First-line Therapy Research Articles

Efficacy and safety of first-line immune checkpoint inhibitor combination therapies in patients with advanced esophageal squamous cell carcinoma: a network meta-analysis.

We performed a network meta-analysis of phase III trials to compare the efficacy and safety of first-line regimens for patients with advanced esophageal squamous cell carcinoma (ESCC). A systematic review and Bayesian network meta-analysis were conducted by retrieving relevant literature from PubMed, Embase, the Cochrane Library, and the Web of Science. We included published sources of randomized clinical trials comparing immunotherapy combinations for treating advanced ESCC. We analyzed seven studies involving eight immunotherapy combinations and 4688 patients. For patients without programmed death-ligand 1 (PD-L1) selection, it was found that the combination of toripalimab and chemotherapy provided better overall survival than chemotherapy alone (hazard ratio = 0.58, 95% confidence interval (CI) 0.43-0.78). Compared with chemotherapy alone, Sintilimab or camrelizumab plus chemotherapy seemed to achieve the best progression-free survival (hazard ratio = 0.56, 95% CI 0.46-0.68). Nivolumab plus chemotherapy appeared to provide the best objective response rate, with significant differences versus chemotherapy alone (odds ratio = 0.49, 95% CI 0.38-0.64). Nivolumab plus ipilimumab resulted in a relatively lower incidence of adverse events of grade ≥3 than other regimens. The combination of immune checkpoint inhibitors (ICIs) with chemotherapy provided a high probability of more effective treatment in comparison with chemotherapy alone for patients with advanced ESCC. Toripalimab and sintilimab plus chemotherapy were ranked as providing the highest OS and PFS benefit in the first-line setting, respectively.

Abstract 4136116: Metformin Therapy for Reperfusion Injury Consolidates Cardioprotection in the High-Risk Elderly Heart

Introduction: Metformin (MET), a first-line diabetes therapy, exhibits cardioprotective effects during acute ischemia and reperfusion (I/R). Cardiac injury is enhanced in the aging heart in murine and humans. Acute, high dose MET treatment at the onset of reperfusion (R) markedly reduced infarct size (MI) in the high risk aged heart via modulation of mitochondrial complex I. However, the effect of subsequent chronic, standard dose MET to consolidate and possibly enhance cardioprotection and survival following I/R in the aged heart remains unknown. Hypothesis: Administration of chronic standard dose of MET will ameliorate mortality and morbidity following MI through rescuing an impaired adaptive metabolic remodeling. Methods: Aged (22-24 month) C57BL6/J mice were subjected to sham operations or 45 min of ischemia by LAD ligation followed by R. All mice received acute, high dose MET (2 mM, i.v.) at the onset of R followed by randomization to chronic MET (300 mg/kg/day) in drinking water versus vehicle (VEH) administered for 14 days. Cardiac function was determined by echocardiography weekly. IonOptix Myocyte Calcium and Contractility System measured the contractile functions and transient calcium signaling of isolated cardiomyocytes. Results: The Kaplan-Meier survival analysis showed that chronic MET treatment following acute treatment at the onset of R significantly reduced mortality compared to VEH group. Although chronic MET treatment did not further reduce MI size, echo and histology showed that chronic MET preserved diastolic function, prevented left ventricular hypertrophy and reduced collagen deposition following I/R in aging. Moreover, isolated cardiomyocytes from MET treated hearts showed improvements in contractile function, transit calcium signaling, and the coupling between contractility and calcium levels as compared to the cardiomyocytes from VEH group hearts. Immunoblotting results showed that Sens2/AMPK metabolic signaling was significantly upregulated by chronic MET post-MI, indicating the metabolic homeostasis modulated by MET is a critical factor involved in the beneficial effects of chronic MET on limiting I/R-induced myocardial damage that leads to deleterious remodeling in aging. Conclusions: The mortality and morbidity of MI in the high risk aged heart is attenuated with acute, high dose of MET treatment followed by chronic standard dose MET treatment to consolidate protection via rescuing the impaired adaptive metabolic response in aging.

Abstract 4122080: Outcomes of Left Atrial Appendage Occlusion With and Without Concurrent Catheter Ablation for Patients at High Bleeding Risk: A Systematic Review and Meta-analysis

Introduction: The prevalence of non-valvular atrial fibrillation (NVAF) and stroke-related morbidity is rising. First-line therapy remains rate or rhythm control with anticoagulation, with catheter ablation (CA) also considered in suitable candidates. Left atrial appendage closure (LAAC) is increasingly used due to mounting evidence of non-inferiority compared to anticoagulation. Despite improved pre-procedural planning and patient selection reducing complications, adverse outcomes such as pericardial effusion and device-related thrombus occur in about 5% of patients. This study evaluates the outcomes of LAAC with CA versus standalone LAAC in NVAF patients with contraindications to anticoagulation. Methods: We searched PubMed, EMBASE, and Cochrane databases for all cohort studies comparing LAAC with CA to LAAC alone in patients with NVAF. Case series, reviews, and non-English language studies were excluded. The assessed outcomes included device compression rate at implant, device-related thrombosis, pericardial effusion, need for pericardiocentesis, and peri-device leak at 6 weeks. Statistical analysis was performed using Review Manager 5.1.7. Heterogeneity was assessed with I 2 statistics. Results: We included 6 studies with 51,545 patients, of whom 1,221 (2.3%) underwent both procedures. LAAC with CA and standalone LAAC cohorts had similar baseline demographics including age (68, 69 years), percentage of women (48%, 46%), CHA2DS2-VASc score (3.6, 3.7), and HAS-BLED score (3.1, 3.2). LAAC with CA was associated with a reduced incidence of device-related thrombosis (OR=0.18; 95% CI= 0.04-0.89; p=0.04) without an increase in pericardial effusion rates (OR=0.85; 95% CI= 0.48-1.51; p=0.59). There were no significant differences in device compression rates at implant (MD=0.34; 95% CI= -0.77-1.45; p=0.55), the need for pericardiocentesis (OR=1.01; 95% CI= 0.30-3.48; p=0.98), or rates of peri-device leak at 6 weeks (OR=0.61; 95% CI= 0.21-1.78; p=0.37). Conclusion: Concomitant LAAC with CA may reduce rates of device-related thrombosis compared to standalone LAAC without increasing the risk of pericardial effusion or peri-device leak at 6 weeks. These findings support the consideration of combining these procedures in the management of high-risk NVAF patients unable to tolerate anticoagulation.

Pembrolizumab 400 mg every 6 weeks as first-line therapy for advanced melanoma (KEYNOTE-555): Results from cohort B of an open-label, phase 1 study.

Intravenous pembrolizumab 400 mg every 6 weeks was approved across tumor types based on pharmacokinetic modeling, which showed exposures consistent with previous standard dosing of 200 mg or 2 mg/kg every 3 weeks, and early results of cohort B of the phase 1 KEYNOTE-555 study. Results after ≥1 year of potential follow-up for all patients in cohort B of KEYNOTE-555 are presented. Patients aged ≥18 years with previously untreated stage III/IV melanoma received pembrolizumab 400 mg every 6 weeks for ≤18 cycles. The primary endpoint was objective response rate per RECIST v1.1 by blinded independent central review. Secondary endpoints included duration of response, progression-free survival, pharmacokinetics, and safety. Overall, 101 patients received pembrolizumab. Median projected follow-up was 21.9 months (range, 17.0-25.7). The objective response rate was 50.5% (95% CI: 40.4-60.6; 19 complete responses, 32 partial responses). Median duration of response was not reached (NR; range, 2.4+ to 21.0+ months). Median progression-free survival was 13.8 months (95% CI: 4.1-NR). Observed pharmacokinetic exposures were consistent with model predictions for pembrolizumab 400 mg every 6 weeks and other approved and tested schedules (2 mg/kg or 200 mg every 3 weeks). Grade 3-4 treatment-related adverse events occurred in 13 patients (12.9%). No deaths were considered treatment related. These results support the pharmacokinetic modeling and demonstrate that the benefit-risk profile of pembrolizumab 400 mg Q6W is consistent with that of 200 mg or 2 mg/kg every 3 weeks. Clinically meaningful objective response rate and durable progression-free survival within the expected range for first-line pembrolizumab were observed. Clinical trial registry: ClinicalTrials.gov, NCT03665597.

Abstract 4148095: The Impact of Body-Mass Index on Ventricular Tachycardia Outcomes Post-Catheter Ablation

Background: In recent years, catheter ablation has emerged as a sustainable, first-line therapy for the management of ventricular tachycardia (VT). Given the rise of the “obesity paradox” theory in atrial ablation outcomes, we sought to study the effect of BMI on patients undergoing structural VT ablation. Purpose: To assess the outcomes of VT ablation, specifically VT recurrence, in patients with elevated vs. normal BMI. Methods: Clinical characteristics and demographic data were collected for VT patients who underwent ablation at Mayo Clinic Rochester from 2012-2022. Patient BMI was classified as non-obese (<30 kg/m2), obese (30-40 kg/m2), and morbidly obese (≥40 kg/m2). The endpoint was a composite of initial monomorphic VT recurrence and repeat ablation after adjusting for age, sex, and comorbidities. Results: A total of 399 patients underwent 508 ablations. 51.4% of ablations had a BMI <30, 39.2% were between 30-40, and 9.4% were ≥40. There was a greater prevalence of hypertension and type 2 diabetes mellitus in morbidly obese patients (p <0.01). Morbidly obese individuals also had a significantly increased rate of general anesthesia during ablation and long VT cycle lengths. The Kaplan-Meier curve demonstrates no statistically significant differences in time to VT recurrence among the three BMI groups (p = 0.324). Neither morbid-obesity (aHR= 1.20; CI = 0.94-1.56, p = 0.14) nor nonmorbid-obesity (aHR = 0.92; CI = 0.76-1.10, p = 0.4), compared to non-obesity was a significant independent predictor of VT recurrence or repeat ablation on multivariate regression after adjusting for age, sex and comorbidities. Conclusion: There was no significant association between BMI groups and VT recurrence or repeat ablation, and no difference in complications. We did not find the obesity paradox to be relevant for VT ablation in our patient population. Further study would be needed with larger samples to corroborate these findings.

Abstract 4136023: Eligibility and Barriers of Mavacamten Therapy in Patients with Hypertrophic Cardiomyopathy: A Retrospective Analysis

Background: Hypertrophic Cardiomyopathy (HCM) is a common genetic heart disorder characterized by the thickening of the myocardium. Mavacamten has emerged as a novel medication for targeted therapy in HCM patients, but its adoption faces multiple hurdles. This study aims to evaluate the eligibility of HCM patients for Mavacamten treatment based on certain clinical criteria and to promote consideration of potential barriers patients face in obtaining this medication. Methods: We conducted a retrospective analysis of 115 HCM patients at Truman Medical Center that included demographic data, clinical characteristics, and treatment histories. Patient eligibility for Mavacamten was determined based on ejection fraction (EF) > 55%, symptomatic obstructive HCM, and intolerance to first-line therapy (beta-blockers, calcium channel blockers). Statistical analysis was performed using standard deviation and mean comparisons to estimate the proportion of eligible patients. Results: Out of 115 patients, 96 patients have an EF>55%. 76 patients (66.1%) have a clinical heart failure diagnosis. 94 patients (81.7%) are taking beta-blockers. 49 patients (42.6%) have uncontrolled hypertension indicated by blood pressure >140. Considering these factors, 49 (42.6%) met the clinical criteria for Mavacamten treatment. Of these patients eligible to receive Mavacamten treatment, only one patient was actively taking Mavacamten. The most common obstacles to receiving the drug included lack of insurance coverage, high medication cost, and limited awareness among healthcare providers regarding new treatment options. Conclusion: While a considerable proportion of HCM patients qualify for Mavacamten based on clinical criteria, external factors significantly impede access to this potentially life-altering treatment. Efforts should address this treatment gap through raising awareness to healthcare professionals and improving insurance coverage. This will enhance patient access to Mavacamten, ultimately improving outcomes in HCM management. This study summarizes the eligibility and obstacles to Mavacamten in a sample of HCM patients, emphasizing the need for systemic changes to facilitate access to advanced therapies.

DDDR-24. REAL WORLD EXPERIENCE USING THE IDH INHIBITOR IVOSIDENIB IN IDH MUTANT GLIOMA: TOLERABILITY AND OUTCOMES

Abstract BACKGROUND Mutant isocitrate dehydrogenase (IDHm) inhibitors represent a novel therapeutic strategy for treating IDHm glioma, though their optimal use outside of clinical trials remains undefined. This study describes real world utilization of the IDH1 inhibitor, ivosidenib, in patients with IDHm glioma. METHODS We retrospectively reviewed clinical and radiographic data from IDHm glioma patients treated with ivosidenib monotherapy at Dana-Farber Cancer Institute and Massachusetts General Hospital from 2020-2024. Patients with a baseline MRI at ivosidenib initiation and at least 2 subsequent scans while on ivosidenib were included in radiographic response analysis (452 scans). RESULTS This cohort included 77 patients (39 males) age 17-75 years (median 41). Thirty-eight patients (49%) had astrocytomas and 39 (51%) had oligodendrogliomas; 48 (62%) had grade 2, 26 (34%) grade 3, and 3 (4%) grade 4 gliomas. Twenty-four patients (31%) received ivosidenib as first-line therapy and 53 (69%) received ivosidenib after failing prior treatments. Among those in the radiographic analysis, 4 (6%) demonstrated partial response, 4 (6%) minor response, 44 (62%) stable disease, and 19 (27%) progressive disease (PD). Significantly higher PD rates were seen in those with enhancing disease (p<0.001) or received ivosidenib as subsequent-line therapy (p=0.002); PD rate was similar between grades 2 and 3 in the first-line group (p=0.64). One-year progression free survival was 100% in the first-line group and 66% in the subsequent-line group. At the time of our analyses, 4 patients (5%) had died (all in the subsequent-line group). Infrequent side effects included CK elevation, QTc prolongation, transaminitis, and diarrhea. One patient (1%) was dose reduced and 3 (4%) discontinued drug due to side effects. CONCLUSIONS In this real world IDHm glioma cohort, ivosidenib was well-tolerated. Better response rates were seen in patients without enhancing disease at ivosidenib initiation and those who received the drug as first-line therapy.

Comparative analysis of efficacy and safety of combined immunotherapy and immune targeted therapy in the first-line treatment of advanced renal cell carcinoma: a real-world study

Aim. To compare of efficacy and safety of combined immune therapy (dual immune-oncology – IO combination therapies, IO-IO) and immune targeted therapy (ITT) in the first line treatment of patients with advanced renal cell carcinoma (RCC) treated in real world clinical practice. Materials and methods. The ambispective study enrolled patients with metastatic RCC aged ≥18 years, with measurable neoplastic lesions, who were treated with first-line IO-IO therapy or ITT. The primary endpoint was progression-free survival (PFS). Results. The study included data from 126 patients treated with IO-IO [46 (36.5%) patients of the IMDC intermediate and poor prognostic groups] or ITT [80 (63.5%) patients of all IMDC prognostic groups]. In a median follow-up of all patients of 16.1 (0.1–44.9) months, the median PFS was 16.1 (10.9–21.3) months, the median overall survival (OS) was not reached; one-year OS was 83.0%; the objective response rate on the first line of therapy was 44.4% with a complete response rate of 3.2%. The rate of tumor control was 88.1%. In the overall population, ITT versus IO-IO provided a significant benefit in terms of ORR (51.2% vs 32.6%; p=0.032), PFS (median 22.9 months vs 8.0 months; p=0.004) and one-year OS (87.5% vs 65.2%; p=0.042). In the IPTW population, multivariate analysis confirmed the independent prognostic significance of the treatment regimen for PFS (hazard ratio, 2.3; 95% confidence interval, 1.1–4.8; p=0.037) and OS (hazard ratio, 2.3; 95% confidence interval 1.1–4.8; p=0.037). No difference in the safety profile of IO-IO and ITT was identified. Conclusion. The results support the hypothesis that ITT is more effective than IO-IO in the first-line treatment of advanced RCC in patients of IMDC intermediate and poor prognostic groups.

QLTI-03. REAL-WORLD PARADIGM FOR TREATMENT OF PRIMARY CNS LYMPHOMA PATIENTS IN CLINICAL PRACTICE

Abstract Although high-dose methotrexate (HD-MTX) is the foundation of induction therapy for primary CNS lymphoma (PCNSL), a gold-standard regimen has yet to be established. A 10-case-based survey, to assess the practice patterns at key decision-points in adult PCNSL management outside of clinical trials, was distributed through IPCG, HOVON, and AAN Neuro-Oncology Section. Eighty-five responses were collected from North American (N=42), European (N=33), Asian (N=7), and other countries (N=3) from neurologist neurooncologists (N=35), hem-onc neurooncologists (N=24), hematologist-oncologists (N=18), neurosurgeons (N=5), radiation-oncologist (N=2), and hematopathologist (N=1). The most common first-line induction regimen was R-MP+/-V: rituximab, HD-MTX, procarbazine, +/-vincristine (N=28) followed by MATRix: HD-MTX, cytarabine, thiotepa, rituximab (N=23), then R-MT: rituximab, HD-MTX, temozolomide (N=19). For elderly patients, R-MP+/-V remained most common (N=32). The majority preferred to omit intra-CSF chemotherapy (N=50). The most preferred consolidation after complete response was high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT, N=57), or high-dose cytarabine (N=17) in elderly patients. In cases of partial response, the most common approach was still HDC-ASCT (N=24). For stable disease, participants would move to various salvage chemotherapy (N=33), continue additional induction (N=39), or to move to radiotherapy (N=10). If early progression was noted, the most preferred approach was non-methotrexate chemotherapy (N=31). For recurrences after previous complete response and HDC-ASCT consolidation, the majority preferred to try chemotherapy before moving to radiotherapy in scenarios < 1 year (N=64) or > 1 year from consolidation (N=68), and even if the performance status was poor (N=57). Close to half (N=34) participants felt there is a role for stereotactic radiosurgery in various clinical settings. This survey noted clear consensus to use multi-drug MD-MTX based chemotherapy, and common induction regimens, however, highlighted a great variety of treatment preferences after first-line therapy even amongst disease experts through clinical consortiums, suggesting likely wider range of treatments and disease response in larger community settings.

CTNI-67. AI BASED PREDICTION OF CLINICAL TTFIELDS RESPONSE IN GLIOBLASTOMA PATIENTS (RETROSPECTIVE ANALYSIS)

Abstract RESEARCH QUESTION Accurate and individualized prediction of response to therapies is central to precision medicine and a major goal in neuro-oncology. An extension of overall survival (OS) and progression-free survival (PFS) was observed in patients treated with tumor treating fields (TTFields) plus maintenance temozolomide compared to those treated with maintenance temozolomide alone and TTFields have become an integral part of the treatment of glioblastoma. To identify patients who benefit most from TTFields, we aim to implement a state-of-the-art machine learning approach to create a model capable of identifying responding patients early in treatment. METHODOLOGY In this retrospective analysis, patients with IDH-wildtype glioblastoma treated with TTFields, in addition to RT and temozolomide, as first-line therapy are included. Clinical data and MRI raw data (in DICOM format) are collected. The preprocessing of the MRI data includes reorientation, bias field correction, registration, segmentation, and intensity normalization. This is followed by the extraction of a Radiomics signature. The latter, along with the clinical data, is trained using various machine learning models. The model validation occurs on an independent test cohort. Data collection from various neuro-oncological centers across Europe is ongoing. RESULTS So far, data from 134 TTFields patients and 131 control patients have been collected. Initial results, providing detailed insights into the model architecture and performance, will be presented at the time of the SNO meeting. CONCLUSION This study has the potential to optimize the treatment of glioblastoma patients by using machine learning to allow the early identification of patients that respond to first line therapy.

Topical 5-fluorouracil as monotherapy for ocular surface squamous neoplasia

Ocular surface squamous neoplasia (OSSN) comprises a gamut of diseases, which encompass conjunctival intraepithelial neoplasia, conjunctival carcinoma in situ, and squamous cell conjunctival neoplasia. Gold standard treatment for OSSN entails excision with cryotherapy. A lot of progress has been made recently that shows that chemotherapeutic drugs, such as mitomycin C, 5-fluorouracil (5-FU), and interferon alfa2b, can be just as effective. This is a case report that includes two cases: An 81-year-old Filipino female and a 65-year-old Filipino male who presented with a pinkish lesion on the bulbar conjunctiva. Documentation was done through clinical observation, slit-lamp examination, and the use of anterior segment optical coherence tomography (OCT). 1% topical 5-FU was given as chemotherapy administered at 1 drop 4×/day for 1 week with a 3-week drug holiday. During the course of treatment, we noted clinical resolution of the lesions grossly on slit-lamp examination. On anterior segment OCT, a decrease in diameter and thickness was noted, but with remaining areas of hyperreflectivity and thickened epithelium at the site of the lesion. No decrease in visual acuity was noted during the course of treatment, as well as any adverse effects such as eye pain or inflammation. Considering its safety and efficacy profile, 5-FU has great potential to be considered as a first-line therapy in the topical treatment of OSSN. Topical chemotherapy can target microscopic diseases that may be missed surgically and decrease adverse effects. As seen in this case report, 5-FU shows much promise as a possible alternative in the treatment of OSSN.

CTNI-68. UPDATES ON A POTENTIALLY PIVOTAL TRIAL CNS-201: A RANDOMIZED, CONTROLLED TRIAL OF BERUBICIN VS. LOMUSTINE AFTER FIRST-LINE THERAPY FOR GLIOBLASTOMA MULTIFORME (GBM)

Abstract Berubicin, derived from doxorubicin (Dox), appears to cross the BBB and has shown significant central nervous system (CNS) uptake and anti-tumor activity. A current, potentially pivotal trial for patients with recurrent GBM after first-line therapy has completed enrollment in the US and Europe: a total of 252 patients were randomized 2:1 (Berubicin:Lomustine) after failure of prior therapy. All patients had to have certification of progression by a central reader, were Grade 4 IDH WT, and were stratified by MGMT methylation status. The primary endpoint, overall survival (OS), is maturing in this blinded trial; however, data will be presented that will document the demographics of the Berubicin and Lomustine arms, and provide a comparison of safety profiles and disposition of the patients enrolled on the study. Recently, a pre-planned non-binding futility analysis of the primary endpoint, OS, was evaluated when the trial reached ~30% of expected events (44 events). This interim analysis was performed by an independent statistician under the supervision of the Data Safety Monitoring Board (DSMB), which was additionally comprised of two oncologists. The DSMB’s charter mandated that they review the primary endpoint, OS, as well as secondary endpoints and safety data to determine whether these data for the risk-benefit profile warranted modification or discontinuation of the study. The DSMB recommended that the study continue as it was currently planned, with no modifications required, having met a pre-determined conditional endpoint. After the results of this interim analysis, CNS Pharmaceuticals completed enrollment with 252 patients evaluable for efficacy based on OS evaluations. Based on the decision of the DSMB, as well as the data presented herein, which includes comparative safety and balanced randomization of the arms, we will provide our recommendations and highlight our further development of Berubicin as a therapeutic option for patients with recurrent GBM as well as other CNS malignancies.

NIMG-34. CXCR4-TARGETED PET IMAGING OF CENTRAL NERVOUS SYSTEM LYMPHOMA AND GLIOMA USING [68GA]GA-PENTIXAFOR

Abstract BACKGROUND Initial results suggest that PET imaging of the chemokine receptor CXCR4 is of considerable interest for differential diagnosis and theranostic approaches. Here, we summarized findings of CXCR4 PET imaging in an institutional series of lymphoma of the central nervous system (CNSL) and glioma. METHODS Twenty-three patients with CNSL and 16 patients with glioma (IDH-wildtype, n=9) underwent PET imaging using the CXCR4-directed tracer [68Ga]Ga-Pentixafor. In 18 patients, serial PET imaging was performed (range, 2-14 scans), resulting in a total of 104 PET scans. For evaluation, PET scans were classified as [68Ga]Ga-Pentixafor-positive and -negative visually, and the maximum standardized uptake value (SUVmax) was obtained from [68Ga]Ga-Pentixafor-PET. RESULTS Twenty-four of all 39 patients (62%) had at least one [68Ga]Ga-Pentixafor-positive PET (CNSL, 57%; glioma, 69%). [68Ga]Ga-Pentixafor-positive PET scans were more common in patients with IDH-wildtype gliomas (89%) than in IDH-mutant gliomas (43%). In patients with [68Ga]Ga-Pentixafor-positive PET, the average SUVmax was 6.4±4.0 in CNSL, and 3.4±1.0 in gliomas (P=0.155). Besides visualization of tumors, [68Ga]Ga-Pentixafor uptake was observed in two patients with radionecrosis. In four CNSL patients who had undergone methotrexate/cytarabine-based first-line therapy, serial PET revealed a significant reduction of SUVmax after chemotherapy completion (average decrease of SUVmax from 4.5±3.8 to 0.6±0.7; P=0.044). In three of those four patients, tumor progression has not been reached (range of time after the follow-up PET, 4-55 months); one patient deceased 44 months after the follow-up PET. In contrast, another patient with an increase in SUVmax from 6.9 to 11.0 after first-line treatment died one month after the follow-up PET. DISCUSSION [68Ga]Ga-Pentixafor PET seems to be of value for non-invasively visualizing and quantifying CXCR4 receptor binding. In CNSL, changes in [68Ga]Ga-Pentixafor uptake following therapy may indicate potential for response assessment. CXCR4-targeting radioligand therapies might be more promising in CNSL than in glioma.

Real-world data on direct oral anticoagulants in BCR::ABL1-negative myeloproliferative neoplasms (MPNs): a multicenter retrospective study on behalf of scientific subcommittee on MPNs for Turkish society of hematology.

BCR::ABL1-negative myeloproliferative neoplasms (MPNs) pose a substantial risk of thrombosis, leading to significant morbidity and mortality. Anticoagulant therapy, historically based on vitamin K antagonists (VKAs), has limitations in preventing recurrent thrombotic events and managing bleeding complications. Direct oral anticoagulants (DOACs) offer a potential alternative with improved pharmacokinetics and compliance. However, evidence on DOAC efficacy and safety in MPNs remains limited, necessitating further investigation. In this multicenter retrospective study in Türkiye, we assessed real-world usage patterns and outcomes of DOACs in MPN patients. Data from 220 patients with PV, ET, or PMF receiving DOACs or VKAs for thrombosis or nonvalvular atrial fibrillation (NVAF) were collected from medical records. Thrombotic events and bleeding episodes were documented based on ISTH criteria. DOACs were used in 126 patients as first-line anticoagulant therapy or following VKAs. Ninety-four patients were on VKAs, of which 83 as a first-line treatment. There were eight thromboses (6.3%) seen in 126 DOAC patients, and similarly, seven episodes (9.4%) of thrombosis were observed in 94 patients using VKA. Major bleeding occurred in seven patients (5.6%) on DOAC and 3 (3.2%) in VKA. Thrombotic and bleeding risks were comparable between DOACs and VKAs (p = 0.708 and p = 0.158, respectively). The incidence rate of thrombosis in the VKA group is 1.1% and in the DOAC group is 1.9%. The incidence of major bleeding in the VKA group is 0.6% and 1.6% in the DOAC group. To the best of our knowledge, our study included the largest number of MPN patients to date, comparing DOACs with VKA in terms of both efficacy and safety, which suggests DOACs as promising alternatives to VKAs for managing thrombotic risk in MPNs with manageable toxicity. Despite the limitations of retrospective studies, DOACs' benefits in terms of efficacy and compliance warrant further investigation through prospective trials. Individualized treatment decisions should consider patient-specific factors, emphasizing collaborative efforts between specialists to optimize DOAC therapy in patients with MPNs. Comparable efficacy and safety between DOACs and VKAs were observed in MPN patients.

Role of immunohistochemical prognostic factors in various types of immunotherapy for metastatic melanoma: A retro-prospective study

Background. Anti-PD-1 immunotherapy (IT) is the standard of care for patients with metastatic melanoma. However, in the real world, IT is effective only in a fraction of patients. The lack of valid prognostic factors for various immunotherapy agents warrants a comprehensive and advanced study of this topic. Aim. To improve the outcomes of the first-line therapy for disseminated melanoma based on identifying immunohistochemical predictors of IT efficacy. Materials and methods. Data from 130 patients who were treated with immune checkpoint inhibitors nivolumab or prolgolimab in the first-line therapy for disseminated melanoma between 2017 and 2024 were analyzed. Results. The expression of PD-L110 on tumor cells was found to be a predictor of effective therapy: in the nivolumab group, the 2-year disease-free survival (DFS) with PD-L1 level 10% was high at 79% (95% confidence interval – CI 61–100); the 1-year DFS was 89% (95% CI 78–100) compared to 17% (95% CI 3.2–88) with a lower level of PD-L1 expression (p0.0001). In the prolgolimab group, the 2-year DFS with PD-L110% was also high at 78% (p0.0001; CI 54–100), the 1-year DFS was 94% (95% CI 84–100) compared to 35% (95% CI 17–73) with a lower level of PD-L1 expression (p0.0001). A less severe course of the disease was observed in patients with both peritumoral and intratumoral locations versus those with only peritumoral locations of the immune infiltrate. The study of the presence and form of lymphoid infiltration of the tumor showed the following direct relationship: in the nivolumab group, the 2-year DFS was 94% (95% CI 83–100) compared to 8.3% (95% CI 1.3–54), in the prolgolimab group, the 1-year DFS was 82% (95% CI 68–100) compared to 15% (95% CI 2.6–86); p0.0001. It was found that the predominance of CD8+ over CD4+ is associated with better results of IT: in the nivolumab group, the 2-year DFS was 87% (95% CI 74–100) compared to 19% (95% CI 4–91) in the absence of CD8+ predominance over CD4+; in the prolgolimab group, the 2-year DFS was 73% (95% CI 51–100) in patients with CD8+ predominance over CD4+ (p=0.0001). In patients without CD8 predominance over CD4, 2-year DFS was not achieved. The one-year DFS was 85% (95% CI 70–100) and 25% (95% CI 8.4–76), respectively; p=0.0001. Conclusion. The results of the study suggest that immunohistochemical characteristics such as a PD-L1 expression level 10%, the simultaneous presence of peri- and intratumoral lymphoid infiltration of the tumor, the ratio of the intensity of lymphoid infiltration with tumor-infiltrating lymphocytes (TILs), and the predominance of CD8+ over CD4+ can be considered predictors of IT efficacy with nivolumab and prolgolimab.

CNSC-16. ASSOCIATION BETWEEN RESTING-STATE-NETWORK FUNCTIONAL CONNECTIVITY AND SURVIVAL IN RECURRENT GLIOMAS DIAGNOSED USING FET PET

Abstract BACKGROUND Functional connectivity between glioma-infiltrated brain tissue and remote cortical regions has been linked to overall survival (OS) in patients with newly diagnosed glioblastoma. We studied the association of functional connectivity between tumor and resting-state networks and OS in patients with recurrent gliomas. PATIENTS AND METHODS The study included 82 patients (26-81 years; median ECOG performance score, 0) with recurrent gliomas (grade 4 glioblastoma, n=57; grade 3 and 4 astrocytoma, n=12; grade 2 and 3 oligodendroglioma, n=13) who had undergone first-line therapy. Diagnosis of recurrence was confirmed by amino acid PET using the tracer O-(2-[18F]-fluoroethyl)-L-tyrosine (FET). FET PET and resting-state functional MRI were simultaneously acquired on a 3T hybrid PET/MR scanner. We performed a seed-based dual regression analysis to determine the functional connectivity between metabolically active tumors and seven canonical resting state networks. RESULTS Average functional connectivity was highest in oligodendrogliomas (z-score, 6.9±1.9) and was inversely related to the tumor grade (p=0.031). Univariate Cox regression analysis revealed a significant (p<0.05) positive association between OS and tumor connectivity with the visual, somatomotor, and dorsal attention networks. Subsequent stepwise multivariate Cox regression analysis refined this association to the dorsal attention network alone (HR, 0.88; 95% CI, 0.80-0.97; p=0.007). Patients with the highest functional connectivity (z-score>8.3, n=21) had a median OS of 31.4 months, while those with the lowest functional connectivity (z-score<4.3, n=21) had 10.6 months. Functional connectivity between tumors and the dorsal attention network showed an independent association with OS (HR, 0.90; 95% CI, 0.81-0.99; p=0.033) in a multivariate model, including various prognostic factors. CONCLUSION Recurrent gliomas exhibit significant functional connectivity to most of the major known resting-state networks, highest in oligodendrogliomas. The data suggest that high functional connectivity between the tumor and the dorsal attention network is an independent prognostic factor for improved OS.

FDA Approval Summary: Polatuzumab Vedotin in the First-Line Treatment of Select Large B-cell Lymphomas.

In April 2023, the U.S. Food and Drug Administration granted regular approval to polatuzumab vedotin-piiq in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (pola+R-CHP) for adult patients who have previously untreated diffuse large B-cell lymphoma, not otherwise specified or high-grade B-cell lymphoma and who have an International Prognostic Index score of 2 or greater. Approval was based on POLARIX, a randomized, double-blinded, placebo-controlled trial evaluating the superiority of substituting vincristine with polatuzumab vedotin in the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen as first-line therapy for patients with large B-cell lymphoma (LBCL). Efficacy was based on investigator-assessed progression-free survival (PFS) in 879 patients who were randomized to receive pola+R-CHP or R-CHOP, followed by two cycles of rituximab alone. PFS was statistically significantly longer with pola+R-CHP with a HR of 0.73 [95% CI: 0.57, 0.95] and log-rank p-value of 0.0177 (two-sided α=0.05). There was no improvement demonstrated in the key secondary endpoints of CR rate at the end of therapy or overall survival (OS). Several issues raised uncertainty about the benefit-risk of polatuzumab vedotin in this curative-intent setting including the modest PFS benefit of pola+R-CHP and lack of OS benefit. The application was therefore presented at an Oncology Drug Advisory Committee. This article summarizes key aspects of the regulatory review, including perspectives on PFS and OS results and other endpoints.

INNV-06. ADULT GLIOBLASTOMA WITH MISMATCH REPAIR DEFICIENCY FORMS A DISTINCT HIGH-RISK MOLECULAR SUBGROUP FOR WHICH TREATMENT WITH IPILIMUMAB-NIVOLUMAB SHOWS SURVIVAL ADVANTAGE

Abstract Glioblastoma is the most frequent and malignant primary brain tumor. Although the survival is generally dismal for glioblastoma patients, risk stratification and the identification of high-risk subgroups is important for prompt and aggressive management. The G1-G7 molecular subgroup classification based on the MAPK pathway activation has offered for the first time a non-redundant, all-inclusive classification of adult glioblastoma. Five patients from the large, 220-patient prospective cohort showed germline mutations in mismatch repair (MMR) genes and significantly worse median survival (3.25 months post-surgery) than those from other subgroups or from the rest of the cohort adjusted for age. These tumors were assigned to a new subgroup, G3/MMR, a spin-off from the major G3/NF1 subgroup, as they generally show genomic alterations leading to RAS activation. An integrated clinical, histological, immunohistochemical and molecular analysis of the G3/MMR tumors showed distinct characteristics as compared to other glioblastomas, including those with iatrogenic high tumor mutation burden (TMB), warranting a separate subgroup. Among these, prior history of cancer, midline location or multifocality, presence of multinucleated giant cells, positive p53 and MMR immunohistochemistry, and specific molecular characteristics, including high TMB, alert to this high-risk G3/MMR subgroup. High TMB constitutes the criterium for treatment with immune checkpoint inhibitors in solid cancers. The FDA-approved first-line therapy for advanced non-small cell lung cancer and high-TMB colorectal cancer is with the dual ipilimumab-nivolumab regimen. One of the five G3/MMR subgroup patients received the dual ipilimumab-nivolumab regimen and survived much longer than the rest of the G3/MMR patients, setting a proof-of-principle example for the treatment of these very aggressive G3/MMR glioblastomas.

Cost-Effectiveness of Vibrant System vs. Linaclotide in Chronic Idiopathic Constipation.

Chronic idiopathic constipation (CIC) is a common disorder that has a large unmet clinical need, affecting 8.0-12.0% of the US population and disproportionately affecting female individuals more than male individuals. Patients and physicians are equally dissatisfied with over-the-counter and prescription treatments. Physician dissatisfaction is at 78%. CIC has a significant negative impact on quality of life (QoL). The objective of this analysis was to compare the total cost and QoL of the Vibrant System vs. linaclotide, over 1-3years of treatment. Markov models were utilized to project 1-3-year US costs and health outcomes (quality adjusted life years, QALYs) comparing theVibrant System to the current standard of care pharmacologic therapy (linaclotide). One model examined direct (D) costs plus QALYs. Direct (D) costs included list price of product and medical treatment costs due to adverse events. Costs (D) were as of 2024; derived from themedical literature. A second model examined D as well as indirect (I)costs (absenteeism, presenteeism) [D + I] and QALYs. Longitudinal 12-month persistence prescription data for linaclotide was obtained from IQVIA claims data. The Vibrant System persistence data was derived from post market collection. One-way sensitivity analyses were also performed. Years1-3 direct costs were lower with Vibrant System with improved QALYs. Cumulative D + I data analysis for the Vibrant System at 12months, and for years2 and 3 show increased cost savings from $345 to $3866 with improved effectiveness. On the basis of lower costs and improved QALYs, the Vibrant System should be considered a first-line therapy for CIC and should be covered by insurers.

NIMG-42. ANALYSIS OF TUMOR RELAPSE PROBABILITY AND OVERALL SURVIVAL PREDICTION FOLLOWING TEMOZOLOMIDE CHEMORADIATION USING FET PET INCLUDING RADIOMICS IN PATIENTS WITH GLIOBLASTOMA

Abstract BACKGROUND Early after surgery and completion of first-line concomitant chemoradiation with temozolomide, the evaluation of tumor relapse probability and overall survival prediction is of considerable interest for the management of patients with glioblastoma METHODS Sixty-three newly diagnosed patients with glioblastoma (age range, 19-82) who received static and dynamic PET imaging using the radiolabeled amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (FET) after surgery or biopsy and completion of concomitant chemoradiation with temozolomide were evaluated. Static FET PET parameters such as maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) and metabolic tumor volumes (MTV), and the dynamic FET PET parameter time-to-peak (TTP) were obtained. Additionally, FET PET radiomics features (n=1,303) were extracted for each patient and a test-retest analysis was performed to identify robust features prior to feature selection. The prognostic value of FET PET parameters and radiomics features was evaluated using receiver-operating-characteristic (ROC) analyses with regard to a significantly prolonged progression-free and overall survival (PFS, OS). Subsequently, univariate and multivariate survival estimates were performed to assess the prognostic value of these parameters to predict a significantly longer PFS and OS RESULTS ROC analyses revealed that the parameter TBRmax was a powerful parameter to predict both a significantly longer PFS (20.3 vs. 8.9 months; P=0.002; threshold, 2.75) and OS (34.9 vs. 18.7 months; P=0.005; threshold, 2.75). MTV had a similar prognostic value for both PFS (16.7 vs. 7.2 months; P=0.002; threshold, 34.0 mL) and OS (30.6 vs. 14.8 months; P=0.002; threshold, 32.6 mL). After feature selection, 3 of 15 selected radiomics features predicted a significantly longer PFS and OS in univariate analyses. TBRmax, MTV, and one of 15 radiomics features remained significant in multivariate survival analysis (all P≤0.03) CONCLUSION Our results suggest that FET PET and radiomics parameters were highly prognostic in this group of patients at an early stage of first-line therapy.