: We enrolled patients with advanced HCC, Child-Pugh A liver function reserve, and untreated chronic active hepatitis B. Initially, only patients naïve to ICIs were eligible, and patients received 1500mg of durvalumab intravenously every four weeks for up to two years except for disease progression or occurrence of unacceptable toxicities. After the positive results of the HIMALAYA study, we shifted to the STRIDE (single tremelimumab regular interval durvalumab) regimen, adding one dose of 300mg tremelimumab on the first day to regular durvalumab treatment, and allowed patients who had received prior programmed cell death-1 blockade therapy to be enrolled. Anti-HBV treatment with entecavir was initiated within seven days before starting ICI therapy. The primary endpoint was the rate of HBV reactivation (defined as a ≥2 log increase in serum HBV DNA from baseline) during the first six months. Results: Following the protocol design, 30 patients were enrolled. Two patients were female, and the mean age was 66.9 years. Ten patients received durvalumab alone, and 20 received the STRIDE regimen. Macrovascular invasion and extrahepatic spread were present in 16 (53.3%) and 20 (66.7%) patients, respectively; 18 (60%) patients had alpha-fetoprotein level ≥ 400 ng/mL. More than half (60.0%) of the patients had received prior systemic therapy for HCC, including 2 patients who had received PD-1 blockade therapy. Seven patients received the study treatment as the 3 rd or later line of systemic therapy. The mean±standard deviation baseline HBV viral load was 771.0±354.1 KIU/mL. No patients experienced HBV reactivation or HBV-associated hepatitis. Hepatitis flare was noted in 8 (26.7%) patients, but none of them were associated with HBV reactivation. The objective tumor response rate was 10% and 25% for the durvalumab treatment alone and the STRIDE regimen, respectively. No unexpected toxicities were identified in this study. The most common treatment-related adverse events were skin rash and liver function test abnormalities. Conclusions: For patients with chronic active hepatitis B, ICI therapy could be promptly initiated as long as anti-HBV medications were administered simultaneously. This study was partially supported by AstraZeneca. Clinical trial information: NCT04294498 .

Long-term efficacy and safety of perampanel monotherapy in patients with newly diagnosed or currently untreated recurrent focal-onset seizures: Results from the open-label extension phase of FREEDOM (Study 342).

FREEDOM (Study 342; NCT03201900) assessed the long-term treatment effect of perampanel monotherapy in adolescent and adult patients (12-74 years of age) with untreated focal-onset seizures (FOS), with or without focal to bilateral tonic-clonic seizures (FBTCS). In the Core Study, after a 4-week Pretreatment Phase, perampanel was up-titrated to 4 mg/day during a 6-week Titration Period followed by a 26-week Maintenance Period. Patients experiencing seizure(s) during the 4-mg/day Maintenance Period could have perampanel up-titrated to 8 mg/day over 4 weeks then could enter the 26-week 8-mg/day Maintenance Period. Patients could enter Extension to continue treatment upon the completion of the Core Study. Seizure-freedom rates, time to seizure recurrence or withdrawal since the initiation of maintenance treatment, and safety outcomes were assessed. In FREEDOM, 89 patients who received ≥ 1 perampanel dose were included for safety assessments (Safety Analysis Set), and 73 of them entered the 4-‍‍‍mg/day Maintenance Period (the modified Intent-to-Treat Analysis set) with 21 patients having perampanel up-titrated to 8 mg/day; 46 patients entered Extension with 38 patients completing. Overall, 42/89 (47.2 %) patients had cumulative exposure to perampanel for > 52 weeks. Among patients who entered Extension, 52.2 % (n = 24/46; 95 % confidence interval [CI] 36.9, 67.1) remained seizure free for 52 weeks at perampanel 4 mg/day and 67.4 % (n = 31/46; 95 % CI 52.0, 80.5) at 4-8 mg/day. The cumulative probabilities of seizure recurrence and withdrawal at 4-8 mg/day over 52 weeks were 28.9 % (95 % CI 19.0, 42.4) and 43.8 % (95 % CI 33.4, 55.9), respectively. Treatment-emergent adverse events (TEAEs) occurred in 74/89 (83.1 %) patients, with 9/89 (10.1 %) discontinuing because of TEAEs. Dizziness occurred in 34/89 (38.2 %) patients and was the most common event. Patients with untreated FOS (with or without FBTCS) are able to maintain seizure freedom for up to 52 weeks with perampanel monotherapy at a dose of 4-8 mg/day. The tolerability profile was manageable, and the safety profile was consistent with previous findings.

Colorectal cancer legal and administrative burden support (COLLABS): A pilot clinical trial.

TPS307 Background: Patients with colorectal cancer often have health-related social needs (e.g. food insecurity, housing instability, employment loss). Failure to adequately address these is associated with financial hardship, worse quality-of-life, psychosocial distress, lower rates of treatment receipt, and worse survival. Cancer clinical care teams often lack the resources, knowledge, and processes to resolve these issues, many of which are actually legal in nature. Engagement with legal teams—medical-legal partnerships—can screen for, prevent, and resolve health-related social needs, as well as address related legal issues such as insurance denials, employment rights and protections, disability benefits, debt management, and estate planning. Cancer Legal Care (CLC) is a nonprofit providing free legal services to persons affected by cancer in MN. Past CLC clients have indicated a preference for proactive connection to CLC to prevent crises and overcome barriers to access such as concerns regarding perceived costs of legal services. Methods: This is a single-arm, pilot study to evaluate the feasibility, acceptability, and preliminary efficacy of proactive and free legal care support for patients with colorectal cancer at the University of Minnesota. The enrollment goal is 20 patients and the trial duration is 6 months. Inclusion criteria include English-speaking adults with advanced stage colorectal cancer and estimated life expectancy of &gt;6 months. There is no requirement for baseline health-related social need(s) or time from diagnosis. After participants complete baseline surveys, we will connect them to a CLC attorney for an initial “legal care checkup”— the timing and method of connection (in-person, video visit, or phone call) is based on patient preference. Patients can bring up self-identified or active issues themselves, while CLC will also screen for needs. CLC will provide any required legal services and engage with the cancer care team as needed. CLC will follow-up with participants at 3 and 6 months, though services may continue after the study period off trial. Participants will complete surveys at baseline, 3 months, and 6 months. Surveys will assess patient-reported outcomes on financial toxicity, quality-of-life, comfort levels with accessing cancer care, status of health-related social and legal needs, perceived stress, life mastery and engagement, relationship with CLC contact, and acceptability of the intervention. The primary outcomes are feasibility (rates of initial engagement, continued engagement, and intervention completion; feasible if &gt;50% on each metric) and acceptability. We will conduct exit qualitative interviews. We will collect sociodemographics, rates of treatment adherence/ completion, legal services provided, outcome of legal issues, and monetary savings or recovery for patients. Enrollment opened August 2024 and we have enrolled 15/20 participants. Clinical trial information: NCT06475664 .

Incidence trends, demographic disparities, and survival outcomes of gastrointestinal malignancies in young adults: A focus on stomach and pancreatic cancers.

339 Background: The incidence of gastrointestinal (GI) cancers has been rising among younger populations. While prior research has highlighted the increasing incidence of colorectal cancer (CRC) in adolescents and young adults (AYA), defined as individuals aged 15-39, there is less focus on non-CRC GI malignancies, such as stomach and pancreatic cancers, within this age group. This study aims to further elucidate the incidence, mortality, and demographic disparities in the AYA population for stomach and pancreatic cancers compared to older populations (&gt;50 years old). Methods: Data was extracted from the SEER database spanning from 2000 to 2020. Demographic, clinical, and secondary cancer characteristics were summarized across the sample, stratified by cancer type. Overall survival (OS) and disease-specific survival (DSS) were analyzed using the Kaplan-Meier method, with comparisons performed via the log-rank test. Univariate and multivariate analyses were conducted to identify predictors of survival outcomes. Results: We identified 19,983 AYA patients diagnosed with non-CRC GI malignancies (including esophageal, stomach, small intestine, anal, hepatobiliary, and pancreatic cancers) between 2000 and 2020. Among these patients, the majority were male (58%), White (47%), and resided in metropolitan areas (90%). The median age at diagnosis was 38 years. Pancreatic cancer was 20% more common in the AYA group compared to those over 50 years old (12%), while stomach cancer was also more prevalent in the AYA group (27% vs. 17%). Survival outcomes were significantly better in the AYA group, with a median OS of 24 months compared to 9 months in the older population, and a median DSS of 52 months versus 13 months (p&lt;0.001). Predictors of worse OS and DSS included male sex, African American race, income below $45,000/year, lack of surgical intervention, and delayed initiation of treatment. Conclusions: The incidence of stomach and pancreatic cancers is notably higher in the AYA population compared to older adults, with AYA patients demonstrating better overall and disease-specific survival outcomes. However, certain demographic factors, such as male sex, African American race, and lower income, are associated with worse survival, underscoring the need for targeted interventions to address these disparities. Early diagnosis and timely treatment are critical to improving outcomes in this younger population.

Colorectal cancer care disparities in an urban diverse population: A tale of two hospitals in the nation’s capital.

38 Background: Colorectal cancer (CRC) disparities by race and ethnicity are well-documented nationally. In the District of Columbia (DC), Black Americans have an 18% higher incidence and 46% higher mortality rate compared to overall rates among all races/ethnicities. These disparities often stem from long-standing inequities in the social determinants of health, which affect access to cancer prevention, early detection, and treatment. MedStar Georgetown serves a large, urban, diverse population at 2 hospitals: the MedStar Georgetown University Hospital (MGUH) and the MedStar Washington Hospital Center (MWHC). MWHC serves a higher proportion of minoritized patients (pts) with multiple social determinant barriers to care, including those without private health insurance. We hypothesized that disparities would be found in CRC pt care and outcomes when comparing MWHC with MGUH. Methods: We conducted a retrospective study of all CRC pts treated during the 2021-2023 period at MGUH and MWHC using the COTA real-world database. Pt demographics, insurance status, and selected clinical data, including but not limited to treatment site, disease stage, tumor molecular testing, and pt survival, were abstracted for analysis. Descriptive, bivariate, and multivariate analyses focused on gender, race/ethnicity, insurance status, receipt of tumor testing, and the interval between diagnosis and therapy initiation and explored survival by these factors in addition to the site of care (MGUH versus MWHC). Results: Of the 379 CRC pts receiving care at the Lombardi Comprehensive Cancer Center during the study period, 53% were treated at MGUH and 47% at MWHC. CRC pts at MWHC were more likely than CRC pts at MGUH to be Black Americans (65% vs. 28%, p&lt;0.001) and have 3 or more comorbidities (16% vs. 8%, p=0.22) but were less likely to have early onset CRC (p&lt;0.01) and be on private insurance (36% vs. 23%, p=0.01). Pts treated at advanced stages (stages 3-4) were similar between the two hospitals (64%). In spite of these differences, we did not find any differences between MWHC and MGUH in molecular tumor testing (83% vs. 86%, p=0.41), median time (days) to treatment initiation (28 vs. 26 days, p=0.18), or short-term survival (90% vs. 91%, p=0.95). In analyses comparing care/treatment-related factors with race/ethnicity and insurance status across the 2 hospitals, we did not find any statistically significant differences. Conclusions: Contrary to our expectations of finding significant cancer care disparities, we did not observe any differences in molecular tumor testing rates, time to initiation of therapy, or short-term survival by treatment site or race/ethnicity status. Our results suggest that integrated, specialized, guideline-concordant care in comprehensive cancer centers has the potential to eliminate CRC outcome disparities among pts diagnosed at these centers.

Real-world biomarker testing and first-line treatment patterns among locally advanced, unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma patients in the US.

348 Background: Advanced-stage gastric cancer and gastroesophageal junction adenocarcinoma (advG/GEJC) are leading causes of cancer-related morbidity and mortality. Chemotherapy is the traditional first-line (1L) therapy for patients in the advanced setting, with targeted and immunotherapy considered based on biomarker expression. This study aimed to describe real-world HER2 and PD-L1 testing practices and 1L treatment patterns among advG/GEJC patients. Methods: A retrospective cohort study was conducted among adult patients diagnosed with advG/GEJC between 01 Jan 2017 and 30 Jun 2023 usingthe US-based Flatiron Health electronic health record-derived de-identified database. HER2 and PD-L1 testing practices were evaluated prior to and up to 1-month post-1L treatment initiation or 6 months post-advG/GEJC diagnosis date in untreated patients. 1L treatment regimens were described overall and stratified by HER2 and PD-L1 expression. Results: Among 4,256 advG/GEJC patients, the average age was 67 years with the majority male (68%), non-Hispanic white (44%), and with metastatic disease (64%). Nearly three quarters (72%) of patients included received a HER2 test and 55% had a HER2 test with a valid result within the timeframe mentioned above. More than a quarter of patients (27%) received a PD-L1 test and 25% had a PD-L1 test with a valid result. PD-L1 testing before the approval of nivolumab in 1L (i.e. before 2021) showed testing at 19% (490/2,629; 17% with a valid result) and from 2021 onward at 40% (643/1,627; 37% with a valid result). Across the full cohort, half of the patients received chemotherapy alone (52%) and one quarter received no treatment (25%). Similar treatment patterns were observed in the subset of 1,117 patients who did not receive a HER2 or PD-L1 test; 54% received chemotherapy alone and 36% no treatment. Of the 340 patients who were tested for HER2 and were HER2 positive, half (52%) received trastuzumab combination therapy, 23% received chemotherapy alone, and 18% had no treatment. Of the 301 patients who received a PD-L1 test with a combined positive score (CPS) ≥5 from 2021 onward, 41% received immunotherapy, 34% received chemotherapy alone and 18% had no treatment. Prior to 2021, most patients with a PD-L1 test and CPS &gt;5 used chemotherapy alone (57%; 132/233), 13% (31/233) received PD-L1 targeted therapies and 19% (43/233) received no treatment. Conclusions: This study describes a potential subset of US advG/GEJC patients who do not receive a HER2 or PD-L1 test and/or do not receive eligible targeted or immunotherapy as part of routine clinical practice. As precision medicine options continue to evolve, these data suggest an opportunity to further understand the drivers for biomarker testing as well as the factors impacting the use of biomarker-informed treatment options.

Liver Disease Complicating Familial Mediterranean Fever: A Study on 66 Patients Out of 533 Adult From the JIR Cohort.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, associated with MEFV mutations. FMF patients can experience liver involvement, potentially leading to cirrhosis. This study aimed to evaluate liver involvement in FMF patients at a French tertiary centre for adult FMF. We conducted an observational study with FMF patients displaying 2 pathogenic MEFV mutations at the National Reference Center for Autoinflammatory Diseases and Inflammatory Amyloidosis (CEREMAIA) in Paris and included in the JIR cohort. MEFV heterozygous patients and those with other liver disease causes were excluded. Among 533 FMF patients 12.4% had chronic liver abnormalities, with 30% who developed cirrhosis 54 years [36-57] in median after disease onset. Forty-seven per cent were colchicine resistant, and 41% received interleukin-1 inhibitors. Cirrhotic patients experienced delayed hepatopathy diagnosis, prolonged FMF diagnosis delay and late-onset treatment initiation compared to those with only liver function test abnormalities. Colchicine resistance and interleukin-1 inhibitor use were more common in cirrhotic patients. Body mass index and AA amyloidosis rates did not differ significantly between groups. Twenty-one patients had undergone liver biopsies including 14 cirrhotic patients revealing steatohepatitis in 12 cases and probable steatohepatitis in 4. Other lesions, like iron overload and sinusoidal dilatation, were sporadically observed. FMF patients are at risk of chronic liver disease. Regular liver function monitoring is crucial, particularly in case of persistent inflammation, due to the risk of progression to cirrhosis and its associated morbidity and mortality.

Retrospective study of fluoropyrimidine chemotherapy dosing and toxicity in patients with screen-detected deleterious DPYD gene variants.

293 Background: Fluoropyrimidine chemotherapy agents are commonly used to treat solid tumors. Fluoropyrimidines are degraded by the enzyme dihydropyridine dehydrogenase (DPD), encoded by the DPYD gene. Deleterious variants in DPYD leads to functional DPD deficiency and increased toxicity risk. Methods: We conducted a retrospective study of patients with screen-detected deleterious DPYD variants who were treated with fluoropyrimidine chemotherapy between 01/01/15-04/15/23. Outcomes of interest were initial fluoropyrimidine dosing, dose adjustments (cycles 2-6), and early toxicities. Results: We identified 12 patients with heterozygous DPYD variants, including *2A (n=5), c.2846A&gt;T (3), c.1129-5923C&gt;G (2) and *13 (2). Initial chemotherapy regimens included FOLFOX (7), mFOLFIRINOX (3) and CAPEOX (1). Of 11 patients receiving FOLFOX/mFOLFIRINOX, nine began treatment with a 50-60% reduction of the 5-FU infusion dose, one received a 25% reduction, and one received a standard dose (due to treatment initiation prior to return of the genotype result). Seven patients tolerated the initial 5-FU infusion dose without further dose reductions, including three who tolerated limited dose-escalation. Four patients required further dose reduction from the cycle 1 dose, due to toxicity. The patient who received a standard 5-FU infusion dose in cycle 1 experienced grade 3 toxicity, but tolerated subsequent treatment after 50% dose reduction. The patient treated with CAPEOX tolerated 4 planned cycles with a 50% capecitabine dose reduction. Conclusions: Most patients who screened positive for deleterious DPYD gene variants tolerated fluoropyrimidine chemotherapy with a 50% dose reduction. However, 3 of 12 patients experienced toxicity requiring treatment discontinuation or dose reduction to less than 50% of the standard 5-FU dose.