Patients Discontinued Treatment Research Articles

Neoadjuvant everolimus in renal angiomyolipoma with or without tuberous sclerosis complex: Results from a multicenter, retrospective study.

To assess the efficacy and safety of preoperative neoadjuvant everolimus in renal angiomyolipomas (AML) patients with or without Tuberous Sclerosis Complex (TSC). This multi-institutional retrospective study enrolled renal AML patients who underwent partial nephrectomy (PN) or total nephrectomy after receiving at least 1 month of pre-operative everolimus. Imaging evaluations were collected before and after treatment, along with demographic, surgical, and follow-up information. The primary outcome was tumor volume reduction of ≥25%, with additional outcomes including recurrence, perioperative outcomes, renal function, and safety. From January 2015 to July 2022, 68 renal AML patients were studied-41 with TSC and 27 without. During everolimus treatment, 61.0% (25/41) of TSC patients and 44.4% (12/27) of non-TSC patients achieved tumor reduction of ≥25%. Additionally, 41.5% (17/41) of TSC patients and 18.5% (5/27) of non-TSC patients achieved a ≥ 50% reduction. Three TSC patients and 1 non-TSC patient discontinued treatment due to side-effects. Most patients (92.7% TSC, 85.2% non-TSC) underwent PN. After everolimus treatment, the necessary total nephrectomy decreased to 41.2% (7/17) from baseline. Postoperatively, 1 grade 3 and 3 grade 2 complications occurred, with no grade 4 or 5 complications. After a median follow-up of 24 months, only 1 TSC patient recurred with a diameter >3 cm. Retrospective nature is the major limitation of this study. Everolimus was effective and well-tolerated in neoadjuvant treatment for renal AML, especially in TSC patients. This neoadjuvant combination strategy of everolimus and PN could effectively controls recurrence and preserves renal function.

Sabatolimab in combination with spartalizumab in patients with non-small cell lung cancer or melanoma who received prior treatment with anti-PD-1/PD-L1 therapy: a phase 2 multicentre study

ObjectiveThis study evaluates the safety/efficacy of sabatolimab plus spartalizumab in patients with melanoma or non-small cell lung cancer (NSCLC).Design, setting and participantsThis is a phase 1–1b/2, open-label, multinational, multicentre study...

Adverse events associated with benznidazole treatment for Chagas disease in children and adults.

Chagas disease (ChD) affects approximately 7 million people in Latin America, with benznidazole being the most commonly used treatment. Data from a retrospective cohort study in Argentina, covering January 1980 to July 2019, was reanalysed to identify and characterize benznidazole-related adverse drug reactions (ADRs). The study included 518 patients: 449 children and 69 adults (median age in children: 4years; adults: 25 years; age ranges: 1month-17.75 years and 18-59 years, respectively). The median benznidazole doses received were 6.6mg/kg/day for at least 60 days in children and 5.6mg/kg/day for a median of 31 days in adults. Overall, 29.34% (152/518) of patients developed benznidazole-related ADRs, with an incidence of 25.83% (116/449) in children and 52.17% (36/69) in adults (odds ratio [OR] = 0.32, 95% confidence interval [CI] = 0.19-0.54, P < .001). The incidence rate was 177 cases per 1000 person-years (95% CI = 145-214) in children and 537 per 1000 person-years (95% CI = 360-771) in adults. There were 240 ADRs identified, primarily mild to moderate. Severe ADRs occurred in 1.11% (5/449) of children and 1.45% (1/69) of adults. The skin was the most affected system. A total of 10.23% (53/518) of patients discontinued treatment. More adults than children discontinued treatment (OR = 3.36, 95% CI = 1.7-6.4, P < .001). Although 29.34% of patients experienced ADRs, most were mild to moderate, indicating a manageable safety profile for benznidazole. While optimized dosing schedules and new drugs are needed, avoiding benznidazole solely due to safety concerns is not justified.

Real-world safety and effectiveness of pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis.

Multiple randomized controlled studies have shown that pirfenidone and nintedanib are effective and safe for treating idiopathic pulmonary fibrosis. This study aimed to evaluate their efficacy, safety, and tolerability in a real-world setting. We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases for real-world studies published up to March 3, 2023, on pirfenidone and nintedanib for idiopathic pulmonary fibrosis. A total of 74 studies with 23,119 participants were included. After 12months of treatment, the change from baseline in percent predicted FVC (%FVC) was - 0.75% for pirfenidone and - 1.43% for nintedanib. The change from baseline in percent predicted DLCO (%DCLO) was - 2.32% for pirfenidone and - 3.95% for nintedanib. The incidence of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) was 12.5% for pirfenidone and 14.4% for nintedanib. The IPF-related mortality rates of pirfenidone and nintedanib were 13.4% and 7.2%, respectively. The all-cause mortality was 20.1% for pirfenidone and 16.6% for nintedanib. In the pirfenidone group, 16.6% of patients discontinued treatment because of adverse events, and in the nintedanib group, 16.2% of patients discontinued treatment because of adverse events. The incidence of adverse events was 56.4% and 69.7% for pirfenidone and nintedanib, respectively. The results of this study indicate that pirfenidone and nintedanib are both effective in slowing down the decline of lung function in IPF patients in real-world settings. The incidence of adverse events with pirfenidone is lower than that with nintedanib, but both are below the clinical trial data, and no new major adverse events have been observed. The discontinuation rates due to adverse reactions of the two drugs are consistent with clinical trial data, indicating good tolerability. However, the mortality rates and AE-IPF incidence rates of these two drugs in real-world settings are higher than those in previous clinical trials, with pirfenidone patients showing a higher mortality rate. Further large-sample studies are needed to investigate the risks of these drugs in these aspects. Additionally, we recommend that future real-world studies pay more attention to patients' subjective symptoms and conduct stratified analyses of the efficacy and safety of pirfenidone and nintedanib based on factors such as patients' baseline lung function, comorbidities, and age, in order to provide more personalized medication advice for IPF patients in clinical practice.

Safety and Efficacy of Directly Acting Antivirals (Sofosbuvir &amp; Daclatasvir) in Treatment of Chronic HCV

Abstract Background The introduction of direct-acting antiviral agents, has revolutionized the treatment for chronic HCV with higher cure rates, shorter duration of treatment and more tolerability have been achieved. Aim of the Work The aim of our study is to estimate the efficacy and safety of DAAs in treatment of chronic HCV in patients co-infected with HIV. Patients and Methods This study of previously untreated HCV infection in patients with HCV and HIV co-infection conducted at Abbasia Fever Hospital, from July 2019 to February 2020. Patients included are chronic HCV infection and were receiving antiretroviral therapy for the HIV with a CD4 T-lymphocyte count of 200 cells/mL or greater. Serial measurements of safety parameters, virologic and host immune correlates, and adherence were performed during treatment by combination of daclatasvir 90mg and sofosbuvir 400mg+/- ribavirin 800mg daily for 12 weeks. Results In this study, the rate of a sustained virologic response (SVR) at post-treatment week 12 (SVR 12) were high (29/30, 96.67%). The most common adverse events were fatigue (73.33%), headache (46.67%), and there was a high safety profile on using DAAs. No patient discontinued treatment because of adverse events. No serious adverse events or mortality were reported. In this study, AST &amp; ALT were significantly decreased at end of treatment and 12 weeks after treatment, CD4 count was significantly increased. Otherwise there are no significant changes in both hematological and biochemical laboratory results. Conclusion Combination of daclatasvir and sofosbuvir have showed 96.67% sustained virologic response at 12 weeks after treatment (SVR 12) among HIV/HCV co-infected patients, with a very good safety profile. Moreover, the treated patients showed a significant increase in CD4 count. Accordingly, HIV/HCV co-infected patients should be treated with sofosbuvir and daclatesvir containing regimens.

Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial.

This multicenter phase II basket trial investigated the efficacy, safety and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion. Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2) or other histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events. Between March 22, 2019 and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, four in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted and the trial was terminated. Three of 58 evaluable patients had partial responses, representing an ORR of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events. Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors.

Machine learning prediction of the case-fatality of COVID-19 and risk factors for adverse outcomes in patients with non-small cell lung cancer.

Since the emergence of coronavirus disease 2019 (COVID-19) across the globe, patients with cancer have been found to have an increased risk of infection with COVID-19 and are highly likely to experience a severe disease course. This study analyzed the clinical outcomes of COVID-19 in patients with non-small cell lung cancer (NSCLC) and identified the risk factors for adverse outcomes. The study included patients diagnosed with COVID-19 between January 2020 and April 2022 at the Samsung Medical Center in Seoul, Republic of Korea, who have a history of NSCLC. The case-fatality rate and risk factors for COVID-19 were analyzed using a machine-learning prediction method. Additionally, the study investigated the effect of COVID-19 on the systemic treatment of patients with advanced-stage NSCLC. Overall, 1,127 patients were included in this study, with 10.3% of the patients being older than 75 years; of these patients, 51.8% were ex- or current smokers. Among the 584 patients cured after surgery, 91 had stable disease after concurrent chemo-radiotherapy, and 452 had recurrent or metastatic NSCLC. Among 452 patients with recurrent or metastatic NSCLC, 387 received systemic treatment in a palliative setting during COVID-19. Of these, 188 received targeted therapy, 111 received cytotoxic chemotherapy, 63 received immunotherapy +/- chemotherapy, and 26 received other agents. Among them, 94.6% of patients continued systemic treatment after the COVID-19 infection. Only one patient discontinued treatment because of complications of the COVID-19 infection, and 18 patients changed their systemic treatment because of disease progression. The case fatality rates were 0.86% for patients with early-stage NSCLC, 4.4% for patients with locally advanced NSCLC, and 9.96% for patients with advanced NSCLC. The factors associated with fatalities included palliative chemotherapy, type of palliative chemotherapy, age (≥75 years), diabetes, smoking history, history of lung radiotherapy, hypertension, sex, and chronic obstructive pulmonary disease (COPD). The predictive model using logistic regression and eXtreme Gradient Boosting (XGB) performed well [area under the curve (AUC) for logistic regression =0.84 and AUC for XGB =0.84]. The case fatality rate in patients with NSCLC was 4.8%, while most patients with advanced NSCLC continued to receive systemic treatment. However, patients with risk factors require careful management of COVID-19 complications.

Tislelizumab in previously treated, locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors.

The open-label, phase II RATIONALE-209 study evaluated tislelizumab (anti-programmed cell death protein 1 antibody) as a tissue-agnostic monotherapy for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) tumors. Adults with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled. Patients received tislelizumab 200 mg intravenously every 3 weeks. Objective response rate (ORR; primary endpoint), duration of response (DoR), and progression-free survival (PFS) were assessed by independent review committee (Response Evaluation Criteria in Solid Tumors v1.1). Eighty patients were enrolled and treated; 75 (93.8%) patients had measurable disease at baseline. Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease (n=79; 98.8%). At primary analysis (data cutoff July 8, 2021; median follow-up 15.2 months), overall ORR [46.7%; 95% confidence interval (95% CI), 35.1-58.6; one-sided P<0.0001] and ORR across tumor-specific subgroups [colorectal (n=46): 39.1% (95% CI, 25.1-54.6); gastric/gastroesophageal junction (n=9): 55.6% (95% CI, 21.2-86.3); others (n=20): 60.0% (95% CI, 36.1-80.9)] were significantly greater with tislelizumab vs. a prespecified historical control ORR of 10%; five (6.7%) patients had complete responses. Median DoR, PFS, and overall survival were not reached with long-term follow-up (data cutoff December 5, 2022; median follow-up 28.9 months). Tislelizumab was well tolerated with no unexpected safety signals. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 53.8% of patients; 7.5% of patients discontinued treatment due to TRAEs. Tislelizumab demonstrated a significant ORR improvement in patients with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.

Safety and efficacy of iparomlimab and tuvonralimab in combination with gemcitabine and cisplatin as first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma: A multicenter, single-arm, phase 2 trial (DUBHE-N-302).

6026 Background: Programmed cell death 1 (PD-1) inhibitor plus chemotherapy has been the standard first-line (1L) treatment for patients with recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). Iparomlimab and tuvoralimab (QL1706), a novel bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen 4, indicated promising anti-tumor activity for advanced solid tumors including NPC in phase 1/1b trial. This study aimed to evaluate the safety and efficacy of QL1706 combined with chemotherapy as 1L treatment in R/M NPC. Methods: This multicenter, single-arm, phase 2 study (NCT05576272) recruited patients with NPC who had no prior systemic therapy in the R/M setting. Intravenous injection of QL1706 5 mg/kg (day 1) combined with gemcitabine 1000 mg/m² (days 1 and 8) and cisplatin 80 mg/m² (day 1) was administered for four to six cycles (21 days per cycle), followed by maintenance treatment of QL1706. The primary endpoint was safety and tolerability. Key secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS). Results: From May 19 2022 to Dec 9 2022, 29 patients were included. The median age was 50 years (range, 25-65), with 24 (83%) being male. Seven patients (24%) had an Eastern Cooperative Oncology Group Performance Status of 1. Nineteen (66%) had recurrent disease. As of the data cut-off on Dec 31 2023, the median follow-up was 15.5 months. Treatment-related adverse events (TRAEs) occurred in 29 patients (100%). TRAEs of grade 3 or 4 occurred in 18 patients (62%), with the most common being decreased neutrophil count (41%), decreased white blood cell count (35%), anemia (21%), and decreased platelet count (21%). Twenty patients (69%) experienced immune-related adverse events, with the most common being grade 1-2 hypothyroidism (38%). Serious TRAEs occurred in five patients (17%). Three patients (10%) discontinued treatment due to adverse events. No treatment-related deaths occurred. Among the 28 evaluable patients, the ORR was 82.1% (95% confidence interval [CI], 63.1% to 93.9%), including one achieving complete response. The DCR was 96.4% (95% CI, 81.7% to 99.9%). The median PFS was 12.5 months (95% CI, 5.7 to not evaluable [NE]), and the median DoR was 14.1 months (95% CI, 7.6 to NE). In 14 patients with high expression level of programmed cell death ligand 1 (combined positive score≥50), the median PFS was 16.2 months (95% CI, 9.9 to NE). The median OS was not reached. Conclusions: Iparomlimab and tuvoralimab combined with chemotherapy showed tolerable safety and promising efficacy as 1L treatment for patients with R/M NPC. Clinical trial information: NCT05576272 .

A phase I/II open-label clinical trial of CPI-613 in combination with modified FOLFIRINOX in patients with locally advanced (LAPC) or borderline resectable pancreatic cancer (BRPC).

4172 Background: Pancreatic ductal adenocarcinoma (PDA) carries a poor prognosis with a 5-year relative survival rate of 13%. Surgical resection is the only curative treatment option, but less than 20% of patients are eligible at diagnosis. A subset of patients with locally advanced disease can become candidates for resection with neoadjuvant (NA) therapy. mFOLFIRINOX is the standard of care in the adjuvant setting, with extrapolated data supporting its use in the NA setting. CPI-613/Devimistat (D) is a small molecule that targets mitochondrial metabolism in tumor cells leading to ROS-mediated apoptosis. A phase III trial of mFOLFIRINOX + D at 500 mg/m2 in metastatic PDA did not meet primary endpoint of overall survival (OS). Here we present the results of the combination’s use at standard and escalated doses in LAPC and BRPC. Methods: In this investigator-initiated, single-center, phase I/II, open-label trial treatment-naïve patients with investigator assessed LAPC or BRPC were treated with mFOLFIRINOX in 14 day cycles + D. In the standard dosing (SD) cohort, patients received D at 500mg/m2 while in the dose escalation (DE) cohort; D at 750 mg/m2 or 1000 mg/m2 was used. Radiographic response was assessed every 8 weeks. Patients who remained unresectable after 12 cycles could receive additional standard treatments, including chemoradiotherapy. The primary endpoint was median overall survival (mOS), with the study powered to show a mOS improvement from the historical standard of 14 months to 28 months with mFOLFIRINOX + D. Secondary endpoints were median progression free survival (mPFS), percent resected, and safety outcomes. NCT03699319 Results: Between Dec 2018 and Mar 2022, 37 patients and 11 patients enrolled in the SD and DE cohorts. Median age 69 years (range 47-78), male/female (27/21), Caucasian (83%), LAPC/BRPC (34/14). One patient (2%) withdrew, 4 patients (8%) discontinued treatment due to toxicity, 9 patients (19%) had progressive disease prior to completion of 12 cycles. In all patients mOS was 16.3 months and mPFS was 10.7 months. By cohort: SD/DE mOS: 16.2/17.6 months (p=0.56). Fourteen patients (29%) had partial response by RECIST 1.1. Twenty patients (41.7%) had resection; mOS 29.7 months. In the SD cohort, 78% and 24% of patients had grade 3 and/or 4 AEs. There were no dose limiting toxicities (DLT) in the DE cohort, and eight patients received the maximum dose of 1000 mg/m2 of D. After the DLT period, 100% patients in DE cohort had grade 3 toxicity and 55% had grade 4 toxicity. For all the most common toxicities (gr3,4) were neutropenia (27%,25%), diarrhea (25%,0), anorexia wt. loss (23%,0), nausea/vomiting (23%,0). Conclusions: The combination of mFOLFIRINOX and D is feasible in the LAPC/BRPC population at increased dose levels of D; however, it did not meet the primary endpoint of doubling OS compared to historical controls. Clinical trial information: NCT03699319 .

Real-world safety and discontinuation rates of fam-trastuzumab deruxtecan in advanced HER2-positive and HER2-low cancer.

e12518 Background: Fam-trastuzumab deruxtecan’s (Enhertu) 2022 approval for HER2-low breast cancer spurred widespread adoption of its utilization. DESTINY-Breast04 trial reported 9.9 months median progression-free survival (PFS); however, 16.2% experienced adverse events leading to treatment discontinuation. Our study evaluates real-world adverse event rates causing treatment discontinuation, to assess Enhertu's safety in patients with advanced metastatic cancer. Methods: A retrospective analysis was conducted at a community-based practice in Kansas, USA from 2020 to 2024. 99 patients with HER2-positive and HER2-low cancer, treated with Enhertu, with ECOG performance status of 0 and 1 were identified. Absolute values and proportions were used to represent categorical and nominal variables. Proportions between groups were analyzed using the likelihood ratio chi-square, Fisher's test, and the z-test. Statistical analyses were performed using SAS 9.4. The primary objective was to determine treatment discontinuation rates due to adverse events, while secondary objectives included assessing discontinuation rates due to disease progression, mortality rates, as well as progression-free survival, and dose interruption rates. Results: The average age of patients was 62 years, with 92% being females. The most common cancer types treated were Stage IV metastatic Breast Cancer (87%) and Gastric/Gastroesophageal Junction Cancer (9.1%). Of these cases, 44% were HER2-positive, while the rest were HER2-low. A total of 74% of patients discontinued treatment, with a mean duration of 5.4 months (95% Confidence Interval [CI] 4.2-6.7). Adverse events accounted for 9% of discontinuations, including interstitial lung disease/pneumonitis (33%), thrombocytopenia (11%), diarrhea (11%), nausea (22%), and dysgeusia (11%). 77% experienced grade 2 and 3 adverse events. Disease progression and death resulted in 49.4% and 11% of Enhertu discontinuation respectively. Among patients still on Enhertu (26%), the mean treatment duration was 13.5 months (95% CI 9.5-17.5). The mean PFS was 9.3 months (95% CI 6.2-9.4). Dose interruptions due to adverse events with subsequent resumption occurred in 18% of patients. Conclusions: In our community-based observational study on Enhertu discontinuation rates due to treatment-emergent adverse events (TEAEs), we found a 9% discontinuation rate—significantly lower than the 16.2% reported in the Breast04 trial, (P=0.045). The incidence of interstitial lung disease was 3%, considerably less than the 12% reported in Breast04. Importantly, no deaths related to TEAEs were observed, suggesting a lower occurrence of serious adverse events in clinical practice compared to clinical trials. These results underscore Enhertu's safety profile in advanced metastatic HER2-positive and low cancer.

Avutometinib/defactinib and gemcitabine/nab-paclitaxel combination in first-line metastatic pancreatic ductal adenocarcinoma: Initial safety and efficacy of phase 1b/2 study (RAMP 205).

4140 Background: More than 90% of pancreatic ductal adenocarcinomas (PDAC) harbor an activating KRASmutation .Avutometinib (avuto) is an oral RAF/MEK clamp. Defactinib (defact) is an oral selective FAK inhibitor. Avuto/defact combined with gemcitabine/paclitaxel have shown synergistic antitumor activity in preclinical PDAC models. RAMP 205 (NCT05669482) is a Phase 1b/2 study assessing the safety and efficacy of avuto/defact + gemcitabine/nab-paclitaxel (GnP) in first-line metastatic PDAC. Methods: Eligible patients (pts) were enrolled and treated in 3+3 cohorts with escalating doses of avuto orally (PO) twice weekly (BIW) and defact PO twice daily (BID), both 3 out of 4 weeks, in combination with GnP dosed intravenously (IV) on a D1, D8, D15 or D1, D15 (modified) 4wk schedule (Table 1). Key eligibility criteria include histologically confirmed newly diagnosed metastatic PDAC with measurable disease, ECOG performance status (PS) ≤1, adequate organ function, and no prior treatment. Results: At the 24Jan2024 data cutoff, 18 pts were enrolled, 44% were male, 65 y median age, and 61% ECOG PS 1. Pts were enrolled to DL-1 (n=3), DL1 (n=6), DL1a (n=6), and DL2a (n=3). No dose-limiting toxicities (DLTs) were reported and the majority of treatment related adverse events (TRAEs) were mild to moderate. The most frequently reported TRAEs of any grade in the safety population (N=18) were nausea (50%), alopecia (44%), fatigue (39%), maculo-papular rash (33%), and peripheral edema (28%). The most common grade ≥3 TRAEs included alanine aminotransferase increase (17%), neutropenia (17%), peripheral edema (11%), anemia (11%), and sepsis (11%). Four patients experienced serious AEs (SAEs). Grade ≥3 treatment emergent SAEs included pulmonary embolism (n=2; unrelated), sepsis (n=2), febrile neutropenia (n=1; did not meet DLT criteria), and neutropenia (n=1). One patient discontinued treatment due to TRAE (febrile neutropenia and blood bilirubin increased). All efficacy evaluable pts (n=8) experienced a reduction in target lesions (100% disease control rate) and partial responses were observed in 6/8 (75%), 3 being confirmed at data cutoff. All efficacy evaluable pts with an elevated CA19-9 at baseline (n=7) had a ≥60% CA19-9 reduction from baseline. Conclusions: Avuto/defact and GnP are combinable and show notable preliminary efficacy in first-line metastatic PDAC based on RECIST v.1.1 criteria and CA19-9 levels. No DLTs were reported across the 4 dosing cohorts/schedules and safety signals were consistent with previous clinical data. Updated safety and efficacy will be reported. Clinical trial information: NCT05669482 . [Table: see text]

PBP1510, a novel monoclonal antibody targeting pancreatic adenocarcinoma upregulated factor (PAUF): Phase 1/2a monotherapy and combination with gemcitabine in patients with advanced/metastatic pancreatic cancer.

e16296 Background: PAUF, a protein overexpressed in pancreatic cancer but not in non-cancerous tissues, plays a key role in cancer progression and metastasis. PBP1510 is a novel first-in-class humanized IgG1 monoclonal antibody that binds to and neutralizes PAUF with high specificity and affinity. PAUF-I (NCT05141149) is a first-in-human, multicenter, open-label study in patients with advanced/metastatic pancreatic cancer. Early Phase 1 results are presented here. Methods: Key eligibility criteria for Phase 1 include: locally advanced/metastatic pancreatic cancer; at least 1 previous line of chemotherapy; ECOG 0-1; and measurable disease by RECIST v1.1. A 3+3 dose escalation design is planned for 5 dose levels of intravenous PBP1510 (doses of 1, 3, 6, 10, and 15 mg/kg), either alone (monotherapy cohorts) or in combination with gemcitabine at a dose of 1000 mg/m2 (combination cohorts), in 28-day cycles. Tumor assessments are performed every 8 weeks from the first dose of PBP1510. Dose is escalated following a safety review committee meeting, if all patients in a cohort complete the dose-limiting toxicity (DLT) observation period (28 days from first dose) without any DLTs. Primary endpoints are safety parameters including treatment emergent adverse events (TEAEs) and laboratory findings. Results: As of January 2024, 6 patients (4 males, 2 females), aged 54-71 years, were enrolled. All patients had stage IV ductal adenocarcinoma and had received at least 2 prior lines of chemotherapy. Five patients received 2 cycles of PBP1510 each at 1 mg/kg or 3 mg/kg based on their cohort. One patient received 1 cycle of PBP1510 at 3 mg/kg. Seventeen TEAEs were assessed to be related to study treatment. The most frequently reported treatment-related TEAE was asthenia (n = 7). Most treatment-related TEAEs were NCI-CTCAE Grade 1 in severity (n = 14). Five serious TEAEs not related to study treatment were reported in 2 patients. There was 1 death reported due to disease progression. No patient discontinued treatment due to TEAEs. No clinically significant abnormalities in ECG, LVEF, and clinical laboratory assessments were reported during the DLT observation period. All patients in the first 2 monotherapy cohorts completed the DLT observation period without any DLTs. Conclusions: PBP1510 was well tolerated by all patients at 1 mg/kg or 3 mg/kg in the first 2 monotherapy cohorts. The next monotherapy (PBP1510, 6 mg/kg) and combination (PBP1510, 1 mg/kg; gemcitabine 1000 mg/m2) cohorts are open for recruitment. Clinical trial information: NCT05141149 .

Clinical profile of Spanish hepatitis C virus-infected treatment-naïve patients with compensated cirrhosis in the CREST study

Background and aim of the studyThere are still patients with hepatitis C in Spain who have yet to be diagnosed, but their clinical profile is unclear. In 2021, 21.93% of patients diagnosed had cirrhosis and were mostly treatment-naïve. MethodsThis sub-analysis describes the clinical profile of the 60 Spanish treatment-naïve patients with compensated cirrhosis who were included in the CREST study. Major resultsSixty percent of patients were male, median age 56 years, and 33% had a history of drug use. Almost three-quarters (71.3%) had more than one comorbidity and 78.3% took concomitant medication. At treatment initiation, median platelet count was 139 × 103/µL and FibroScan® 17 kPa. No virological failure was observed and no patient discontinued treatment due to adverse events. No clinically significant changes were noted during or after treatment in the median platelet, albumin, bilirubin, and transaminase levels. ConclusionsTreatment with glecaprevir/pibrentasvir for 8 weeks in this cohort of treatment-naïve patients with compensated cirrhosis in Spain was safe and effective. This information reinforces the use of this short antiviral regimen even when there is compensated cirrhosis, simplifying the approach to hepatitis C among those patients still to be diagnosed and treated in Spain.

Treatment Discontinuation in Patients with Psoriasis Treated with Biologics: A Retrospective Analysis of German Health Claims Data.

Plaque psoriasis is a common, often debilitating, chronic autoimmune inflammatory skin disease. Moderate-to-severe forms of psoriasis can be treated with biologics such as anti-interleukin and anti-tumor necrosis factor antibodies. We aimed to investigate treatment discontinuation among patients with psoriasis who initiated biologic treatment. We conducted a retrospective, non-interventional cohort study based on anonymized claims data from the German statutory health insurance which covered the years from 2016 to 2021. We included adult patients with psoriasis who initiated biologic treatment in drug-specific cohorts. Over a 365-day follow-up period, we assessed the frequencies and the time until treatment discontinuation for different biologics. Differences in discontinuation rates were compared using a multivariate Cox proportional hazards model. A total of 2565 patients with psoriasis who initiated treatment with secukinumab (n = 612), adalimumab (n = 454), guselkumab (n = 354), ixekizumab (n = 259), ustekinumab (n = 241), tildrakizumab (n = 205), brodalumab (n = 166), risankizumab (n = 145), etanercept (n = 91), certolizumab (n = 29), and infliximab (n = 9) were included. A total of 1290 patients (50.29%) discontinued treatment during the follow-up period, ranging from 30.34% (risankizumab) to 69.23% (etanercept). Median time until discontinuation of treatment ranged from 102days (etanercept) to 208days (risankizumab). Once the biologic treatment was discontinued, 45.05% of patients restarted the treatment with the same agent, 23.10% of patients switched to another biologic, and 31.86% received no further biologic agent. Compared to patients treated with risankizumab, the treatment discontinuation rate was significantly higher (p < 0.05) in patients treated with the other biologics except ustekinumab (p = 0.12). Further research should explore reasons leading to treatment discontinuation in order to support treatment choices for patients with moderate-to-severe psoriasis.

#2066 Treatment patterns of patients with complement 3 glomerulopathy (C3G): a retrospective linked electronic medical record (EMR) and claims analysis

Abstract Background and Aims C3G is characterised by C3 deposition in the glomeruli, caused by dysregulation of the alternative complement pathway. Currently, there are no approved therapies for C3G. The aim of this analysis was to evaluate treatment patterns in patients with C3G in the United States (US). Methods This was a retrospective cohort study of patients with C3G, with an EMR and linked pharmacy and medical claims data in the US HealthVerity database, who were diagnosed between Jan 1, 2017 and Sep 30, 2021 and aged ≥12 years at diagnosis. Included patients had database records for ≥12 months before (baseline period) and after (follow-up period) the index date (date of first C3G diagnosis, identified by International Classification of Diseases 10th Revision Clinical Modification [ICD-10-CM] and Systematized Nomenclature of Medicine [SNOMED] diagnosis codes). Endpoints included: proportion of patients receiving a treatment, including supportive care (angiotensin-converting enzyme inhibitors [ACEi]/angiotensin II receptor blockers [ARB]), immunosuppressants (IM; including corticosteroids [CS]/glucocorticoids [GC] and mycophenolate mofetil [MMF]), and eculizumab; proportion of patients discontinuing treatment; and duration of treatment. Discontinuing treatment was defined as the absence of a subsequent claim for medication for ≥60 days. Results were assessed using descriptive statistics and analysed by Fisher's exact test, Mann–Whitney U test, or Student's t-test, as appropriate. Results The final cohort included 683 patients. Overall, 346 (50.7%) patients had ≥1 treatment record for C3G during follow-up (median follow-up 24.0 months; median time from index to first treatment 1.1 months). Mean age (standard deviation) of treated and untreated patients was 47.7 (19.4) and 39.6 (18.0) years (P &amp;lt; 0.0001), respectively; 54.3% of treated patients and 72.7% of untreated patients were female (P &amp;lt; 0.0001). Comorbidities reported in treated and untreated patients, respectively, included: hypertension (75.1% and 33.5%; P &amp;lt; 0.0001) and type II diabetes (34.7% and 12.8%; P &amp;lt; 0.0001). Baseline proteinuria data were available for 39 (11.3%) treated patients and 11 (3.3%) untreated patients (P &amp;lt; 0.0001). Median (lower quartile, upper quartile) proteinuria levels were 1.9 (0.7, 3.3) g/g and 0.2 (0.1, 2.3) g/g for the treated and untreated populations, respectively (P = 0.05). Among treated patients (n = 346), most (76.0%) received an ACEi/ARB alone in the first line, 14.2% received IM alone, and 5.8% received concomitant ACEi/ARB and IM (Table 1). A small number of remaining patients received a sodium-glucose cotransporter-2 inhibitor (SGLT2i) ± ACEi/ARB (2.9%), or eculizumab ± IM (1.2%). Less than half of treated patients (43.9%) received second-line therapy, and 17.6%, 6.6%, and 2.0%, respectively, received subsequent lines of treatment. Among treated patients, the most common treatment sequence was ACEi/ARB alone in the first line, without subsequent lines of therapy (42.2%); 30.9% of treated patients received IM (alone or in combination with other treatments) at any time during follow-up. Median duration of treatment in months (95% confidence interval) in any line was 14.9 (9.9, 18.4) for ARB, 8.6 (7.5, 11.1) for ACEi, 7.4 (3.3, 22.6) for SGLT2i, 4.7 (3.0, 6.6) for MMF, and 1.0 (0.9, 3.0) for CS/GC. During follow-up, 225 (65.0%) patients discontinued treatment: 22 (9.8%) and 203 (90.2%) patients restarted and did not restart therapy, respectively. Conclusions These real-world data show that only half of patients with C3G had a record of treatment during follow-up. Compared with the untreated population, patients who received treatment were older, more likely to be male, and more likely to have hypertension or type II diabetes. Among treated patients, the most common treatment sequence was supportive care with an ACEi/ARB alone, and less than one-third received IM at any time during follow-up. Use of the complement inhibitor, eculizumab, was low in this population. A large proportion of patients discontinued treatment during follow-up; given the progressive nature of C3G, these data may highlight the need for novel therapies in the treatment of C3G.

Oral Semaglutide in Routine Clinical Practice: Characteristics of People with Type 2 Diabetes Started on the Drug and Changes in Their Clinical Parameters after 24 Weeks of Treatment.

Background/Objectives: Semaglutide is the unique once-daily oral glucagon-like receptor agonist presently available. Aims of this study were to describe clinical characteristics of patients with type 2 diabetes (T2D) initiating oral semaglutide, to assess its effects on glycemic control, body weight (BW) and its tolerability in routine clinical practice. Methods: Electronic medical records from two Italian diabetes clinics were evaluated. Mean glycated hemoglobin (HbA1c) and BW were assessed in adults with T2D before and 6 months after oral semaglutide prescription. Treatment discontinuation and safety data were reported. Results: A total of 192 patients initiating oral semaglutide (44% female) presented a mean age of 66 years, a diabetes duration of 10 years, HbA1c of 7.9% and a BW of 82.6 kg. Almost 50% of patients were obese. Mean HbA1c and BW changes from baseline to follow up were -0.7% and -2.6 kg, respectively. Greater HbA1c reduction was observed in patients with baseline HbA1c ≥ 8% and with diabetes duration <5 years. The composite endpoint of HbA1c ≤7% and a weight loss ≥5% was achieved in 22.5% of the participants. A total of 40 patients (20.8%) discontinued treatment: 26 because of gastrointestinal adverse events, and 10 due to limited effectiveness in lowering HbA1c and/or BW. Conclusions: In a real clinical setting, patients initiating oral semaglutide showed suboptimal metabolic control, short diabetes duration and obesity; a significant improvement in HbA1c and BW was achieved mainly in patients with a more recent diabetes diagnosis, supporting the use of oral semaglutide in the early phase of the disease.

#2631 Efficacy and safety of Telitacicept combined with low-dose mycophenolate mofetil in IgA nephropathy

Abstract Background and Aims Currently, there is no specific agent blocking for IgA nephropathy. The KDIGO guideline recommends basic treatment with renin-angiotensin-aldosterone system (RAAS) antagonists. MMF can be used for Chinese patients. Telitacicept is a fusion protein composed of transmembrane activator and calcium modulating cyclophilin ligand interactor and fragment crystallizable portion of immunoglobulin G (IgG), which neutralizes the B lymphocyte stimulator and a proliferation-inducing ligand. Telitacicept (240 mg qw ih) treatment led to a clinically meaningful reduction in proteinuria in patients with IgAN in the present phase 2 clinical trial. This study intends to observe the efficacy of Telitacicept (160 mg qw ih) combined with low-dose MMF in the treatment of IgA nephropathy. Method Retrospective analysis involving all biopsy proven IgA nephropathy patients with complete clinical data in our department. After RAAS inhibitor treatment for 3 months, the patient's urinary protein more than 0.75 g/24 h, he or she was given Telitacicept (160 mg qw) combined with Mycophenolate mofetil (1 g, twice a day) was treated for 6 months, and follow-up for 6-12 months. The quantification of 24-hour urinary protein and immunity functional, renal function was observed. Results 25 patients with IgA nephropathy confirmed by renal biopsy were enrolled, 14 males and 11 females, aged 34.32 ± 9.68 years’ old, 3 patients with Lee's grade II, Grade III 17 patients, Grade IV 3 patients, and Grade V 2 patients. For Oxford classification, there were 3 cases with M0, 22 cases with M1 lesions, 20 cases with E0, 5 cases with E1 lesions, 1 case with S0, 24 cases with S1 lesions, 10 cases with T0, 15 cases with T1 lesions, and 17 cases with C0, 8 cases with C1 lesions. The patient's urine protein quantification was 2.52 ± 1.82 g before treatment, after Telitacicept and MMF treatment for 2 months, the proteinuria was 1.05 ± 0.55 g (compared with that before treatment, P = 0.0004), and at 4 months, it was 0.71 ± 0.39 g (compared with that before treatment, P &amp;lt; 0.0001), 0.53 ± 0.31 g at 6 months (compared with than before treatment, P &amp;lt; 0.0001). And the 24-hour urine protein quantification of 13 patients was all lower than 0.5 g/24 hours. The renal function of all patients was stable during the observation period. The serum creatinine before treatment was 83.16 ± 21.85 μmol/L and it was 81.88 ± 19.48 μmol/L (P = 0.83) after 6 months. There were no patients with worsening renal function after treatment. Among them, the renal function of 3 patients was better than that after treatment. During follow-up period for 6- to 12-month, the patient did not develop any pulmonary infection requiring for hospitalization or other infections. Some patients experienced adverse reactions such as pain at the site of injection, but no patient discontinued treatment due to adverse reactions. Conclusion Telitacicept combined with low-dose mycophenolate mofetil is a alternative method for the treatment of IgA nephropathy. It is more effective than mycophenolate mofetil or Telitacicept use alone, and with fewer adverse reactions, especially with S or C lesions of Oxford classification. This is an observational retrospective study with a few cases, it's worthy further randomized clinical study to prove.

Investigation of colistin utilization in the treatment of multidrug-resistant gram-negative nosocomial bloodstream ınfections in children and literature review.

This retrospective study aimed to assess the effectiveness and safety of colistin used in combination therapy for treating nosocomial bloodstream infections caused by multi-drug resistant gram-negative pathogens in pediatric patients. Patients aged between 1month and 18years consecutively hospitalized with healthcare-associated bloodstream infections necessitating the administration of intravenous colistin at Dr. Sami Ulus Training and Research Hospital between January 2015 and January 2020 were included in the study. Patient-specific detailed clinical information, prognoses, and laboratory findings on days 1, 3, and 7 of colistin treatment were obtained from medical records. The study included 45 pediatric patients receiving intravenous colistin; 26 (57.8%) were male and 19 (42.2%) were female, with a median age of 18months. While the clinical response was observed at 82.2% and microbiological response at 91.1% with colistin treatment, two patients (4.4%) discontinued treatment due to side effects without assessing treatment response. The most common adverse effect associated with the use of colistin was nephrotoxicity, which occurred in eight patients (17.8%). Among these patients, only one had pre-existing chronic kidney failure. Conclusion: Colistin used in combination therapy may be effective and safe for treating nosocomial infections caused by multi-drug resistant gram-negative bacteria in pediatric patients, who often have high mortality rates and limited treatment options. What is Known: • Colistin is an antibacterial agent used in the treatment of infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) and is associated with significant adverse effects such as nephrotoxicity. • The increasing prevalence of hospital-acquired infections has led to the expanded use of colistin in clinical practice. What is New: • The study demonstrates a high clinical and microbiological response rate to combination therapy with colistin in the treatment of infections caused by MDR-GNB. • The study highlights the importance of monitoring nephrotoxicity in pediatric patients receiving colistin, showing that these effects can be reversible after treatment cessation.

Feasibility, safety, efficacy and potential scaling-up of sofosbuvir-based HCV treatment in Central and West Africa: (TAC ANRS 12311 trial)

Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.