A novel quinoline with airway relaxant effects and anti-inflammatory properties.

BACKGROUND: In chronic pulmonary diseases characterized by inflammation and airway obstruction, such as asthma and COPD, there are unmet needs for improved treatment. Quinolines is a group of small heterocyclic compounds that have a broad range of pharmacological properties. Here, we investigated the airway relaxant and anti-inflammatory properties of a novel quinoline (RCD405). METHODS: The airway relaxant effect of RCD405 was examined in isolated airways from humans, dogs, rats and mice. Murine models of ovalbumin (OVA)-induced allergic asthma and LPS-induced airway inflammation were used to study the effects in vivo. RCD405 (10 mg/kg) or, for comparisons in selected studies, budesonide (3 mg/kg), were administered intratracheally 1 h prior to each challenge. Airway responsiveness was determined using methacholine provocation. Immune cell recruitment to bronchi was measured using flow cytometry and histological analyses were applied to investigate cell influx and goblet cell hyperplasia of the airways. Furthermore, production of cytokines and chemokines was measured using a multiplex immunoassay. The expression levels of asthma-related genes in murine lung tissue were determined by PCR. The involvement of NF-κB and metabolic activity was measured in the human monocytic cell line THP-1. RESULTS: RCD405 demonstrated a relaxant effect on carbachol precontracted airways in all four species investigated (potency ranking: human = rat > dog = mouse). The OVA-specific IgE and airway hyperresponsiveness (AHR) were significantly reduced by intratracheal treatment with RCD405, while no significant changes were observed for budesonide. In addition, administration of RCD405 to mice significantly decreased the expression of proinflammatory cytokines and chemokines as well as recruitment of immune cells to the lungs in both OVA- and LPS-induced airway inflammation, with a similar effect as for budesonide (in the OVA-model). However, the effect on gene expression of Il-4, IL-5 and Il-13 was more pronounced for RCD405 as compared to budesonide. Finally, in vitro, RCD405 reduced the LPS-induced NF-κB activation and by itself reduced cellular metabolism. CONCLUSIONS: RCD405 has airway relaxant effects, and it reduces AHR as well as airway inflammation in the models used, suggesting that it could be a clinically relevant compound to treat inflammatory airway diseases. Possible targets of this compound are complexes of mitochondrial oxidative phosphorylation, resulting in decreased metabolic activity of targeted cells as well as through pathways associated to NF-κB. However, further studies are needed to elucidate the mode of action.

A single-institution retrospective exploratory analysis on the effectiveness and safety of lenvatinib plus pembrolizumab for advanced endometrial cancer: insights from ProMisE molecular classification system.

BACKGROUND: The Proactive Molecular Risk Classifier for Endometrial Cancer has identified four risk groups for the prognosis of endometrial cancer. Lenvatinib plus pembrolizumab was recently approved as a second-line treatment for unresectable endometrial cancer, but reports in clinical practice are lacking. The relationship between the efficacy of lenvatinib/pembrolizumab and Proactive Molecular Risk Classifier for Endometrial Cancer classification is unclear. METHODS: This single-centre retrospective study included patients who underwent lenvatinib/pembrolizumab therapy at Iwate Medical University Hospital between January 2022 and March 2023. Formalin-fixed paraffin-embedded specimens obtained from patients before treatment were collected and classified into the mismatch repair-deficient, p53 abnormal and no specific molecular profile subtypes using immunohistochemistry. The response rate, progression-free survival and adverse events were evaluated using electronic medical records. The study was approved by the hospital's ethics committee (approval number: MH2022-093). RESULTS: This study enrolled 20 patients, who underwent a median follow-up of 17.8 months (95% confidence interval: 16.6-18.9). The best overall response rate was 60.0% (36.1-80.9), and the median progression-free survival was 11.6 months (2.9-20.3). The median progression-free survival in the p53 abnormal group (n = 9) was 3.4 months (3.0-3.8); however, progression-free survival did not reach the median (P < 0.001) in the mismatch repair-deficient/no specific molecular profile group (n = 11). Symptomatic immune-related adverse events (except hypothyroidism) occurred in 4/20 (25.0%) patients, and partial responses were observed in all cases. No treatment-related deaths occurred. CONCLUSION: The p53abn group in the Proactive Molecular Risk Classifier for Endometrial Cancer classification has a poor prognosis even after treatment with lenvatinib/pembrolizumab.

Lenvatinib, sintilimab plus transarterial chemoembolization for advanced stage hepatocellular carcinoma: A phase II study.

BACKGROUND & AIMS: Our retrospective study has suggested encouraging outcomes of lenvatinib combined with PD-1 inhibitor and transarterial chemoembolization (TACE) on advanced hepatocellular carcinoma (HCC). This phase II trial was conducted to prospectively investigate the efficacy and safety of lenvatinib, sintilimab (a PD-1 inhibitor) plus TACE (Len-Sin-TACE) in patients with advanced stage HCC. METHODS: This was a single-arm phase II trial. Patients with BCLC stage C HCC were recruited. They received lenvatinib (bodyweight ≥60 kg, 12 mg; bodyweight <60 kg, 8 mg) orally once daily, sintilimab (200 mg) intravenously once every 3 weeks, and on demand TACE. The primary endpoint was progression-free survival (PFS) per mRECIST. RESULTS: Thirty patients were enrolled. The primary endpoint was met with a median PFS of 8.0 (95% confidence interval [CI]: 6.1-9.8) months per mRECIST, which was the same as that per RECIST 1.1. The objective response rate was 60.0% per mRECIST and 30.0% per RECIST 1.1. The disease control rate was 86.7% per mRECIST/RECIST 1.1. The median duration of response was 7.4 (95% CI: 6.6-8.2) months per mRECIST (n = 18) and 4.3 (95% CI: 4.0-4.6) months per RECIST 1.1 (n = 9). The median overall survival was 18.4 (95% CI: 14.5-22.3) months. Treatment-related adverse events (TRAEs) occurred in 28 patients (93.3%) and grade 3 TRAEs were observed in 12 patients (40.0%). There were no grade 4/5 TRAEs. CONCLUSIONS: Len-Sin-TACE showed promising antitumour activities with a manageable safety profile in patients with advanced stage HCC. The preliminary results need to be further evaluated with phase III randomized trials.

Targeting HER2-mutant metastatic cervical cancer with neratinib: Final results from the phase 2 SUMMIT basket trial.

OBJECTIVE: HER2 mutations are associated with poor prognosis and are detected in 3-6% of cervical cancers. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, had activity in several HER2-mutant cancer types in the phase 2 SUMMIT basket study. We present updated and final results from the cervical cancer cohort of SUMMIT. METHODS: Eligible patients had HER2-mutant, metastatic or recurrent cervical cancer progressing after platinum-based treatment for advanced/recurrent disease. Patients received neratinib 240 mg/day; loperamide was mandatory during cycle 1. Confirmed objective response rate (ORR) was the primary endpoint. Duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and safety were secondary endpoints. RESULTS: Twenty-two patients were enrolled; 18 (81.8%) had endocervical adenocarcinoma; median two prior systemic chemotherapy regimens (range 1-4). The most common HER2 variant was S310F/Y mutation (n = 13; 59.1%). Four patients had confirmed partial responses (ORR 18.2%; 95% CI 5.2-40.3); 6 had stable disease ≥16 weeks (CBR 45.5%; 95% CI 24.4-67.8). Median DoR was 7.6 months (95% CI 5.6-12.3). Median PFS was 5.1 months (95% CI 1.7-7.2). All-grade diarrhea (90.9%), nausea (54.5%), and constipation (54.5%) were the most common adverse events. Five patients (22.7%) reported grade 3 diarrhea. There were no grade 4 adverse events, no diarrhea-related treatment discontinuations, and two grade 5 adverse events, unrelated to neratinib: dyspnea (n = 1) and embolism (n = 1). CONCLUSIONS: Neratinib resulted in durable responses and disease control in patients with HER2-mutant metastatic/recurrent cervical cancer in SUMMIT. These findings support next-generation sequencing and tailored therapy for select patients with advanced cervical cancer. All responses occurred in patients with endocervical adenocarcinoma. Further assessment of neratinib in this setting is warranted. TRIAL REGISTRATION NUMBER: NCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).

Bosutinib: Pediatric First Approval.

Bosutinib (BOSULIF®), an orally administered BCR-ABL tyrosine kinase inhibitor (TKI) developed by Pfizer Inc., is well established in the EU and the USA as a treatment for adults with newly diagnosed (ND) chronic phase (CP) Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), and for CP, accelerated phase and blast phase Ph+ CML that is resistant or intolerant (R/I) to prior therapy. In September 2023, based on clinical data from patients aged ≥ 1 to < 18 years, bosutinib was approved in the USA for the treatment of pediatric patients aged ≥ 1 year with CP Ph+ CML that is ND or R/I to prior therapy. This article summarizes the milestones in the development of bosutinib leading to this first pediatric approval.

Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921.

PURPOSE: Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. PATIENTS AND METHODS: In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. RESULTS: Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 µg h/mL, 2.52 µg h/mL, and 2.66 µg h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. CONCLUSION: Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience.

Impact of age and comorbidities on the efficacy and tolerability of bosutinib in previously treated patients with chronic myeloid leukemia: results from the phase 4 BYOND study.

In the phase 4 BYOND trial, patients with pretreated chronic myeloid leukemia (CML) received bosutinib (starting dose: 500 mg/day). Efficacy and safety after ≥3 years of follow-up in 156 patients with Philadelphia chromosome-positive chronic phase CML by age and Charlson Comorbidity Index scores (without the age component; mCCI) is reported. Cumulative major molecular response rates at any time on treatment were 73.6%, 64.5%, and 74.1% in patients <65, 65-74, and ≥75 years of age, and 77.9%, 63.0%, and 59.3% in patients with mCCI scores 2, 3, and ≥4, respectively. Patients <65, 65-74, and ≥75 years of age experienced grade 3/4 treatment-emergent adverse events (TEAEs) at rates of 74.7%, 78.8%, and 96.4% and permanent discontinuations due to AEs at rates of 22.1%, 39.4%, and 46.4%, respectively. In patients with mCCI 2, 3, and ≥4, respective rates of grade 3/4 TEAEs were 77.8%, 77.8%, and 86.7%, and permanent discontinuations due to AEs were 25.3%, 33.3%, and 43.3%. In conclusion, a substantial proportion of patients maintained/achieved cytogenetic and molecular responses across age groups and mCCI scores. Older patients (≥75 years) and those with high comorbidity burden (mCCI ≥4) may require more careful monitoring due to the increased risk of TEAEs. Clinicaltrials.gov: NCT02228382.

Phase Ib study of anlotinib in combination with anti-PD-L1 antibody (TQB2450) in patients with advanced acral melanoma.

BACKGROUND: Acral melanoma, the most common subtype of melanoma in Asians, is often diagnosed at an advanced stage and responds poorly to current programmed cell death protein 1 (PD-1) inhibitors. OBJECTIVES: To evaluate the safety and efficacy of TQB2450 and anlotinib in patients with advanced acral melanoma in a phase Ib study (NCT03991975). METHODS: Patients received TQB2450 (1200 mg every 3 weeks) and anlotinib (10 mg or 12 mg once daily, 2-week on/1-week off) in the dose-escalation and dose-expansion phases. The primary endpoints were dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and objective response rate (ORR). RESULTS: Nineteen patients were enrolled between June 2019 and June 2022. The majority of patients (16 of 19 patients) received anlotinib and TQB2450 as first-line treatment. No DLTs were observed, and MTD was not reached. Eighteen (94.7%) out of 19 patients experienced treatment-related adverse events (TRAEs), but most were grade 1 or 2. Grade 3 or greater TRAEs occurred in seven patients (36.8%). The ORR was 26.3% (two complete responses and three partial responses). The disease control rate was 73.7%. The median duration of response was 30.3 months [95% confidence interval (CI): 5.8-NA]. The median progression-free survival (PFS) was 5.5 months (95% CI: 2.8-NA), and median overall survival was 20.3 months (95% CI: 14.8-NA). Whole-exome sequencing suggested that acquired drug resistance might be attributed to activation of the MAPK signalling pathway and transformation to an immunosuppressive tumour environment. CONCLUSIONS: TQB2450 combined with anlotinib showed favourable tolerance and promising anti-tumour activity with a prolonged PFS compared with anti-PD1 monotherapy in patients with advanced acral melanoma.

[Optimizing the use of bosutinib in patients with chronic-phase chronic myeloid leukemia: Recommendations of a panel of experts from the Fi-LMC (French CML working group)]. / Optimisation du bosutinib dans la leucémie myéloïde chronique : recommandations du Fi-LMC (France Intergroupe des leucémies myéloïdes chroniques).

The treatment of chronic myeloid leukemia relies on orally available tyrosine kinase inhibitors targeting the BCR::ABL1 oncoprotein. Bosutinib is a second generation adenosine triphosphate-competitive inhibitor approved for use in frontline adult chronic phase-chronic myeloid leukemia and all phases-chronic myeloid leukemia in the second line setting or beyond. Its efficacy was demonstrated in several pivotal clinical trials at 400mg once daily in the first line context and at 500mg once daily beyond first line. Bosutinib-related adverse events frequently occur early after treatment initiation and include gastro-intestinal symptoms and cytolytic hepatitis. These drug-related adverse events must be properly managed in order to preserve safety, efficacy and treatment acceptability. The French chronic myeloid leukemia study group gathered a panel of experts in hematology, pharmacology and hepatology in order to elaborate practical recommendations on the management of bosutinib treatment. These recommendations aim at optimizing the short and long-term tolerance and benefit/risk balance of bosutinib, mainly focusing at gastro-intestinal and liver toxicities.

An efficacy and safety evaluation of montelukast + fluticasone propionate vs. fluticasone propionate in the treatment of cough variant asthma in children: a meta-analysis.

PURPOSE: This study aimed to evaluate the efficacy and safety of montelukast (Mon) + fluticasone propionate (Flu) versus Flu in the treatment of cough variant asthma (CVA) in children. METHODS: Eligible documents were selected from various databases. Weighted mean difference (WMD) and 95% confidence interval (CI) were used to evaluate continuous variables, and categorical variables were evaluated using risk ratio (RR) and 95% CI. Heterogeneity analysis was performed using Cochran's Q test and I2 statistics, followed by sensitivity analysis and publication bias evaluation. RESULTS: Nine studies were included, and Flu + Mon was found to significantly improve the total effective rate and reduce cough recurrence compared to Flu. The cough remission and disappearance times in the Mon + Flu group were significantly lower than those in the Flu group. FEV1% recovery in the Mon + Flu group was significantly better than that in the Flu group. CONCLUSION: Mon + Flu is effective and safe for the treatment of CVA in children.

Factors associated with lenvatinib adherence in thyroid cancer and hepatocellular carcinoma.

BACKGROUND: Lenvatinib is an oral anticancer medication used to treat radioiodine-refractory thyroid cancer and unresectable hepatocellular carcinoma. The purpose of this study is to evaluate lenvatinib adherence by patients and to identify factors associated with decreased lenvatinib adherence. METHODS: Among 153 patients who started treatment with lenvatinib for unresectable thyroid cancer or unresectable hepatocellular carcinoma between May 1, 2015 and August 31 2021 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 102 were eligible for this study (55 thyroid cancer, 47 hepatocellular carcinoma). The lenvatinib adherence rate in a treatment cycle was defined as the number of times a patient took lenvatinib in a 28-day cycle divided by the prescribed 28 doses. The rate was determined by pill counting and self-reporting at the pharmaceutical outpatient clinic. Reasons for non-adherence were established by interview and analyzed. RESULTS: The median adherence rate of lenvatinib in the first cycle was 90.1% (n = 55) in thyroid cancer and 94.9% (n = 47) in hepatocellular carcinoma. In thyroid cancer, there were 255 incidents of lenvatinib non-adherence. Non-adherence was mainly associated with bleeding events (18.6%), followed by hand-foot skin reactions (10.6%). In hepatocellular carcinoma, there were 97 incidents of non-adherence. Hypertension accounted for 20.6%, followed by hoarseness (18.6%) and diarrhea (17.5%). CONCLUSION: The adherence rate for lenvatinib in Japanese patients with thyroid and hepatocellular carcinoma in real-world clinical practice was more than 90% in this study. Hypertension was a major reason for non-adherence, followed by hand-foot skin reactions and diarrhea.

Research Progress on Mechanism and Management of Adverse Drug Reactions of Anlotinib.

Anti-angiogenesis therapy plays a vital role in the treatment of tumors, with anlotinib as its representative targeted drug. Anlotinib is a novel oral tyrosine kinase inhibitor (TKI) with inhibitory effects on tumor growth tumor angiogenesis. In Phase III clinical trials, anlotinib demonstrated better overall survival and progression-free survival than placebo in patients with advanced non-small cell lung cancer (NSCLC), and was approved for the first time as a third-line treatment for refractory advanced NSCLC. Going far beyond that, anlotinib has shown encouraging results in a variety of malignancies, including medullary thyroid carcinoma, renal cell carcinoma, gastric cancer and esophageal squamous cell carcinoma. Nevertheless, anlotinib has been subject to some controversy in terms of adverse events due to its widespread use. In this review, the mechanism of action, pharmacokinetic characteristics, adverse reactions in clinical use and management of anlotinib were summarized.