Efficacy Of Kinase Inhibitors Research Articles

Janus kinase inhibition (JAKi) therapy in refractory anti-synthetase syndrome: A retrospective cohort study

ObjectivesTo evaluate the efficacy and safety of Janus kinase inhibitors (JAKi) in the treatment of refractory anti-synthetase syndrome (ASS) in real-world clinical settings. MethodsThe medical records of all refractory ASS patients who were treated with JAKi from October 2020 to June 2023 were retrospectively reviewed. ResultsTwenty patients were included, and all (100 %) patients had interstitial lung disease (ILD). After treatment with JAKi, 14 (70 %) of the refractory ASS patients showed significant improvement in clinical manifestations, including arthritis (56.3 % vs. 6.3 %, p = 0.002), rash (77.8 % vs. 27.8 %, p = 0.012), shortness of breath (55.6 % vs. 16.7 %, p = 0.039), cough (61.1 % vs. 11.1 %, p = 0.012). Improvement was noted for myalgia (50 % vs. 11.1 %, p = 0.016) and muscular weakness (61.1 % vs. 11.1 %, p = 0.012), while creatine kinase (CK) levels, which were abnormally elevated in five patients prior treatment, were significantly lowered (1096 ± 1042.98 IU/L vs. 199.2 ± 144.66 IU/L, p = 0.043). A decrease in levels of inflammatory markers, including erythrocyte sedimentation rate (ESR) (p = 0.001) and C-reactive protein (CRP) (p = 0.023) was observed in the patients. In ASS-ILD, the CT score reduced (188.75 ± 69.67 vs. 156.35 ± 74.62, p = 0.001). Furthermore, the glucocorticoid dose significantly reduced (21.42 ± 13.26 mg vs. 11.32 ± 8.59 mg; p = 0.001). ConclusionsJAKi were effective in most refractory ASS patients as evidenced by improved skin rash, myositis, and ILD. However, larger prospective controlled studies are required to evaluate its efficacy.

Neoadjuvant sintilimab plus chemotherapy in EGFR-mutant NSCLC: Phase 2 trial interim results (NEOTIDE/CTONG2104).

The clinical efficacy of neoadjuvant immunotherapy plus chemotherapy remains elusive in localized epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Here, we report interim results of a Simon's two-stage design, phase 2 trial using neoadjuvant sintilimab with carboplatin and nab-paclitaxel in resectable EGFR-mutant NSCLC. All 18 patients undergo radical surgery, with one patient experiencing surgery delay. Fourteen patients exhibit confirmed radiological response, with 44% achieving major pathological response (MPR) and no pathological complete response (pCR). Similar genomic alterations are observed before and after treatment without influencing the efficacy of subsequent EGFR-tyrosine kinase inhibitors (TKIs) invitro. Infiltration and Tcell receptor (TCR) clonal expansion of CCR8+ regulatory T (Treg)hi/CXCL13+ exhausted T (Tex)lo cells define a subtype of EGFR-mutant NSCLC highly resistant to immunotherapy, with the phenotype potentially serving as a promising signature to predict immunotherapy efficacy. Informed circulating tumor DNA (ctDNA) detection in EGFR-mutant NSCLC could help identify patients nonresponsive to neoadjuvant immunochemotherapy. These findings provide supportive data for the utilization of neoadjuvant immunochemotherapy and insight into immune resistance in EGFR-mutant NSCLC.

Predictive factors and treatment outcomes associated with difficult-to-treat rheumatoid arthritis conditions: the ANSWER cohort study.

To investigate the predictive factors for difficult-to-treat rheumatoid arthritis (D2T RA) and assess the efficacy of biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKi). Retrospective analysis was conducted on data from the ANSWER cohort comprising 3,623 RA patients treated with bDMARDs or JAKi in Japan. Multivariate Cox proportional hazards modelling was used to analyse the hazard ratios (HRs) for treatment retention. Of these, 450 (12.4%) met the first two criteria of EULAR D2T RA definition (defined as D2T RA in this study). Factors contributing to D2T RA included age over 75 (compared to those under 65, HR = 0.46, 95% CI: 0.31 to 0.69), higher rheumatoid factor (RF) titres (HR = 1.005, 95% CI: 1.00 to 1.01), higher clinical disease activity index (HR = 1.02, 95% CI: 1.01 to 1.03), lower methotrexate dosage (HR = 0.97, 95% CI: 0.95 to 0.99), and comorbidities like hypertension (HR = 1.53, 95% CI: 1.2 to 1.95) and diabetes (HR = 1.37, 95% CI: 1.09 to 1.73). Anti-interleukin 6 receptor antibodies (aIL-6R, HR = 0.53, 95% CI: 0.37 to 0.75) and JAKi (HR = 0.64, 95% CI: 0.46 to 0.90) were associated with fewer discontinuations due to ineffectiveness compared to tumour necrosis factor inhibitors. Oral glucocorticoids usage (HR = 1.65, 95% CI: 1.11 to 2.47) was linked to increased discontinuation due to toxic adverse events. Younger onset, higher RF titres, and comorbidities predicted D2T RA development. For managing D2T RA, aIL-6R and JAKi exhibited superior drug retention.

Abstract PO4-16-07: Cyclin-dependent kinase inhibitor plus endocrine therapy in HR+/HER2- invasive breast cancer with bone marrow and pancytopenia: a new standard of care? Collaborative multicentric Argentinean real-world study (SUMA-02)

Abstract Introduction Bone marrow involvement is a rare occurrence in patients with advanced breast cancer (ABC), and the prognosis in this context is generally poor. Prompt initiation of treatment to improve the patient's hematological status is crucial. However, this condition is often excluded from clinical trials, making it challenging to determine the effectiveness of new drugs. Limited data and evidence are available to guide treatment decisions, but guidelines recommend starting with chemotherapy for the need of a rapid response. This study aims to analyze the real-world efficacy of cyclin-dependent kinase inhibitors (CDKis) in HR+/HER2- ABC with bone marrow infiltration. Methods Retrospective multicenter cohort study including HR+/HER2- ABC patients from public and private facilities in Argentina. Patients with confirmed bone marrow involvement (blood smear or histological biopsy analysis) and treated with CDKi were eligible. Bone marrow response was defined as an increase in at least one of the previously abnormal blood series to Hb >10.0, platelets >100,000, and leukocytes >4,000. Results A total of 22 patients from different medical centers in Argentina were included. The median age was 55.5 (IQR 46.25-65). Histological confirmation of bone marrow involvement was reported in 81.8% (18) of patients. Among them, 54.5% (12) had initial diagnosis at an early stage, and 13.6% (3) experienced relapse during or within 1 year of completing adjuvant hormonal treatment. Bone-only metastasis was observed in 50% (11) of patients, while the remaining 50% (11) had both visceral and bone disease. Anemia, thrombocytopenia, and leukopenia were present in 95.5% (21), 90.9% (20), and 40.9% (9) of patients, respectively. In 68.2% (15) of patients, bone marrow involvement was detected at the first-line treatment setting. The selected CDKis were palbociclib in 40.9% (9) of patients, ribociclib in 31.8% (7), and abemaciclib in 27.3% (6). The bone marrow response rate was 68.2% (15), with a median of 2 cycles (range 1-5) required for a response. Dose reduction was necessary in 31.8% (7) of patients. Discussion Managing patients with uncommon sites of metastasis, such as bone marrow, poses significant challenges for oncologists. Bone marrow infiltration leads to hematopoietic alterations that adversely affect the quality of life, resulting in increased risk of infections, bleeding, and other comorbidities with fatal consequences. While chemotherapy is the standard treatment in such cases, our study demonstrates that CDKis are a safe and effective option for managing these complications. Conclusion The findings of this study support the evaluation of CDKis as a standard treatment for HR+/HER2- ABC patients. Our results are in line with the recently published phase 2 clinical trial RIGHT CHOICE, which showed a prolonged progression free survival in patients treated with ribociclib and HT with HR+/HE2- ABC and visceral crisis. Citation Format: Alexis Ostinelli, Pablo Mandó, Carolina Almada, Melina Winocur, M. Agustina Ipiña, Viviana Paez, Silvia Aparicio, Sergio Rivero, Federico Waisberg, Laura Sabina Lapuchesky, Cristian Micheri, M. Belen Montenegro, Cristina Rusz Maidana, Carolina Reinhardt, Evelina Rovera, Gonzalo Gómez Abuin, Santiago Bella, Florencia Perazzo, Adrian Nervo, Andrea Aguilar, Matías Chacón, Victoria Costanzo, Valeria Caceres, Jorge Nadal. Cyclin-dependent kinase inhibitor plus endocrine therapy in HR+/HER2- invasive breast cancer with bone marrow and pancytopenia: a new standard of care? Collaborative multicentric Argentinean real-world study (SUMA-02) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-16-07.

Potential Efficacy of Janus Kinase Inhibitors in the Treatment of a Patient With Coexisting Peripheral and Axial Spondyloarthritis and Ulcerative Colitis.

Tumor necrosis factor inhibitors are effective and recommended in treating patients with coexisting spondyloarthritis (SpA) and ulcerative colitis (UC); however, the evidence of their superiority over other drugs is insufficient.1 Although Janus kinase inhibitors (JAKi) have shown effectiveness in treating UC and psoriatic arthritis, there are no reports of treating coexisting SpA and UC with JAKi monotherapy.

Beyond Clinical Trials: Understanding Neurotrophic Tropomyosin Receptor Kinase Inhibitor Challenges and Efficacy in Real-World Pediatric Oncology.

Our study aimed to explore real-world treatment scenarios for children and adolescents with neurotrophic tropomyosin receptor kinase (NTRK)-fused tumors, emphasizing access, responses, side effects, and outcomes. Pooled clinical data from 17 pediatric cases (11 soft-tissue sarcomas, five brain tumors, and one neuroblastoma) treated with larotrectinib and radiologic images for 14 patients were centrally reviewed. Testing for gene fusions was prompted by poor response to treatment, tumor progression, or aggressiveness. Six different NTRK fusion subtypes were detected, and various payment sources for testing and medication were reported. Radiologic review revealed objective tumor responses (OR) in 11 of 14 patients: Complete responses: two; partial responses: nine; and stable disease: three cases. Grades 1 or 2 Common Terminology Criteria for Adverse Events adverse effects were reported in five patients. Regarding the entire cohort's clinical information, 15 of 17 patients remain alive (median observation time: 25 months): four with no evidence of disease and 11 alive with disease (10 without progression). One patient developed resistance to the NTRK inhibitor and died from disease progression while another patient died due to an unrelated cause. This real-world study confirms favorable agnostic tumor OR rates to larotrectinib in children with NTRK-fused tumors. Better coordination to facilitate access to medication remains a challenge, particularly in middle-income countries like Brazil.

Advances of Molecular Targeted Therapy in EGFR-mutated Squamous Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is a prevalent tumour type in our country, with lung squamous carcinoma being a commonly observed NSCLC subtype besides lung adenocarcinoma. Epidermal growth factor receptor (EGFR) is a significant driver gene in lung cancer, and EGFR mutation frequency is considerably lower in lung squamous carcinoma in comparison to lung adenocarcinoma. Although targeted therapy against EGFR has demonstrated significant advancements in lung adenocarcinoma, while progress in lung squamous carcinoma has been relatively sluggish. This paper reviews recent studies on molecular targeted therapy for EGFR-mutated lung squamous carcinoma and summarises the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in treating squamous carcinoma of the lung, in order to provide a reference for treating patients with EGFR-mutated squamous carcinoma of the lung. .

Efficacy of third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in advanced NSCLC with different T790M statuses tested via digital droplet polymerase chain reaction ddPCR and next-generation sequencing

ABSTRACT Objectives We hypothesize that digital droplet polymerase chain reaction (ddPCR) would optimize the treatment strategies in epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) relapsed patients. In this study, we compared the efficacy of third-generation TKIs with various T790M statuses via ddPCR and next-generation sequencing (NGS). Methods NGS was performed on blood samples of patients progressed from previous EGFR-TKIs for resistance mechanism. T790M-negative patients received further liquid biopsy using ddPCR for T790M detection. Results A cohort of 40 patients were enrolled, with 30.0% (12/40) T790M-positive via NGS (Group A). In another 28 T790M-negative patients by NGS, 11 (39.3%) were T790M-positive (Group B) and 17 (60.7%) were T790M-negative (Group C) via ddPCR. A relatively longer progression-free survival (PFS) was observed in group A (NR) and group B (10.0 months, 95% CI 7.040–12.889) than in group C (7.0 months, 95% CI 0.000–15.219), with no significant difference across all three groups (p = 0.196), or between group B and C (p = 0.412). EGFR-sensitive mutation correlated with inferior PFS (p = 0.041) and ORR (p = 0.326), and a significantly lower DCR (p = 0.033) in T790M-negative patients via NGS (n = 28). Conclusion This study indicates that ddPCR may contribute as a supplement to NGS in liquid biopsies for T790M detection in EGFR-TKIs relapsed patients and help to optimize the treatment strategies, especially for those without coexistence of EGFR-sensitive mutation. Trial registration www.clinicaltrials.gov identifier is NCT05458726.

Safety and effectiveness of Janus kinase inhibitors in the management of inflammatory bowel disease following liver transplantation.

The management of inflammatory bowel disease (IBD) patients with concurrent liver transplantation is challenging, and data regarding the safety and efficacy of Janus kinase (JAK) inhibitors with anti-rejection medications are required. We report the experience of all liver transplant recipients receiving tofacitinib and/or upadacitinib for IBD across three states in Australia. All liver transplant recipients from the Australian states of Victoria, New South Wales and Tasmania who required tofacitinib or upadacitinib for the treatment of IBD were identified using prospectively maintained liver transplant databases. Patients were followed up until medication cessation or last follow up. Clinical safety and efficacy data were collected. Eight patients (median age 30 years) were included, seven of whom received first-line JAK inhibition with tofacitinib. All patients had failed one or more biologic therapies prior to commencing JAK inhibition, including six patients who had failed two or more agents. JAK inhibition was continued for a median of 17 months, with 143 patient-months of combined follow-up. The anti-rejection medication tacrolimus was prescribed in all patients. Overall, seven (88%) patients achieved clinical remission, including all three patients who were switched from tofacitinib to upadacitinib. One patient required colectomy after 1 month of treatment. There were no other cases of serious infection, venous thromboembolism or major adverse cardiovascular events during follow-up. As the largest case series to-date, these data indicate that combining JAK inhibition with transplant anti-rejection medication may be a safe and clinically effective method of treating IBD in patients with prior biologic failure.

Efficacy and Safety of Rho Kinase Inhibitors vs. Beta-Blockers in Primary Open-Angle Glaucoma: A Systematic Review with Meta-Analysis.

Background: In order to support the positioning of Rho kinase inhibitors (Rhokis) in the European market for the treatment of glaucoma, scientific evidence comparing the efficacy and safety of Rhokis and beta-blockers (β-βs) in the treatment of open-angle glaucoma after 3 months was assembled through a systematic review and meta-analysis (meta-A) of randomized controlled trials (RCTs). Methods: Relevant articles were searched for on PubMed, EMBASE, and the Cochrane Library. Of the 251 articles found, three met all eligibility criteria. These three articles were assessed for risk of bias. Data were extracted and a random effects meta-A was performed. The studies' methods were homogeneous but there was great heterogeneity within the data (I2 = 92-93%; p < 0.001). Results: All studies had low risk of bias. The meta-A showed statistically better efficacy of β-βs, resulting in an intraocular pressure (IOP) reduction mean difference of 1.73 (1.19-2.27) at 8 a.m., 0.66 (0.19-1.15) at 10 a.m. and 0.49 mmHg (0.001-0.98) at 4 p.m., compared to Rhokis. This difference is not clinically significant as intra-operator variability of IOP measurements varies from ±2 to ±3 mmHg The adverse effects of Rhokis were essentially topical, whereas β-βs mainly caused systemic side effects. Conclusions: This Meta-A showed that Rhokis are clinically non-inferior to beta-blockers in reducing IOP. Rhokis have a better safety profile.

An epidermal growth factor receptor compound mutation of L858R with S768I in advanced non-small-cell lung cancer: a case report

BackgroundIn the current treatment landscape for non-small cell lung cancers, epidermal growth factor receptor-tyrosine kinase inhibitors have emerged as a well-established treatment option for patients with advanced or metastatic disease. This is particularly true for those with commonly occurring epidermal growth factor receptor mutations. However, the therapeutic efficacy of these agents for so-called rare epidermal growth factor receptor mutations, and in particular those characterized by a high degree of complexity, such as double mutations, remains a subject of clinical uncertainty.Case presentationIn this context, we present the case of a 64-year-old man of Moroccan descent, a lifelong non-smoker, diagnosed with metastatic non-small cell lung cancer characterized by a complex epidermal growth factor receptor mutation encompassing L858R and S768I. The patient subsequently underwent afatinib-based treatment, showing notable clinical results. These included a remarkable overall survival of 51 months, with a median progression-free survival of more than 39 months.ConclusionsThis case report is a compelling testimony to the evolving therapeutic landscape of non-small cell lung cancers, providing valuable insight into the potential therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors in the realm of rare and complex epidermal growth factor receptor mutations.

Chronic myeloid leukemia with e6a2 fusion gene: a case report and literature review

Chronic myeloid leukemia (CML) with e6a2 transcript type is very rare in clinic,which is usually related to disease aggressiveness. Its clinical characteristics and relationship with tyrosine kinase inhibitor efficacy are still unclear. In this paper, the clinical characteristics and related laboratory tests of a patient with e6a2 fusion gene positive CML characterized by multiple osteolytic bone destruction throughout the body and eosinophil infiltration in gastrointestinal tract, lymph nodes and other organs were retrospectively analyzed, and the relevant literature was reviewed. The patient was Ph chromosome positive with chromosome +8, and the common BCR::ABL1 transcript of CML was negative, but e6a2 transcript was positive detected by RT-PCR. The patient was treated with dasatinib 100 mg/d. Three months later, the patients achieved CHR, CCyR and MR4.0. However, the e6a2 transcript is very rare in clinical practice, and more cases of e6a2 transcript need to be studied to clarify its clinical characteristics and improve the treatment effect of these rare cases.

The highly selective and oral phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib induces apoptosis in mesothelioma cells and increases immune effector cell composition

Targeting aberrantly expressed kinases in malignant pleural mesothelioma (MPM) is a promising therapeutic strategy. We here investigated the effect of the novel and highly selective Phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib (IOA-244) on MPM cells and on the immune cells in MPM microenvironment.To this aim, we analyzed the expression of PI3K-δ by immunohistochemistry in specimens from primary MPM, cell viability and death in three different MPM cell lines treated with roginolisib alone and in combination with ipatasertib (AKT inhibitor) and sapanisertib (mTOR inhibitor). In a co-culture model of patient-derived MPM cells, autologous peripheral blood mononuclear cells and fibroblasts, the tumor cell viability and changes in immune cell composition were investigated after treatment of roginolisib with nivolumab and cisplatin. PI3K-δ was detected in 66/89 (74%) MPM tumors and was associated with reduced overall survival (12 vs. 25 months, P=0.0452). Roginolisib induced apoptosis in MPM cells and enhanced the anti-tumor efficacy of AKT and mTOR kinase inhibitors by suppressing PI3K-δ/AKT/mTOR and ERK1/2 signaling. Furthermore, the combination of roginolisib with chemotherapy and immunotherapy re-balanced the immune cell composition, increasing effector T-cells and reducing immune suppressive cells. Overall, roginolisib induces apoptosis in MPM cells and increases the antitumor immune cell effector function when combined with nivolumab and cisplatin.These results provide first insights on the potential of roginolisib as a therapeutic agent in patients with MPM and its potential in combination with established immunotherapy regimen.

Efficacy of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Metastatic Non-Small Cell Lung Cancer Patients with Poor Performance Status and Epidermal Growth Factor Receptor Mutations: Findings from the Japanese Lung Cancer Registry Database

BackgroundIn advanced non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations, those with impaired performance status (PS) treated with EGFR-tyrosine kinase inhibitors (TKIs) have demonstrated comparable activities to good-PS patients. Due to the limited sample size and inclusion of older adult patients with good PS, these findings may not accurately depict the efficacy of EGFR-TKI in poor-PS patients. We investigated the benefit of EGFR-TKIs in this population and identified relevant prognostic factors. Patients and MethodsThis nationwide prospective registry study included 9872 patients with local or advanced NSCLC. Outcomes were compared between poor- and good-PS patients treated with EGFR-mutated lung cancer therapies. ResultsOf 9872 NSCLC patients, 1965 (19.9%) had EGFR mutations, with 1846 (93.9%) presenting common EGFR mutations. Poor PS (PS score ≥ 3) was noted in 171 patients (8.7%) and identified as an independent prognostic factor; those with poor PS had a significantly lower 1-year survival rate. The median overall survival (OS) for EGFR-TKI-treated good-PS patients was 31.5 (95% confidence interval, 29.6-33.4) months. Among poor-PS patients with EGFR mutations, 135 (78.9%) of whom were treated with EGFR-TKI had an OS of 15.5 (12.7-18.3) months, while those receiving only supportive care had an OS of 2.5 (1.4-3.6) months (P < .001). Hypoalbuminemia (< 3.5 g/dL), liver metastasis, and uncommon EGFR mutations were associated with poor prognosis. ConclusionPoor PS at diagnosis was rare and associated with limited EGFR-TKI efficacy and a dismal prognosis. Liver metastasis and hypoalbuminemia may reduce EGFR-TKI efficacy in these patients.

Negative impact of ratio of the microvascular area to tumor area on the response to EGFR-TKI in non-small cell lung cancer with an EGFR mutation.

The clinical impact of tumor microvessels on the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutation-positive non-small cell lung cancer (NSCLC) is unclear. Thus, the aim of this study was to investigate whether a tumor microenvironment, abundant in microvessels, affects EGFR-TKI efficacy in patients with NSCLC and EGFR mutations. We retrospectively studied the data of 40 post-operative patients with recurrent NSCLC and EGFR mutations who received EGFR-TKIs as a first-line treatment at Kumamoto University Hospital from January 2010 to February 2021. Tumor sections were retrieved from the tissue registry and analyzed for CD34-positive microvessels using immunohistochemical techniques. The ratio of microvascular area to tumor area (RMV), which is the CD34-positive microvascular area compared to the total tumor area, was measured using StrataQuest. The predictive value of RMV on treatment outcome, assessed via progression-free survival (PFS), was evaluated using a multivariate Cox proportional hazard model. The median PFS in the high RMV group (≥0.058) was significantly shorter than that in the low RMV group [<0.058; 296 days, 95% confidence interval (CI): 217-374 vs. 918 days, 95% CI: 279-1,556, P=0.002]. Multivariate analysis revealed that high RMV was an independent negative predictor of PFS (hazard ratio, 3.21; 95% CI: 1.18-8.76, P=0.022). High RMV may critically affect EGFR-TKI resistance in patients with NSCLC and EGFR mutations.

Predictors of Efficacy of Janus Kinase Inhibitors in Patients Affected by Ulcerative Colitis

Personalised medicine and the identification of predictors of the efficacy of specific drugs represent the ultimate goal for the treatment of ulcerative colitis (UC) in order to break the current therapeutic ceiling. JAK inhibitors are a new class of advanced therapies, orally administered, showing a good profile of efficacy and safety in both randomised controlled trials (RCTs) and real-world studies. Unfortunately, to date, it is not possible to draw the ideal profile of a patient maximally benefiting from this class of drugs to guide clinicians’ therapeutic choices. Baseline clinical activities and inflammatory biomarkers, as well as their early variation after treatment initiation, emerged as the main predictors of efficacy from post hoc analyses of RCTs with tofacitinib. Similar findings were also observed in the real-life studies including mainly patients with a history of pluri-refractoriness to biological therapies. At last, a few new biomarkers have been explored, even though they have not been validated in large cohorts. This paper provides a review of the current knowledge on clinical variables and biomarkers predicting response to JAK inhibitors in UC.

Janus kinase inhibitors vs. abatacept about safety and efficacy for patients with rheumatoid arthritis-associated interstitial lung disease: a retrospective nested case-control study

BackgroundInterstitial lung disease (ILD) related to rheumatoid arthritis (RA) is among the leading causes of death and an essential prognostic factor. There is only limited evidence for the safety of anti-rheumatic drugs for patients with RA-ILD. The aim of this study is to investigate the safety and efficacy of Janus kinase inhibitors (JAKis) by comparing it with abatacept (ABT) in patients with RA-ILD.MethodsThis single centre, retrospective nested case–control study enrolled patients with RA-ILD treated with JAKi or ABT. To determine the safety of the two drugs for existing ILD, we compared their drug persistency, incidence rates of pulmonary complications, and change of chest computed tomography (CT) image. For their efficacy as RA treatment, disease activity scores and prednisolone (PSL)-sparing effect were compared. We performed propensity score matching to match the groups’ patient characteristics.ResultsWe studied 71 patients with RA-ILD (ABT, n = 45; JAKi, n = 26). At baseline, the JAKi group had longer disease duration, longer duration of past bDMARD or JAKi use and higher usual interstitial pneumonia rate. After propensity score matching, no significant differences in patient characteristics were found between the two groups. No significant difference in the drug persistency rate for the first 2 years (ABT, 61.9%; JAKi, 42.8%; P = 0.256) was observed between the two matched groups. The incidence rate of pulmonary complications did not differ significantly between the two groups (P = 0.683). The CT score did not change after the treatment for the ABT group (Ground-glass opacities (GGO): P = 0.87; fibrosis: P = 0.78), while the GGO score significantly improved for the JAKi group (P = 0.03), although the number was limited (ABT: n = 7; JAKi: n = 8). The fibrosis score of the JAKi group did not change significantly.(P = 0.82). Regarding the efficacy for RA, a significant decrease in disease activity scores after the 1-year treatment was observed in both groups, and PSL dose was successfully tapered, although no significant differences were observed between the two drugs.ConclusionsJAKi is as safe and effective as ABT for patients with RA-ILD. JAKi can be a good treatment option for such patients.

P718 Observational real-world evidence on the efficacy and safety of Janus Kinase inhibitors (JAKi) in the treatment of moderate to severe Active Ulcerative Colitis (UC)

Abstract Background Janus kinase inhibitors (JAKi) are the first orally administered treatment for Ulcerative Colitis (UC). The JAK family comprises of four intracellular tyrosine kinases inhibitors (JAK1, JAK2, JAK3 and Tyrosine Kinase 2). Inhibition of the JAK kinases lead to dampening of the inflammatory cytokines which drive Inflammatory Bowel Disease (IBD). Tofacitinib was the first generation pan-JAKi. This was followed by second generation JAKi: Filgotinib and Upadacinib which preferentially inhibit JAK1. We report on the real-world evidence on the efficacy and safety of JAKi in the treatment of UC in a tertiary IBD treatment centre. Methods Patients attending the IBD clinic at weeks 8-12 of initiation of therapy were included. Baseline demographics, disease activity and previous therapies were recorded. Clinical response was measured using the SCCAI and biochemical response was measured using calprotectin and CRP. We defined clinical response as ≥3 points reduction from baseline SCCAI, and clinical remission as SCCAI Score of &amp;lt;2.5, and / or biochemical remission as a CRP of less than 5 mg/L and a calprotectin level of &amp;lt; 250 mg/g. We also assessed treatment persistence, and the reasons for treatment cessation. Results The UC populations are shown in Table 1. 52 patients were included and an additional 24 patients who discontinued therapy early on were assessed to review secondary outcomes. Table 1 summarises the comparative outcomes of the JAKi. 81% and 63% of patients achieved clinical and biochemical remission respectively. Overall, 31% discontinued treatment due to lack of efficacy or adverse events. 60% of patients reported adverse events (AEs), 25 % of patients discontinued treatment due to AEs and 84% of patients continued treatment despite reporting AEs. The most common AEs were hypercholesteremia and cold and flu like symptoms and the most common AEs related with treatment discontinuation were recurrent infection or persistent deranged liver functions contributed to patients’ history of primary sclerosing cholangitis. No Serious Adverse Events were reported. 60% of patients on tofacitinib developed side effects and persisted with therapy, which included hypercholesteremia (67%), shingles (11%), flu like symptom (11%) and hair loss (11%). 53% had side effects with Filgotinib; hypercholesteremia (25%), cold like symptoms (25%), chest infection (13%), shingles (13%), acne (13%). 68% developed side effects with Upadacitinib; reports of acne (20%), cold and flu (33%), shingles and mood swings (7%) and high cholesterol (67%). Conclusion In this real-world cohort of UC patients, JAKi was effective in inducing remission and had an acceptable safety profile. The observed safety profile was as expected compared to clinical data results.

The efficacy of upfront craniocerebral radiotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors in patients with epidermal growth factor receptor-positive non-small cell lung cancer with brain metastases.

This is a retrospective study that involved 213 patients with EGFR-NSCLC and BMs, with the patients divided into two groups: the upfront cranial RT (ucRT) group (n = 96) and the non-ucRT group (n = 117). All patients were administered with osimertinib, and those in the ucRT group also underwent RT. The overall survival (OS), progression-free survival (PFS) and intracranial PFS (IPFS) of the two groups were compared. The ucRT group manifested a markedly higher IPFS than the non-ucRT group (29.65 months vs 21.8 months; P < 0.0001). The subgroup analysis revealed that patients with oligometastases (OLOGO-BMs; 1-3 BMs) demonstrated a notably longer OS (44.5 months vs 37.3 months; P < 0.0001), PFS (32.3 months vs 20.8 months; P = 0.6884) and IPFS (37.8 months vs 22.1 months; P < 0.0001) in the ucRT group than in the non-ucRT group. However, for patients with multiple BMs, there was no significant difference in OS (27.3 months vs 34.4 months; P = 0.0710) and PFS (13.7 months vs 13.2 months; P = 0.0516) between the ucRT group and the non-ucRT group; the ucRT group exhibited a higher IPFS (26.4 months vs 21.35 months; P = 0.0028). Cox's multivariate analysis of patients with OLOGO-BM indicated that the use of ucRT was linked to a better OS (heart rate [HR] = 0.392; 95% confidence interval [CI]: 0.178-0.863; P = 0.020) and PFS (HR = 0.558; 95% CI: 0.316-0.986; P = 0.044). Upfront cerebral cranial stereotactic radiosurgery can improve outcomes in EGFR-positive patients with NSCLC and OLOGO-BM. However, for patients with multiple BMs, the preferable strategy may be pre-treatment with EGFR-TKIs.

The efficacy and safety of different Janus kinase inhibitors as monotherapy in rheumatoid arthritis: A Bayesian network meta-analysis.

This study aims to evaluate the efficacy and safety of JAK inhibitors in the treatment of patients with RA. The databases CNKI, VIP, Wanfang, CBM, and PubMed, Embase, Cochrane Library and Web of Science were searched to identify relevant randomized controlled trials (RCTs), all from the time of database creation to April 2024. Screening, data extraction, and risk of bias assessment (using Review Manager-5.3 software) were independently performed by at least two authors. The network meta-analysis was conducted using R 4.1.3 software. PROSPERO registration number: CRD42022370444. Thirty-three RCTs included 15,961 patients The experimental groups involved six JAK inhibitors (filgotinib, tofacitinib, decernotinib, baricitinib, upadacitinib and peficitinib) and 12 interventions (different doses of the six JAK inhibitors), and the control group involved adalimumab (ADA) and placebo. Compared with placebo, all JAK inhibitors showed a significant increase in efficacy measures (ACR20/50/70). Compared with ADA, only tofacitinib, low-dose decernotinib, and high-dose peficitinib showed a significant increase in ACR20/50/70. Decernotinib ranked first in the SUCRA ranking of ACR20/50/70. In terms of safety indicators, only those differences between low-dose filgotinib and high-dose upadacitinib, low-dose tofacitinib and high-dose upadacitinib were statistically significant. Low-dose filgotinib ranked first in the SUCRA ranking with adverse events as safety indicators. Only the efficacy and safety of tofacitinib ranked higher among different SUCRA rankings. Six JAK inhibitors have better efficacy than placebo. The superior efficacy of decernotinib and safety of low-dose filgotinib can be found in the SUCRA. However, there are no significant differences in safety between the different JAK inhibitors. Head-to-head trials, directly comparing one against each other, are required to provide more certain evidence.