Failure Of Monotherapy Research Articles

Obesity and methotrexate treatment failure in rheumatoid arthritis patients in Cipto Mangunkusumo Hospital, Indonesia

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease which mainly manifests in the joints. Methotrexate (MTX) is a widely used pharmacological treatment for RA. To date, no prior research has investigated the effect of obesity on MTX treatment outcomes among RA patients in Indonesia. This research aimed to investigate the effect of obesity on MTX monotherapy failure in RA patients. We conducted a retrospective cohort study using medical records from the Rheumatology Clinic at Cipto Mangunkusumo Hospital from March 2017 to December 2021. Descriptive and estimation analyses were performed to assess the sample characteristics based on each variable and a logistic regression analysis was conducted to evaluate the association between obesity and MTX treatment failure. Out of 72 subjects, the proportion of MTX treatment failure was 57.1% (20/35) among obese patients and 37.8% (14/37) among non-obese patients. Obese subjects exhibited a 2.11-fold increased risk of MTX treatment failure compared to non-obese patients (OR 2.11; 95% CI 0.81-5.45). The number of joints involved was found to emerge as a confounding factor in this study. Our findings suggest that RA patients with obesity potentially have an increased risk of MTX treatment failure compared to non-obese RA patients.

A transparent machine learning algorithm uncovers HbA1c patterns associated with therapeutic inertia in patients with type 2 diabetes and failure of metformin monotherapy

AimsThis study aimed to identify and categorize the determinants influencing the intensification of therapy in Type 2 Diabetes (T2D) patients with suboptimal blood glucose control despite metformin monotherapy. MethodsEmploying the Logic Learning Machine (LLM), an advanced artificial intelligence system, we scrutinized electronic health records of 1.5 million patients treated in 271 diabetes clinics affiliated with the Italian Association of Medical Diabetologists from 2005 to 2019. Inclusion criteria comprised patients on metformin monotherapy with two consecutive mean HbA1c levels exceeding 7.0%. The cohort was divided into “inertia-NO” (20,067 patients with prompt intensification) and “inertia-YES” (13,029 patients without timely intensification). ResultsThe LLM model demonstrated robust discriminatory ability among the two groups (ROC-AUC = 0.81, accuracy = 0.71, precision = 0.80, recall = 0.71, F1 score = 0.75). The main novelty of our results is indeed the identification of two main distinct subtypes of therapeutic inertia. The first exhibited a gradual but steady HbA1c increase, while the second featured a moderate, non-uniform rise with substantial fluctuations. ConclusionsOur analysis sheds light on the significant impact of HbA1c levels over time on therapeutic inertia in patients with T2D, emphasizing the importance of early intervention in the presence of specific HbA1c patterns.

Clinical Course, Antifungal Susceptibility, and Genomic Sequencing of Trichophyton indotineae

Trichophyton indotineae is an emerging dermatophyte causing outbreaks of extensive tinea infections often unresponsive to terbinafine. This species has been detected worldwide and in multiple US states, yet detailed US data on infections with T indotineae are sparse and could improve treatment practices and medical understanding of transmission. To correlate clinical features of T indotineae infections with in vitro antifungal susceptibility testing results, squalene epoxidase gene sequence variations, and isolate relatedness using whole-genome sequencing. This retrospective cohort study of patients with T indotineae infections in New York City spanned May 2022 to May 2023. Patients with confirmed T indotineae infections were recruited from 6 New York City medical centers. Improvement or resolution at the last follow-up assessment. Among 11 patients with T indotineae (6 male and 5 female patients; median [range] age, 39 [10-65] years), 2 were pregnant; 1 had lymphoma; and the remainder were immunocompetent. Nine patients reported previous travel to Bangladesh. All had widespread lesions with variable scale and inflammation, topical antifungal monotherapy failure, and diagnostic delays (range, 3-42 months). Terbinafine treatment failed in 7 patients at standard doses (250 mg daily) for prolonged duration; these patients also had isolates with amino acid substitutions at positions 393 (L393S) or 397 (F397L) in squalene epoxidase that correlated with elevated terbinafine minimum inhibitory concentrations of 0.5 μg/mL or higher. Patients who were treated with fluconazole and griseofulvin improved in 2 of 4 and 2 of 5 instances, respectively, without correlation between outcomes and antifungal minimum inhibitory concentrations. Furthermore, 5 of 7 patients treated with itraconazole cleared or had improvement at the last follow-up, and 2 of 7 were lost to follow-up or stopped treatment. Based on whole-genome sequencing analysis, US isolates formed a cluster distinct from Indian isolates. The results of this case series suggest that disease severity, diagnostic delays, and lack of response to typically used doses and durations of antifungals for tinea were common in this primarily immunocompetent patient cohort with T indotineae, consistent with published data. Itraconazole was generally effective, and the acquisition of infection was likely in Bangladesh.

Successful medical management of a pituitary macroadenoma with features of resistant acromegaly and hyperprolactinemia using pasireotide.

The somatostatin analog, pasireotide, is used for the treatment of acromegaly after the failure of surgery and/or first-line medical treatment. A 48-year-old male reported that during a workup for obesity in his home country, hyperprolactinemia was diagnosed and a 3.5 × 3.5 cm pituitary macroadenoma was identified on pituitary MRI. He received cabergoline for 6 months; then he was lost to follow-up. He presented at our Endocrine clinic 2 years later for treatment of obesity (BMI 49.5 kg/m2). Biochemical workup revealed that in addition to hyperprolactinemia (7,237 [normal: 85-323 mIU/L), he had acromegaly, evident by elevated insulin-like growth factor 1 (IGF-1) level (450 [normal: 88-210 µg/L]), and a positive growth hormone suppression test, secondary hypothyroidism, and secondary hypogonadism. Pituitary MRI showed that the adenoma encased parts of the left and right internal carotid arteries and encroached on the optic chiasm. Surgical excision was therefore not feasible. He was treated with cabergoline and later, long-acting release (LAR) octreotide. Prolactin levels were reduced with cabergoline, but IGF-1 levels did not respond to octreotide, and it was discontinued. The patient abandoned radiotherapy after two sessions. He was started on LAR pasireotide 40 mg every 4 weeks and continued on cabergoline 0.5 mg per week. His biochemical response was dramatic, with a near normalization of IGF-1 levels in 3 months. After 6 months from starting pasireotide, we increased cabergoline dose from 0.5 mg/week to 3 mg/week. Three months later, IGF-1 level was normalized. The patient developed type 2 diabetes as a side effect of pasireotide; however, this was well-controlled with medications. The case suggests that pasireotide can provide marked biochemical improvement in acromegaly after the failure of both cabergoline monotherapy and cabergoline plus octreotide. This further confirms a potentially efficacious treatment regimen in treatment-resistant acromegaly with hyperprolactinemia.

Efficacy and Safety of Alogliptin-Pioglitazone Combination for Type 2 Diabetes Mellitus Poorly Controlled with Metformin: A Multicenter, Double-Blind Randomized Trial.

Guidelines for switching to triple combination therapy directly after monotherapy failure are limited. This study investigated the efficacy, long-term sustainability, and safety of either mono or dual add-on therapy using alogliptin and pioglitazone for patients with type 2 diabetes mellitus (T2DM) who did not achieve their target glycemic range with metformin monotherapy. The Practical Evidence of Antidiabetic Combination Therapy in Korea (PEAK) was a multicenter, placebo-controlled, double-blind, randomized trial. A total of 214 participants were randomized to receive alogliptin+pioglitazone (Alo+Pio group, n=70), alogliptin (Alo group, n=75), or pioglitazone (Pio group, n=69). The primary outcome was the difference in glycosylated hemoglobin (HbA1c) levels between the three groups at baseline to 24 weeks. For durability, the achievement of HbA1c levels <7% and <6.5% was compared in each group. The number of adverse events was investigated for safety. After 24 weeks of treatment, the change of HbA1c in the Alo+Pio, Alo, and Pio groups were -1.38%±0.08%, -1.03%±0.08%, and -0.84%±0.08%, respectively. The Alo+Pio group had significantly lower HbA1c levels than the other groups (P=0.0063, P<0.0001) and had a higher proportion of patients with target HbA1c achievement. In addition, insulin sensitivity and β-cell function, lipid profiles, and other metabolic indicators were also improved. There were no significant safety issues in patients treated with triple combination therapy. Early combination triple therapy showed better efficacy and durability than the single add-on (dual) therapy. Therefore, combination therapy with metformin, alogliptin, and pioglitazone is a valuable early treatment option for T2DM poorly controlled with metformin monotherapy.

Treatment Failure and Long-Term Prescription Risk for Guideline-Recommended Hypnotics in Japan

Although insomnia guidelines recommend the use of several individual hypnotics, the most useful hypnotic for treating insomnia in a clinical setting remains unclear. To determine which guideline-recommended hypnotics have lower risks of monotherapy failure and which hypnotics have a higher risk of long-term prescription for insomnia treatment. This retrospective observational cohort study used data from the Japan Medical Data Center Claims Database from April 1, 2005, to March 31, 2021. Participants included adults whose first prescribed pharmaceutical treatment for insomnia was guideline-recommended hypnotic monotherapy. Data were analyzed from December 24, 2022, to September 26, 2023. Suvorexant, ramelteon, eszopiclone, zolpidem, and triazolam monotherapy. The primary outcome was monotherapy failure, defined as a change in hypnotic or having an additional hypnotic prescribed for insomnia within 6 months of the first prescription of a guideline-recommended hypnotic monotherapy. The secondary outcome was monotherapy discontinuation, defined as no prescription of any hypnotic for 2 consecutive months within 6 months after prescribing a guideline-recommended hypnotic in patients for whom monotherapy did not fail. Monotherapy failure and discontinuation were compared using Cox proportional hazards and logistic regression models, respectively. The study included 239 568 adults (median age, 45 [IQR, 34-55] years; 50.2% women) whose first prescription for insomnia was guideline-recommended hypnotic monotherapy. During the 6-month follow-up period, 24 778 patients (10.3%) experienced failure of monotherapy with a guideline-recommended hypnotic. In comparison with eszopiclone, there were more cases of monotherapy failure for ramelteon (adjusted hazard ratio [AHR], 1.23 [95% CI], 1.17-1.30; P < .001), fewer cases for zolpidem (AHR, 0.84 [95% CI, 0.81-0.87]; P < .001) and triazolam (AHR, 0.82 [95% CI, 0.78-0.87]; P < .001), and no significant difference between suvorexant and eszopiclone. Among those without monotherapy failure, monotherapy was discontinued in 84.6% of patients, with more discontinuations for ramelteon (adjusted odds ratio [AOR], 1.31 [95% CI, 1.24-1.40]; P < .001) and suvorexant (AOR, 1.20 [95% CI, 1.15-1.26]; P < .001) than for eszopiclone and no significant difference between zolpidem or triazolam and eszopiclone. Due to uncontrolled confounding factors in this cohort study, no conclusions regarding the pharmacologic properties of guideline-recommended hypnotics can be drawn based on these results. Further studies accounting for confounding factors, including diagnoses of chronic vs acute insomnia disorder, insomnia and psychiatric symptom severity, and physician attitudes toward hypnotic prescription, are needed.

Efficacy of bupropion and varenicline genetic markers in choosing pharmacological treatment for smoking cessation, and implications for combining drugs: A randomized controlled trial - GENTSMOKING.

Smoking cessation is the best strategy for reducing tobacco-related morbimortality. The goal of this randomized controlled trial was to test whether using the genetically favorable markers to choose a smoking cessation drug treatment (precision medicine) was superior to using the most effective drug (varenicline) in terms of abstinence rates. Additionally, combination therapy was tested when monotherapy failed. This partially blind, single-center study randomized (1:1) 361 participants into two major groups. In the genetic group (n=184), CYP2B6 rs2279343 (genotype AA) participants started treatment with bupropion, and CHRNA4 rs1044396 (genotype CT or TT) participants started treatment with varenicline; when genetic favorable to both, participants started treatment with bupropion, and when favorable to neither, on both drugs. In the control group (n=177), participants started treatment with varenicline, regardless of genetic markers. Drug treatment lasted 12 weeks. Efficacy endpoints were abstinence rates at Weeks 4, and Weeks 8-12, biochemically validated by carbon monoxide in exhaled air. Participants who did not achieve complete abstinence at Week 4, regardless of group, were given the choice to receive combination therapy. Abstinence rates were 42.9% (95% CI: 36-64) in the control group versus 30.4% (95% CI: 23-37) in the genetic group at Week 4 (p=0.01); and 74% (95% CI: 67-80) versus 52% (95% CI: 49-64) at Week 12 (p<0.001), respectively. The strategy of combining drugs after Week 4 increased abstinence rates in both groups and the significant difference between genetic and control groups was maintained. Results show that using these selected genetic markers was inferior to starting treatment with varenicline (control group), which is currently the most effective smoking cessation drug; moreover, the addition of bupropion in cases of varenicline monotherapy failure improves the efficacy rate until the end of treatment. NCT03362099.

P647 Effectiveness of combined treatment with two biologics or advanced molecules in inflammatory bowel disease

Abstract Background Treatment with a combination of biologic drugs or advanced molecules represents a seldom-used therapeutic option for inflammatory bowel disease (IBD). Data on the effectiveness of these combinations of treatment are limited. The objective of this study is to assess the effectiveness of combination therapy in IBD patients. Methods A retrospective, single-center observational study was conducted. Patients with IBD treated with a combination of biologic drugs or advanced molecules from January 2020 to September 2023 were analyzed. Clinical, demographic, and therapeutic variables were collected. The clinical response rate was evaluated using the Harvey-Bradshaw Index for Crohn's disease (CD) and the partial Mayo score for ulcerative colitis (UC) at the initiation and 6 months into treatment. Bivariate analysis was performed to identify variables associated with clinical response. Long-term treatment survival was studied using Kaplan-Meier curve. Results A total of 9 patients were included: 7 (77.8%) with CD and 2 (22.2%) with UC. The majority (66.6%) had received more than two biologic treatments. Patient characteristics are described in Table 1. Combination treatment was initiated due to partial response to monotherapy in 2 patients (22.2%) and monotherapy failure in 7 (77.8%). The most commonly used combination was ustekinumab-vedolizumab (n=6, 66.6%). Three patients (33.3%) had a clinical response at 6 months, with one patient achieving clinical remission. In the bivariate analysis, partial response to monotherapy as an indication for a second biologic and elevated PCR at the start of treatment were associated with a higher clinical response (p=0.03 and p=0.04, respectively). The median survival of the combination treatment was 309 days (±109) (Fig. 1). At the end of the follow-up, 2 patients (22.2%) continued with combination treatment (average of 251 days). In 4 cases the treatment was switched to a JAK inhibitor, one patient required surgery and, finally, two patients needed surgery and treatment change. Conclusion The combination treatment have a low long term effectiveness in patients refractory to conventional treatment, although it may be a valid option for that subgroup of patients showing a partial response to monotherapy.

Impact of salvage chemotherapy after immune checkpoint inhibitor for recurrent or metastatic head and neck cancer.

It is unclear witch regimen is optimal as salvage chemotherapy (SCT) after immune checkpoint inhibitor (ICI) monotherapy for recurrent or metastatic head and neck cancer (RM-HNC). This study enrolled 109 patients. Overall survival (OS) and progression-free survival 2 (PFS2) were compared between patients stratified by SCT regimen. Of the 109 patients, 55 underwent SCT after the failure of ICI monotherapy. The OS of these 55 patients was longer than that of patients who did not undergo SCT. The OS and PFS2 were similar between patients treated with paclitaxel (PTX) and cetuximab (Cmab) combination and those treated with PTX monotherapy. The occurrence of irAEs did not impact PFS2 nor OS. SCT can improve the survival outcomes of patients with RM-HNC. In addition to PTX and Cmab, PTX monotherapy is also considered an effective SCT regimen. SCT is effective regardless of the presence or absence of irAEs.

Bendamustine Plus Brentuximab Has Superior Efficacy to Brentuximab Monotherapy As Third-Line Treatment for Classical Hodgkin Lymphoma: A Real-World, Multicentre UK Analysis

Purpose: The introduction of targeted agents has been a major advance in the treatment of classical Hodgkin lymphoma (HL) but the optimal application and sequencing of these agents is unclear. The CD30-targeted antibody-drug conjugate brentuximab vedotin (BV) is licensed for treatment of relapsed and refractory (R/R) HL as monotherapy and is available in the United Kingdom as third-line (3L) therapy for HL. BV has been evaluated in combination with chemotherapy in single-arm trials with very promising results, but randomised data are lacking. The aim of this analysis was to compare the efficacy of BV monotherapy with BV plus bendamustine (BVB) as 3L treatment of HL in a real-world UK cohort. Methods: Data were retrospectively collectively for consecutive patients receiving treatment for R/R HL with intent to consolidate with stem cell transplant (SCT) between 01/2015 and 12/2019 at 11 UK centres. Use of BVB was principally determined by availability, due to regional differences in BV funding in the UK, rather than patient disposition. Response was assessed by PET according to the Lugano Classification. Most analyses use descriptive statistics. Time-to-event analyses are measured from the start of 3L treatment until the first event (death for overall survival and death or further therapy for treatment failure) with groups compared using Kaplan Meier survival analysis and Cox regression. Results: 96 patients received BV and 30 received BVB. Baseline demographics are provided in the Table. Patients receiving BVB were slightly younger in age at diagnosis (p=0.031), but a slightly higher proportion had primary refractory disease (p=0.16) and failed to respond to second-line therapy (p=0.034). Numerically fewer patients in the BVB arm had received prior SCT (p=0.16). Patients received a median of 4 cycles of BV monotherapy (range 3 - 5). Patients treated with BVB received a median of 3 cycles of bendamustine (IQR 2 - 4) and 4 cycles of BV (IQR 3 - 5); 2 patients discontinued bendamustine after 1 cycle due to adverse reactions. Complete metabolic response was achieved in 34 patients (37.4%) with BV and 22 patients (73.3%) with BVB, with overall response rates of 57.3% and 93.3%, respectively (OR 9.2; 95% CI: 2.06 - 40.86; p=0.004). SCT consolidation was performed after 3L treatment in 33 patients (34.4%) following BV (26 autologous, 7 allogeneic) and 22 patients (73.3%) after BVB (17 autologous, 5 allogeneic). Median follow-up was 30.1 months after BV (IQR: 15.3 - 46.8) and 18.1 months after BVB (15.4 - 29.8). Freedom-from-treatment-failure (FFTF) rates at 18 months were 41.5% (95% CI: 30.8 - 51.8) after BV and 62.9% (39.3 - 79.4) after BVB (HR 0.45, 95% CI 0.23 - 0.88; p=0.019; see Figure). Overall survival rates at 18 months were 76.9% (66.0 - 84.7) after BV and 88.4% (68.1 - 96.1) after BVB (HR 0.37, 95% CI 11 - 1.23; p=0.11. There were 29 deaths following BV, including 17 (17.7%) due to HL, 6 (6.3%) due to toxicity of SCT or subsequent treatment and 6 (6.3%) due to other causes/unknown. There were 3 deaths following BVB, all due to toxicity of SCT or subsequent treatment (10%). Eight patients received single-agent bendamustine after failure of BV monotherapy, at a median of 2.4 months after commencing BV. The median number of bendamustine cycles delivered was 2 (range 1 - 6). The overall response rates was 62.5%. Two patients (25%) achieved complete metabolic response; both underwent subsequent SCT. Conclusion: In this retrospective analysis, use of BVB as 3L treatment for R/R HL was associated with higher response rates, transplant rates and FFTF compared with BV monotherapy. Although toxicity data were not available, our results are otherwise consistent with phase 2 trial data with BVB as second-line therapy (LaCasce, Blood 2018;132:40, Broccoli, Blood Cancer Journal 2019;9:100). These data demonstrate that BVB is a highly effective regimen in R/R HL, and support its use in transplant-fit patients.

Pramlintide an Adjunct to Insulin Therapy: Challenges and Recent Progress in Delivery.

Dysregulation of various glucoregulatory hormones lead to failure of insulin monotherapy in patients with diabetes mellitus due to various reasons, including severe hypoglycemia, glycemic hypervariability, and an increased risk of microvascular complications. However, pramlintide as an adjunct to insulin therapy enhances glucagon suppression and thereby offers improved glycemic control. Clinical studies have shown that pramlintide improves glycemic control, reduces postprandial glucose excursions, and promotes weight loss in patients with type 1 and type 2 diabetes. Although clinical benefits of pramlintide are well reported, there still exists a high patient resistance for the therapy, as separate injections for pramlintide and insulin must be administered. Although marketed insulin formulations generally demonstrate a peak action in 60-90 minutes, pramlintide elicits its peak concentration at around 20-30 minutes after administration. Thus, owing to the significant differences in pharmacokinetics of exogenously administered pramlintide and insulin, the therapy fails to elicit its action otherwise produced by the endogenous hormones. Hence, strategies such as delaying the release of pramlintide by using inorganic polymers like silica, synthetic polymers like polycaprolactone, and lipids have been employed. Also, approaches like noncovalent conjugation, polyelectrolyte complexation, and use of amphiphilic excipients for codelivery of insulin and pramlintide have been explored to address the issues with pramlintide delivery and improve patient adherence to the therapy. This approach may usher in a new era of diabetes management, offering patients multiple options to tailor their treatment and improve their quality of life. SIGNIFICANCE STATEMENT: To our knowledge, this is the first report that summarizes various challenges in insulin and pramlintide codelivery and strategies to overcome them. The paper also provides deeper insights into various novel formulation strategies for pramlintide that could further broaden the reader's understanding of peptide codelivery.

A Prognostic Model to Predict Ruxolitinib Discontinuation and Death in Patients with Myelofibrosis.

Most patients with myelofibrosis (MF) discontinue ruxolitinib (JAK1/JAK2 inhibitor) in the first 5 years of therapy due to therapy failure. As the therapeutic possibilities of MF are expanding, it is critical to identify patients predisposed to early ruxolitinib monotherapy failure and worse outcomes. We investigated predictors of early ruxolitinib discontinuation and death on therapy in 889 patients included in the "RUX-MF" retrospective study. Overall, 172 patients were alive on ruxolitinib after ≥5 years (long-term ruxolitinib, LTR), 115 patients were alive but off ruxolitinib after ≥5 yrs (short-term RUX, STR), and 123 patients died while on ruxolitinib after <5 yrs (early death on ruxolitinib, EDR). The cumulative incidence of the blast phase was similar in LTR and STR patients (p = 0.08). Overall survival (OS) was significantly longer in LTR pts (p = 0.002). In multivariate analysis, PLT < 100 × 109/L, Hb < 10 g/dL, primary MF, absence of spleen response at 3 months and ruxolitinib starting dose <10 mg BID were associated with higher probability of STR. Assigning one point to each significant variable, a prognostic model for STR (STR-PM) was built, and three groups were identified: low (score 0-1), intermediate (score 2), and high risk (score ≥ 3). The STR-PM may identify patients at higher risk of failure with ruxolitinib monotherapy who should be considered for alternative frontline strategies.

Elevated serum thyroid stimulating immunoglobulin linked to failure of first-line intravenous methylprednisolone monotherapy in moderate-to-severe thyroid eye disease.

To assess factors associated with failure of intravenous methylprednisolone (IVMP) monotherapy as the first-line treatment for thyroid eye disease (TED) and to identify patients who might benefit from supplementing mycophenolate mofetil (MMF) to IVMP. Data for all patients with TED treated with IVMP according to the EUGOGO protocol in our center between 2016-2021 were retrospectively analysed. Forty-seven patients (mean age 51.32 ± 14 years, 27 females) were enrolled. The mean time from first reported symptoms to first IVMP treatment was 12.1 ± 5.59 months (range 0-120). The mean clinical activity score (CAS) before treatment and at a mean of 5 and 12.2 weeks after treatment initiation was 6.00, 2.96, and 1.81, respectively (P < 0.01). Twenty-one patients (44.68%) were recommended second-line treatment: nine due to no response or worsening of CAS, six due to partial response, four with good response but early relapse after completion of treatment, and one due to late relapse. Eighteen of those 21 patients received second-line treatment which included rituximab (n = 7), MMF (n = 6), a second course of IVMP (n = 4), and tocilizumab (n = 1). Serum thyroid-stimulating immunoglobulin (TSI) levels were higher in patients who received second-line treatment compared with patients who responded well to first-line IVMP monotherapy at presentation (2135% vs 1159%, P = 0.05) and after completion of first-line treatment (2201% vs. 986%, P = 0.043). TED patients requiring second-line treatment after failed IVMP monotherapy had higher baseline and post-first-line treatment serum TSI levels. Those with elevated TSI may benefit from dual therapy (IVMP and MMF) and require closer monitoring.

Efficacy of salvage therapies for advanced acral melanoma after anti-PD-1 monotherapy failure: a multicenter retrospective study of 108 Japanese patients.

Anti-programmed cell death protein 1 (PD-1) monotherapy is one of the standard systemic therapies for advanced melanoma; however, the efficacy of salvage systemic therapies after PD-1 monotherapy failure (PD-1 MF), particularly in acral melanoma (AM), the main clinical melanoma type in Japanese patients, is unclear. This study aimed to investigate the efficacy of salvage systemic therapies in Japanese patients with AM after PD-1 MF. The study included 108 patients with advanced AM (palm and sole, 72; nail apparatus, 36) who underwent salvage systemic therapy at 24 Japanese institutions. We mainly assessed the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Thirty-six (33%) patients received ipilimumab, 23 (21%) received nivolumab and ipilimumab (nivo/ipi), 10 (9%) received cytotoxic chemotherapy, 4 (4%) received BRAF and MEK inhibitors (BRAFi/MEKi), and the remaining 35 (32%) continued with PD-1 monotherapy after disease progression. The ORRs in the ipilimumab, nivo/ipi, cytotoxic chemotherapy, and BRAFi/MEKi groups were 8, 17, 0, and 100%, respectively. The nivo/ipi group showed the longest OS (median, 18.9 months); however, differences in ORR, PFS, and OS between the groups were insignificant. The OS in the nivo/ipi group was higher in the palm and sole groups than in the nail apparatus group (median: not reached vs. 8.7 months, p < 0.001). Cox multivariate analysis demonstrated that nail apparatus melanoma independently predicted unfavorable PFS and OS (p = 0.006 and 0.001). The total OS (from PD-1 monotherapy initiation to death/last follow-up) was insignificant between the groups. Nivo/ipi was not more effective than cytotoxic chemotherapy and ipilimumab after PD-1 MF in patients with advanced AM. The prognosis after PD-1 MF would be poorer for nail apparatus melanoma than for palm and sole melanoma.

Association between intrapleural urokinase monotherapy and treatment failure in patients with pleural infection: a retrospective cohort study

BackgroundPleural infection, an infection of the pleural space, is frequently treated with antibiotics and thoracic tube drainage. In case of insufficient drainage, an intrapleural fibrinolytic agent is considered before surgical intervention. However, the effectiveness of fibrinolytic monotherapy is still controversial. Therefore, we aimed to examine the association between urokinase monotherapy and treatment failure in patients with pleural infection.MethodsIn this retrospective observational study, patients with pleural infection underwent chest tube insertion were divided into two groups including patients treated with or without intrapleural instillation of urokinase. The propensity score overlap weighting was used to balance the baseline characteristics between the groups. Treatment failure was defined by the composite primary outcome of in-hospital death and referral for surgery.ResultsAmong the 94 patients, 67 and 27 patients were in the urokinase and non-urokinase groups, respectively. Urokinase monotherapy improved the composite outcome between the groups (19.4% vs. 48.1%, p = 0.01). After adjusting using propensity score overlap weighting, urokinase monotherapy improved the composite outcome compared to the non-urokinase group (19.0% vs. 59.5%, p = 0.003).ConclusionsUrokinase monotherapy can be an important nonsurgical treatment option for patients with pleural infection.Trial registrationThe participants were retrospectively registered.

Model-Informed Precision Dosing Guidance of Ethosuximide Developed from a Randomized Controlled Clinical Trial of Childhood Absence Epilepsy.

Ethosuximide was identified as the optimal option for new-onset childhood absence epilepsy (CAE) in a randomized, two-phase dose escalation comparative effectiveness trial of ethosuximide, lamotrigine, and valproic acid. However, 47% of ethosuximide initial monotherapy participants experienced short-term treatment failure. This study aimed to characterize the initial monotherapy ethosuximide exposure-response relationship and to propose model-informed precision dosing guidance. Dose titration occurred over a 16-20-week period until patients experienced seizure freedom or intolerable side effects. Subjects with initial monotherapy failure were randomized to one of the other two medications and dose escalation was repeated. A population pharmacokinetic model was created using plasma concentration data (n = 1,320), collected at 4-week intervals from 211 unique participants during both the initial and second monotherapy phases. A logistic regression analysis was performed on the initial monotherapy cohort (n = 103) with complete exposure-response data. Eighty-four participants achieved seizure freedom with a wide range of ethosuximide area under the curves (AUC) ranging from 420 to 2,420 μg·h/mL. AUC exposure estimates for achieving a 50% and 75% probability of seizure freedom were 1,027 and 1,489 μg·h/mL, respectively, whereas the corresponding cumulative frequency of intolerable adverse events was 11% and 16%. Monte Carlo Simulation indicated a daily dose of 40 and 55 mg/kg to achieve 50% and 75% probability of seizure freedom in the overall population, respectively. We identified the need for adjusted mg/kg dosing in different body weight cohorts. This ethosuximide proposed model-informed precision dosing guidance to achieve seizure freedom carries promise to optimize initial monotherapy success for patients with CAE.

Multiple Pharmacotherapy Adaptations for Smoking Cessation Based on Treatment Response in Black Adults Who Smoke

Adapting to different smoking cessation medications when an individual has not stopped smoking has shown promise, but efficacy has not been tested in racial and ethnic minority individuals who smoke and tend to have less success in quitting and bear a disproportionate share of tobacco-related morbidity and mortality. To evaluate efficacy of multiple smoking cessation pharmacotherapy adaptations based on treatment response in Black adults who smoke daily. This randomized clinical trial of adapted therapy (ADT) or enhanced usual care (UC) included non-Hispanic Black adults who smoke and was conducted from May 2019 to January 2022 at a federally qualified health center in Kansas City, Missouri. Data analysis took place from March 2022 to January 2023. Both groups received 18 weeks of pharmacotherapy with long-term follow-up through week 26. The ADT group consisted of 196 individuals who received a nicotine patch (NP) and up to 2 pharmacotherapy adaptations, with a first switch to varenicline at week 2 and, if needed, a second switch to bupropion plus NP (bupropion + NP) based on carbon monoxide (CO)-verified smoking status (CO ≥6 ppm) at week 6. The UC group consisted of 196 individuals who received NP throughout the duration of treatment. Anabasine-verified and anatabine-verified point-prevalence abstinence at week 12 (primary end point) and weeks 18 and 26 (secondary end points). The χ2 test was used to compare verified abstinence at week 12 (primary end point) and weeks 18 and 26 (secondary end points) between ADT and UC. A post hoc sensitivity analysis of smoking abstinence at week 12 was performed with multiple imputation using a monotone logistic regression with treatment and gender as covariates to impute the missing data. Among 392 participants who were enrolled (mean [SD] age, 53 [11.6] years; 224 [57%] female; 186 [47%] ≤ 100% federal poverty level; mean [SD] 13 [12.4] cigarettes per day), 324 (83%) completed the trial. Overall, 196 individuals were randomized to each study group. Using intent-to-treat and imputing missing data as participants who smoke, verified 7-day abstinence was not significantly different by treatment group at 12 weeks (ADT: 34 of 196 [17.4%]; UC: 23 of 196 [11.7%]; odds ratio [OR], 1.58; 95% CI, 0.89-2.80; P = .12), 18 weeks (ADT: 32 of 196 [16.3%]; UC: 31 of 196 [15.8%]; OR, 1.04; 95% CI, 0.61-1.78; P = .89), and 26 weeks (ADT: 24 of 196 [12.2%]; UC: 26 of 196 [13.3%]; OR, 0.91; 95% CI, 0.50-1.65; P = .76). Of the ADT participants who received pharmacotherapy adaptations (135/188 [71.8%]), 11 of 135 (8.1%) were abstinent at week 12. Controlling for treatment, individuals who responded to treatment and had CO-verified abstinence at week 2 had 4.6 times greater odds of being abstinent at week 12 (37 of 129 [28.7%] abstinence) than those who did not respond to treatment (19 of 245 [7.8%] abstinence; OR; 4.6; 95% CI, 2.5-8.6; P < .001). In this randomized clinical trial of adapted vs standard of care pharmacotherapy, adaptation to varenicline and/or bupropion + NP after failure of NP monotherapy did not significantly improve abstinence rates for Black adults who smoke relative to those who continued treatment with NP. Those who achieved abstinence in the first 2 weeks of the study were significantly more likely to achieve later abstinence, highlighting early treatment response as an important area for preemptive intervention. ClinicalTrials.gov Identifier: NCT03897439.

Effects of dapagliflozin compared with glimepiride on body composition in Asian patients with type 2 diabetes inadequately controlled with metformin: The BEYOND study.

To evaluate the effect of dapagliflozin on body composition such as total body fat (BF) mass, abdominal visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) areas compared with glimepiride in Korean patients with type 2 diabetes. This was a 52-week, multicentre, randomized, parallel-group, open-label, Phase IV (NCT02564926) study. Patients with inadequate glycaemic control (glycated haemoglobin ≥7.0% and <10.0%) on metformin monotherapy (≥1000 mg/day) were randomized 1:1 to receive dapagliflozin 10 mg/day or glimepiride 1-2 mg/day for 12 months as an add-on to metformin. Baseline and end of study body composition evaluations included dual-energy X-ray absorptiometry and abdominal computed tomography scans. Of 124 enrolled patients from 14 centres, 121 received study treatment (dapagliflozin: 60; glimepiride: 61) and 106 (85.5%) completed the study. Over 52 weeks, the dapagliflozin group showed the following differences versus the glimepiride group: -2.59 kg BF mass, -1.94% BF%, -17.55 cm2 VAT area, -18.39 cm2 SAT area, -0.46% glycated haemoglobin, -18.25 mg/dl fasting blood glucose, -3.7 kg weight, -2.21 cm waist circumference, -1.37 kg/m2 body mass index, -6.81 mmHg systolic blood pressure and +657.71 ng/ml in adiponectin; all were statistically significant. Both groups had similar incidences of adverse events; however, hypoglycaemic events were mainly (12 of 15) reported in the glimepiride group. Dapagliflozin reduced total BF mass, abdominal VAT and SAT areas, and showed better glycaemic control than glimepiride. Being safe and well-tolerated, dapagliflozin appears to be a more favourable alternative to sulphonylureas as add-on therapy after metformin monotherapy failure in Korean patients with type 2 diabetes.

Ex-vivo analysis of programmed cell death on fibrolamellar carcinoma.

4103 Background: Fibrolamellar carcinoma (FLC) is a rare liver cancer with surgery as the only established treatment. Relapse is common (&gt;80%) and with 40% unresectable, there is a need for rationale systemic therapy. Empiric combinations, especially with lenvatinib (LEN) and gemcitabine (GEM), show promise, but are lacking a CLIA licensed laboratory rationale. Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD), from Nagourney Cancer Institute, is an attempt to meet this need. Methods: Nagourney Institute analyzed FLC tissue (as previously described), with a panel of 34 single/26 combinations of available/promising agents from 18 drug classes. Drug concentration with 50% cell death (LC50), below, within, or above 1-standard deviation of the mean (n ≥ 15), define Highly-Sensitive/Intermediate/Resistant, respectively. Active/Moderate/Inactive are similarly defined but with n &lt; 15. Actionable defines clinically available drug(s), not resistant/inactive and ≥ 6 assays. Results: Forty-four samples from 40 patients (17M,23F, age 6-56, 23 states/4 countries) were analyzed: 80% were viable and 69% of high quality for a total of 378 assays (avg 12/patient). However, all patients had actionable agents, and 78% of the assays showed activity in at least some patients. All the universally resistant/inactive assays (22%) were single agent. 76% of assays were actionable in at least one patient (100% for combinations compared to 62% for single agents). EVA-PCD replicate FLC studies and experience, such as the failure of monotherapy and the importance of LEN. Of 11 patients who had treatment that matched testing, 72% responded as predicted, including 6 with 100% response to LEN and/or QUE as predicted. Overall LEN/QUE, LEN/EVE, TRE, REG, QUE, 5FU/INF performed the best, while single agent ALP, CAB, LAR, VOR, GEM, DAS and IBR all showed 0% activity when tested &gt; 5 times. The largest challenge is the need for an adequate amount of viable tissue to arrive within 24 hours. However our experience demonstrates that it is feasible from other countries and across the US. Conclusions: This is the first demonstration of CLIA approved human FLC tumor testing. Data are in line with literature and correlates clinically. Prospective data are needed to fully incorporate EVA-PCD testing into the clinic. [Table: see text]

Efficacy of subsequent immunotherapy-tyrosine kinase inhibitor combinations after TKI monotherapy failure in patients with intermediate/poor risk metastatic clear cell renal cell carcinoma: A real-world retrospective study.

e16537 Background: The randomized phase 3 trials KEYNOTE-426, CheckMate 9ER, and CLEAR have demonstrated the efficiency of immunotherapy-based drug combinations as first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC). Immunotherapy-tyrosine kinase inhibitor (IO-TKI) has shown significant benefits over sunitinib monotherapy with respect to overall survival in mccRCC patients with intermediate/poor international metastatic database consortium (IMDC risk group). However, most of the patients received second-line TKI or immune checkpoint inhibitors therapy after TKI monotherapy failure in those clinical trials. The role of IO-TKI after disease progression in sunitinib monotherapy cohort was not fully investigated. We sought to evaluate the efficacy of second-line IO-TKI for mccRCC patients with IMDC intermediate/poor risk who had previously received at least one line of TKI monotherapy. Methods: We conducted retrospective analysis of IMDC intermediate/poor risk mccRCC patients treated with IO-TKI during any treatment line at our center from June 2019 to April 2022. Demographic, clinicopathological, and systemic therapy data were collected. The primary end point was overall survival (OS), defined as the time from initiation of treatment to death from any cause or last follow-up. The secondary end point was progression-free survival (PFS), defined as the time to the first documented disease progression. Results: Overall, 81 IMDC intermediate/poor risk mccRCC patients were enrolled, with a median follow-up of 17 months. 49 patients received first-line IO-TKI therapy, 32 patients who had previously received at least one line of TKI monotherapy received second-line IO-TKI after disease progression. The objective response rate (ORR) and median PFS of second-line IO-TKI after TKI monotherapy failure was 28.6% and 9 months, respectively. OS between first-line IO-TKI therapy and second-line IO-TKI after TKI monotherapy failure was not statistic significant (30 months vs. 26 months, p = 0.630). Conclusions: In this real-world retrospective study, we observed antitumor activity of second-line IO-TKI for mccRCC patients with IMDC intermediate/poor risk after disease progression. Notably, first-line IO-TKI therapy did not have superior OS when TKI monotherapy patients received second-line IO-TKI therapy. Randomized trials are needed to evaluate optimal combination strategies and sequencing of therapies in mccRCC.