Inhibitor-treated Patients Research Articles

Safety and efficacy of cobimetinib plus atezolizumab in patients with solid tumors: a phase II, open-label, multicenter, multicohort study

Although introduction of immune checkpoint inhibitors has revolutionized the treatment of cancer, their response rates are generally low. Preclinical and early phase clinical data suggest that MEK inhibition may sensitize tumors to immune checkpoint inhibitors by upregulating tumor antigen expression, programmed death-ligand 1 (PD-L1) expression, and tumor T-cell infiltration. We evaluated the efficacy and safety of cobimetinib plus atezolizumab in patients with advanced solid tumors in the open-label, multicohort phase II COTEST study. This analysis of the COTEST trial included patients from cohorts 1-4 [1-3: anti-programmed cell death protein 1 (PD-1)/PD-L1 treatment-naive patients; 4: patients with disease progression on anti-PD-1/anti-PD-L1 treatment] who received cobimetinib 60 mg once daily for the first 21 days and intravenous infusions of atezolizumab 840 mg on days 1 and 15 of each 28-day cycle. Efficacy endpoints included objective response rate, overall survival, progression-free survival (PFS), and disease control rate. Overall, 77 patients were enrolled in cohorts 1-4 (78% male; median age 62.8 years). Objective response rate was 20% in cohort 1 [squamous cell carcinoma of the head and neck (SCCHN)], 30% in cohort 2 (urothelial carcinoma), and 18% in cohort 3 (renal cell carcinoma); there were no responders among 20 patients in cohort 4 (SCCHN). The disease control rates in cohorts 1-4 were 50%, 40%, 24%, and 25%, respectively. The median PFS was 5.5, 3.4, 3.4, and 3.6 months in cohorts 1-4, respectively, and the median overall survival was 16.8, 18.7, 21.7, and 7.7 months, respectively. Most adverse events were of grade 1/2 and were manageable. Cobimetinib plus atezolizumab had moderate activity in patients with anti-PD-1/PD-L1 treatment-naive SCCHN and urothelial carcinoma, and weak activity in anti-PD-1/PD-L1 treatment-naive renal cell carcinoma, and no activity in checkpoint inhibitor-treated patients.

Response to checkpoint inhibition and targeted therapy in melanoma patients with concurrent haematological malignancies

BackgroundPatients diagnosed with haematologic malignancies (HMs) have a higher risk of developing subsequent solid tumours, such as melanoma. Patients with HM were mostly excluded from clinical trials but potentially derive less benefit from immune checkpoint inhibitors (ICIs) due to disease- or treatment-related T- or B-cell dysfunction. MethodsAll advanced melanoma patients treated with anti-PD-1-based treatment or targeted therapy between 2015 and 2021 were included from the prospective nationwide Dutch Melanoma Treatment Registry. Progression-free survival (PFS) and melanoma-specific survival (MSS) were analysed for patients with HM (HM+) and without HM (HM−). A cox model was used to account for confounders associated with PFS and MSS. ResultsIn total, 4638 advanced melanoma patients received first-line anti-PD-1 monotherapy (n = 1763), ipilimumab-nivolumab (n = 800), or BRAF(/MEK) inhibitors (n = 2075). Concurrent HMs were present for 46 anti-PD1-treated patients, 11 ipilimumab-nivolumab-treated patients and 43 BRAF(/MEK)-inhibitor-treated patients. In anti-PD-1-treated patients, the median PFS was 2.8 months for HM+ and 9.9 months for HM− (p = 0.01). MSS was 41.2 months for HM+ and 58.1 months for HM− (p = 0.00086). In multivariable analysis, the presence of an HM was significantly associated with higher risk of melanoma progression (HRadj 1.62; 95% confidence interval [95% CI] 1.15–2.29; p = 0.006) and melanoma-related death (HRadj 1.74; 95% CI 1.09–2.78; p = 0.020). Median PFS and MSS for first-line BRAF(/MEK-) inhibitor-treated HM+ and HM− patients were not significantly different. ConclusionsPatients with HM and advanced melanoma show significantly worse melanoma-related outcomes when treated with ICI, but not targeted therapy, compared to patients without HM. Clinicians should be aware of potentially altered effectiveness of ICI in patients with active HM.

LAL deficiency induced myeloid-derived suppressor cells as targets and biomarkers for lung cancer

BackgroundMyeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells in tumor microenvironment, which suppress antitumor immunity. Expansion of various MDSC subpopulations is closely associated with poor clinical outcomes in...

Functional Engagement of the PD-1/PD-L1 Complex But Not PD-L1 Expression Is Highly Predictive of Patient Response to Immunotherapy in Non-Small-Cell Lung Cancer.

In many cancers, the expression of immunomodulatory ligands leads to immunoevasion, as exemplified by the interaction of PD-L1 with PD-1 on tumor-infiltrating lymphocytes. Profound advances in cancer treatments have come with the advent of immunotherapies directed at blocking these immuno-suppressive ligand-receptor interactions. However, although there has been success in the use of these immune checkpoint interventions, correct patient stratification for these therapies has been challenging. To address this issue of patient stratification, we have quantified the intercellular PD-1/PD-L1 interaction in formalin-fixed paraffin-embedded tumor samples from patients with non-small cell lung carcinoma, using a high-throughput automated quantitative imaging platform (quantitative functional proteomics [QF-Pro]). The multisite blinded analysis across a cohort of 188 immune checkpoint inhibitor-treated patients demonstrated the intra- and intertumoral heterogeneity of PD-1/PD-L1 immune checkpoint engagement and notably showed no correlation between the extent of PD-1/PD-L1 interaction and PD-L1 expression. Importantly, PD-L1 expression scores used clinically to stratify patients correlated poorly with overall survival; by contrast, patients showing a high PD-1/PD-L1 interaction had significantly better responses to anti-PD-1/PD-L1 treatments, as evidenced by increased overall survival. This relationship was particularly strong in the setting of first-line treatments. The functional readout of PD-1/PD-L1 interaction as a predictive biomarker for the stratification of patients with non-small-cell lung carcinoma, combined with PD-L1 expression, should significantly improve the response rates to immunotherapy. This would both capture patients excluded from checkpoint immunotherapy (high PD-1/PD-L1 interaction but low PD-L1 expression, 24% of patients) and additionally avoid treating patients who despite their high PD-L1 expression do not respond and suffer from side effects.

Computed tomography-detected extramural venous invasion-related gene signature: a potential negative biomarker of immune checkpoint inhibitor treatment in patients with gastric cancer

BackgroundTo investigate the association between computed tomography (CT)-detected extramural venous invasion (EMVI)-related genes and immunotherapy resistance and immune escape in patients with gastric cancer (GC).MethodsThirteen patients with pathologically proven locally advanced GC who had undergone preoperative abdominal contrast-enhanced CT and radical resection surgery were included in this study. Transcriptome sequencing was multidetector performed on the cancerous tissue obtained during surgery, and EMVI-related genes (P value for association < 0.001) were selected. A single-sample gene set enrichment analysis algorithm was also used to divide all GC samples (n = 377) in The Cancer Genome Atlas (TCGA) database into high and low EMVI-immune related groups based on immune-related differential genes. Cluster analysis was used to classify EMVI-immune-related genotypes, and survival among patients was validated in TCGA and Gene Expression Omnibus (GEO) cohorts. The EMVI scores were calculated using principal component analysis (PCA), and GC samples were divided into high and low EMVI score groups. Microsatellite instability (MSI) status, tumor mutation burden (TMB), response rate to immune checkpoint inhibitors (ICIs), immune escape were compared between the high and low EMVI score groups. Hub gene of the model in pan-cancer analysis was also performed.ResultsThere were 17 EMVI-immune-related genes used for cluster analysis. PCA identified 8 genes (PCH17, SEMA6B, GJA4, CD34, ACVRL1, SOX17, CXCL12, DYSF) that were used to calculate EMVI scores. High EMVI score groups had lower MSI, TMB and response rate of ICIs, status but higher immune escape status. Among the 8 genes used for EMVI scores, CXCL12 and SOX17 were at the core of the protein–protein interaction (PPI) network and had a higher priority in pan-cancer analysis. Immunohistochemical analysis showed that the expression of CXCL12 and SOX17 was significantly higher in CT-detected EMVI-positive samples than in EMVI-negative samples (P < 0.0001).ConclusionA CT-detected EMVI gene signature could be a potential negative biomarker for ICIs treatment, as the signature is negatively correlated with TMB, and MSI, resulting in poorer prognosis.

The impact of smoking on response to tumor necrosis factor-α inhibitor treatment in patients with ankylosing spondylitis.

To investigate the impact of smoking on disease activity, treatment retention, and response in patients with ankylosing spondylitis (AS) treated with their first tumor necrosis factor-α inhibitor (TNFi). AS patients who started their first TNFi treatment for the active axial disease (BASDAI ≥ 4) from TURKBIO Registry were included. Treatment response of smoker (current and ex-smokers) and nonsmoker (never smoker) patients were primarily evaluated as achievement of BASDAI50 or improvement in BASDAI at least 20 mm at 3 months and 6 months compared to baseline. There were 322 patients with AS (60% male, 59% smoker, mean age: 38.3 years). The median follow-up time was 2.8 years (Q1- Q3: 1.3-3.8), and disease duration was 3.5 years (Q1-Q3: 0.7-8.2). Smokers had male predominance (p < 0.001), lower ESR (p = 0.03), higher BASDAI (p = 0.02), BASFI (p = 0.05), HAQ-AS (p = 0.007), and ASDAS-CRP (p = 0.04) compared with nonsmokers at baseline. In the multivariate analysis, male gender [OR 2.7 (95%CI 1.4-5), p = 0.002], and concomitant conventional synthetic disease-modifying antirheumatic drug use [OR 2.4 (95%CI 1.1-5.2), p = 0.03] were associated with better treatment response. There was an association of male gender [HR 2.4 (95%CI 1.6-3.7), p < 0.001], older age (≥30years) [HR 1.8 (95%CI 1.1-2.8), p = 0.01], and response to treatment [HR 1.8 (95%CI 1.2-2.9), p = 0.008] with better treatment retention. No impact of smoking status was found on treatment retention and response in univariate and multivariate analyses. This study suggested that smoking was associated with poorer patient-reported outcomes in biologic naïve AS patients initiating their first TNFi treatment, but it had no impact on the TNFi treatment response and retention rate.

Inflammatory biomarkers may predict response to phosphodiesterase type 5 inhibitor treatment in patients with erectile dysfunction.

In this study, we aimed to evaluate the clinical utility of the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and monocyte/high-density lipoprotein cholesterol ratio (MHR) in predicting response to a phosphodiesterase type 5 inhibitor (PDE5i) when used as the first-line medical treatment of erectile dysfunction (ED). This study prospectively included 185 patients who were diagnosed with ED and started PDE5i treatment. After PDE5i treatment, 107 (57.8%) patients with an International Index of Erectile Function-5 (IIEF-5) score below 22 were assigned to Group 1, and 78 (42.2%) patients with an IIEF-5 score of 22 or above were assigned to Group 2. The outcome measures of the study were demographic characteristics and inflammation markers between the groups. The mean IIEF-5 change after PDE5i treatment was 6.1±4.2 points in Group 1 and 11.5±3.2 points in Group 2 (p=0.001). The mean age was 54.6±9.2 years in Group 1 and 47.8±10.3 years in Group 2 (p<0.001), and the median fasting blood glucose values of Groups 1 and 2 were 105 (36) mg/dL and 97 (23) mg/dL, respectively (p=0.010). The LMR and MHR values were 2.39±0.23 and 13.8±7, respectively, for Group 1, and 2.03±0.22 and 17±6.6, respectively, for Group 2 (p=0.044 and p=0.002, respectively). On multivariable analysis, younger age and increased MHR were independent predictors of benefit from PDE5i treatment. This study showed that only MHR as an inflammatory biomarker was an independent predictor for response to PDE5i in the treatment of ED. Also, several factors were predictive of treatment failure.

Targeting the FGF/FGFR axis and its co-alteration allies

We analyzed the FGF/FGFR and co-alteration cancer landscape, hypothesizing that combination therapy might be useful in the presence of co-drivers. We describe FGF/FGFR-altered pathways, prognosis, and co-alterations [cBioPortal (N= 7574)] and therapeutic outcomes [University of California San Diego Molecular Tumor Board (MTB) (N= 16)]. Patients whose cancers harbored FGF/FGFR alterations (N= 1074) versus those without them (N= 6500) had shorter overall survival (OS) (median: 23.1 versus 26.4 months, P= 0.038) (cBioPortal). Only 6.1% (65/1074 patients) had no pathogenic co-alterations accompanying FGF/FGFR axis abnormalities. The most frequently co-altered pathways/genes involved: TP53 (70%); cell cycle (58%); PI3K (55%); and receptor tyrosine kinases and mitogen-activated protein kinase (MAPK) (65%). Harboring alterations in both FGF/FGFR and in the TP53 pathway or in the cell cycle pathway correlated with shorter OS (versus FGF/FGFR-altered without those co-altered signals) (P= 0.0001 and 0.0065). Four of 16 fibroblast growth factor receptor (FGFR) inhibitor-treated patients presented at MTB attained durable partial responses (PRs) (9, 12, 22+, and 52+ months); an additional two, stable disease (SD) of ≥6 months (13+ and 15 months) [clinical benefit rate (SD ≥ 6 months/PR)= 38%]. Importantly, six patients with cyclin pathway co-alterations received the CDK4/6 inhibitor palbociclib (75 mg p.o. 3 weeks on, 1 week off) and the multikinase FGFR inhibitor lenvatinib (10 mg p.o. daily); three (50%) achieved a PR [9 (ovarian), 12 (biliary), and 52+ months (osteosarcoma)]. Palbociclib and lenvatinib were tolerated well. FGF/FGFR alterations portend a poor prognosis and are frequently accompanied by pathogenic co-aberrations. Malignancies harboring co-alterations that activate both cyclin and FGFR pathways can be co-targeted by CDK4/6 and FGFR inhibitors.

Short-term efficacy of angiotensin receptor-neprilysin inhibitor treatment in patients with ST-segment elevation myocardial infarction with reduced ejection fraction after primary percutaneous coronary intervention: a propensity score matching study

BackgroundAcute myocardial infarction (AMI) causes a series of pathophysiological changes, including myocardial necrosis, myocardial edema, and microvascular damage. These changes eventually lead to severe cardiovascular events, such as ventricular remodeling, heart failure, and papillary dysfunction. Impaired cardiac function after ST-segment elevation myocardial infarction (STEMI) often manifests as a decrease in left ventricular ejection fraction (LVEF). Clinical trials have shown that angiotensin receptor-neprilysin inhibitor (ARNI) treatment has the potential to improve LVEF in patients with STEMI after primary percutaneous coronary intervention (PPCI).ObjectiveThe purpose of this study was to evaluate the short-term efficacy of ARNI versus angiotensin-converting enzyme inhibitor (ACEI) treatment in patients with STEMI who exhibit reduced LVEF after PPCI.MethodsA total of 169 patients with STEMI exhibiting post-PPCI LVEF below 50% who were orally treated with ARNI between December 2017 and August 2020 were selected as the experimental group. A total of 136 patients with STEMI exhibiting post-PPCI LVEF below 50% who were orally treated with an ACEI between January 2016 and August 2020 were selected as the control group. LVEF was measured using cardiac ultrasonography during hospitalization and 3 months after discharge. Linear and logistic regression analyses were performed to compare patient demographics and hospitalization variables to evaluate the risk factors for change and rate of improvement in LVEF. Propensity score matching (PSM) was used to account for confounding factors.ResultsAfter PSM, the study cohort consisted of 81 patients in the ARNI group and 123 in the ACEI group. After an average follow-up period of 3 months, no significant difference was noted in the LVEF improvement rate between the experimental and control groups (P = 0.475, 95% CI: -0.062 to 0.134). Multivariate logistic regression analysis also indicated no significant correlation between the change in LVEF and oral ARNI treatment in patients with STEMI exhibiting reduced LVEF after PPCI (P > 0.05).ConclusionThe short-term effect of ARNI treatment on the cardiac function of patients with STEMI and reduced LVEF after PPCI is not superior to that of ACEI treatment.

Characteristics, treatment, and outcome of diverticulitis after immune checkpoint inhibitor treatment in patients with malignancies.

Immune checkpoint inhibitors (ICIs) are efficacious for treating various malignancies. In addition to immune-related adverse events (irAEs), growing evidence suggests that ICIs might also be associated with diverticulitis. We aim to assess the clinical presentations and management of colonic diverticulitis among cancer patients after ICI treatment. A retrospective study was conducted on ICI-treated adult cancer patients between 01/2010 and 06/2020. Patients were grouped based on when diverticulitis developed relative to ICI treatment, either before (controls) or after (cases). Patient clinical characters, treatment, and outcomes were compared between both groups. 77 eligible patients were included: 63 patients developed diverticulitis after ICI exposure (46 had initial episode after ICI exposure, 17 had a history of diverticulitis prior then recurred after ICI exposure), and 14 had diverticulitis before ICI exposure. Diverticulitis occurred after a median of 129days after ICI initiation. Clinical characteristics overlapped with traditional diverticulitis. 93% of patients had symptom resolution after treatment, while 23.8% experienced complications. These patients exhibited higher rates of hospitalization (87% vs 48%, P = 0.015) and surgery/interventional radiology procedures (27% vs 0, P = 0.002), and worse overall survival (P = 0.022). History of diverticulitis was not associated with a more severe disease course. Immunosuppressants (e.g., corticosteroids) were rarely required unless for concurrent ICI-mediated colitis. Colonic diverticulitis can occur after ICI therapy at very low incidence (0.5%). Its clinical presentation, evaluation, and management are similar to traditional diverticulitis, but associated with higher complication rates requiring surgical intervention and has lower overall survival.

Effect of SGLT-2 inhibitors on cardiac autonomic function in type 2 diabetes mellitus: a meta-analysis of randomized controlled trials.

Cardiac autonomic neuropathy (CAN) is a common complication of type 2 diabetes mellitus (T2DM). We sought to determine whether sodium-glucose co-transporter-2 (SGLT-2) inhibitors affect indices of CAN in patients with T2DM. We searched for parallel group or cross-over randomized controlled trials (RCTs) enrolling adult subjects with T2DM, assigned to a SGLT-2 inhibitor versus placebo or active comparator and addressing their effect on CAN. PubMed, Cochrane Library and gray literature sources were searched. We set as primary efficacy outcome the change in the low-frequency-to-high-frequency (LF/HF) ratio. We set as secondary efficacy outcomes: first, the change in the standard deviation of all 5min mean normal RR intervals and second, the change in the square root of the mean of the sum of the squares of differences between adjacent RR intervals (r-MSSD). Protocol has not been registered at a publicly available repository. We pooled data from four RCTs in a total of 247 subjects with T2DM. SGLT-2 inhibitor treatment did not have a significant effect on LF/HF ratio (MD = - 0.11, 95% CI - 0.35 to 0.12, I2 = 0%, p = 0.36). SGLT-2 inhibitor treatment did not have a significant impact either on SDNN (MD = - 2.83, 95% CI - 7.41 to 1.75, I2 = 31%, p = 0.23), or on r-MSSD (MD = - 0.14, 95% CI - 3.52 to 3.25, I2 = 46%, p = 0.94). Overall risk of bias was graded as low across the selected RCTs. SGLT-2 inhibitor treatment in patients with T2DM does not seem to provide any significant beneficial effect on CAN indices.

Absolute eosinophil count may be an optimal peripheral blood marker to identify the risk of immune-related adverse events in advanced malignant tumors treated with PD-1/PD-L1 inhibitors: a retrospective analysis

BackgroundThis study aimed to investigate the predictive values of serum biomarkers including absolute eosinophil count (AEC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) with respect to immune-related adverse events (irAEs) during anti-PD-1/PD-L1 inhibitor treatment in patients with advanced malignant tumors.MethodsWe retrospectively analyzed 95 patients with advanced cancer who were treated with anti-PD-1/PD-L1 inhibitors from January 1, 2017, to May 1, 2020, in our cancer center. We then analyzed associations between irAEs and anti-PD-1/PD-L1 inhibitor responses and evaluated the predictive values of serum biomarkers with respect to the risk of irAEs.ResultsThe incidence of irAEs was 55.8%. There were no statistically significant differences between the irAEs and no-irAEs groups in an objective response rate (ORR) or disease control rate (DCR). However, landmark analysis showed that the irAEs group had better survival after 120 days following the initiation of anti-PD-1/PD-L1 inhibitor treatment, compared with the no-irAEs group. The incidences of irAEs were greater in the high-AEC and low-NLR groups than in the low-AEC and high-NLR groups. Univariate logistic analysis showed that low NLR, ECOG performance status (0–1), and high AEC were risk factors for irAEs. Multivariate logistic analysis showed that high AEC and good ECOG performance status were independent predictors for irAEs.ConclusionsirAEs may be associated with a survival benefit. Baseline AEC is a strong predictor of irAEs in patients undergoing treatment with anti-PD-1/PD-L1 inhibitors.

Thyroid dysfunction during PD-1 inhibitor treatment in patients with cancer: Incidence and association with progression-free survival.

The use of programmed cell death-1 (PD-1) inhibitors has recently been approved in China. As a consequence, the identification of relevant prognostic markers that can assess the efficacy of these compounds is required. Therefore, the present study aimed to explore the incidence of thyroid dysfunction and its ability to predict progression-free survival (PFS) in Chinese patients with cancer who received PD-1 inhibitor treatment. Data from 72 patients with cancer who received treatment with PD-1 inhibitors alone or in combination with chemotherapy or targeted drugs were analyzed. Moreover, the expression levels of free triiodothyronine, thyroxine, and thyrotropin during treatment were assessed to evaluate thyroid dysfunction. A total of 26 (36.1%) patients who had received PD-1 inhibitors developed thyroid dysfunction. Specifically, the incidence of thyroid dysfunction was 35.6% in patients with lung cancer, 25.0% in patients with malignant melanoma, and 46.7% in patients with other types of cancer. In addition, the median PFS was 7.0 (95% confidence interval, 4.9-9.1) months, whereas the 1- and 2-year PFS rates were 35.1 and 26.2%, respectively. Generally, patients with thyroid dysfunction exhibited longer PFS compared with those without thyroid dysfunction (P=0.001). Subgroup analyses were subsequently performed, which demonstrated that thyroid dysfunction was associated with longer PFS in patients with malignant melanoma (P=0.039) and other types of cancer (P=0.002), but not in those with lung cancer (P=0.083). These findings were noted in patients who received PD-1 inhibitor monotherapy (P=0.003), but not PD-1 inhibitor plus chemotherapy (P=0.172) or PD-1 inhibitor plus targeted therapy (P=0.582). Finally, thyroid dysfunction [P=0.001; hazard ratio (HR)=0.260] and PD-1 inhibitor monotherapy (P=0.015; HR=2.231) were identified as independent factors that could predict PFS. In conclusion, the present study demonstrated that thyroid dysfunction during PD-1 inhibitor treatment could be used as a potential marker for the prognosis of favorable PFS in patients with cancer.

Absolute and Relative Risk of New-Onset Psoriasis Associated With Tumor Necrosis Factor-α Inhibitor Treatment in Patients With Immune-Mediated Inflammatory Diseases

Tumor necrosis factor-α inhibitor (TNFi)-associated psoriasis is a rare adverse event following TNFi treatment. Data on the risk of developing TNFi-associated psoriasis when treated with TNFi are sparse. To investigate the associated risk between new-onset psoriasis and TNFi treatment compared with nonbiologic conventional treatment. Using Danish national registries (1995-2018), this cohort study included patients with inflammatory bowel disease (IBD) and/or rheumatoid arthritis (RA) who received either conventional therapy or TNFi treatment. Patients may not have been diagnosed with psoriasis prior to initiation of treatment. Patients were followed up for up to 5 years. Cox regression models with robust variance were used to compare the risk of developing any type of psoriasis, nonpustular psoriasis, and pustular psoriasis. Patients receiving conventional therapy were used as reference. Data analysis was performed from January 1995 to December 2018. For the present study, the term conventional therapy was used for the nonbiological therapy. For biological therapy, a distinction was made between TNFi treatment and non-TNFi biological therapy. The outcome of psoriasis was defined as a registered International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code of psoriasis and/or having 2 consecutive prescriptions of topical vitamin D analogues. The study included 109 085 patients, of which 62% were female. Median (IQR) age was 50 (34-64) years. Of the included patients, 108 024 received conventional therapy and 20 910 received TNFi treatment. During follow-up, 1471 (1.4%) patients developed any type of psoriasis, of which 1332 developed nonpustular psoriasis, 127 patients developed palmoplantar pustulosis, and 12 patients developed generalized pustulosis. The incidence rates for developing any type of psoriasis per 1000 patient-years were 3.0 (95% CI, 2.9-3.2) for conventional therapy and 7.8 (95% CI, 7.5-8.9) for TNFi. During treatment with TNFi, the hazard ratio was 2.12 (95% CI, 1.87-2.40; P < .001) for developing nonpustular psoriasis and 6.50 (95% CI, 4.60-9.23; P < .001) for pustular psoriasis compared with conventional treatment. Exposure needed for 1 additional patient to be harmed was 241 patient-years for any type of TNFi-associated psoriasis, 342 patient-years for nonpustular psoriasis, and 909 patient-years for pustular psoriasis. In a Danish nationwide cohort of patients with immune-mediated inflammatory diseases treated with TFNi or conventional treatment and no history of psoriasis, in TFNi-treated patients, nonpustular types of psoriasis constituted the most events, whereas pustular types of psoriasis had the highest relative risk. Although the risk of new-onset psoriasis increased for both nonpustular and pustular types of psoriasis in TFNi-treated patients, the absolute risk remained modest at 241 patient-years of exposure need for 1 additional event and an estimated absolute risk difference around 5 per 1000 patient-years, indicating that the approach to treatment of patients in need of TNFi treatment should not change.

CO126 Effectiveness of Six PD-1/PD-L1 Inhibitors in Treatment of Patients with Advanced Squamous Non-Small Cell Lung Cancer: An Indirect Comparison and Partitioned Survival Model

Since 2019, six PD-1/PD-L1 inhibitors (sugemalimab, sintilimab, pembrolizumab, camrelizumab, atezolizumab and tislelizumab) are already in or about to be launched in the Chinese market, but there are no head-to-head RCT studies reporting the comparative efficacy nor the long-term effectiveness. Therefore, this study aims to indirectly compare these six drugs and project to the final outcome in order to provide evidence for clinical decision and Chinese national reimbursement drug listing.

MTOR Inhibitor Treatment in Patients with Tuberous Sclerosis Complex Is Associated with Specific Changes in microRNA Serum Profile.

The aim of this study was to determine the serum profiles of miRNAs in patients with tuberous sclerosis (TSC) upon sirolimus treatment and compare them with those previously treated with everolimus in a similarly designed experiment. Serum microRNA profiling was performed in ten TSC patients before sirolimus therapy and again after 3–6 months using qPCR panels (Exiqon). Of 752 tested miRNAs, 28 showed significant differences in expression between TSC patients before and after sirolimus treatment. Of these, 11 miRNAs were dysregulated in the same directions as in the sirolimus groupcompared with the previously described everolimus group, miR-142-3p, miR-29c-3p, miR-150-5p, miR-425-5p, miR-376a-3p, miR-376a-3p, miR-532-3p, and miR-136-5p were upregulated, while miR-15b-3p, miR-100-5p, and miR-185-5p were downregulated. The most significant changes of expression, with fold changes exceeding 1.25 for both treatments, were noted for miR-136-5p, miR-376a-3p, and miR-150-5p. The results of a pathway analysis of the possible target genes for these miRNAs indicated the involvement of the Ras and MAPK signaling pathway. Upregulation of miR-136, miR-376a-3p, and miR-150-5p was noted in TSC patients treated with mTOR inhibitors, indicating a role in the downregulation of the mTOR pathway. Further studies are needed to determine the relationship between upregulated microRNAs and treatment efficacy.

Outcome of Elective Checkpoint Inhibitor Discontinuation in Patients with Metastatic Melanoma Who Achieved a Complete Remission: Real-World Data.

Checkpoint inhibitor therapy for metastatic melanoma has dramatically improved outcomes. Currently, 20 to 40% of treated patients achieve lengthy remissions. It is not clear whether patients in remission require ongoing therapy or if treatment can be safely discontinued. A retrospective chart review was performed of patients who underwent elective treatment discontinuation after two negative scans three months apart. Of 132 checkpoint inhibitor-treated patients, 46 achieved a complete response (34.8%) and electively discontinued therapy. The progression-free survival was 97.5% at 1 year and 94.7% at 3 years following treatment discontinuation. The median duration of follow-up was 26 months. In total, 4 of 46 individuals (8.7%) eventually relapsed (median time to relapse: 27 months). The median disease-specific survival of the entire cohort was not reached and was 100% at 4 years from the start of therapy. Two patients eventually died, one from melanoma and the other from an unrelated illness. We have identified an elective treatment discontinuation strategy that is generalizable to a variety of checkpoint inhibitor ± targeted therapy regimens. We found that most complete remissions remained durable after elective treatment discontinuation. We hypothesize that this approach could decrease potential drug toxicities, reduce the treatment-related financial burden, and improve patients’ quality of life.

Neutrophil to Lymphocyte ratio is significantly reduced after Sodium glucose cotransporter-2 inhibitor treatment in patients with type 2 diabetes mellitus

Background. Sodium glucose cotransporter-2 inhibitors (SGLT2i) are novel therapeutic agents that became available in the treatment of type 2 diabetes mellitus (T2DM). This group of antidiabetic agents are associated with reduced glycated hemoglobin (HbA1c), fasting glucose, body weight and body mass index (BMI) in diabetic patients. All those beneficial effects may also be associated with a reduction in inflammatory burden. The purpose of the study is to compare neutrophil to lymphocyte ratio (NLR), a novel inflammatory marker derived from hemogram, before and 6 months after SGLT2i treatment in diabetic subjects. We also aimed to compare fasting glucose, HbA1c and other metabolic parameters as well as anthropometric measures (weight, BMI) before and 6 month after initiation of SGLT2i therapy. Materials and methods. The subjects with type T2DM that show up in internal medicine outpatient clinics of Abant Izzet Baysal University Hospital between January 2021 and December 2021 were enrolled to the study. Pretreatment and posttreatment NLR and other parameters were compared. We also obtained pretreatment and posttreatment laboratory data including urea, creatinine, fasting glucose, HbA1c, glomerular filtration rate, aspartate and alanine transaminases, plasma sodium and potassium. Results. Fasting glucose was reduced from 195±72 mg/dl in pretreatment period to 146±53 mg/dl in posttreatment period (p&lt;0.001). HbA1c was reduced from 9.1±1.7% in pretreatment period to 7.7±1.7% in posttreatment period (p&lt;0.001). The NLR before treatment was 2.6±1.2% before SGLT2i treatment and was reduced to 2.2±0.6% in 6th month of SGLT2i therapy. NLR was significantly decreased after treatment (p=0.003). Conclusions. We suggest that NLR levels could be a marker of reduced inflammatory burden in T2DM subjects receiving SGLT2i treatment.

Stop of proton-pump inhibitor treatment in patients with liver cirrhosis (STOPPIT): study protocol for a prospective, multicentre, controlled, randomized, double-blind trial

BackgroundProton-pump inhibitors (PPI) are liberally prescribed in patients with liver cirrhosis. Observational studies link PPI therapy in cirrhotic patients with an increased risk for infectious complications, hepatic encephalopathy and an increased risk for hospitalization and mortality. However, patients with liver cirrhosis are also considered to be at risk for peptic ulcer bleeding. The STOPPIT trial evaluates if discontinuation of a pre-existing PPI treatment delays a composite endpoint of re-hospitalization and/or death in patients (recently) hospitalized with liver cirrhosis compared to patients on continued PPI medication.MethodsThe STOPPIT-trial is a prospective, multicentre, randomized, double-blinded, placebo-controlled, parallel-group trial. In total, 476 patients with complicated liver cirrhosis who already receive long-term PPI therapy without evidence-based indication are 1:1 randomized to receive either esomeprazole 20 mg (control group) or placebo (intervention group) for 360 days. Patients with an indication for PPI therapy (such as a recent diagnosis of peptic ulcers, severe reflux esophagitis, severe hemorrhagic gastritis, recent endoscopic therapy for oesophageal varices) are excluded. The primary composite endpoint is the time-to re-hospitalization and/or death. Secondary endpoints include rates of re-hospitalization, mortality, occurrence of infections, hepatic decompensation and acute-on-chronic liver failure. The safety endpoint is defined as manifestation of an evidence-based indication for PPI re-therapy. The impact of PPI continuation or discontinuation on the intestinal microbiota will be studied. The recruitment will take place at 18 study sites throughout Germany. Recruitment has started in April 2021.DiscussionThe STOPPIT trial is the first clinical trial to study the effects of PPI withdrawal on relevant outcome variables in patients with complicated liver cirrhosis. If the hypothesis that PPI withdrawal improves clinical outcomes of cirrhosis patients is confirmed, this would argue for a strong restriction of the currently liberal prescription practice of PPIs in this population. If, on the other hand, the trial demonstrates an increased risk of gastrointestinal bleeding events in patients after PPI withdrawal, this could create a rationale for a more liberal, prophylactic PPI treatment in patients with liver cirrhosis.Trial registrationEU clinical trials register EudraCT 2019-005008-16 (registered December 27, 2019). ClinicalTrials.gov NCT04448028 (registered June 25, 2020). German Clinical Trials Register DRKS00021290 (registered March 10, 2021).

IDF21-0150 A dose-based comparison of safety among sodium-glucose co-transporter inhibitor-treated type1 diabetes patients

Background: The dose-wise variation in sodium-glucose co-transporter inhibitor (SGLTi) treated type 1 diabetes mellitus (T1DM) patients' safety profile remains poorly understood. Aim: Therefore, this study aims to study it. Method: A database search occurred in PubMed, Embase, and Scopus databases for double-blinded randomized controlled trials reporting the above outcomes. The risk of bias assessment of the reviewed RCTs happened using the Cochrane tool. Pairwise random-effect meta-analysis (DerSimonian and Laird method) was used to compare SGLTis’ safety between its mega (maximum dose in which it got tested in the reviewed trials) and low dosages and between SGLTi dosage irrespectively and placebo. The relative safety between respective and different generic SGLTi dosages was contrasted by network meta-analysis (NMA). The NMA models included double-blinded RCTs' data and excluded pooled safety data from RCTs with different follow-up duration to reduce the intransitivity risk. Effect-sizes got estimated in risk ratio (RR). The statistical significance estimation occurred at p<0.05 and 95% confidence interval (CI). Stata software, v16, was used for analysis. Results: This review incorporated fifteen studies sourcing data from 7,330 participants from 120 countries. The risk of bias among these studies was primarily low. Dose irrespectively SGLTis increased the risk of any adverse event-led study discontinuation (RR: 1.42; 95% CI: 1.04-1.93; I2: 14.8%), genital infection (RR: 3.18; 95% CI: 2.48-4.09; I2: 0%), and diabetic ketoacidosis (RR: 2.40; 95% CI: 1.23-4.64; I2: 27.4%). The mega and low doses were indifferent safety-wise. On NMA, compared to the respective different generic SGLT type 2 inhibitors (SGLT2i), the risk of any side effect, any adverse event-led study discontinuation, documented hypoglycemia, severe hypoglycemia, and urinary tract infection were lower with 2.5 mg empagliflozin, 50 mg ipragliflozin, 2.5 mg dapagliflozin, 10 mg dapagliflozin, and 50 mg ipragliflozin, respectively. The surface under the cumulative ranking curves for outcomes with statistically significant differences between two SGLT2i dosages supported these findings chiefly. Supplementary NMA that included trials of identical follow-up duration or mechanism of action closely replicated the preliminary NMA findings. Discussion: Using the GRADE Working Group’s (2004) approach, the statistically significant findings from all direct pairwise and indirect NMA comparisons were downgraded to moderate and low-quality evidence, respectively. The key strengths of this review include its comprehensive database search strategy, incorporation of double-blinded RCTs only (highest level of epidemiological evidence), and the intransitivity risk reduction strategies. Its main limitations include the poor representation of certain SGLTis tested by fewer trials (e.g., canagliflozin), a few unclear risks of bias components in the reviewed trials, and dependence of relative safety between two generic SGLT2i-dosages on indirect NMA comparisons. Regarding its implication, besides providing SGLTi-associated safety information, it will plausibly aid physicians in choosing T1DM patient-specific generic SGLTi type and dosage. Also, it emphasizes the need for different generic SGLTi-based multi-arm RCTs. To conclude, SGLTi treatment increases any adverse event-led study discontinuation, genital infection, and ketoacidosis risk in T1DM patients; however, the safety profile doesn't vary between its mega and low dosages. A relatively safer SGLTi dosage is available to ensure individualized diabetes care for specific SGLTi-dosage-related side effects in T1DM patients.