Erdafitinib in Asian patients with advanced solid tumors: an open-label, single-arm, phase IIa trial.

BACKGROUND: FGFR genomic aberrations occur in approximately 5-10% of human cancers. Erdafitinib has previously demonstrated efficacy and safety in FGFR-altered advanced solid tumors, such as gliomas, thoracic, gastrointestinal, gynecological, and other rare cancers. However, its efficacy and safety in Asian patients remain largely unknown. We conducted a multicenter, open-label, single-arm phase IIa study of erdafitinib to evaluate its efficacy in Asian patients with FGFR-altered advanced cholangiocarcinoma, non-small cell lung cancer (NSCLC), and esophageal cancer. METHODS: Patients with pathologically/cytologically confirmed, advanced, or refractory tumors who met molecular and study eligibility criteria received oral erdafitinib 8 mg once daily with an option for pharmacodynamically guided up-titration to 9 mg on a 28-day cycle, except for four NSCLC patients who received erdafitinib 10 mg (7 days on/7 days off) as they were recruited before the protocol amendment. The primary endpoint was investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, duration of response, disease control rate, overall survival, safety, and pharmacokinetics. RESULTS: Thirty-five patients (cholangiocarcinoma: 22; NSCLC: 12; esophageal cancer: 1) were enrolled. At data cutoff (November 19, 2021), the objective response rate for patients with cholangiocarcinoma was 40.9% (95% CI, 20.7-63.6); the median progression-free survival was 5.6 months (95% CI, 3.6-12.7) and median overall survival was 40.2 months (95% CI, 12.4-not estimable). No patient with RET/FGFR-altered NSCLC achieved objective response and the disease control rate was 25.0% (95% CI, 5.5-57.2%), with three patients with stable disease. The single patient with esophageal cancer achieved partial response. All patients experienced treatment-emergent adverse events, and grade ≥ 3 treatment-emergent adverse events were reported in 22 (62.9%) patients. Hyperphosphatemia was the most frequently reported treatment-emergent adverse event (all-grade, 85.7%). CONCLUSIONS: Erdafitinib demonstrated efficacy in a population of Asian patients in selected advanced solid tumors, particularly in those with advanced FGFR-altered cholangiocarcinoma. Treatment was tolerable with no new safety signals. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (NCT02699606); study registration (first posted): 04/03/2016.

Effect of Erdafitinib on the Pharmacokinetics of Midazolam and Metformin in Patients With Advanced Solid Tumors Harboring FGFR Gene Alterations.

Erdafitinib, an oral pan-FGFR inhibitor, is used in locally advanced or metastatic urothelial carcinoma for adults with FGFR3 genetic alterations and whose disease progressed following prior systemic therapy. This drug-drug interaction substudy evaluated the effect of erdafitinib on the pharmacokinetics of midazolam (cytochrome P450 3A4 substrate), and metformin (organic cation transporter 2 substrate). Twenty-five patients with advanced solid tumors harboring FGFR gene alterations received pretreatment with single doses of midazolam and metformin, followed by a daily dose of erdafitinib. Drug-drug interaction assessments were performed at erdafitinib steady state following coadministration of single doses of midazolam and metformin, respectively. Geometric mean ratios for maximum plasma concentration and area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration, and AUC from time 0 to infinity were estimated using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). The 90% confidence intervals of geometric mean ratios for maximum plasma concentration, AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity of midazolam (86.3%, 88.5%, and 82.1%), 1-OH midazolam (99.8%, 97.4%, and 101.5%), and metformin (108.7%, 119.0%, and 113.9%) were either contained or slightly outside the 80%-125% interval and not considered clinically meaningful. Adverse events were consistent with the known erdafitinib safety profile; no new safety signals emerged. Thus, repeated dosing of erdafitinib had no clinically meaningful effect on the pharmacokinetics of midazolam or metformin.

Toxicities of Novel Agents for the Treatment of Advanced Bladder Cancer.

Enfortumab vedotin and erdafitinib have specific toxicities that need careful management in order to optimise drug exposure while maintaining patients' quality of life. Patient education, meticulous monitoring, and a multidisciplinary approach are key to optimising outcomes so that patients can reap the benefits of these new treatments.

A phase 1/1b, open-label, dose-escalation study of PD-1 inhibitor, cetrelimab alone and in combination with FGFR inhibitor, erdafitinib in Japanese patients with advanced solid tumors.

Immune checkpoint inhibitors are the leading approaches in tumor immunotherapy. The aim of the study was to establish recommended phase 2 doses (RP2Ds) of intravenous cetrelimab, a checkpoint inhibitor, alone and with oral erdafitinib in Japanese patients with advanced solid tumors. This open-label, non-randomized, dose-escalation phase 1/1b study enrolled adults with advanced solid tumors who were ineligible for standard therapy. Study was conducted in two parts: phase 1a assessed cetrelimab at three dosing levels (80 mg every 2 weeks [Q2W], 240 mg Q2W, and 480 mg Q4W); phase 1b assessed cetrelimab+erdafitinib at two dosing levels (240 mg Q2W + 6 mg once daily [QD] and 240 mg Q2W + 8 mg QD). Primary endpoint was frequency and severity of dose-limiting toxicities (DLTs) of cetrelimab ± erdafitinib. In total 22 patients (phase 1a, n = 9; phase 1b, n = 13) were enrolled. Median duration of follow-up was 8.64 months in phase 1a and 2.33 months in phase 1b. In phase 1a, DLTs weren't reported while in phase 1b, 1 patient who received 240 mg cetrelimab + 6 mg erdafitinib reported Stevens-Johnson syndrome (grade 3, immune-related). Overall, 88.9% patients in phase 1a (grade ≥ 3: 44.4%) and 100.0% in phase 1b (grade ≥ 3: 53.8%) experienced ≥ 1 treatment-related adverse events (TEAEs); 33.3% in phase 1a and 38.5% in phase 1b reported serious TEAEs, of which 11.1% patients in phase 1a and 15.4% in phase 1b had TEAEs which led to treatment discontinuation. Cetrelimab alone and in combination with erdafitinib showed manageable safety in Japanese patients with advanced solid tumors. RP2Ds were determined as 480 mg cetrelimab Q4W for monotherapy, and cetrelimab 240 mg Q2W + erdafitinib 8 mg QD for combination therapy.

Evaluation of the effectiveness of cytisine for the treatment of smoking cessation: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Smoking is considered the main cause of preventable death world-wide. This study aimed to review the efficacy and safety of cytisine for smoking cessation. METHODS: This review included an exhaustive search of databases to identify randomized controlled trials (RCTs) in health centers of any level with smokers of any age or gender investigating the effects of cytisine at standard dosage versus placebo, varenicline or nicotine replacement therapy (NRT). RESULTS: We identified 12 RCTs. Eight RCTs compared cytisine with placebo at the standard dose covering 5922 patients, 2996 of whom took cytisine, delivering a risk ratio (RR) of 2.25 [95% confidence interval (CI) = 1.42-3.56; I2  = 88%; moderate-quality evidence]. The greater intensity of behavioral therapy was associated directly with the efficacy findings (moderate-quality evidence). The confirmed efficacy of cytisine was not evidenced in trials conducted in low- and middle-income countries. We estimate a number needed to treat (NNT) of 11. Two trials compared the efficacy of cytisine versus NRT, and the combination of both studies yields modest results in favor of cytisine. Three trials compared cytisine with varenicline, without a clear benefit for cytisine. Meta-analyses of all non-serious adverse events in the cytisine group versus placebo groups yielded a RR of 1.24 (95% CI = 1.11-1.39; participants = 5895; studies = 8; I2 = 0%; high-quality evidence). CONCLUSIONS: Cytisine increases the chances of successful smoking cessation by more than twofold compared with placebo and has a benign safety profile, with no evidence of serious safety concerns. Limited evidence suggests that cytisine may be more effective than nicotine replacement therapy, with modest cessation rates.

Patient interest in acupuncture for smoking cessation: a survey.

BACKGROUND/OBJECTIVE: Tobacco use remains the leading cause of preventable death in the United States. The most widely available treatment options to assist patients in smoking cessation are limited by side effects and moderate efficacy at best. Acupuncture may be an effective option for smoking cessation. The goal of this study was to establish the need for and interest in acupuncture therapy to potentially assist with smoking cessation from a patient perspective. METHODS: We conducted a cross-sectional survey study among patients aged 18 years or older whose medical record reported current tobacco use with English as their preferred language. REDCap surveys were administered to patients during office visits and included questions regarding opinions and use of all treatments available for smoking cessation (including acupuncture) as well as perceived barriers to acupuncture treatment. RESULTS: A total of 57 surveys were distributed, and 42 (74%) were completed. Most patients reported previous attempts at quitting (76%) and had tried a variety of treatments including nicotine replacement (45%), Chantix (varenicline; 23%), Wellbutrin (bupriopion; 19%), "cold turkey" (65%) and hypnosis (3%). No respondents reported having tried acupuncture for smoking cessation. CONCLUSION: When comparing treatment options, patients reported more interest in acupuncture than other treatment options with a statistically significant difference in the level of interest between acupuncture and bupropion. All barriers (cost, time and effectiveness) were equally rated on a Likert-type scale with a median of 50 on a 101-point scale.

Cytisine as a smoking cessation aid: Preliminary observations with a modified therapeutic scheme in real life.

INTRODUCTION: Cigarette smoke accounts for over 90,000 deaths each year in Italy. Tobacco dependence treatment guidelines suggest adopting an integrated pharmacological-behavioral model of intervention. Cytisine is a partial agonist of nicotinic receptors. Trials conducted to date have demonstrated its good efficacy in promoting smoking cessation. The cytisine scheme of treatment consists of 25 days of treatment. A 40-day regimen, with an escalating dose and an extended duration of the treatment, has been in use in many anti-smoking centers in Italy for several years, but to date there are no reports on the use of cytisine with this scheme. METHODS: A retrospective, real-life, observational study was conducted between January 2016 and September 2022. The 300 patients who had received at least one dose of study medication were selected. Continuous variables were compared by the Wilcoxon-Mann-Whitney test. Univariate and multivariate logistic regression models were implemented for self-reported seven-day point prevalence for abstinence at three, six and 12 months. RESULTS: The median age of the patients was 59 years, 57% were women. The median smoking exposure was 33.8 pack-years. Self-reported smoking abstinence at three, six and 12 months was 68.7%, 56.3% and 47.3% respectively. 84% completed the cytisine treatment, 31.3% reported adverse events and in 8.3% these led to dropping out of the treatment. CONCLUSION: Cytisine, administered with a novel therapeutic scheme in the real-life setting of a specialized anti-smoking center, significantly promotes smoking abstinence. However, more studies are needed to assess the tolerability and efficacy of this new regimen.

Competitive inhibition of nicotine acetylcholine receptors using microneedles of nicotine and varenicline for smoking withdrawal therapy.

Current strategies for smoking withdrawal conditions involve monotherapy of nicotine and combinational therapy of nicotine with varenicline or bupropion as per the CDC and FDA. The available dosage forms for nicotine are patches, gums, inhalers and nasal sprays, bupropion and varenicline are available in tablet form. This research work focused on developing a microneedle delivery system to deliver combination drug for overcoming the obstacles encountered by oral route of administration of varenicline such as severe side effects (mood swings, agitation, depressed behaviour, seizures, etc), and nicotine therapy challenges such as short half-life, repeated dosing, nausea, and vomiting. The nanoparticles of nicotine prepared by nanoprecipitation method showed particle size PTZ (356.6 ± 65.98), percentage entrapment efficiency (35.55 % ± 0.007), in-vitro drug release (47.89 % ± 0.7) for 72 h. Microneedles showed height (600 µm), width (350 µm), and tip diameter (10 µm). The nanoparticles encapsulated in microneedles showed in-vitro sustained delivery of nicotine (67.00 % ± 4.92) and varenicline (79.78 % ± 1.09) in 48 h. Nicotine released in a sustained manner attaches to the nicotine acetylcholine receptors (nAchR) to release dopamine for controlling the withdrawal challenges such as anxiety, irritability, cravings, disturbed sleep pattern, etc. The varenicline released from microneedles binds to the nAchR and inhibits dopamine release responsible for the euphoric effect induced by nicotine, and thus assists in curbing the nicotine withdrawal symptoms. This combination microneedle system offers prolonged treatment in a single application for smoking withdrawal conditions wherein patients are not in stage of oral dosing because of repeated dosing resulting in adverse effects like seizures, hypertension, sleep disturbances, insomnia, and nausea.

Varenicline-induced drug eruption: case and review of the literature.

Cutaneous side-effects of varenicline, a selective partial agonist of the a4B2 nicotinic acetylcholine receptor used to treat smoking addiction, are relatively rare and mainly consist of acute generalized exanthematous pustulosis. We describe an atypical clinical presentation of a varenicline-induced drug eruption, which occurred one day after drug initiation. We report this case since we believe no drug reaction to varenicline has had this clinical presentation or rapidity of onset. Clinicians should be aware of this potential adverse cutaneous reaction in patients taking varenicline for smoking cessation.

Psychopharmacology of smoking cessation medications: focus on patients with mental health disorders.

The adverse effects of smoking cessation in individuals with mental health disorders have been a point of concern, and progress in the development of treatment has been slow. The primary first-line treatments for smoking cessation are Nicotine Replacement Therapy, Bupropion, Varenicline, and behavioural support. Nortriptyline and Clonidine are second-line treatments used when the first-line treatments are not effective or are contraindicated. Smoking cessation medications have been shown to be effective in reducing nicotine cravings and withdrawal symptoms and promoting smoking cessation among patients living with mental disorders. However, these medications may have implications for patients' mental health and need to be monitored closely. The efficacy and side effects of these medications may vary depending on the patient's psychiatric condition, medication regimen, substance use, or medical comorbidities. The purpose of this review is to synthesise the pharmacokinetics, pharmacodynamics, therapeutic effects, adverse effects, and pharmacological interactions of first- and second-line smoking cessation drugs, with an emphasis on patients suffering from mental illnesses. Careful consideration of the risks and benefits of using smoking cessation medications is necessary, and treatment plans must be tailored to individual patients' needs. Monitoring symptoms and medication regimens is essential to ensure optimal treatment outcomes.

Abstinence Rate, Adverse Events and Withdrawal Symptoms after Varenicline Use and Predicting Factors of Smoking Abstinence: A Multicentre Single-State Study in Malaysia.

(1) Background: Varenicline is a widely prescribed agent in smoking cessation. However, the abstinence rate, the incidence of adverse events and withdrawal symptoms, have not been widely studied locally. This study aimed to determine the prevalence of smoking abstinence, adverse events and withdrawal symptoms associated with varenicline use, as well as possible factors contributing to successful smoking abstinence. (2) Methods: This was a retrospective, cohort study conducted in twenty-two government-operated smoking cessation clinics across the state of Perak, Malaysia. The medical records of adult smokers (age ≥ 18 years old) who were prescribed with varenicline between January 2017 and June 2018 were traced. The medical records of smokers who used pharmacotherapy other than varenicline, those who received less than four weeks of varenicline treatment, and with missing data were excluded. (3) Results: Sixty-eight out of 114 subjects (59.6%) successfully achieved smoking abstinence. Probable varenicline-induced chest pain was documented in three subjects. Altered behaviour (n = 2) and auditory hallucinations (n = 1) were also reported. Varenicline treatment duration is a significant predictive factor for successful smoking abstinence (odds ratio (OR) = 2.45; 95% confidence interval (CI) 1.74−3.45; p < 0.001), followed by age (OR = 1.25; 95% CI 1.005−1.564; p = 0.045), the presence of adverse events (OR = 0.096; 95% CI 0.014−0.644; p = 0.016) and withdrawal symptoms (OR = 0.032; 95% CI 0.016−0.835; p = 0.032). (4) Conclusion: Almost two-thirds of the subjects achieved smoking abstinence with varenicline. The duration of the treatment, as well as the patients' ages had a significant influence on successful smoking abstinence. Rare cases of cardiovascular and neuropsychiatric-related adverse events were reported, warranting continuous surveillance and adverse drug reaction reporting.

[Tobacco cessation treatment for people with schizophrenia]. / Traitement pharmacologique d'aide au sevrage tabagique chez les patients souffrant de schizophrénie.

Among patients suffering from schizophrenia, tobacco smoking prevalence is extremely high and represents a major burden in terms of morbidity and mortality. Tobacco smoking is under-diagnosed and under-treated by mental health professionals, mostly due to an overestimated risk of jeopardizing the patient's mental condition, but also due to a lack of expertise on tobacco cessation treatment. Despite the extent of this problem, pharmacological approaches haven't been studied enough. However, treatments such as varenicline, bupropion and nicotine replacement are effective and well tolerated and their prescription should be recommended for tobacco withdrawal among these patients.

La prévalence du tabagisme chez les patients souffrant de schizophrénie est extrêmement élevée et il constitue une charge majeure de morbidité et mortalité pour ces patients. Cependant, cette problématique reste sous-diagnostiquée et sous-traitée par les professionnels de santé mentale, notamment en raison d'une surestimation du risque de décompensation du trouble psychiatrique et par manque de compétences dans le domaine de la tabacologie. Malgré l'ampleur de la problématique, les approches pharmacologiques ont été peu étudiées pour cette population. Néanmoins, la prescription de traitements comme la varénicline, le bupropion et la substitution en nicotine, qui sont bien tolérés et efficaces, est recommandée pour l'aide au sevrage tabagique chez ces patients.

Erdafitinib in locally advanced/metastatic urothelial carcinoma with certain FGFR genetic alterations.

FGFR inhibitors represent a new and promising therapeutic approach to urothelial cancer (UC). Erdafitinib (Balversa©) was the first FGFR inhibitor approved for the treatment of metastatic UC, showing proper pharmacological activity and a consistent safety profile in a population with limited or no therapeutic alternatives. While results from comparative phase II and III trials are needed to assess the efficacy of erdafitinib in different clinical settings, there are still questions unsolved regarding a typical class effect of FGFR inhibitors, hyperphosporemia. In this review, the authors focus on the state-of-art administration of erdatifinib in advanced UC, pointing out the more recent evidence, pitfalls and possible future research. Insight on the management of hyperphosporemia in patients undergoing treatment with FGFR inhibitors is also provided.

Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study.

BACKGROUND: Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study. METHODS: The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0-2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597. FINDINGS: Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7-26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30-49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3-4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3-4 treatment-emergent adverse events of any cause were stomatitis (in 14 [14%] of 101 patients) and hyponatraemia (in 11 [11%]). There were no treatment-related deaths. INTERPRETATION: With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations. FUNDING: Janssen Research & Development.

Exposure-response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma.

BACKGROUND: Exposure-response analyses were conducted to explore the relationship between selected efficacy and safety endpoints and serum phosphate (PO4) concentrations, a potential biomarker of efficacy and safety, in locally advanced or metastatic urothelial carcinoma patients with FGFR alterations treated with erdafitinib. METHODS: Data from two dosing regimens of erdafitinib in a phase 2 study (NCT02365597), 6 and 8-mg/day with provision for pharmacodynamically guided titration per serum PO4 levels, were analyzed using Cox proportional hazard or logistic regression models. Efficacy endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Safety endpoints were adverse events typical for FGFR inhibitors. RESULTS: Exposure-efficacy analyses on 156 patients (6-mg = 68; 8-mg = 88) showed that patients with higher serum PO4 levels within the first 6 weeks showed better OS (hazard ratio 0.57 [95% CI 0.46-0.72] per mg/dL of PO4; p = 0.01), PFS (hazard ratio 0.80 [0.67-0.94] per mg/dL of PO4; p = 0.01), and ORR (odds ratio 1.38 [1.02-1.86] per mg/dL of PO4; p = 0.04). Exposure-safety analyses on 177 patients (6-mg = 78; 8-mg = 99) showed that the incidence of selected adverse events associated with on-target off-tumor effects significantly rose with higher PO4. CONCLUSIONS: The exploratory relationship between serum PO4 levels and efficacy/safety outcomes supported the use of pharmacodynamically guided dose titration to optimize erdafitinib's therapeutic benefit/risk ratio. CLINICAL TRIAL REGISTRATION NUMBER: NCT02365597.

Risk of neuropsychiatric adverse events associated with varenicline treatment for smoking cessation among Dutch population: A sequence symmetry analysis.

PURPOSE: Varenicline is an effective treatment for smoking cessation. While clinical trials did not confirm a causal role, case reports suggested a possible link of varenicline with neuropsychiatric adverse drug events (NPAEs). This study aims to investigate the risk of NPAEs associated with varenicline initiation among the general population in a real-world setting. METHODS: We conducted a sequence symmetry analysis (SSA) based on the University of Groningen IADB.nl prescription database. We selected incident users of both varenicline and marker drugs for NPAEs, including depression, anxiety and sleep disorder within different time-intervals. Adjusted sequence ratios (aSR) were calculated for each time-interval. RESULTS: Within 365-days' time-interval 1066 patients were incident users of both varenicline and NPAE marker drugs. In total, 505 patients were prescribed varenicline before NPAE marker drugs and 561 vice versa (crude sequence ratio [cSR] 0.90, 95% CI: 0.80-1.02). After adjustments for trends in prescriptions, overall a null association was found (aSR 1.00, 95% CI: 0.89-1.13). Regarding specific NPAEs, no increased risks were found for depression nor anxiety within any time-interval. A small transient increased risk was found for sleep disorders, particularly in earlier time-intervals 3 and 6 months (aSRs 1.52, 95% CI: 1.10-2.11 and 1.45, 95% CI: 1.15-1.83, respectively). Subgroup and sensitivity analyses showed similar findings. CONCLUSIONS: Varenicline initiation was unlikely to be associated with an increased risk of taking anti-depressants nor anti-anxiety drugs. Yet a small, but statistically significant, transient association with drugs for sleep disorders was noticed, possibly associated with withdrawal symptoms caused by smoking cessation.

Safety of Patients with Hepatitis C Virus Treated with Glecaprevir/Pibrentasvir from Clinical Trials and Real-World Cohorts.

INTRODUCTION: More than 70 million people are estimated to be infected with hepatitis C virus (HCV) globally. If left untreated, HCV infection can lead to complications such as extensive liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Evolution of treatments has resulted in highly effective and well-tolerated all-oral direct-acting antivirals. The pangenotypic regimen of glecaprevir/pibrentasvir is approved for treating HCV for patients without cirrhosis or with compensated cirrhosis (CC). Guidelines have evolved to simplify treatment to enable non-specialists to manage and treat HCV-infected patients. Simultaneously, such treatment algorithms provide guidance on the pretreatment identification of small subsets of patients who may require specialist treatment and long-term follow-up for advanced liver disease, including those at risk of developing HCC. This study describes the safety profile of glecaprevir/pibrentasvir in patients identified using previously described noninvasive laboratory measures who may be eligible for treatment by non-liver specialists. METHODS: This post hoc analysis of glecaprevir/pibrentasvir in patients, identified by noninvasive laboratory measures, intended to exclude patients with advanced liver disease and severe renal impairment, who can be managed within non-liver specialist settings. Patients were included from clinical trials and real-world studies of glecaprevir/pibrentasvir for HCV treatment. Baseline demographics, clinical characteristics, and safety assessments, including adverse events and laboratory abnormalities, were summarized. RESULTS: Data across these large-scale studies confirm that glecaprevir/pibrentasvir is well tolerated across different patient populations, with fewer than 0.1% of patients experiencing a serious adverse event related to treatment drugs, and few patients developing HCC during or after treatment. CONCLUSION: The safety profile of glecaprevir/pibrentasvir enhances the confidence of non-liver specialists to treat the majority of HCV-infected patients, and provides an opportunity to expand the treater pool, potentially increasing diagnosis and treatment rates for HCV, contributing to elimination of HCV.