Higher Probability Of Response Research Articles

Intravenous Immunoglobulin Therapy for Pyoderma Gangrenosum: A Multicenter Retrospective Analysis in 81 Patients.

Pyoderma gangrenosum (PG) is rare neutrophil skin disease causing painful, progressively enlarging ulcers. Among the treatment options, intravenous immunoglobulin (IVIG) is a therapy of first choice for paraneoplastic PG. Otherwise, it is used in therapy-refractory courses. To assess the efficacy and safety of IVIG therapy in patients with PG. A retrospective chart review for patients in five dermatologic wound centres in Germany was performed. Overall, 81 patients were included. IVIG was used as adjunct therapy with (methyl-) prednisolone and/or a steroid sparing therapy in 77 (95.1%) cases. Response to treatment (combined complete and partial, defined as tendency to heal and cessation of lesion progression, respectively) was 49.3% 1 month after initiation of IVIG. In total 18.8% had a complete response after 6 months. Statistically significantly higher response rates were observed in patients with diabetes mellitus and thyroid disease [odds ratio (OR) 3.49, confidence interval (CI) 1.13-10.80 and OR 6.64, CI 1.01-43.57, respectively]. Patients with solid malignancy tended to have better response (OR 4.36, CI 0.79-23.91). A higher IVIG dose was also associated with a tendency towards better response rates (OR 2.70, CI 0.84-8.63). In total, 1 (1.2%) severe adverse event (myocardial infarction with consequent death) was observed as well as three moderate adverse events, with two thromboembolic events (2.5%) and one acute kidney injury (1.2%). Other adverse events were mild or unlikely to be associated with IVIG therapy, with 14 events in 10 patients overall (12.3%). This multicentre retrospective study shows the important role of adjunctive IVIG therapy in patients with PG with recalcitrant courses. Identifying subgroups with a higher probability of response could improvefuture response rates and save patients from ineffective treatment and potential adverse events.

Calibration, Clinical Utility and Specificity of Clinical Decision Support Tools in Inflammatory Bowel Disease

Background and AimsClinical decision support tools (CDSTs) have been developed to predict response to vedolizumab (VDZ) and ustekinumab (UST) in Crohn’s disease (CD) and ulcerative colitis (UC). In addition to assessing their discrimination performance, our study aimed to evaluate their calibration, clinical utility and specificity. MethodsWe included 280 CD and 218 UC patients initiating VDZ, and 194 CD patients initiating UST. We assessed discrimination by comparing rates of effectiveness outcomes between response probability groups forecasted by CDSTs. Calibration curves and decision curve analysis evaluated the calibration and clinical utility of VDZ-CDSTs. Additionally, we examined the agreement between UST-CDST and VDZ-CDST in assigning response probability groups among CD patients starting UST. ResultsIn the overall cohort, CDSTs allocated 7.2%, 50.0% and 42.8% of the patients to the low, intermediate and high response probability groups, respectively. VDZ-CDSTs groups demonstrated significant differences in the rates of clinical and endoscopic response and remission, while UST-CDST groups showed significant discrimination only for clinical remission. Although VDZ-CDSTs overestimated clinical remission rates, they more accurately predicted rates of VDZ persistence without need for surgery or dose escalation. Compared to empirically treating all patients with VDZ, VDZ-CDSTs yielded higher net benefits in selecting patients who would continue VDZ without need for surgery or dose escalation. Finally, the agreement between UST-CDST and VDZ-CDST in predicting response was 73.7%. ConclusionVDZ-CDSTs significantly discriminated response to VDZ and were more beneficial in identifying patients who would continue therapy without requiring surgery or dose escalation, compared to treating all patients empirically.

Late gadolinium enhancement and outcome of cardiac resynchronization therapy in non-ischemic cardiomyopathy

BackgroundIt is uncertain whether CRT with defibrillator (CRTD) is superior to CRT with pacemaker (CRTP) in NICM. Patients with low arrhythmic risk and high probability of response to CRT might be ideal candidates for CRTP.We aimed to evaluate predictors of ventricular arrhythmias and of echocardiographic response to cardiac resynchronization therapy (CRT) in non-ischemic cardiomyopathy (NICM). MethodsMulticenter, retrospective observational study of NICM patients with left ventricular ejection fraction (LVEF) ≤35 %, cardiac magnetic resonance with analysis of late gadolinium enhancement (LGE) available and de-novo CRT implant. Echocardiographic response to CRT was defined as an improvement in LVEF ≥10 %. The combined arrhythmic endpoint included sustained ventricular tachycardia, appropriate ICD therapy, resuscitated cardiac arrest and sudden death. ResultsWe included 167 patients, with a median follow-up of 63 months. LGE was present in 77 (46 %). Response to CRT occurred in 68 % of patients, more frequently in LGE- than in LGE+ (81 % vs 53 %, p < 0.001). Absence of LGE (OR 3.4, p = 0.002), was an independent predictor of response to CRT. The arrhythmic endpoint occurred in 19 patients (11 %). Among LGE- patients there were zero arrhythmic events as compared to a 25 % cumulative incidence in LGE+ (p < 0.001). Presence of LGE (HR 22.5, p < 0.001), was an independent predictor of the arrhythmic endpoint. ConclusionAbsence of LGE identifies patients at minimal arrhythmic risk and with high probability of response to CRT. Thus, they might be ideal candidates to CRT-P.

Baseline tumor-infiltrating lymphocyte patterns and response to immune checkpoint inhibition in metastatic cutaneous melanoma

IntroductionThe presence of tumor-infiltrating lymphocytes (TILs) in melanoma has been linked to survival. Their predictive capability for immune checkpoint inhibition (ICI) response remains uncertain. Therefore, we investigated the association between treatment response and TILs in the largest cohort to date and analyzed if this association was independent of known clinical predictors. MethodsIn this multicenter cohort study, patients who received first-line anti-PD1 ± anti-CTLA4 for advanced melanoma were identified. TILs were scored on hematoxylin and eosin (H&E) slides of primary melanoma and pre-treatment metastases using the validated TILs-WG, Clark and MIA score. The primary outcome was objective response rate (ORR), with progression free survival and overall survival being secondary outcomes. Univariable and multivariable logistic regression and Cox proportional hazard were performed, adjusting for known clinical predictors. ResultsMetastatic melanoma specimens were available for 650 patients and primary specimens for 565 patients. No association was found in primary melanoma specimens. In metastatic specimens, a 10-point increase in the TILs-WG score was associated with a higher probability of response (aOR 1.17, 95 % CI 1.07–1.28), increased PFS (HR 0.93, 95 % CI 0.87–0.996), and OS (HR 0.94, 95 % CI 0.89–0.99). When categorized, patients in the highest tertile TILs-WG score (15–100 %) compared to the lowest tertile (0 %) had a longer median PFS (13.1 vs. 7.3 months, p = 0.04) and OS (49.4 vs. 19.5 months, p = 0.003). Similar results were noted using the MIA and Clark scores. ConclusionIn advanced melanoma patients, TIL patterns on H&E slides of pre-treatment metastases, regardless of measurement method, are independently associated with ICI response. TILs are easily scored on readily available H&Es, facilitating the use of this biomarker in clinical practice.

Dose optimization and exposure-response analyses to support optimal dose of ABBV-400, a novel C-met–targeting antibody drug conjugate, in patients with metastatic colorectal cancer (mCRC).

3030 Background: ABBV-400 is an antibody drug conjugate (ADC) consisting of a c-Met targeting antibody conjugated to a potent inhibitor of topoisomerase 1 (Top1) payload. ABBV-400 has shown encouraging activity and demonstrated tolerability of dosages up to 3.0 mg/kg Q3W as monotherapy in patients with advanced solid tumors in an ongoing phase 1 study (1). Dosage optimization is a critical aspect of oncology drug development and FDA Project Optimus has focused on reformulating the dosage selection paradigm for oncology products. The phase 1 study included a dose optimization phase in mCRC patients in which 3 doses were evaluated (1.6, 2.4 and 3.0 mg/kg Q3W) to determine the optimal dose for further development. Herein, exposure-response analyses are reported to determine optimal monotherapy dose in mCRC patients. Methods: Data across a range of doses (1.6 – 6.0 mg/kg Q3W) from the phase 1 study (NCT05029882) were used. Population pharmacokinetics (PK) and exposure-response (E-R) analyses were conducted to characterize ABBV-400 conjugate and unconjugated payload PK and the relationship between exposures and efficacy (objective response rate [ORR]) and safety (Grade (Gr) ≥ 3 neutropenia, anemia and thrombocytopenia) endpoints. Relative dose intensity (RDI) analysis was performed. Results: ABBV-400 conjugate and payload PK were adequately described by a combined multi-analyte population PK model with first order kinetics (n=204). ABBV-400 conjugate average concentration was a better predictor of response and showed that higher exposure correlated with higher probability of response (n=122 CRC, ORR, p &lt; 0.05) and safety events (n=204, Gr ≥ 3 neutropenia, anemia and thrombocytopenia, p &lt; 0.001). Dose intensity analyses showed greater number of dose reductions for 3 mg/kg Q3W with effective (actual) dose received of 2.6 mg/kg Q3W in mCRC patients. E-R analyses for safety and efficacy and dose intensity analyses in mCRC 3L+ patients indicate that both 2.4 and 3.0 mg/kg doses provided meaningful efficacy (ORR); while the 3.0 mg/kg dose may provide higher response rates, the 2.4 mg/kg Q3W dosing regimen provides an optimal balance of safety and efficacy compared to 3.0 mg/kg Q3W. Conclusions: Population PK, E-R for efficacy and safety and RDI analyses and totality of clinical data supported the selection of 2.4 mg/kg Q3W as optimal ABBV-400 monotherapy dose for further study in mCRC patients. 1. Sharma M, et al. ASCO 2023. Abstract 3015. Clinical trial information: NCT05029882 .

Absence of late gadolinium enhancement and outcomes of cardiac resynchronization therapy in non-ischemic dilated cardiomyopathy

Abstract Background Among patients with non-ischemic dilated cardiomyopathy (DCM) with indication for cardiac resynchronization therapy (CRT), there are no clear recommendations about who should receive a CRT-defibrillator (CRT-D) and who should have CRT-pacemaker (CRT-P). Absence of late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) has a high negative predictive value for ventricular arrhythmias (VA) and sudden death (SD) in DCM and is a predictor of reverse remodelling in several scenarios. Purpose To evaluate the association between absence of LGE and VA/SD or echocardiographic response to CRT in DCM patients treated with CRT. Methods Multicenter retrospective observational cohort study including consecutive DCM patients with de-novo CRT implant and with available CMR. The primary endpoints were: 1) a combined arrhythmic endpoint including appropriate defibrillator therapies, sustained VA and sudden death. 2) echocardiographic response to CRT, intended as an increase ≥10% in left ventricular ejection fraction (LVEF). Results We included 167 patients, 55% males, with median QRS duration of 160ms and median LVEF of 25%. LGE was present in 46% of cases (LGE+). A CRT-D was implanted in 73% of patients. Median follow-up was 63 months. Of note, among patients without LGE (LGE-) we did not record any event of the combined arrhythmic endpoint. The cumulative incidence of the arrhythmic endpoint was significantly higher in LGE+ than in LGE- patients (25% vs 0%, p&amp;lt;0.001) and LGE was an independent predictor of this endpoint (adjusted HR 42, p&amp;lt;0.001). The proportion of responders to CRT was significantly higher in LGE- than in LGE+ cases (81% vs 53%, p&amp;lt;0.001); absence of LGE was the strongest predictor of echocardiographic response to CRT at multivariate analysis (adjusted OR 4.1, p=0.001). Super-responders (i.e. those with LVEF≥50% at follow-up) were also more frequent among LGE- than LGE+ patients (46% vs 21%, p=0.001) and absence of LGE was an independent predictor of LVEF normalization (HR 2.6, p=0.03). Conclusions Among DCM patients who receive CRT, those without LGE have an extremely low (or null in this case) arrhythmic risk and, at the same time, they have a high probability of echocardiographic response to CRT. Thus, LGE- patients could be ideal candidates for CRT-P instead of CRT-D.

Investigation of yield-limiting nutrients for rain-fed lowland rice production in the Fogera floodplain of the Amhara Region in Northwest Ethiopia

The productivity of rice (Oryza sativa L.) in Ethiopia is below the potential due to spatial and temporal soil fertility variability and sub-optimal fertilization. This on-farm study was conducted in 2019 and 2020 to determine yield-limiting nutrients, quantify yield gaps, and determine indigenous soil nutrient supply (ISNS) for lowland rice in Fogera floodplain of Northwest Ethiopia. The study comprised the following treatments; NPKSZnB, -N (PKSZnB), -P (NKSZnB), -K (NPSZnB), -S (NPKZnB), -Zn (NPKSB), -B (NPKSZn), and Zero fertilizer (F0). The treatments were arranged in a randomized complete block design considering farmers’ fields as replications. The results revealed that the growth and yield of rice were significantly affected by the -N and F0 treatments. However, the other nutrient omissions did not significantly influence the mentioned parameters. The highest (2299.5 kg ha−1) yield response was recorded from the -N treatment. However, very low and insignificant yield responses were recorded from the other nutrient omissions. The average agronomic N use efficiency was 16.7 kg kg−1, which indicated a high probability of yield response to the application of N fertilizer. The lowest (42.4%) ISNS was found for N, while the highest ISNS (>90%) were recorded for P, K, S, Zn, and B. The yield gaps due to the omission of N was 57.6%, while the yield gaps due to the omission of P, K, S, Zn, and B were very low. Therefore, N was found to be the most yield-limiting and most deficient nutrient for the lowland rice production in the study area.

P1028 Clinical decision support tool for vedolizumab can predict treatment persistence in Crohn's disease but not in ulcerative colitis

Abstract Background Vedolizumab (VDZ) has displayed up to 82.9% treatment persistence as a first-line biologic for ulcerative colitis (UC) and ranked third in the second line. It ranked fourth in treatment persistence as the first or second-line biological therapy in Crohn's disease (CD). Factors most commonly associated with treatment outcomes have been indicators of more aggressive disease, like refractoriness to corticosteroids and tumour necrosis factor (TNF) alpha inhibitors, elevated baseline patient-related outcomes (PROs), comorbidities in CD and faecal calprotectin. Pre-treatment prediction of response and long-term persistence could help optimise treatment in an individual patient. Methods We performed a retrospective single-centre cohort study based on the UR-CARE registry. Data for 129 patients treated with VDZ from July 2016 until April 2023 were analysed. A validated clinical decision support tool (CDST) for CD and UC was used to stratify patients according to the probability of response to VDZ. We used Kaplan-Meier survival curves to analyse treatment persistence at week 52, depending on the CDST group for CD and UC. The association between the CDST group and the optimisation of VDZ therapy was evaluated using the chi2 test. Results The study included 57 CD patients, median age 34 years, 38.6% male, and 72 UC patients, median age 32.1 years, 59.7% male. Patients with CD had longer disease duration (4.1 years) than UC patients (2.6 years). 33.3% of CD patients had ileo-colonic disease, 24.6% had upper GI involvement, 33.3% had fistulising disease, and 56.1% had prior surgery. 63.9% of patients with UC had pancolitis, and 34.7% had concomitant corticosteroids at baseline. Before VDZ, more than half of patients were exposed to TNF alpha inhibitors in both CD and UC (57.9% and 52.8%, respectively). We found significantly higher treatment persistence in CD patients stratified into groups with intermediate (group 1) and high (group 2) probability of response, according to CDST compared to the group with low (group 0) probability of response. The VDZ therapy was discontinued in 76.9%, 28.6% and 6.3% of patients within CDST groups 0, 1, and 2, respectively. The association was statistically significant (p &amp;lt; 0.001). In UC, however, we could not confirm any significant difference in treatment persistence between CDST groups. The VDZ therapy was discontinued in 50.0%, 34.9%, and 21.9% in groups 0, 1, and 2, respectively. While the trend between discontinuation of the VDZ and CDST groups can be observed, the association was not statistically significant (p = 0.165). Conclusion In our study, treatment persistence for VDZ could be predicted using CDST for CD, but not for UC.

Blood CD8+ Naïve T-Cells Identify MS Patients with High Probability of Optimal Cellular Response to SARS-CoV-2 Vaccine.

This single-center study included 68 multiple sclerosis (MS) patients who received the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination from one of several approved vaccine preparations in Spain. Blood samples were collected one to three months after the second dose of the vaccine had been administered. Cellular immune responses to the vaccine were assessed using QuantiFERON analysis, and peripheral blood mononuclear cell subsets were assayed using flow cytometry. Response associated with higher percentages of total lymphocytes, naïve CD4+ T-cells (p = 0.028), CD8+ T-cells (p = 0.013), and, mostly, naïve CD8+ T-cells (p = 0.0003). These results were confirmed by analyzing absolute numbers (p = 0.019; p = 0.002, and p = 0.0003, respectively). Naïve CD8 T-cell numbers higher than 17 cells/μL were closely associated with an optimal cellular response to SARS-CoV-2 vaccination (odds ratio: 24.0, confidence interval: 4.8-460.3; p = 0.0001). This finding clearly shows that independent of the treatment received, higher numbers of naïve CD8+ T-cells yield a strong cellular response to SARS-CoV-2 vaccines in MS patients. If this finding is validated with other viruses/vaccines, it could provide a good tool for identifying MS patients undergoing treatment who will develop strong cellular responses to anti-virus vaccines.

Molecular landscape and survival outcomes on early phase clinical trials in sporadic young onset colorectal cancer.

3600 Background: Sporadic young onset colorectal cancer (YOCRC, ages 30-49) is a public health crisis with a persistent rise in incidence globally. While a proportion of patients (pts) develop YOCRC due to hereditary predisposition, the majority develop sporadic microsatellite stable (MSS) colorectal cancer with limited options beyond standard of care in advanced settings. We report the early phase clinical trial experience at a large academic cancer center to elucidate clues regarding molecular landscape and impact of clinical trials in refractory MSS YOCRC. Methods: Patient and clinical characteristics were summarized using descriptive statistics. Kaplan-Meier method was used to estimate the probabilities of overall survival (OS) and progression free survival (PFS). Log-rank tests were used to assess the differences in OS and PFS between subgroups. Cox proportional hazards regression models were fit to assess the association between OS or PFS and patient characteristics. Statistical analyses were performed using SAS and Splus. Results: 240 MSS YOCRC pts were analyzed. Median age 42.8 (20.5-49), &gt; 80% were white and only 10% black. 21% received at least 3 lines of therapy. The top five mutations were TP53, KRAS, APC, PI3CKA and BRAFV600E. Median OS was 39.2 months (95% CI: 34.8 – 42.5 months). CTNNB1 mutation was associated with a lower risk of death (HR = 0.28, 95% CI: 0.09 – 0.87, p-value = 0.03) while BRAFV600E mutation was associated with an increased risk (HR = 3.28, 95% CI: 2.00 – 5.38, p-value &lt; 0.001). Multivariable Cox model for OS revealed both CTNNB1 and BRAFV600E mutations are significant prognostic factors for OS, unlike KRAS. There was no difference in OS or PFS among pts who entered a mutation specific clinical trial vs. those enrolled on an unmatched clinical trial (p = 0.35, p = 0.68, respectively, log-rank test). Median PFS was 1.9 months (95% CI: 1.8 – 2.1 months). CTNNB1 mutation was associated with a lower risk of progression/death (HR = 0.29, 95% CI: 0.09 – 0.92, p-value = 0.04) while NRAS mutation was associated with an increased risk (HR = 2.13, 95% CI:1.19– 3.80, p-value = 0.01). Among 145 pts who have data on response, 9 had partial response, 41 had stable disease and 95 had progressive disease. BRAFV600E mutation is associated with a higher probability of response (OR = 6.89, 95% CI: 1.64 – 28.94, p-value = 0.01) and pts enrolled on matched clinical trials had a higher probability of response (OR = 6.23; 95% CI: 1.24 – 31.09, p-value = 0.03). However, increased response did not translate to improved OS. No survival differences were appreciated based on a pts race or BMI. Conclusions: CTNNB1, BRAFV600E &amp; NRAS mutations may have prognostic implications in YOCRC. Pts enrolled on mutation specific clinical trials did not achieve improved outcomes compared to unselected trials, highlighting aggressive biology, current lack of therapeutic targets and need for novel drug development in sporadic YOCRC.

Comparative efficacy of zanubrutinib (ZANU) versus rituximab (RTX) in relapsed marginal zone lymphoma (MZL): Matching-adjusted indirect comparison (MAIC).

e19526 Background: ZANU is a Bruton tyrosine kinase inhibitor that has been evaluated for relapsed/refractory MZL in two phase 2, single-arm (MAGNOLIA, n=66, NCT03846427; BGB-3111-AU-003, n=20, NCT02343120). At 28 and 35 months of study follow-up in MAGNOLIA and BGB-3111-AU-003, respectively, median progression-free survival (PFS) and overall survival (OS) were not reached. Here, we conducted an unanchored MAIC to estimate relative treatment effects of ZANU vs RTX, a commonly used treatment for patients with relapsed MZL. Note the comparison was restricted to the relapsed population because RTX refractory patients would not be retreated with RTX. Methods: The MAIC was performed using pooled individual patient-level data from MAGNOLIA and BGB-3111-AU-003. Study level-data of RTX in relapsed patients were used from CHRONOS-3 (Özcan et al., Ann Oncol 2021) which was identified as the most suitable comparator study via a systematic literature review. A logistic propensity score model was used to estimate weights for patients in ZANU trials such that their weighted mean baseline characteristics matched those of CHRONOS-3. The following characteristics were identified as key prognostic factors and included in the base case propensity score model: prior lines of therapy, MZL subtype, relapse after prior therapy, and age. Sensitivity analyses incorporating additional characteristics were not possible owing to a lack of reporting from CHRONOS-3, but the impact of each covariate in the base model was explored via a leave-one-out analysis. Comparisons were conducted for OS, PFS, and objective response rate (ORR) by independent review committee using weighted statistical models, with relative treatment effects presented as hazard ratios (HRs), odds ratios (ORs), and 95% CIs. Results: After applying weights estimated from the base case propensity score model, the effective sample size (ESS) for ZANU was 39. ZANU reduced the risk of progression (HR 0.29; 95% CI 0.13–0.65) and had a higher probability of response (OR 5.09; 95% CI: 1.84–14.08) when compared with RTX (Table). OS was comparable for ZANU and RTX, which is consistent with the survival expectancy for indolent lymphomas. The leave-one-out analysis showed that removing any of the characteristics from the propensity score model yielded comparable results. Conclusions: MAIC results suggest ZANU is associated with improved PFS and ORR compared with RTX in relapsed MZL. [Table: see text]

Serum 25-hydroxyvitamin D as a predictive biomarker of clinical outcomes in patients with primary membranous nephropathy.

Primary membranous nephropathy (PMN) is an immune-related disease with increased morbidity and the most common cause of adult nephrotic syndrome (NS). The serum 25-hydroxyvitamin D [25(OH)D)], a biomarker of vitamin D (VD) status, tends to decline in patients with kidney disease. However, the relationship between 25(OH)D and PMN is still unclear. Therefore, this study aims to clarify the association between 25(OH)D and disease severity and therapy response of PMN. A total of 490 participants diagnosed with PMN by biopsy from January 2017 to April 2022 were recruited at the First Affiliated Hospital of Nanjing Medical University. The correlations between baseline 25(OH)D and manifestations of nephrotic syndrome (NS) or seropositivity of anti-PLA2R Ab were confirmed by univariate and multivariate logistic analyses. Spearman's correlations were used to examine the associations between baseline 25(OH)D and other clinical parameters. In the follow-up cohort, Kaplan-Meier analysis was used to assess remission outcomes among groups with low, medium, and high levels of 25(OH)D. Furthermore, the independent risk factors for non-remission (NR) were explored by COX regression analysis. At baseline, 25(OH)D was negatively related to 24-h urinary protein and serum anti-PLA2R Ab. The lower level of baseline 25(OH)D was associated with an increased risk for the incidence of NS in PMN (model 2, OR 6.8, 95% CI 4.4, 10.7, P < 0.001) and seropositivity of anti-PLA2R Ab (model 2, OR 2.4, 95% CI 1.6, 3.7, P < 0.001). Furthermore, the lower level of 25(OH)D during follow-up was demonstrated as an independent risk factor for NR even after adjusting age, gender, MBP, 24 h UP, serum anti-PLA2R Ab, serum albumin, and serum C3 [25(OH)D (39.2-62.3 nmol/L): HR 4.90, 95% CI 1.02, 23.53 P = 0.047; 25(OH)D < 39.2 nmol/L: HR 17.52, 95% CI 4.04, 76.03 P < 0.001); vs. 25(OH)D ≥ 62.3 nmol/L]. The Kaplan-Meier survival analysis also demonstrated that the higher level of follow-up 25(OH)D had a higher possibility of remission than the lower one (log-rank test, P < 0.001). Baseline 25(OH)D was significantly correlated with nephrotic proteinuria and seropositivity of anti-PLA2R Ab in PMN. As an independent risk factor for NR, a low level of 25(OH)D during follow-up might serve as a prognostic tool for sensitively identifying cases with a high probability of poor treatment response.

Predicting Response of Triple-Negative Breast Cancer to Neoadjuvant Chemotherapy Using a Deep Convolutional Neural Network-Based Artificial Intelligence Tool.

Achieving a pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is associated with improved patient outcomes in triple-negative breast cancer (TNBC). Currently, there are no validated predictive biomarkers for the response to NAC in TNBC. We developed and validated a deep convolutional neural network-based artificial intelligence (AI) model to predict the response of TNBC to NAC. Whole-slide images (WSIs) of hematoxylin and eosin-stained core biopsies from 165 (pCR in 60 and non-pCR in 105) and 78 (pCR in 31 and non-pCR in 47) patients with TNBC were used to train and validate the model. The model extracts morphometric features from WSIs in an unsupervised manner, thereby generating clusters of morphologically similar patterns. Downstream ranking of clusters provided regions of interest and morphometric scores; a low score close to zero and a high score close to one represented a high or low probability of response to NAC. The predictive ability of AI score for the entire cohort of 78 patients with TNBC ascertained by receiver operating characteristic analysis demonstrated an area under the curve (AUC) of 0.75. The AUC for stages I, II, and III disease were 0.88, 0.73, and 0.74, respectively. Using a cutoff value of 0.35, the positive predictive value of the AI score for pCR was 73.7%, and the negative predictive value was 76.2% for non-pCR patients. To our knowledge, this study is the first to demonstrate the use of an AI tool on digitized hematoxylin and eosin-stained tissue images to predict the response to NAC in patients with TNBC with high accuracy. If validated in subsequent studies, these results may serve as an ancillary aid for individualized therapeutic decisions in patients with TNBC.

The clinical impact of testing for biomarkers in gastric cancer patients: a real-world cohort.

In gastric cancer (GC), HER2 was the first biomarker for guided therapy registered for clinical use. Considering the recent approvals of immune check-point blockade (ICB) in gastro-oesophageal cancers, testing for mismatch repair deficiency (dMMR), Epstein-Barr virus (EBV) and PD-L1 combined positive score (CPS) is becoming increasingly important. Here we describe a real-world cohort on biomarker assessment in GC patients. Patients diagnosed with GC between 2017 and 2021 were included. Biomarker results were retrieved from electronic patient files. PD-L1 CPS was determined retrospectively on dMMR and EBV-positive (EBV+) tumours. Data on genomic sequencing were analysed separately. Of 363 patients identified, 45% had metastatic disease. In 335 patients (92%) at least one biomarker was tested. The prevalence of HER2+, dMMR and EBV+ tumours was 10% (32 of 319), 7% (20 of 294) and 1% (three of 235), respectively. Of the dMMR and EBV+ tumours, 95% had a PD-L1 CPS ≥ 5. Therapeutic strategy was adjusted in 31 of 55 patients and consisted of anti-HER2 therapies as well as ICB in clinical trials. Genomic alterations were found in 44 of 60 tested patients. TP53 (73%) and PIK3CA (20%) mutations were most common, followed by KRAS mutations (11%) and amplifications (11%). In this real-world cohort, testing for HER2, dMMR and EBV status affected treatment decisions in 56% of the patients. Although most dMMR and EBV+ tumours had a PD-L1 CPS ≥ 5, not all patients with a high probability of treatment response are identified. Based on these results, a stepwise diagnostic strategy is proposed.

P354 Application of the clinical decision support tool to predict treatment outcomes in Crohn’s Disease patients treated with vedolizumab subcutaneous formulation

Abstract Background There is a need to identify Crohn’s Disease (CD) patients who will obtain most clinical benefit from treatment with vedolizumab (VDZ), an anti-α4β7 integrin inhibitor for the treatment of ulcerative colitis and Crohn’s Disease (CD). Previously, a clinical decision support tool (CDST) has been developed and validated to guide treatment decisions in CD patients (pts) treated with intravenous VDZ.1 In this study, we aimed to test the ability of the CDST to predict clinical outcomes in CD pts receiving maintenance treatment with the subcutaneous (SC) formulation of VDZ. Methods Pts with moderate to severe CD receiving maintenance treatment with VDZ SC in the VISIBLE 2 study were categorized using the CDST into low (≤13 points), intermediate (&amp;gt;13 and ≤19 points) and high response probability groups (&amp;gt;19 points) based on the scoring system detailed in Table 1. Clinical outcomes evaluated included clinical remission: CD Activity Index (CDAI) ≤ 150 at Week 6, 14, 30, and 52, and enhanced clinical response: decrease from baseline in CDAI score ≥ 100 points at Week 52. All outcomes were evaluated as observed. Results There were 275 pts who completed induction treatment with VDZ 300 mg IV and continued into maintenance treatment with VDZ 108 mg SC until Week 52. Using the CDST, at baseline, 14 pts (5.1%) had a low, 98 (35.6%) had an intermediate, and 163 (59.3%) had a high probability of treatment response with VDZ. Due to the low number of pts in the low probability group, the low and intermediate groups were combined. At Week 6, 99 pts (61.1%) in the high probability group had achieved clinical remission vs 38 pts (33.9%) in the low/intermediate probability group (Fig 1). Rates of clinical remission in the high probability group continued to exceed those of the low/intermediate group through until Week 52 when 89 pts (86.4%) in the high probability group were in clinical remission vs 43 pts (79.6%) in the low/intermediate probability group (Fig 1). In the high probability group, 97 pts (94.2%) had an enhanced clinical response at Week 52 compared with 46 pts (85.2%) in the low/intermediate group. Conclusion Compared with the low/intermediate group, pts categorized by the CDST as having the highest probability of treatment response to VDZ achieved clinical remission sooner, as early as Week 6. These findings provide further confirmation of the CDST as a means of identifying pts with CD likely to benefit from treatment with VDZ in either IV or SC formulations.

Immune Checkpoint Inhibitors in Malignant Pleural Mesothelioma: A Systematic Review and Meta-Analysis.

Many clinical trials have investigated the role of ICIs in PM, with contrasting results. We performed a systematic review and meta-analysis of clinical trials testing single-agent anti-Programmed Death -1 (PD-1)/Programmed Death-Ligand 1 (PD-L1), anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) or combined treatment in PM patients, analyzing response and survival rate as well as safety data. We selected 17 studies including 2328 patients. Both OS and PFS rates were significantly higher with combined ICI treatments than with single agent anti-PD-1/PD-L1 (p &lt; 0.001 and p = 0.006, respectively) or anti CTLA-4 (p &lt; 0.001) treatments. ORR and DCR for all ICI treatments were 20% (95% CI 13-27%) and 56% (95% CI 45-67%), respectively, and they did not significantly differ between combined and single agent treatments (p = 0.088 and p = 0.058, respectively). The 12-month OS and 6-month PFS rates did not differ significantly (p = 0.0545 and p = 0.1464, respectively) among pre-treated or untreated patients. Combined ICI treatments had a significantly higher rate of Adverse Events (AEs) (p = 0.01). PD-L1-positive patients had a higher probability of response and survival. In conclusion, combined ICI treatments have higher efficacy than single agents but are limited by higher toxicity. Efficacy was independent of treatment line, so a customized sequential strategy should still be speculated. PD-L1 expression could influence response to ICIs; however, reliable biomarkers are warranted.

Pembrolizumab in combination with gemcitabine for patients with HER2-negative advanced breast cancer: GEICAM/2015–04 (PANGEA-Breast) study

BackgroundWe evaluated a new chemoimmunotherapy combination based on the anti-PD1 monoclonal antibody pembrolizumab and the pyrimidine antimetabolite gemcitabine in HER2- advanced breast cancer (ABC) patients previously treated in the advanced setting, in order to explore a potential synergism that could eventually obtain long term benefit in these patients.MethodsHER2-negative ABC patients received 21-day cycles of pembrolizumab 200 mg (day 1) and gemcitabine (days 1 and 8). A run-in-phase (6 + 6 design) was planned with two dose levels (DL) of gemcitabine (1,250 mg/m2 [DL0]; 1,000 mg/m2 [DL1]) to determine the recommended phase II dose (RP2D). The primary objective was objective response rate (ORR). Tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumors and myeloid-derived suppressor cells (MDSCs) levels in peripheral blood were analyzed.ResultsFourteen patients were treated with DL0, resulting in RP2D. Thirty-six patients were evaluated during the first stage of Simon’s design. Recruitment was stopped as statistical assumptions were not met. The median age was 52; 21 (58%) patients had triple-negative disease, 28 (78%) visceral involvement, and 27 (75%) ≥ 2 metastatic locations. Progression disease was observed in 29 patients. ORR was 15% (95% CI, 5–32). Eight patients were treated ≥ 6 months before progression. Fourteen patients reported grade ≥ 3 treatment-related adverse events. Due to the small sample size, we did not find any clear association between immune tumor biomarkers and treatment efficacy that could identify a subgroup with higher probability of response or better survival. However, patients that experienced a clinical benefit showed decreased MDSCs levels in peripheral blood along the treatment.ConclusionPembrolizumab 200 mg and gemcitabine 1,250 mg/m2 were considered as RP2D. The objective of ORR was not met; however, 22% patients were on treatment for ≥ 6 months. ABC patients that could benefit of chemoimmunotherapy strategies must be carefully selected by robust and validated biomarkers. In our heavily pretreated population, TILs, PD-L1 expression and MDSCs levels could not identify a subgroup of patients for whom the combination of gemcitabine and pembrolizumab would induce long term benefit.Trial registrationClinicalTrials.gov and EudraCT (NCT03025880 and 2016–001,779-54, respectively). Registration dates: 20/01/2017 and 18/11/2016, respectively.

Probability of Response as Defined by a Clinical Decision Support Tool Is Associated With Lower Healthcare Resource Utilization in Vedolizumab-Treated Patients With Crohn's Disease.

A previously developed clinical decision support tool (CDST) identified patients with Crohn's disease (CD) most likely to respond to vedolizumab. This study evaluated the ability of the CDST to predict real-world healthcare resource utilization (HRU). The Optum and Truven healthcare databases were searched for patients with CD treated with vedolizumab (Optum, n = 358; Truven, n = 1445) or an anti-tumor necrosis factor (TNF) agent (Optum, n = 814). Patients were stratified using the 5-variable (prior bowel surgery, prior fistulizing disease, prior anti-TNF exposure, albumin, C-reactive protein) and a new modified 3-variable (without laboratory data) CDST. Annualized expenditures and HRU were compared with both CDSTs across response probability groups for a 12-month period. In the Optum data set, the 5- and 3-variable CDSTs identified lower rates of surgery or hospitalization in CD patients with higher probability of vedolizumab response. Per-patient total costs were 2.5 times lower for CD patients with high versus low probability of vedolizumab response ($12 943 vs $32 931). The 5- and 3-variable CDSTs did not consistently identify anti-TNF-treated CD patients with higher HRU. The 3-variable CDST also identified vedolizumab-treated CD patients with higher probability of response and lower probability for surgery or hospitalization in the Truven data set. The 5-variable CDST identified CD patients treated with vedolizumab, but not an anti-TNF agent, at higher risk for HRU. The 3-variable CDST offers similar performance but more flexibility by removing laboratory data requirements for prediction. These validated CDSTs can be integrated into population health monitoring algorithms using real-world data.

Prediction of Cardiac Resynchronization Therapy Response Using a Lead Placement Score Derived From 4-Dimensional Computed Tomography.

Cardiac resynchronization therapy (CRT) is an effective treatment for patients with heart failure; however, 30% of patients do not respond to the treatment. We sought to derive patient-specific left ventricle maps of lead placement scores (LPS) that highlight target pacing lead sites for achieving a higher probability of CRT response. Eighty-two subjects recruited for the ImagingCRT trial (Empiric Versus Imaging Guided Left Ventricular Lead Placement in Cardiac Resynchronization Therapy) were retrospectively analyzed. All 82 subjects had 2 contrast-enhanced full cardiac cycle 4-dimensional computed tomography scans: a baseline and a 6-month follow-up scan. CRT response was defined as a reduction in computed tomography-derived end-systolic volume ≥15%. Eight left ventricle features derived from the baseline scans were used to train a support vector machine via a bagging approach. An LPS map over the left ventricle was created for each subject as a linear combination of the support vector machine feature weights and the subject's own feature vector. Performance for distinguishing responders was performed on the original 82 subjects. Fifty-two (63%) subjects were responders. Subjects with an LPS≤Q1 (lower-quartile) had a posttest probability of responding of 14% (3/21), while subjects with an LPS≥ Q3 (upper-quartile) had a posttest probability of responding of 90% (19/21). Subjects with Q1<LPS<Q3 had a posttest probability of responding that was essentially unchanged from the pretest probability (75% versus 63%, P=0.2). An LPS threshold that maximized the geometric mean of true-negative and true-positive rates identified 26/30 of the nonresponders. The area under the curve of the receiver operating characteristic curve for identifying responders with an LPS threshold was 87%. An LPS map was defined using 4-dimensional computed tomography-derived features of left ventricular mechanics. The LPS correlated with CRT response, reclassifying 25% of the subjects into low probability of response, 25% into high probability of response, and 50% unchanged. These encouraging results highlight the potential utility of 4-dimensional computed tomography in guiding patient selection for CRT. The present findings need verification in larger independent data sets and prospective trials.

Prediction of Response to Cisplatin-Based Neoadjuvant Chemotherapy of Muscle-Invasive Bladder Cancer Patients by Molecular Subtyping including KRT and FGFR Target Gene Assessment.

Patients with muscle-invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NAC) have improved prognosis. Molecular subtypes of bladder cancer differ markedly regarding sensitivity to cisplatin-based chemotherapy and harbor FGFR treatment targets to various content. The objective of the present study was to evaluate whether preoperative assessment of molecular subtype as well as FGFR target gene expression is predictive for therapeutic outcome—rate of ypT0 status—to justify subsequent prospective validation within the “BladderBRIDGister”. Formalin-fixed paraffin-embedded (FFPE) tissue specimens from transurethral bladder tumor resections (TUR) prior to neoadjuvant chemotherapy and corresponding radical cystectomy samples after chemotherapy of 36 patients were retrospectively collected. RNA from FFPE tissues were extracted by commercial kits, Relative gene expression of subtyping markers (e.g., KRT5, KRT20) and target genes (FGFR1, FGFR3) was analyzed by standardized RT-qPCR systems (STRATIFYER Molecular Pathology GmbH, Cologne). Spearman correlation, Kruskal–Wallis, Mann–Whitney and sensitivity/specificity tests were performed by JMP 9.0.0 (SAS software). The neoadjuvant cohort consisted of 36 patients (median age: 69, male 83% vs. female 17%) with 92% of patients being node-negative during radical cystectomy after 1 to 4 cycles of NAC. When comparing pretreatment with post-treatment samples, the median expression of KRT20 dropped most significantly from DCT 37.38 to 30.65, which compares with a 128-fold decrease. The reduction in gene expression was modest for other luminal marker genes (GATA3 6.8-fold, ERBB2 6.3-fold). In contrast, FGFR1 mRNA expression increased from 33.28 to 35.88 (~6.8-fold increase). Spearman correlation revealed positive association of pretreatment KRT20 mRNA levels with achieving pCR (r = 0.3072: p = 0.0684), whereas pretreatment FGFR1 mRNA was associated with resistance to chemotherapy (r = −0.6418: p < 0.0001). Hierarchical clustering identified luminal tumors of high KRT20 mRNA expression being associated with high pCR rate (10/16; 63%), while the double-negative subgroup with high FGFR1 expression did not respond with pCR (0/9; 0%). Molecular subtyping distinguishes patients with high probability of response from tumors as resistant to neoadjuvant chemotherapy. Targeting FGFR1 in less-differentiated bladder cancer subgroups may sensitize tumors for adopted treatments or subsequent chemotherapy.