First-line Treatment Research Articles

801MO Efficacy and safety of a phase II study: Timdarpacept (IMM01) combined with azacitidine (AZA) as the first-line treatment in adults with chronic myelomonocytic leukemia (CMML)

801MO Efficacy and safety of a phase II study: Timdarpacept (IMM01) combined with azacitidine (AZA) as the first-line treatment in adults with chronic myelomonocytic leukemia (CMML)

Targeted agents plus CHOP compared with CHOP as the first-line treatment for newly diagnosed patients with peripheral T-cell lymphoma (GUIDANCE-03): an open-label, multicentre phase 2 clinical trial

Peripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. We conducted an open-label, phase 2 nonrandomised, externally controlled study to evaluate the efficacy and safety of targeted agents plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) (CHOPX) for PTCL in the front-line setting. Eligible patients were ≥18 years of age and newly diagnosed PTCL. Patients in the CHOPX group received standard CHOP at Cycle 1. Specific targeted agents were added from Cycle 2, decitabine if TP53 mut, azacytidine if TET2/KMT2D mut, tucidinostat if CREBBP/EP300 mut, and lenalidomide if without mutations above. Patients in the CHOP group received CHOP for 6 cycles. The primary endpoint was the complete response rate (CRR) at the end of treatment (EOT). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. The study was registered with ClinicalTrials.gov, NCT04480099. Between July 29, 2020, and Sep 22, 2022, 96 patients were enrolled and included for efficacy and safety analysis with 48 in each group. The study met its primary endpoint. CRR at EOT in the CHOPX group was superior to the CHOP group (64.6% vs. 33.3%, OR 0.27, 95%CI 0.12-0.64; p=0.004). At a median follow-up of 24.3 months (IQR 12.0-26.7), improved median PFS was observed in the CHOPX group (25.5 vs. 9.0 months; HR 0.57, 95%CI 0.34-0.98; p=0.041). The median OS was similar between two groups (not reached vs. 30.9 months; HR 0.55, 95%CI 0.28-1.10; p=0.088). The most common grade 3-4 hematological and non-hematological adverse events in the CHOPX group were neutropenia (31, 65%) and infection (5, 10%). Targeted agents combined with CHOP demonstrated effective and safe as first-line treatment in PTCL. Biomarker-driven therapeutic strategy is feasible and may lead to promising efficacy specifically toward molecular features in PTCL. This study was supported by the National Key Research and Development Program (2022YFC2502600) and the General Program of the Shanghai Municipal Health Commission (202040400).

317. PD-L1 DYNAMICS DURING THE CISPLATIN-INDUCED ACQUIRED RESISTANCE PROCESS IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background Immunotherapy combined with chemotherapy has been the first-line treatment and the most widely-used neoadjuvant regimen in esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapy is an inevitable clinical problem, however, the impact of chemoresistance on immunotherapy efficacy remains unclear. This study aimed to investigate the impact of chemoresistance formation on PD-L1 dynamic changes both in vivo and in vitro during the construction of cisplatin-resistant ESCC models, with the goal of exploring the potential influence of chemoresistance on immunotherapy. Methods For in vivo model, fluorescent-labeled ESCC cells (AKR) were implanted into C57 mice, followed by cisplatin administration for six cycles. Surviving tumor cells were isolated using flow cytometry, and reinjected to establish cisplatin-resistant model. Tumors were harvested to evaluate PD-L1 expression by immunohistochemistry. For in vitro model, ESCC cell lines (TE-1, KYSE150) received low-dose cisplatin for 48h. After three cycles, resistance index (RI, RI=IC50 of drug-expose cell/IC50 of parental cell) was determined by CCK8 assay. The process was repeated with escalating cisplatin doses until resistant cell lines were established (RI>5). PD-L1 expression was measured using RT-qPCR/Western-Blot after each generation. Results In vivo (Figure A), cisplatin-resistant tumor exhibited elevated PD-L1 expression compared to control group (H-score: 22.17 vs 2.09, p<0.001). In vitro (Figure B), PD-L1 expression exhibited an initial increase, followed by a gradual decrease during the process of cisplatin-induced resistance. Specifically, in early stages of cisplatin-resistance in TE-1 cells, PD-L1 mRNA expression rose 4.9 times, consistently paralleled by an elevation in protein level. Subsequently, PD-L1 expression gradually decreased in both mRNA and protein levels. KYSE150 cells exhibited a trend of upregulation in PD-L1 expression in the early stages of cisplatin resistance but later decreased, returning to parental cell levels. Conclusion Under in vivo conditions, acquired cisplatin-resistance in ESCC cells significantly upregulated PD-L1 expression, indicating a potential mechanism for PD-L1-mediated immune escape and its impact on immunotherapy efficacy. However, under in vitro conditions, no consistent trend in PD-L1 expression was observed during the acquisition of cisplatin resistance. This suggests a potentially crucial role of the immune system involved in the chemoresistance regulatory mechanism. Further investigations are needed to explore the impact of chemoresistance on tumor immunology.

O90 EFFICACY AND SAFETY OF DUAL COMBINATIONS OF ANTIHYPERTENSIVE DRUGS AS FIRST-LINE THERAPY: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Background: Hypertension remains the primary cause of mortality worldwide, resulting in about 11 million deaths annually. Despite recent hypertension guidelines advocating for dual combination of antihypertensive drugs as the first-line therapy for most patients, many patients do not receive this therapy. Objective: To assess, among adults with hypertension, dual combinations of AHTDs compared to monotherapy as first-line treatment for blood pressure (BP)-lowering efficacy and safety. Methods: We systematically searched multiple electronic databases until December 2022 to identify relevant randomized, double-blind trials. We included trials involving adults with hypertension who were either treatment naive or untreated for at least 2 weeks, compared dual combinations of drugs with monotherapy from 5 major classes of AHTDs (angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta blockers, and diuretics), for a duration of at least 4 weeks and reported data on BP reduction. AHTDs and their combinations were categorized based on standard daily doses. Outcomes were reduction in BP, treatment related adverse events (TRAE) and withdrawals from the treatment due to adverse events (WDAE). Meta-analyses were conducted using random-effects model. Results: We included 98 trials (636 comparisons and 25892 participants). Overall, baseline mean BP was 159/102 mmHg. Overall BP reduction with dual combination compared to monotherapy was 4.4 (CI: 3.8-5.1)/3.5 (CI:3.2-3.9) mmHg. Compared with standard-dose monotherapy, dual combinations of <1 + <1, 1 + <1 and 1 + 1 (i.e. low-to-standard dose), showed a dose-response relationship in reducing BP by 1.4 (CI: 0.01-2.7)/2.3 (CI: 1.4-3.1), 4.4 (CI: 3.6-5.2)/ 3.3 (CI: 2.9-3.8) and 7.8 (CI: 6.2-8.9)/5.2 (CI: 4.4-5.9) mmHg, respectively. TRAEs [4.8% vs 4.9%; RR 0.92 (0.80 to 1.06)] and WDAEs [0.8% vs 0.9%; RR 1.8 (1.5 to 2.1)] were uncommon with low-to-standard dose dual combinations, with no significant difference compared with standard-dose monotherapy. Conclusion: First-line treatment with low-to-standard dose dual combination therapy is more efficacious and equally safe compared to monotherapy to reduce BP.

3D-printed individual template brachytherapy for the treatment of intractable central pelvic recurrent cervical cancer: A single institution experience

OBJECTIVEThe prognosis of recurrent cervical cancer tends to be poor and there are limited effective treatments currently available for these patients. This study was developed to find a safe and effective treatment for patients with central pelvic recurrent cervical cancer. MATERIALS AND METHODSThis retrospective study analyzed patients with central pelvic recurrent cervical cancer who received 3D-printed individual template (3D-PIT) brachytherapy between February 2019 and June 2023. Analyses of dosimetric parameters, toxicity-related complications, and survival were conducted based on the data of these patients. RESULTSTwenty-one patients with central pelvic recurrent cervical cancer patients were enrolled. All of them received 3D-printed individual template (3D-PIT) brachytherapy. The mean respective adjusted cumulative HRCTV-D90 and HRCTV-D98 values for these patients were 86.9 Gy and 75.4 Gy. And the local control (LC) rate of these patients was 57.1%. In these 21 patients, only 2 (9.5%) of them experienced grade 3–4 rectal adverse reactions, while 7 (33.3%) patients experienced grade 3–4 bladder adverse reactions. 5(23.8%) patients had fistula, while 3 of these 5 patients had undergone prior anti-VEGF targeted drug treatment which is a risk factor of fistula. The respective 2-year rates of overall and progression-free survival (OS and PFS) for these patients were 72.9% and 57.4%, with a 26-month median PFS. CONCLUSIONSThese single-institution data highlight the potential viability of 3D-PIT brachytherapy as an approach to managing intractable central pelvic recurrent cervical cancer following first-line treatment.

1329P Fruquintinib combined with sintilimab and chemotherapy as the first-line treatment in advanced naïve EGFR- and ALK-negative non-squamous non-small cell lung cancer (nsq-NSCLC): Updated results

1329P Fruquintinib combined with sintilimab and chemotherapy as the first-line treatment in advanced naïve EGFR- and ALK-negative non-squamous non-small cell lung cancer (nsq-NSCLC): Updated results

Investigating synergy between beta-blockers and transarterial chemoembolization in the treatment of hepatocellular carcinoma: preliminary data from a propensity matched analysis

PurposeFavorable clinical outcomes have been reported with the adjunct use of beta-blockers in cancer treatment, hypothetically secondary to their anti-angiogenic/anti-proliferative effects. Hereby, we investigate whether there is synergy between beta-blockers and TACE in the treatment of HCC. Methods36 HCC patients on beta-blockers (mean dose of 48 mg daily) at the time of first-line treatment with TACE at our institution were retrospectively identified out of a cohort of 221 patients between 2008 and 2019. Using propensity scoring, a matched cohort of 36 patients not exposed to beta-blockers was generated based on age, gender, ethnicity, etiology of liver disease, BCLC, child Pugh score, PS/ECOG, cirrhosis, largest mass treated, type of TACE and treated liver segments. Tumor response was assessed at 1st and 2nd post-TACE imaging timepoints (1.4 and 4.1 months on average respectively). Variables were compared using chi-square test and Student's t-test. Kaplan-Meier transplant-free survival plots were generated using IBM® SPSS® software. Cox regression analysis was used to evaluate survival predictors. A p values < 0.05 was considered significant. ResultsComparing the control and beta-blocker cohorts, there were no differences in baseline characteristics, post-TACE imaging timepoints, tumor response or transplant free survival (p > 0.05). Tumor size was found to be a predictor of survival when the two cohorts were combined (p = 0.03). ConclusionTransplant-free survival and HCC response to first-line TACE treatment were similar in the control and beta-blocker groups. Large tumor sizes were associated with higher mortality in combined analysis of the cohorts.

1322P A phase II trial of autologous cytokine-induced killer (CIK) therapy plus toripalimab with or without chemotherapy as first-line treatment in advance NSCLC

1322P A phase II trial of autologous cytokine-induced killer (CIK) therapy plus toripalimab with or without chemotherapy as first-line treatment in advance NSCLC

CLL-247 Venetoclax Plus Ibrutinib As First-line Treatment in Patients With Chronic Lymphocytic Leukemia: Meta-Analysis of Randomised Controlled Trials

CLL-247 Venetoclax Plus Ibrutinib As First-line Treatment in Patients With Chronic Lymphocytic Leukemia: Meta-Analysis of Randomised Controlled Trials

AML-700 Prolonged Cytopenias After First-Line Treatment With Venetoclax and Hypomethylating Agent in Newly Diagnosed AML/MDS-IB

AML-700 Prolonged Cytopenias After First-Line Treatment With Venetoclax and Hypomethylating Agent in Newly Diagnosed AML/MDS-IB

506. CLINICAL OUTCOMES OF A NEW SURGICAL TREATMENT FOR GASTROESOPHAGEAL REFLUX DISEASE: RETROSPECTIVE CHART REVIEW OF 28 PATIENTS FROM GERMANY

Abstract Background Gastroesophageal reflux disease (GERD) is a troublesome gastrointestinal ailment with significant prevalence worldwide. First-line treatment is attempted with proton pump inhibitor (PPI) therapy, but about 40% of patients experience irresponsiveness. Inadequate response, intolerance, or aversion to long-term therapy are indications for anti-reflux surgery. Fundoplication techniques, magnetic sphincter augmentation, and endoscopic techniques are existing surgical options, but are often associated with postoperative complications like dysphagia. The RefluxStop implant is an emerging technology that has demonstrated effectiveness in managing patients with chronic GERD. This report summarizes the clinical outcomes of 28 patients managed with RefluxStop at a German institution. Methods The RefluxStop procedure was performed on 28 patients with chronic GERD in a German center between July 2021 and November 2023. Data was obtained from a retrospective chart review to present the clinical outcomes following RefluxStop surgery, including GERD Health-Related Quality of Life (GERD-HRQL), PPI use, symptom resolution, patient satisfaction, and perioperative adverse events (AEs). Results Twenty-eight patients were followed for 14.1±4.7 months. Baseline patient characteristics are shown in Table 1. Median GERD-HRQL score decreased by 90% from a baseline of 40 (IQR 17) to 4 (IQR 5) at follow-up. PPI use decreased from 96.4% at baseline to 7.1% at follow-up. Almost 93% of reflux symptoms were eliminated. Only one patient (3.6%) was not satisfied with treatment. All patients with dysphagia at baseline (42.9%) experienced complete resolution. No reoperations or esophageal dilations were required. Seven patients experienced minor intraoperative AEs (e.g., neck emphysema) but none were procedure- or device-related. Conclusion This cohort of GERD patients in Germany demonstrated the safety and effectiveness of the RefluxStop procedure. Significant improvements in quality of life, PPI use, and reflux-related symptoms were observed without consequential safety concerns for over one year. Furthermore, this study corroborates the existing evidence of favorable postoperative safety outcomes associated with RefluxStop. Additional study is necessary to continue validation of this promising new treatment option.

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy in First-Line Metastatic NSCLC: Five-Year Overall Survival Outcomes From the Phase 3 POSEIDON Trial

IntroductionThe primary analysis (median follow-up 34.9 mo across all arms) of the phase 3 POSEIDON study revealed a statistically significant overall survival (OS) improvement with first-line tremelimumab plus durvalumab and chemotherapy (T+D+CT) versus CT in patients with EGFR/ALK wild-type metastatic NSCLC (mNSCLC). D+CT had a trend for OS improvement versus CT that did not reach statistical significance. This article reports prespecified OS analyses after long-term follow-up (median >5 y). MethodsA total of 1013 patients were randomized (1:1:1) to T+D+CT, D+CT, or CT, stratified by tumor cell programmed cell death ligand-1 (PD-L1) expression (≥50% versus <50%), disease stage (IVA versus IVB), and histology (squamous versus nonsquamous). Serious adverse events were collected during follow-up. ResultsAfter a median follow-up of 63.4 months across all arms, T+D+CT had sustained OS benefit versus CT (hazard ratio [HR] = 0.76, 95% confidence interval [CI]: 0.64–0.89; 5-y OS: 15.7% versus 6.8%). OS improvement with D+CT versus CT (HR = 0.84, 95% CI: 0.72–1.00; 5-y OS: 13.0%) was consistent with the primary analysis. OS benefit with T+D+CT versus CT remained more pronounced in nonsquamous (HR = 0.69, 95% CI: 0.56–0.85) versus squamous (HR = 0.85, 95% CI: 0.65–1.10) mNSCLC. OS benefit with T+D+CT versus CT was still evident regardless of PD-L1 expression, including patients with PD-L1 tumor cell less than 1%, and remained evident in STK11-mutant (nonsquamous), KEAP1-mutant, and KRAS-mutant (nonsquamous) mNSCLC. No new safety signals were identified. ConclusionsAfter a median follow-up of more than 5 years, T+D+CT had durable long-term OS benefit versus CT, supporting its use as first-line treatment in mNSCLC, including in patient subgroups with harder-to-treat disease.

Immune checkpoint inhibitors for first-line treatment of advanced esophageal squamous cell carcinoma

Immunotherapy has revolutionized the treatment landscape of esophageal squamous cell carcinoma. He etal. present the final results of the randomized phase 3 ESCORT-1st trial, confirming positive survival outcomes when adding the anti-PD1 inhibitor camrelizumab to first-line chemotherapy treatment in Chinese patients with esophageal squamous cell cancer.1.

879P VERSATILE-002: Survival with first-line treatment with PDS0101 therapeutic vaccine and pembrolizumab in HPV16-positive recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)

879P VERSATILE-002: Survival with first-line treatment with PDS0101 therapeutic vaccine and pembrolizumab in HPV16-positive recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)

1700P Impact of sarcomatoid (S) and rhabdoid (R) components (comp.) on the efficacy of nivolumab (N) +/- ipilimumab (I) in the first-line (L1) treatment of metastatic clear cell renal cell carcinoma (mRCC) in the randomized phase II BIONIKK trial

1700P Impact of sarcomatoid (S) and rhabdoid (R) components (comp.) on the efficacy of nivolumab (N) +/- ipilimumab (I) in the first-line (L1) treatment of metastatic clear cell renal cell carcinoma (mRCC) in the randomized phase II BIONIKK trial

111P Leveraging circulating tumor DNA sequencing for first-line cancer treatment: Insights from two prospective precision medicine studies

111P Leveraging circulating tumor DNA sequencing for first-line cancer treatment: Insights from two prospective precision medicine studies

944TiP Petosemtamab plus pembrolizumab vs. pembrolizumab alone for first-line (1L) treatment of recurrent/metastatic (r/m) PD-L1–positive head and neck squamous cell carcinoma (HNSCC): A randomized, open-label, phase III trial

944TiP Petosemtamab plus pembrolizumab vs. pembrolizumab alone for first-line (1L) treatment of recurrent/metastatic (r/m) PD-L1–positive head and neck squamous cell carcinoma (HNSCC): A randomized, open-label, phase III trial

Atezolizumab Plus Bevacizumab Treatment for Unresectable Hepatocellular Carcinoma: Real-life Experience from a Single Tertiary Centre in Spain and ALBI Score as a Survival Prognostic Factor.

Atezolizumab/bevacizumab (atez/bev) has been established as first-line systemic treatment for hepatocellular carcinoma (HCC). However, concerns regarding safety and efficacy have been raised, and no biomarkers to predict response have yet been identified. We aimed to evaluate the real-life experience of atez/bev in a Spanish tertiary hospital and identify factors associated with overall survival (OS). A prospective study of consecutive patients with HCC treated with atez/bev was conducted from December 2020 to December 2022. Efficacy was assessed through OS and progression-free survival (PFS), whereas safety was evaluated based on adverse events (AE). Twenty-three patients were included; 91% were males with a mean of 70 years. Thirteen patients were classified as having BCLC-C. The median treatment duration was 126 days (range=567). Median OS was 381 days (95%CI=205-557) with a cumulative probability of death of 13%, 30%, and 49% at 3, 6 and 12-month follow-up, respectively. The only factor associated with OS was the ALBI score (HR=5.03; 95%CI=1.3-19.1), which showed an AUROC of 0.906 (95%CI=0.78-1.00) for the risk of death at 18 months follow up. Median PFS was 141 days (95%CI=110-172). Twenty (86.9%) patients experienced AE, which in nine (39.1%) cases led to the definitive discontinuation of the treatment, four of them (17.4%) due to an AE grade 5. The initial experience with atez/bev at our center demonstrated poorer outcomes compared to the original trial (IMbrave150). A careful assessment of the ALBI score may serve as a crucial factor in the selection of systemic treatment for patients with HCC.

TDAH : quels sont les effets cardiovasculaires du méthylphénidate et quelles sont les conséquences éventuelles pour la pratique clinique ?

ContextMethylphenidate is the first-line pharmacological treatment for ADHD, and its prevalence continues to grow, with an increase of 116% over the last ten years in France. Its use in hospitals has been extended to neurologists, psychiatrists and pediatricians, and its prescription can be renewed by a general practitioner. Cardiovascular complications are rare, but life-threatening. Management practices currently vary widely from one medical center or doctor to another. ObjectivesReviewing the cardiovascular effects of methylphenidate in adults and children with ADHD, aiming to propose a practical management plan without intending to replace existing recommendations. MethodsThe subject under study aimed to answer the following PICO question “What are the cardiovascular consequences (outcomes) when using MPH (intervention) for an ADHD population (population) regardless of age”. We carried out systematic review of international reviews and meta-analyses, selected using the PRISMA methodology via the PubMed, Cochrane Library and Google Scholar databases. Their methodological quality was assessed using the AMSTAR-2 scale. Cardiovascular events considered were the adrenergic effects of MPH on the cardiovascular system, looking for changes in blood pressure and heart rate, and the serious cardiovascular effects represented by sudden death/arrhythmia, myocardial infarction and stroke. A total of 17 systematic reviews and meta-analyses met the eligibility criteria. ResultsOf the 734 articles found, twelve were finally selected. Four concerned a population of children, five a mixed population of adults and children and three a population of adults only. They included two systematic reviews and ten meta-analyses. Three reviews included cohort studies and nine included randomized controlled trials. Three clinical situations can be distinguished depending on the age of the patient and the length of exposure to methylphenidate. The first, on initiation of treatment, there was a marked by a short-term increase in blood pressure and heart rate. The second involves a patient under the age of 35 with short- to medium-term exposure to MPH. A persistent adrenergic effect tends to increase the risk of sudden death by 12% (if the resting heart rate increases by ten beats per minute). This risk is further increased if the patient has psychiatric comorbidities and their associated treatments, congenital heart disease and uses recreational substances. Finally, the last situation involves a patient exposed to MPH for several years and aged over 35, whose main risk is the onset of atheromatous disease with myocardial infarction and ventricular arrhythmia. In this case, a comprehensive approach is required, identifying risk factors and behavioral factors likely to exacerbate the risk of CV disease. ConclusionsThe short-term cardiovascular effects of MPH are well documented and statistically significant, with a moderate but significant increase in blood pressure (+2mmHg) and heart rate (+5bpm). Longer-term cardiovascular safety data are often lacking, leading to conflicting conclusions. Meta-analyses of cohort studies conclude that there is an increase in cardiovascular risk, while meta-analyses of randomized trials find no significant statistical association. This means that patients and their families need to be made aware of this lack of data. Personalized management based on age, duration of exposure to MPH and the clinical profile of patients as defined by cohort studies seems to us to be the most appropriate approach. In people under 35, the main risk is sudden death. In this population, it is important to identify any congenital heart disease and to look for psychiatric comorbidities, and by assessing the substance abuse. For people over 35, the main risk is coronary heart disease. In this case, a comprehensive approach is required, identifying risk factors and behavioral factors likely to exacerbate the risk of CV disease. Our daily practice is more in line with cohort studies including patients with co-morbidities associated with their ADHD, as well as a significant risk of having risky behaviors, depressive episodes, heart disease and prolonged exposure to MPH and other drugs. Prescribing MPH in this context is tricky, with a higher risk of cardiovascular events. Close clinical monitoring is therefore necessary, and specialist advice may be required.

541P Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Subgroup efficacy and expanded safety analyses from CheckMate 8HW

541P Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Subgroup efficacy and expanded safety analyses from CheckMate 8HW