UNASSIGNED: Seladelpar (MBX-8025) is a once-daily administered highly specific PPAR-δ agonist in Phase 3 and extension trials for use in patients with primary biliary cholangitis (PBC).
UNASSIGNED: This review provides background on current treatment options for PBC, and summarizes clinical trial data regarding the safety and effectiveness of seladelpar within the context of these treatments.
UNASSIGNED: Clinical trials results demonstrate the safety and tolerability of seladelpar use for PBC, including in patients with cirrhosis. The primary composite endpoint (ALP <1.67 times ULN, decrease ≥ 15% from baseline, and TB ≤ULN) was met in 61.7% of the patients treated with seladelpar and in 20% receiving placebo (p < 0.001). Moreover, pruritus - a cardinal and often intractable symptom of PBC - was improved with seladelpar treatment, as were overall quality of life measurements. Improvements in markers of inflammation were likewise observed. These biochemical and clinical findings therefore represent landmark developments in PBC treatment and offer a therapeutic option for PBC.

OBJECTIVE: To assess the efficacy and safety of concurrent hypofractionated radiotherapy plus anti-PD-1 antibody and SOX chemotherapy in the treatment of metastatic pancreatic cancer (mPC) after failure of first-line chemotherapy.
METHODS: Patients with pathologically confirmed mPC who failed standard first-line chemotherapy were enrolled. The patients were treated with a regimen of hypofractionated radiotherapy, SOX chemotherapy, and immune checkpoint inhibitors at our institution. We collected the patients\' clinical information and outcome measurements. The median progression-free survival (mPFS) was the primary endpoint of the study, followed by disease control rate (DCR), objective response rate (ORR), median overall survival (mOS) and safety. Exploratory analyses included biomarkers related to the benefits.
RESULTS: Between February 24, 2021, and August 30, 2023, twenty-five patients were enrolled in the study, and twenty-three patients who received at least one dose of the study agent had objective efficacy evaluation. The mPFS was 5.48 months, the mOS was 6.57 months, and the DCR and ORR were 69.5% and 30.4%, respectively. Among the seven patients who achieved a PR, the median duration of the response was 7.41 months. On-treatment decreased serum CA19-9 levels were associated with better overall survival. Besides, pretreatment inflammatory markers were associated with tumor response and survival.
CONCLUSIONS: Clinically meaningful antitumor activity and favorable safety profiles were demonstrated after treatment with these combination therapies in patients with refractory mPC. On-treatment decreased serum CA19-9 levels and pretreatment inflammatory markers platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), lactate dehydrogenase (LDH) might be biomarkers related to clinical benefits.
BACKGROUND: https://www.chictr.org.cn/showproj.html?proj=130211 , identifier: ChiCTR2100049799, date of registration: 2021-08-09.

BACKGROUND: There is a significant gap in the literature concerning the effective management of second-line therapy for patients with metastatic renal cell carcinoma (RCC) who have received immune checkpoint inhibitors (ICIs). Most of the published articles were small multicenter series or phase 2 studies. To our knowledge, a systematic review that comprehensively outlines the range of treatment options available for patients with metastatic RCC who do not respond to first-line ICIs has not yet been conducted. Our aim was to synthesize evidence on second-line therapies for patients with metastatic RCC after initial treatment with ICIs and to offer recommendations on the best treatment regimens based on the current literature.
METHODS: We conducted a search in PubMed, Embase, and the Cochrane Library on 29 February 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We selected articles that met the predetermined inclusion criteria (written in English, retrospective observational studies, prospective series, and randomized trials reporting second-line therapy for metastatic RCC after failure of ICI-based therapy). Relevant articles were identified in the reference lists. The main endpoint was the overall response rate (ORR), with the median progression-free survival (PFS) and overall survival (OS) as secondary endpoints.
RESULTS: We included 27 studies reporting the outcomes of 1970 patients. Salvage therapies were classified as targeted therapy (VEGFR TKIs) in 18 studies and ICIs in 8 studies. In studies where TKIs were the second line of choice, the pooled ORR was 34% (95% CI: 30.2-38%). In studies where ICIs, alone or in combination with TKIs, were used as second-line therapies, the ORR was 25.7% (95% CI: 15.7-39.2%). In studies where TKIs and ICIs were the second-line choices, the pooled median PFS values were 11.4 months (95% CI: 9.5-13.6 months) and 9.8 months (95% CI: 7.5-12.7 months), respectively.
CONCLUSIONS: This systematic review shows that VEGFR TKIs and ICIs are effective second-line therapies following an initial treatment with anti-PD(L)1 alone or in combination. The treatment choice should be personalized, taking into account the patient\'s response to first-line ICIs, the site of the disease, the type of first-line combination (with or without VEGFR TKIs), and the patient\'s overall condition.

OBJECTIVE: This phase I trial is to determine the recommended dose of the TAS-102, irinotecan plus bevacizumab regimen and assess its safety and efficacy in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin treatment.
METHODS: A 3 + 3 designed dose escalation was performed. Patients were administered TAS-102 (30-35 mg/m2 twice daily on days 1-5) and irinotecan (150-165 mg/m2 on day 1) combined with a fixed dose of bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the determination of the recommended phase II dose.
RESULTS: Eighteen patients were enrolled: 6 at the Level 1 (TAS-102 30 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), six at the Level 2 (TAS-102 35 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), and six at the Level 3 (TAS-102 30 mg/m2 twice daily, irinotecan 165 mg/m2 plus bevacizumab 5 mg/kg). Five dose-limiting toxicities occurred: one observed at Level 1 (thrombocytopenia), two at Level 2 (neutropenia and diarrhea), and two at Level 3 (fatigue and neutropenia). The RP2D was established as TAS-102 30 mg/m2 twice daily and irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg. The most frequent grade 3/4 treatment-related adverse events were neutropenia (33.3%), diarrhea (16.7%), and thrombocytopenia (11.1%). No treatment-related death occurred. Two patients (11.1%) experienced partial responses and 14 (77.8%) had stable disease.
CONCLUSIONS: The regimen of TAS-102, irinotecan, and bevacizumab is tolerable with antitumor activity for metastatic colorectal cancer patients refractory to first-line fluoropyrimidines and oxaliplatin treatment.

UNASSIGNED: To evaluate the efficacy and safety of nivolumab in the second-line (2L) or later-line (LL) treatment of patients with locally advanced/metastatic non-small cell lung cancer (NSCLC) in real-life setting in Türkiye.
UNASSIGNED: This study was designed as a national, multi-center, retrospective study. The study population was evaluated in two groups for the line of nivolumab therapy: those receiving nivolumab in the 2L (Group 2L) and third-line (3L) or LL (Group 3L/LL). Efficacy was evaluated based on one-year overall survival (OS) and progression-free survival (PFS). Safety was evaluated based on treatment-related adverse events (AEs) and nivolumab discontinuation rate.
UNASSIGNED: Of 244 patients, 52.9% were in Group 2L and 47.1% were in Group 3L/LL. Demographic and clinical characteristics did not differ between the groups. In Group 2L and Group 3L/LL, one-year OS and PFS rates were 60.8% and 61.4% (p = 0.592) and 31.2% and 21.3% (p = 0.078), respectively. The objective response rate (ORR) was 34.7% in Group 2L and 27.3% in Group 3L/LL (p = 0.262). The percentage of patients reporting at least one AE in Groups 2L and 3L/LL was 34.9% and 43.5%, respectively (p = 0.169). Fatigue was the most common (16.4%) treatment-related AE in each group. The groups were comparable regarding the AE frequency. Nivolumab was discontinued in 61 patients in Group 2L and 53 patients in Group 3L/LL, with the most common reason being disease progression (57.4% and 66.0%, respectively).
UNASSIGNED: Nivolumab is safe and effective in the 2L or 3L/LL treatment of locally advanced/metastatic NSCLC and associated with acceptable AEs in real-life setting.
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer (around 85% of all lung cancers). Patients with NSCLC are usually diagnosed at advanced or metastatic stages. When cancer cells spread to other areas from where they first formed, it is called metastatic cancer. Surgery may not be a treatment option for such patients. Currently, immunotherapeutic agents are used in the treatment of NSCLC. Nivolumab is one of the approved immunotherapeutic agents in the treatment of patients with metastatic NSCLC, who have failed after receiving chemotherapy. Our study explored the efficacy and safety of nivolumab in real-life setting in Türkiye. Nivolumab effectiveness was evaluated by overall survival (OS) and progression-free survival (PFS) rates. OS indicates the proportion of patients who are still alive at a given time after diagnosis or treatment initiation. PFS refers to “the length of time during and after cancer treatment that a person lives with the disease but does not get worse.” In the present study, one-year OS for 244 patients who received nivolumab was 61.1% and one-year PFS was 26.4%. Nivolumab safety was evaluated based on the frequency of adverse events observed during nivolumab therapy. Of the patients 38.9% had at least one side effect, with fatigue being the most common (16.4%). Our results support the earlier studies and showed that nivolumab was a safe and effective agent and is associated with acceptable side effects.

BACKGROUND: The increasing use of lenalidomide (Len) in first-line (1L) therapy of multiple myeloma (MM) has led to a significant proportion of patients becoming Len-refractory following 1L treatment. However, there are limited real-world data on treatment strategies and outcomes of patients who become Len-refractory following 1L therapy.
METHODS: This real-world retrospective cohort study analyzed Len-refractory and non-Len-refractory patients who received 1L Len and initiated second-line (2L) therapy at a Greek MM center. The Len-exposed cohort (n = 249) included 55.4% Len-refractory patients after 1L.
RESULTS: Compared to non-Len-refractory patients, Len-refractory patients more frequently had high-risk cytogenetics and Revised-International Staging System-3 disease stage at diagnosis, and had shorter progression-free survival (PFS) following 1L therapy. Len-refractory versus non-Len-refractory patients more frequently received triplets (59% vs. 40%), anti-CD38 agents (20% vs. 9%) and pomalidomide (22% vs. 13%). The overall response rate was 53% for Len-refractory patients and 64% for non-Len-refractory patients in 2L therapy; median PFS was 10.7 vs. 18.3 months, respectively. Median overall survival (OS) was shorter for Len-refractory patients vs non-Len-refractory patients (23.8 vs. 53.6 months). Len refractoriness was an independent prognostic factor for both PFS and OS in Len-exposed patients.
CONCLUSIONS: In this real-world Len-exposed cohort, Len-refractory patients receiving 1L Len experienced poorer survival outcomes than non-Len-refractory patients, highlighting the unmet need in this patient population which has driven the development of novel therapies.

UNASSIGNED: Since the outbreak of COVID-19 in December 2019, countries around the world, including China, have been administering COVID-19 vaccines in response to the pandemic. Our center has observed that treating patients with primary immune thrombocytopenia (ITP) has become more challenging in this context.
UNASSIGNED: This study compared the treatment response of 25 de novo ITP patients who had received a COVID-19 vaccination (Group 1) with an equal number of de novo ITP patients randomly selected from the 2 years prior to the COVID-19 pandemic (Group 2) by using the Mann-Whitney U test and Fisher\'s exact.
UNASSIGNED: Patients in both groups had predominantly female gender with similar age and baseline platelet counts. However, on Day 3, the median platelets were 22 and 49 × 109/L, and on Day 7, they were 74 and 159 × 109/L, respectively (P < 0.05). Compared to Group 2, Group 1 showed a suboptimal short-term response to glucocorticoid monotherapy, with a higher proportion of patients requiring combination therapy with other drugs including intravenous immunoglobulin, thrombopoietin receptor agonists, and rituximab. After subgroup analysis, a significant difference was observed in the proportion of patients requiring second-line therapy between the two groups.
UNASSIGNED: Our study suggests that COVID-19 vaccination may lead to a lower response rate to first-line treatment in de novo ITP patients. Nevertheless, it is crucial to acknowledge the inherent limitations in this conclusion. Further studies are needed to confirm these findings and investigate the underlying mechanisms.

Given the modest efficacy of docetaxel in advanced non-small cell lung cancer (NSCLC), this study assesses the therapeutic potential and safety profile of anlotinib in combination with docetaxel compared to docetaxel monotherapy as a second-line therapy for patients with advanced NSCLC.
In this phase II study, patients with advanced NSCLC experiencing failure with first-line platinum-based regimens were randomized in a 1:1 ratio to receive either anlotinib plus docetaxel or docetaxel alone. Primary endpoint was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety as secondary endpoints.
A total of 83 patients were randomized. The combination of anlotinib and docetaxel significantly extended median PFS to 4.4 months compared to 1.6 months for docetaxel alone (hazard ratio [HR] = 0.38, 95 % confidence interval [CI]: 0.23-0.63, P = 0.0002), and also demonstrated superior ORR (32.5 % vs. 9.3 %, P = 0.0089) and DCR (87.5 % vs. 53.5 %, P = 0.0007). Median OS was observed at 12.0 months in the combination group vs. 10.9 months in the monotherapy group (HR = 0.82, 95 % CI: 0.47-1.43, P = 0.4803). For patients previously treated with immunotherapy, the median PFS was notably longer at 7.8 vs. 1.7 months (HR = 0.22, 95 % CI: 0.09-0.51, P = 0.0290). The incidence of grade ≥ 3 treatment-related adverse events, predominantly leukopenia (15.0 % vs. 7.0 %) and neutropenia (10.0 % vs. 5.0 %), was manageable across both groups.
Anlotinib plus docetaxel offers a viable therapeutic alternative for patients with advanced NSCLC who failed first-line platinum-based treatments.

UNASSIGNED: Immune thrombocytopenia (ITP) is an acquired immune-mediated disease that lacks an underlying etiology. Steroids are the main first-line treatment of ITP, while the second-line treatment consists primarily of splenectomy and rituximab. This study aimed to assess and compare the response to rituximab and splenectomy.
UNASSIGNED: This retrospective comparative study reviewed ITP patients treated at a single private hematology clinic from 2007 to 2019. Seventy-four ITP patients were recruited, 27 were on rituximab, and 47 had undergone splenectomy. The initial platelet counts and bleeding symptoms were recorded, and initial and long-term responses to treatment were evaluated based on the American Society of Hematology guidelines.
UNASSIGNED: The mean age of the patients was 42.1 years with a male-to-female ratio of 1:1.8. The initial mean platelet count was comparable between the rituximab and splenectomy groups (p = 0.749). The initial complete response (CR) differed significantly between the rituximab and splenectomy groups (44.4% versus 83%, p = 0.002). The five-year response rate was significantly higher in the splenectomy than in the rituximab group (74% versus 52%, log-rank 0.038). Splenectomy was the only significant predictive factor for long-term response (OR = 0.193, p = 0.006).
UNASSIGNED: The overall response revealed that splenectomy appeared superior to rituximab as a second-line treatment of ITP. Splenectomy was the only positive prognostic indicator of sustained response.

UNASSIGNED: Recently, several novel programmed cell death protein 1 (PD-1) inhibitors have been approved for second-line treating advanced or metastatic oesophageal squamous cell carcinoma (OSCC), including camrelizumab, nivolumab, pembrolizumab, sintilimab and tislelizumab. However, the optimal treatment regimen remained ambiguous.
UNASSIGNED: The purpose of this study was to investigate the efficacy, safety and economy of available PD-1 inhibitors to determine the optimal treatment from the Chinese healthcare system perspective.
UNASSIGNED: A systematic review and economic evaluation.
UNASSIGNED: A systematic review was undertaken utilizing PubMed, Web of Science, Cochrane Library, Embase and Scopus databases to identify eligible studies until 31 August 2023. Primary outcomes were progression-free survival (PFS), overall survival (OS) and adverse events (AEs). We also developed a partitioned survival model at 3-week intervals based on five clinical trials to predict long-term costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios for various treatment options. Direct medical costs and utility values were obtained from public drug bidding databases, clinical trials or published literature. The parameter uncertainties within the model were determined via one-way and probabilistic sensitivity analyses.
UNASSIGNED: Five randomized controlled trials involving 2837 patients were included in the analysis. Compared with other treatments examined, camrelizumab provided the best PFS benefits [hazard ratio (HR): 0.69, 95% confidence interval (CI): 0.56-0.86], and pembrolizumab provided the best OS benefits (HR: 0.55, 95% CI: 0.37-0.82). Nivolumab caused a relatively lower incidence of treatment-related AEs (HR: 0.10, 95% CI: 0.05-0.20) and grade 3-5 AEs (HR: 0.13, 95% CI: 0.08-0.21) than other immunotherapy regimens. In the economic evaluation, average 10-year costs ranged from $5,433.86 (chemotherapy) to $50,617.95 (nivolumab) and mean QALYs ranged from 0.55 (chemotherapy) to 0.82 (camrelizumab). Pembrolizumab was eliminated because of dominance. Of the remaining strategies, when the willingness-to-pay thresholds were 1, 2 and 3 times GDP per capita in 2022, sintilimab, tislelizumab and camrelizumab were the most cost-effective treatment options, respectively.
UNASSIGNED: Sintilimab might be the optimal treatment alternative for second-line therapy of advanced OSCC in China, followed by tislelizumab and camrelizumab.
UNASSIGNED: This study has been registered on the PROSPERO database with the registration number CRD42023495204.
Immune checkpoint inhibitors versus chemotherapy as second-line therapy for advanced esophageal squamous cell carcinoma: a systematic review and economic evaluation Background: The purpose of this study was to investigate the efficacy, safety and economy of available PD-1 inhibitors to determine the optimal treatment from the Chinese healthcare system perspective.
METHODS: A systematic review was undertaken utilizing PubMed, Web of Science, Cochrane Library, Embase, and Scopus databases to identify eligible studies until August 31, 2023. Primary outcomes were progression-free survival (PFS), overall survival (OS), and adverse events (AEs). We also developed a partitioned survival model at 3-week intervals based on 5 clinical trials to predict long-term costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) for various treatment options. Direct medical costs and utility values were obtained from public drug bidding database, clinical trials or published literatures. The parameter uncertainties within the model were determined via one-way and probabilistic sensitivity analyses.
RESULTS: Compared with other treatments examined, camrelizumab provided the best PFS benefits (HR: 0.69, 95% CI: 0.56-0.86), and pembrolizumab provided the best OS benefits (HR: 0.55, 95% CI: 0.37-0.82). Nivolumab caused a relatively lower incidence of treatment-related AEs (HR: 0.10, 95% CI: 0.05-0.20) and grade 3-5 AEs (HR: 0.13, 95% CI: 0.08-0.21) than other immunotherapy regimens. In the economic evaluation, average 10-year costs ranged from $5,433.86 (chemotherapy) to $50,617.95 (nivolumab) and mean QALYs ranged from 0.55 (chemotherapy) to 0.82 (camrelizumab). Pembrolizumab was eliminated because of dominance. Of the remaining strategies, when the willingness-to-pay thresholds were 1, 2, and 3 times GDP per capita in 2022, sintilimab, tislelizumab, and camrelizumab were the most cost-effective treatment options, respectively.
CONCLUSIONS: Sintilimab might be the optimal treatment alternative for second-line therapy of advanced ESCC in China, followed by tislelizumab and camrelizumab.