Prior Treatment Failure Research Articles

Efgartigimod demonstrates consistent improvements in patients with generalized myasthenia gravis regardless of prior treatment failures

Efgartigimod demonstrates consistent improvements in patients with generalized myasthenia gravis regardless of prior treatment failures

Real-World Progression-Free Survival and Treatment Patterns for t(11;14) Positive Patients with Multiple Myeloma with at Least 2 Prior Lines of Treatment

Background : Multiple myeloma (MM) is a subclonal disease characterized by large heterogeneity with a complex treatment landscape. Patients with MM have a myriad of available treatment options, prescribed based on several factors, including genetic testing, comorbidities, risk status, age, patient preference, and/or prior treatment failures. Cytogenetic abnormalities determines risk stratification and prognosis. The prognostic significance of t(11;14)-positivity has been debated and it is currently considered a standard-risk abnormality; however, testing for t(11;14) may be of potential therapeutic significance. Despite recent advances in treatment that have improved response rates and survival, MM remains incurable. This results in a continuous treat-to-failure approach that eventually leads to a lack of effective therapeutic options. Treatment patterns and outcomes for patients by lines of therapy (LOT) in real-world settings provide important benchmarks for assessments of future targeted therapies. Methods : Data were retrospectively collected from the ConcertAI Patient360 database containing aggregated electronic health record data of patients treated in primarily community-based oncology centers in the US. Adults diagnosed with MM (2011-2022) who received a National Comprehensive Cancer Network-guideline recommended treatment and had ≥2-months follow up were included; this analysis focused on patients with relapsed or refractory (RR) MM who are t(11;14)-positive and received ≥2 prior lines of systemic therapy. Baseline characteristics were determined for the third-line plus (3L+) subgroup of patients with t(11;14) RRMM. Real-world progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results were stratified by the use of doublet or triplet regimens, in which patients were treated with 2 or 3 classes of treatments among 6 options (ie, proteasome inhibitors [PI], immunomodulatory imide drugs [IMID], anti-CD38 monoclonal antibodies, chemotherapy, BCL-2 inhibitors, exportin-1 inhibitors, or steroid therapy), respectively, at any time during the LOT. Results : Eighty-four patients with t(11;14) RRMM received 3L+ of therapy. Of patients, 43% were female, 20% were Black, and 75% were White. The median (range) age at diagnosis was 64 (37-84), and the median (range) follow-up since diagnosis was 76 (10-209) months. At 24 months since the initiation of treatment, the median (range) PFS for all t(11;14)-positive patients that received 3L+ of therapy was 7.5 (5.9-9.4) months, and the median (range) PFS rate was 14.8% (9.7%-22.5%) (Figure); the median (range) OS for all t(11;14)-positive patients that received 3L+ of therapy was 32.1 (25.4-48.0) months, and the median (range) OS rate was 58.3% (51.0%-66.6%). The most common treatment regimens used in 3L+ included Daratumumab + Pomalidomide ± Dexamethasone (12%), Venetoclax monotherapy (9%), Pomalidomide ± Dexamethasone (7%), and Bortezomib ± Dexamethasone (7%). Of doublet regimens used in 3L+ (n = 69 LOT), 18 (26%) were IMID + steroid, 14 (20%) were PI + steroid, and 11 (16%) monoclonal antibody (MA)+ steroid. For triplet regimens used at 3L+ (n = 97 LOT), 28 (29%) were IMID + MA + steroid, 23 (24%) were IMID + PI + steroid, and 12 (12%) were MA + PI + steroid. Triplet regimen use increased from 52% in 3L to 61% in 4L and was associated with slightly longer PFS in 3L, relative to doublet regimen use. For patients that received 3L+ therapies, the median (95% CI) PFS was 6.7 (5.4-11.1) months for patients receiving doublet regimens, and 7.7 (5.9-11.3) months for patients receiving triplet regimens. Conclusions: Triplet regimens were more commonly used than doublet regimens as 3L+ therapy. Triplets were also associated with slightly longer PFS in 3L; however, PFS rates were low and did not translate into longer OS, suggesting an unmet need for novel therapeutic options for patients with t(11;14) RRMM.

Efficacy and Safety of Asciminib in Chinese Patients with Philadelphia Chromosome(Ph)-Positive Leukaemias

Background Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) tyrosine kinase inhibitor (TKI). Its efficacy and safety profile in patients with chronic-phase chronic myeloid leukaemia (CML) have been shown in the Phase 3 ASCEMBL study, comparing asciminib 40 mg twice daily versus bosutinib 500 mg once daily. However, asciminib use in Chinese patients has hitherto not been reported. Moreover, the safety of high-dose asciminib (≥150 mg twice daily) in the Asian population is yet to be addressed. Here we present the real-world clinical outcomes of Chinese patients with Ph+ leukaemias in Hong Kong who received asciminib through a Managed Access Program (MAP). Methods Queen Mary Hospital (QMH) is a university-affiliated tertiary hospital in Hong Kong. Patients with Ph+ leukaemias under the care of QMH for whom asciminib was requested through MAP were included. Details on patient demographics, disease history, prior treatment lines, asciminib usage, adverse events, efficacy and death were collected. Results At data cut-off for analysis on 30 June 2023, 13 patients for whom asciminib was approved had data available. One patient passed away before the commencement of asciminib, and thus was excluded (Table 1). There were 7 patients with CML, who on diagnosis were all in chronic phase at a median age of 53 (22-70) years. All had received imatinib and at least one newer generation TKI, with 5 patients (71%) having received ponatinib. The majority (5 patients, 71%) received asciminib because of lack of efficacy of prior treatment, with 4 patients also having the T315I mutation. The median age at asciminib treatment (median dose: 400 mg, 80-400 mg) was 64 (28-76) years, with a median time from diagnosis of 81 (13-314) months. Two patients received imatinib concomitantly. The median duration of treatment was 12 (6-38) months. Two patients were already in at least major molecular response (MMR) before treatment, and have maintained that response. Two patients had ≥ 1-log reduction of BCR::ABL1 transcript level. Three patients had stable disease. There was one death unrelated to CML (Figure 1). There were 5 patients with Ph-positive acute lymphoblastic leukaemia (ALL), at a median age of 57 (18-68) years at diagnosis. All had received prior chemotherapy in combination with a TKI (imatinib, N=3; dasatinib, N=5; ponatinib, N=5), with 3 patients having undergone allogeneic haematopoietic stem cell transplantation (allo-HSCT). Three patients had detectable kinase domain mutation (T315I, N=2; E255K + E459K, N=1). The majority (3 patients, 60%) received asciminib because of lack of efficacy of prior treatment. The median age at asciminib treatment (median dose: 240 mg, 80-400 mg) was 58 (19-72) years, with a median time from diagnosis of 22 (7-47) months. The median duration of treatment was 16 (2-19) months. Four patients received another ATP-competitive TKI concomitantly (imatinib, N=1; dasatinib, N=1; ponatinib, N=2). For patients receiving asciminib due to prior treatment failure (N=3), complete molecular response (CMR) was achieved in 2 patients with measurable residual BCR:: ABL1; 1 patient with frank leukaemia achieved complete remission with incomplete hematologic recovery with molecular response at 0.06%. For two patients receiving asciminib because of intolerance to prior treatment, one further improved from MR4 to CMR while pre-existing CMR was maintained in the other patient. There were 3 deaths; 2 due to COVID-19 and 1 due to refractory leukaemia (Figure 1). Asciminib showed an acceptable safety profile, with raised lipase leading to dose reduction only in 1 patient. Grade 3 or above toxicities were all haematological, observed in 5 patients, 2 of whom had previous allo-HSCT. One patient on asciminib-ponatinib treatment developed grade 2 renal impairment. Conclusion Asciminib demonstrated promising clinical efficacy with satisfactory tolerance in this cohort of Ph+ leukaemias failing multiple lines of therapy. Further investigation of its therapeutic role in Ph+ ALL is warranted.

2750. Pseudomonas aeruginosa infections treated with cefiderocol: associations of site of infection and time to first dose with outcomes in PROVE (Retrospective Cefiderocol Chart Review) Study

Abstract Background Gram-negative (GN) bacterial resistance is a major global health problem. Cefiderocol (CFDC) is active against Pseudomonas aeruginosa (PA). PROVE is an international, retrospective study of CFDC use in Gram-negative infections (GNI). This analysis examines outcomes by infection site and time of first CFDC dose from culture for patients with PA as of March 2023. Methods Eligible patients received ≥ 72 hours of CFDC as used in routine clinical practice and had a PA culture attributed to the use of CFDC. Patient characteristics, clinical course severity, and treatment patterns were assessed. Associations of infection site, carbapenem resistance (CR), CFDC susceptibility, and time of first (index) culture sample to first CFDC dose were examined with clinical cure and all-cause mortality (ACM) at 30 days. Clinical cure at the end of treatment was defined as resolution or improvement in infection signs and symptoms without evidence of later relapse. Results 253 patients were treated with CFDC at 39 sites in the US and Europe for a primary PA infection; 30.8% were polymicrobial with other GN pathogens (Table 1). The median age was 57 years, interquartile range (IQR) 45-65; 70% were male. The most frequent comorbidities were diabetes (34.0%) and chronic pulmonary disease (20.2%). CFDC was given in an ICU setting in 72.3% with 48.6% requiring mechanical ventilation. The most common sites of infection were respiratory (n=166, 65.6%) of which 22 (15.3%) had secondary bacteremia (Table 1). Most (90.3%) were CR. The median time from a positive culture to start of CFDC was 5 days (IQR 3-8). Clinical cure was 63.6% and 30-day ACM was 22.5% (Table 1). Clinical cure was comparable in respiratory with and without secondary bacteremia (63.2% and 68.2%, respectively) and was lowest in patients with skin structure infections with bacteremia (40.0%). CFDC started 3-4 days after culture had the greatest cure rate (70.8%); those started later (5-7 days) had the lowest (59.2%). 30-day ACM was also greatest for patients treated later ( > 7 days after index culture) (28.1%) and for salvage after prior treatment failure (26.7%) (Table 2). Conclusion CFDC for PA is used in complex patients, most with respiratory disease. The trend of better outcomes with earlier use from culture warrants additional study. Disclosures Stephen Marcella, MD, MPH, Shionogi, Inc: contracting work for Shionogi, Inc Bin Cai, MD, PhD, Shionogi Inc.: Shionogi employee Bruce Friedman, MD, Shionogi: Honoraria Stefano Verardi, MD, Shionogi B.V.: Employee Laurence Gozalo, PhD, Shionogi, Inc: Analyst Christine M. Slover, PharmD, Shionogi,INC: Employee

Long-term effectiveness of eptinezumab in patients with migraine and prior preventive treatment failures: extension of a randomized controlled trial

BackgroundEptinezumab demonstrated efficacy in adults with migraine and prior preventive treatment failures in the placebo-controlled phase of the DELIVER clinical trial; its long-term effectiveness in this population has not yet been reported. The objective of this study was to evaluate the long-term effectiveness of eptinezumab in a migraine patient population during the 48-week extension phase of DELIVER.MethodsDELIVER was conducted June 1, 2020 to September 15, 2022. 865 adults with migraine, with documented evidence of 2–4 prior preventive migraine treatment failures and with completion of the 24-week placebo-controlled period of DELIVER received eptinezumab (100 or 300 mg) during the dose-blinded extension, either continuing their randomized dose or, if originally receiving placebo, were randomized 1:1 to an eptinezumab dose (100 or 300 mg). A mixed model for repeated measures was used to evaluate changes from baseline in the number of monthly migraine days (MMDs).ResultsOf 865 patients entering the extension (eptinezumab 100 mg, n = 433; 300 mg, n = 432), 782 (90.4%) completed and 11 (1.3%) discontinued due to an adverse event. Eptinezumab was associated with early and sustained reductions in migraine frequency. Mean MMDs at baseline were approximately 14 days across groups. Mean (standard error) change from baseline in MMDs over the final dosing interval (weeks 61–72) was −6.4 (0.50) with placebo/eptinezumab 100 mg, –7.3 (0.49) with placebo/eptinezumab 300 mg, –7.1 (0.39) with eptinezumab 100 mg, and −7.0 (0.39) with eptinezumab 300 mg. During weeks 61–72, 63–70% of patients demonstrated ≥ 50% reduction in MMDs, and 36–45% demonstrated ≥ 75% reduction. Headache severity and acute medication use reductions, and patient-reported improvements in most bothersome symptom, disease status, quality of life, and work productivity, were observed. Adverse events were generally mild, transient, and similar in frequency/type to previous eptinezumab trials.ConclusionsThe long-term effectiveness and safety/tolerability of eptinezumab in patients with migraine and 2–4 prior preventive treatment failures was demonstrated by high completion rates and migraine-preventive benefits sustained for up to 18 months, implying that eptinezumab is a viable long-term treatment option for patients still seeking successful migraine treatments.Trial registrationClinicalTrials.gov (Identifier: NCT04418765; URL: https://www.clinicaltrials.gov/ct2/show/NCT04418765); EudraCT (Identifier: 2019-004497-25; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004497-25).Graphical

Transvenous Embolization of Dural Arteriovenous Fistulas Through the Galenic (Deep Venous) System: Multicenter Case Series and Meta-Analysis.

Arteriovenous fistulas involving the deep venous system have often been treated with microsurgery or transarterial embolization. Increasing familiarity with transvenous navigation and improved endovascular access systems may facilitate transvenous embolization (TVE) for these rare and challenging lesions. We performed a retrospective study of neurointerventional databases of 6 high-volume centers. We identified all cases of arteriovenous fistulas with deep transvenous embolizations for arteriovenous fistula. Details regarding demographics, fistula characteristics, treatment considerations, clinical outcomes, and fistula occlusion were obtained and analyzed. The meta-analysis used the same inclusion criteria. Seventeen cases of TVE were identified. The most common reasons for TVE included prior treatment failure with microsurgery (n = 2) or transarterial embolization (n = 3) or inaccessible arterial pedicles (n = 4). For patients with full clinical outcome data (n = 14), 2 patients had worsened modified Rankin Scale, 8 patients had no change, and 4 were improved at a median clinical follow-up of 3.5 months. Angiographic obliteration was achieved in 15/17 cases (88.2%). In 1 case, catheterization around a sharp turn in the basal vein of Rosenthal could not be performed. In another case, despite successful TVE, there was residual lesion which was treated 1 year later by microsurgical clipping and excision. Transvenous approaches for embolization of deep arteriovenous fistulas have become possible with modern endovascular catheter systems and liquid embolics. These lesions can be treated safely and effectively through endovascular approaches, which may spare patients the traversal of deep structures needed for microsurgical approaches to these regions. The outcomes of TVE are comparable with published outcomes of microsurgical interruption.

Upadacitinib (Rinvoq)


 CADTH recommends that Rinvoq be reimbursed by public drug plans for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have demonstrated prior treatment failure (i.e., an inadequate response to, loss of response to, or intolerance to at least 1 of conventional therapy and/or biologic therapy), if certain conditions are met.
 Rinvoq should be covered for a similar patient population and in a similar way to other drugs currently reimbursed by public drug plans for the treatment of moderately to severely active UC.
 Rinvoq should only be reimbursed if it is prescribed by a physician experienced in treating UC, the dosage does not exceed the product monograph’s recommended dosage, and it is not used in combination with biologics for UC. It should not cost more than other biologics or targeted synthetic drugs covered by the public drug plans for the treatment of moderately to severely active UC.

Meta-regression to explain the placebo effects in clinical trials of anti-CGRP monoclonal antibodies for migraine prevention

Background: Commonly used methods of comparison (e.g. network meta-analyses) require common comparator(s) across trials, such as placebo in placebo-controlled trials. Recent literature indicates that route of administration differences across placebo arms of clinical trials in pain disorders may contribute to differences in placebo effect.Methods: We conducted a meta-regression on placebo data from pivotal clinical trials of anti-calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies for migraine prevention to quantify the impact of route of administration, migraine type (episodic/chronic), and number of prior treatment failures on placebo reduction in monthly migraine days (MMDs) across weeks 1–12 of treatment. A systematic literature review of Embase, MEDLINE, the Cochrane Library, and grey literature conducted in June 2021 identified 14 relevant, randomized placebo-controlled trials for analysis.Results: After testing models with different covariates, a meta-regression was fitted to the extracted placebo data with the covariates of route of administration, migraine type, and proportion of patients with ≥2 prior preventive treatment failures. An intravenous route of administration for the placebo arm was a predictor for higher MMD reduction. Predictors of lower MMD reduction were migraine type (episodic migraine) and a higher proportion of patients having ≥2 failed preventive treatments.Conclusions: The efficacy of intravenous anti-CGRP monoclonal antibodies are likely underestimated, and differences in the route of administration of placebo may necessitate use of alternative methods that do not assume the presence of a common comparator when comparing anti-CGRP monoclonal antibodies in migraine prevention. Further research into the contextual effects of the placebo effect is warranted.

DP04 Role of multidisciplinary team meetings in management of inflammatory skin conditions

Abstract The multidisciplinary team (MDT) model has been previously demonstrated to improve early diagnosis and outcomes for psoriatic arthritis [Zheng YX, Zheng M. A multidisciplinary team for the diagnosis and management of psoriatic arthritis. Chin Med J (Engl) 2021; 134:1387–9; Luelomo J, Gratacós J, Martínez-Losa MM et al. A report of 4 years of experience of a multidisciplinary unit of psoriasis and psoriatic arthritis. Reumatol Clin 2014; 10:141–6]. However, there is little evidence for a similar role in inflammatory skin disease (ISD). A monthly psoriasis MDT has been established in our tertiary referral dermatology centre. We analysed referrals from February 2021 to February 2022. A total of 37 patient cases were discussed, 29 from within the geographical region of the centre and eight from outside the region. Reasons for referral were the presence of comorbidities; in the majority of cases, this was the presence of an internal malignancy (n = 15). Additional comorbidities were organ transplantation (n = 2), inflammatory bowel disease (n = 2), coexisting inflammatory arthritis (n = 4) and history of severe infection (n = 2). The secondary reason for referral was a history of multiple treatment failures (n = 8) and/or adverse effects of current biologics (n = 2). Where outcome data for regional patients could be assessed, the majority (n = 16) subsequently demonstrated objective improvement in their skin condition, with a mean reduction in Psoriasis Area and Severity Index score of 79.0% (n = 16) and a concurrent mean improvement of 59.6% in Dermatology Quality of Life Index (n = 11). Three patients died (unrelated to psoriasis/treatment). In summary, the presence of comorbidities and prior treatment failures are the primary reasons for referral to a tertiary referral service psoriasis MDT. Multidisciplinary team discussion results in objective improvements in patient care at early follow-up assessments. Further data on MDT outcomes for ISD are required.

Estimating treatment effects on health utility scores for patients living with migraine: a post hoc analysis of the DELIVER trial

ABSTRACT Background This post hoc analysis aimed to estimate eptinezumab’s therapeutic effect on health utilities and determined to which extent monthly migraine days (MMDs) explain changes in health utilities. Research Design/Methods DELIVER, a randomized, double-blind, placebo-controlled phase 3b trial (NCT04418765), investigated eptinezumab efficacy and safety in patients with 2-4 prior migraine treatment failures. Regression analysis explored the relationship between utility scores and MMDs, with eptinezumab treatment as a covariate along with MMDs to identify any MMD-independent effect on utilities. Path analysis quantified eptinezumab’s impact as mediated through MMD reduction. Results The base case model showed that each reduction in MMD was associated with a mean utility score increase (0.0189; 95% CI: 0.0180, 0.0198; P < 0.001). Mean utility score was generally higher for eptinezumab versus placebo, justifying addition of treatment effect to the base case model. Patients administered eptinezumab had on average 0.0562 (95% CI: 0.0382, 0.0742; P < 0.001) higher utility versus placebo when controlling for number of MMDs. From path analysis, MMD reduction resulting from eptinezumab treatment accounted for 53% additional utility gain observed in patients. Conclusions Changes in MMDs alone inadequately captured migraine’s impact on patient utility, as there was also a positive eptinezumab-driven, treatment-specific impact on utility score. Trial Registration The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04418765).

P.016 Impact of eptinezumab on patient-reported outcomes in patients with prior preventive treatment failures

Background: In DELIVER, eptinezumab reduced migraine frequency and was well tolerated in patients with migraine and prior preventive treatment failures. This analysis evaluated changes in patient-reported outcomes (PROs). Methods: DELIVER (NCT04418765; phase 3b double-blind study) randomized adults with migraine and 2-4 prior preventive treatment failures to eptinezumab or placebo every 12 weeks. The assessed PROs included EuroQol 5-Dimensions 5-Levels visual analogue scale (EQ-5D-5L VAS); 6-item Headache Impact Test (HIT-6), Patient Global Impression of Change (PGIC), most bothersome symptom (MBS), and Migraine-Specific Quality of Life Questionnaire (MSQ, v2.1). Results: Patients received eptinezumab 100mg (n=299), 300mg (n=294), or placebo (n=298). Mean changes from baseline to Wk12 in EQ-5D-5L VAS scores were 2.0 (100mg, P=0.0007) and 4.4 (300mg, P&lt;0.0001) versus -3.1 (placebo), and were maintained or further improved to Wk24 (2.0, 5.2, -2.8, respectively). Mean baseline HIT-6 total scores were ~66.4, with mean changes of -6.9 (100mg, P&lt;0.0001) and -8.5 (300mg, P&lt;0.0001) versus -3.1 (placebo) at Wk12 that were further improved through Wk24 (-8.9 and -9.9 vs -3.9). PGIC, MBS, and MSQ domain scores showed greater improvement for eptinezumab than placebo. Conclusions: In adults with migraine and prior preventive treatment failures, eptinezumab robustly improved health-related quality of life and migraine-related burden over 24 weeks versus placebo.

P.014 Eptinezumab improved work productivity in adults with migraine and prior preventive treatment failures: results from the DELIVER study

Background: This analysis reports the impact of eptinezumab on work productivity and daily activities in patients with migraine and prior preventive treatment failures. Methods: The DELIVER study (NCT04418765) randomized adults with migraine and documented evidence of 2-4 prior preventive treatment failures to receive eptinezumab 100mg, 300mg, or placebo (IV every 12 weeks). At baseline and every 4 weeks, patients completed the migraine-specific 6-question Work Productivity Activity Impairment (WPAI:M) questionnaire (7-day recall). Changes from baseline in WPAI subscores were predefined secondary endpoints and analyzed without control for multiplicity. Results: The full analysis set included 890 patients (100mg, n=299; 300mg, n=293; placebo, n=298). Mean baseline WPAI subscores indicated a negative impact of migraine on work productivity and normal daily activities. Beginning at first post-baseline assessment at Week 4 and through Week 24, eptinezumab demonstrated larger reductions than placebo in absenteeism (P&lt;0.05), presenteeism (P&lt;0.001), work productivity loss (P&lt;0.001), and activity impairment (P&lt;0.001) subscores. Conclusions: In adults with migraine and prior preventive treatment failures, eptinezumab treatment robustly improved migraine-related absenteeism, presenteeism, work productivity loss, and activity impairment as early as Week 4 and throughout the study.

A phase 1 first-in-human study of interferon beta (IFNβ) and membrane-stable CD40L expressing oncolytic virus (MEM-288) in solid tumors including non–small-cell lung cancer (NSCLC).

2569 Background: MEM-288 is a conditionally-replicative oncolytic adenovirus expressing human IFNβ and a recombinant membrane-stable form of CD40L (MEM40). Preclinical studies show MEM-288 induces robust dendritic cell-mediated systemic T cell responses capable of inhibiting abscopal tumor growth as monotherapy and synergizes with immune checkpoint inhibitors (ICI). Methods: MEM-288 is being evaluated in this Phase 1 open-label trial (NCT05076760) in pts with select solid tumors including NSCLC (a) refractory to standard therapy and (b) with a tumor lesion deemed feasible for biopsy and MEM-288 intratumoral (i.t.) injection. The primary objective is to determine using a BOIN design a recommended phase II dose of MEM-288 across 3 dose levels (DL1-3) spanning 1e10 to 1e11 viral particles by i.t. injection once every 3 weeks. Secondary objectives include efficacy assessment, including response rate of injected and non-injected tumors assessed separately. Tumor biopsies obtained immediately prior to the 1st and 2nd injections are used to explore biomarkers and anti-tumor immune responses. Results: As of February 2023, 12 pts (11 NSCLC and 1 pancreatic cancer; n = 3 DL1, n = 5 DL2, n = 4 DL3) have enrolled. The median number of MEM-288 i.t. injections was 2 (1-3), median age was 63 (39-76), and median prior lines of therapy was 3 (1-5). Radiology-guided injections were administered in superficial/palpable tumors and visceral lesions. No dose limiting toxicities occurred. Treatment-related adverse events observed in &gt; 1 pt include grade 1 injection site reaction (42%) and chills (17%). Of 10 response-evaluable pts, 4 (40%) pts had shrinkage of injected tumor (range -26 to -54%): 3 (30%) PR and 1 (10%) SD. Multiple pts also had stabilization or shrinkage of distal non-injected lesions. Best overall response was 3 (30%) stable disease and 7 (70%) progressive disease. After a single MEM-288 injection, biopsies show decreased tumor cell percentage concomitant with substantial increases in overall CD8+ T cells, increased T clonotype diversity in both tumor and peripheral blood, and increased TCF1+ stem-like CD8+ T cells that are strongly associated with response to ICIs. Plasma cytokine analysis showed increases in IFNg and of IFN-inducible cytokines and chemokines, supportive of stimulation of systemic response after MEM-288. Of note, a pt with strong stimulation of tumor and systemic T cell immunity after MEM-288 had subsequent CR (ongoing &gt; 7 months) to docetaxel + ramucirumab following prior treatment failure with platinum doublet + ICI received before MEM-288. Conclusions: Preliminary safety, antitumor and immune response data are encouraging. Updated results and immune data from this study will be presented. An expansion arm is planned with combination MEM-288 and anti-PD1 antibody in pts with advanced NSCLC refractory to ICI. Clinical trial information: NCT05076760 .

Co-mutation of ATM and ASXL1 and relationship to durable response of a novel PARP1/2 inhibitor, venadaparib, in patients with pancreatic cancer.

e15019 Background: Homologous recombination repair (HRR) alterations such as BRCA mutation (BRCAm) and ATM mutation (ATMm) are established predictive biomarkers for poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitor in pancreatic cancer (PC). Mutations in the ASXL1 gene (ASXL1m) have been associated with hematologic malignancies. In solid cancers, however, associations between HRR and non-HRR mutation such as ASXL1m as well as treatment response in patients with those are not well known. The aim of this analysis was to explore genetic alterations co-existing with HRR mutation to better predict efficacy from a monotherapy of venadaparib, a PARP inhibitor under development, in patients with metastatic PC. Methods: Patients with HRR mutation and no standard treatment or prior treatment failure were enrolled in a phase Ib basket trial (NCT04174716) to receive venadaparib monotherapy. Tumor response to treatment was evaluated according to RECIST 1.1. Exploratory blood samples were collected to analyze genetic alterations using ctDNA next-generation sequencing (NGS) (GuardantOMNI Gene Panel version 1.0, Redwood City, CA) on Day 1 pre-dose. Prevalence of co-occurring mutations was estimated and mutual exclusivity between HRR and non-HRR mutations were statistically tested by Fisher’s exact test using the cBioPortal for Cancer Genomics ( http://cbioportal.org ) in The Cancer Genome Atlas (TCGA) Pan-cancer and AACR Project Genie v13.0 registries. Efficacy between patients with co-mutations and single mutation only were presented. Results: In public dataset, the prevalence of ATMm and ASXL1m was 3.0% and 0.9% in TCGA pan-cancer study (n = 10,967), 3.0% and 1.7% in Genie v13.0 (n = 131,996), respectively. In both datasets, co-mutation of ATM and ASXL1 was tested significant (Log2 Odds Ratio 2.663 and 1.176 respectively; q-value 0.001 and 0.006 respectively). In the basket trial, 8 patients were enrolled, with 50% male, and a median age 66 (range 47-72). 6 patients had 2 prior palliative chemotherapy. 6 patients had ATMm and 2 had BRCA2m confirmed by enrolling institution at baseline. All patients had responded to prior platinum containing regimen. ctDNA NGS samples were available in 6 patients. Patients with ATMmASXL1m (n = 3) had a 33% overall response rate (1 partial response, 2 stable disease, range of progression-free survival (PFS), 23-113 weeks), while those with ATMmASXL1wt (n = 1) had a 0% (1 progressive disease (PD), PFS 9 weeks) and others (ATMwtASXL1wt, n = 2, 1 PD; ctDNA not available, n = 2, 2 PD) had a 0% response rate (range PFS 3-16 weeks). Two patients with BRCA2m only had PD on weeks 3 and 8. Conclusions: In this exploratory analysis, patients with co-occurring ATMm and ASXL1m showed higher tumor response. This signals potential value from ATM and ASXL1 co-mutation predicting efficacy of Venadaparib in PC and warrants further validation. Clinical trial information: NCT04174716 .

The efficacy and safety of antibody drug conjugate for high-risk non-muscle-invasive bladder cancer.

e16616 Background: RC48 is a novel antibody drug conjugate that targets the Her2 protein and has shown promising efficacy in advanced urothelial cancer. However, its efficacy and safety in early-stage urothelial carcinoma are yet to be fully explored. To address this, we retrospectively collected the clinical data of patients with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) who received rc48. Methods: In this retrospective study, 19 patients with Her2-overexpressing (IHC 2+ or 3+) HR-NMIBC who were unable to undergo complete tumor resection or tolerate surgery were included， and clinical data were retrospectively collected. Pathological complete response (CR), partial response (PR), stable disease (SD), objective response rate (ORR), duration of response (DOR), cystectomy-free survival (CFS), and event-free survival (EFS) were used for data analysis. Results: We collected clinical data from a total of 19 patients. The median age of patients was 69 years (range: 58 to 81). Seven patients (36.8%) received RC48 monotherapy, while 12 patients (63.2%) received RC48 combined with tislelizumab. A CR was achieved in 14 patients (73.7%, 95% CI: 48.6% to 89.9%), with a partial response (PR) in 1 patient (5.3%, 95% CI: 0.3% to 8.1%) and stable disease (SD) in 4 patients (21.1%, 95% CI: 7.0% to 46.1%). The overall ORR was 78.9% (95% CI: 53.9%, 93.0%). In 14 pts (73.7%) with Her2 IHC 3+, 12 achieved ORR, with an ORR of 85.7% (95% CI: 56.2%, 97.5%). Among the 5 pts with Her2 IHC 2+, 3 achieved ORR, with an ORR of 60.0% (95% CI: 17.0%, 92.7%). In addition, among the 5 pts who had prior PD-1 treatment failure, ORR was 60.0% (95% CI: 17.0%, 92.7%), and 2 achieved CR (40.0%, 95% CI: 7.3%, 83.0%). 1 patient died due to non-treatment-related causes. The duration of response (DOR) rate was 92.9% (95% CI: 80.3%, 100.0%), and the twelve-month DOR rate was 61.9% (95% CI: 27.4%, 100.0%). The twelve-month cystectomy-free survival (CFS) rate was 84.2% (95% CI: 69.3%, 100.0%), and the median CFS was not achieved. The twelve-month EFS rate was 75.8% (95% CI: 48.3%, 100.0%), and the median EFS was not achieved. The most commonly occurring grade 1-2 treatment-related adverse events (TRAEs) were alopecia (36.8%), rash (36.8%), pruritus (36.8%), anorexia (31.6%), and fatigue (26.3%). Grade 3-4 TRAEs were reported in 3 patients (6.3%), including rash, pruritus, leukopenia, and neutropenia. No grade 5 adverse events were reported. Conclusions: The results of this retrospective study show that both RC48 monotherapy and RC48 combined with tislelizumab have promising efficacy in the treatment of NMIBC. The overall response rate was high, with tolerable and manageable treatment-related adverse events. These findings suggest that RC48 monotherapy and RC48 combined with tislelizumab may be successful strategies for the treatment of NMIBC. Now, we are conducting a prospective study to further clarify the value of RC48 combining tislelizumab in NMIBC.

Safety and effectiveness of vonoprazan-based rescue therapy for Helicobacter pylori infection

Vonoprazan (VPZ)-based regimens are an effective first-line therapy for Helicobacter pylori (H. pylori) infection. However, their value as a rescue therapy needs to be explored.To assess a VPZ-based regimen as H. pylori rescue therapy.This prospective, single-center, clinical trial was conducted between January and August 2022. Patients with a history of H. pylori treatment failure were administered 20 mg VPZ twice daily, 750 mg amoxicillin 3 times daily, and 250 mg Saccharomyces boulardii (S. boulardii) twice daily for 14 d (14-d VAS regimen). VPZ and S. boulardii were taken before meals, while amoxicillin was taken after meals. Within 3 d after the end of eradication therapy, all patients were asked to fill in a questionnaire to assess any adverse events they may have experienced. At least 4-6 wk after the end of eradication therapy, eradication success was assessed using a 13C-urea breath test, and factors associated with eradication success were explored.Herein, 103 patients were assessed, and 68 patients were finally included. All included patients had 1-3 previous eradication failures. The overall eradication rates calculated using intention-to-treat and per-protocol analyses were 92.6% (63/68) and 92.3% (60/65), respectively. The eradication rate did not differ with the number of treatment failures (P = 0.433). The rates of clarithromycin, metronidazole, and levofloxacin resistance were 91.3% (21/23), 100.0% (23/23), and 60.9% (14/23), respectively. There were no cases of resistance to tetracycline, amoxicillin, or furazolidone. In 60.9% (14/23) patients, the H. pylori isolate was resistant to all 3 antibiotics (clarithromycin, metronidazole, and levofloxacin); however, eradication was achieved in 92.9% (13/14) patients. All patients showed metronidazole resistance, and had an eradication rate of 91.3% (21/23). The eradication rate was higher among patients without anxiety (96.8%) than among patients with anxiety (60.0%, P = 0.025). No severe adverse events occurred; most adverse events were mild and disappeared without intervention. Good compliance was seen in 95.6% (65/68) patients. Serological examination showed no significant changes in liver and kidney function.VAS is a safe and effective rescue therapy, with an acceptable eradication rate (> 90%), regardless of the number of prior treatment failures. Anxiety may be associated with eradication failure.

Burden of migraine in patients attending Belgian headache specialists: real-world evidence from the BECOME study.

Migraine is a primary headache disorder, which imposes a major burden on the sufferers. The BECOME study (Burden of migrainE in specialist headache Centers treating patients with prOphylactic treatMent failurE) attempted to characterize and assess the prevalence, burden and healthcare resource utilization of migraine patients presenting in specialized headache centers in Europe and Israel. In this paper, we will describe the patient characteristics of the Belgian headache centers. The BECOME study was a prospective, non-interventional, cross-sectional study consisting of two parts. In the first part of the study, data were collected from subjects with a diagnosis of migraine. Subsequently, patients with ≥ 4 monthly migraine days (MMD) and ≥ 1 prior preventive treatment failure (PPTF) filled out validated questionnaires to assess the burden of disease. In part 1 of the Belgian study population (N = 806), 45% of patients reported ≥ 8 MMD and 25% had failed ≥ 4 preventive treatments. In part 2 (N = 90), more than 90% of patients reported having severe impact of headache on daily life and having severe migraine-related disability. The impact was the highest for patients with ≥ 15 MMD, however, even within the patient population with < 8 MMD, the burden was significant. Almost 40% of the study population suffered from anxiety. These findings in the Belgian sample of the BECOME study demonstrate the substantial burden and unmet need for the management of difficult-to-treat migraine.

Responder Rates With Eptinezumab Over 24 Weeks in Patients With Prior Migraine Preventive Treatment Failures (S47.007)

Responder Rates With Eptinezumab Over 24 Weeks in Patients With Prior Migraine Preventive Treatment Failures (S47.007)

Patient-identified most bothersome symptom as a driver of health-related quality of life experienced by patients with migraine (P8-12.010)

Patient-identified most bothersome symptom as a driver of health-related quality of life experienced by patients with migraine (P8-12.010)

Necroptosis-related lncRNAs: establishment of a gene module and distinction between the cold and hot tumors in glioma.

Gliomas are the most common primary tumors of the central nervous system and portend a poor prognosis. The efficacy of emerging and promising immunotherapies varies significantly among individuals. Distinction and transformation of cold and hot tumors may improve the antitumor efficacy of immunotherapy. In this study, we constructed a necroptosis-related lncRNA module based on public databases. The association of this module with survival was assessed using the Cox regression, Kaplan-Meier survival analysis, and nomogram, external validation was also conducted in another public database. Furthermore, we performed gene set enrichment analysis (GSEA), immune checkpoint and tumor microenvironment analysis, and in vitro qRT-PCR validation. Finally, we clustered all samples into 2 clusters based on the expression of model lncRNAs and identified cluster 1 as cold tumors with fewer infiltrating T cells. Identifying cold and hot tumors by necroptosis-related lncRNAs can help available immunotherapeutic strategies to achieve efficacy in the precise treatment of individuals. Prior treatment failure can be overcome by targeting necroptosis-related lncRNAs.