Partial Responders Research Articles

Frequency of axillary nodal complete pathological response of breast cancer patients in neoadjuvant chemotherapy setting: A cross-sectional study.

Pathological complete response (pCR) occurs in about 20-30% of patients undergoing systemic neoadjuvant therapy. This leads to the idea of sparing the patient the morbidity associated with axillary surgery. "Wait and watch" policy for cancers which achieve complete pathological response on neoadjuvant systemic therapy is a well-established practice in various cancers like the esophagus, rectum and larynx. This has led to organ preservation protocols being practiced worldwide for these cancers without affecting the overall survival of the patient. We believe patients undergoing a complete pathological response in the breast may be spared axillary surgery. Axillary surgery leads to morbidity and extra financial burden with no added advantage in survival. A total of 326 patients with breast cancer who had received neoadjuvant systemic chemotherapy from 2015 to 2020 were included in our retrospective study. Final histopathology of the breast and axillary surgery was noted to report the frequency of complete pathological response. The frequency of positive nodal disease with respect to stage, grade and type of cancer was measured. Among 326 patients, our study showed that 53% of patients with complete pathological response in breast also had complete response in the axilla compared to 43% with incomplete pathological response. No significant difference was found for age, menopausal status, initial tumor size when patients with complete pathological response were compared to non or partial responders. The rate of complete pathological response was higher in patients with clinically node negative patients after NACT, hormone negative, HER2 positive and triple negative population. Our results indicated that 53% of the patients who developed complete pathological response in the breast underwent needless axillary procedure. Axillary surgery can be staged after the breast surgery if residual tumor is present on the histopathological specimen. In case of pCR, omission of axillary surgery can be considered. However, a larger population, multi-centric studies are needed for treatment guidelines.

Microbiome, socioeconomic status (SES), fiber intake, and response to checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC): A pilot study.

e14710 Background: Lung cancer affects a disproportional number of socioeconomically disadvantaged patients (pts). Responses to checkpoint inhibitor therapy (CIT) vary. Microbiome diversity may correlate with benefit from CIT. High fiber diets lead to microbiome diversity. We hypothesize that unexplained lung cancer disparities may be in part due to differences in microbiome diversity determined by unhealthy dietary patterns dictated by lower SES. Methods: Following IRB review, 25 pts with metastatic NSCLC starting CIT-based treatment were enrolled. Pre-treatment oral and fecal samples were collected. 24-hour dietary recalls were obtained. SES index was calculated based on education, employment, housing and annual income. High fiber intake was defined as > 20 g/day. Best treatment response per RECIST 1.1 was assessed. Microbial 16s rRNA were sequenced with Illumina MiSeq platform. Sequence analyses utilized QIIME 2 with DADA2 plugin. Taxonomic assignments used the Greengenes database. Microbiome composition was analyzed by calculating alpha diversity (Chao1, Shannon diversity and Simpson index), beta diversity and differential abundance of microbial compositions. Hierarchical linear model was constructed for each SES variable with and without biological covariates. Results: Pts with samples >1000 operational taxonomic unit (OTU) levels were included (N = 22) in the analysis. 50% were male, median age was 71, 36% (8/22) were of Black race and 23% (5/22) were of low SES. Median fiber intake was 11.9 grams. Males had higher alpha diversity than females (p=.038). Pts with high fiber intake had greater fecal Proteobacteria compared to low fiber intake pts (p<0.05). Bacteroides and Firmicutes fecal levels were significantly different for all pts compared to Human Microbiome Project (HMP) reported normal levels (p<0.01). Actinobacteria and Proteobacteria levels for low-fiber intake pts were also significantly elevated compared to HMP normal levels (p<0.05). There were no differences observed in microbiome when comparing SES index. However, high SES index patients had elevated fecal levels of Actinobacteria, Firmicutes and Proteobacteria and lower levels of Bacteroides compared to HMP levels. There was a trend towards higher alpha diversity of oral samples in partial responders pts compared to those with stable or progression of the disease (p=0.08). Conclusions: Pts with metastatic NSCLC exhibited different microbial composition compared to HMP normal levels. Associations between SES and microbial distribution in such pts warrant further investigation. Increased sample size is needed to better determine differences in oral microbiome in responders to immunotherapy and better evaluate the role of sex in this setting.

LBP-20 - Continued treatment of early non-responder or partial virologic responders with bulevirtide monotherapy in patients with chronic hepatitis D through week 96 leads to improvement in virologic and biochemical responses

LBP-20 - Continued treatment of early non-responder or partial virologic responders with bulevirtide monotherapy in patients with chronic hepatitis D through week 96 leads to improvement in virologic and biochemical responses

Imaging response to immune checkpoint inhibitors in patients with advanced melanoma: A retrospective observational cohort study.

e21524 Background: The association of objective imaging response with first line immune checkpoint inhibitor (ICI) therapy regimes in advanced melanoma remains uncharacterized in a real-world context. We compared likelihood of objective response between patients receiving first line anti-programmed cell death protein 1 (anti-PD1) monotherapies (pembrolizumab or nivolumab), or combination nivolumab with the cytotoxic T-cell lymphocyte-antigen 4 inhibitor ipilimumab and outlined the association between objective response and baseline characteristics and survival outcomes. Methods: We conducted a multi-center retrospective cohort analysis of advanced melanoma patients receiving first line ICI therapy from 2013-2020 in Alberta, Canada. Best imaging response was assessed by Response Evaluation Criteria in Solid Tumors, Version 1.1. The primary outcome was likelihood of objective imaging response (complete or partial response) between patients receiving anti-PD1 monotherapy and those receiving combination nivolumab-ipilimumab. Secondary outcomes were the identification of baseline characteristics associated with non-response and the association of imaging response with overall survival (OS) and time to next treatment (TTNT) endpoints. Results: Of the 255 patients included, 49/255 (19.2%) had complete response 112/255 (43.9%) had partial response, 28/255 (11.0%) had stable disease, and 66/255 (25.9%) had progressive disease. Median OS was not evaluable (NE) (95% CI NE-NE) for complete responders, NE (95% CI 52.93 months-NE) for partial responders, 21.30 months (95% CI 15.20 months-NE) for stable disease, and 7.72 months (95% CI 5.77-10.6 months) for progressive disease (log rank p < 0.0001). A robust delineation of TTNT by imaging response was also seen. Likelihood of objective response was similar between patients treated with nivolumab-ipilimumab compared to those receiving anti-PD1 monotherapy (OR 1.87 95% CI 0.85-4.20, p = 0.124). Normal LDH level (OR 2.13; 95% CI 1.01-4.35, p = 0.047), non-mucosal primary site (OR 9.09; 95% CI 2.44-33.33, p < 0.001), and absence of BRAF V600E mutation (OR 3.23; 95% CI 1.39-7.69, p = 0.007) were independently associated with likelihood of objective imaging response in multivariable analysis. Conclusions: In this real-world analysis, we demonstrate no significant difference in likelihood of objective response between patients treated with anti-PD1 monotherapy and combination nivolumab-ipilimumab, and demonstrate that a normal LDH level, non-mucosal primary site, and absence of BRAF V600E mutation are associated with response. Imaging response was also strongly associated with both OS and TTNT irrespective of therapy received. These results may help inform treatment selection, and aid in counseling of advanced melanoma patients treated with first line ICI therapy in a routine clinical practice setting.

Phase II clinical trial of olaparib plus pembrolizumab in the treatment of patients with advanced biliary tract cancer.

4087 Background: Over 20% of biliary tract cancers (BTCs) carry mutations in homologous recombination DNA damage repair (HR-DDR) pathways. The PARP inhibitor olaparib (O) blocks tumor DNA repair and may induce response in BTCs with such mutations. Furthermore, HR-DDR mutations may engender neoantigens that improve response to immune checkpoint inhibitors. We propose that treatment with O and the anti-PD-1 monoclonal antibody pembrolizumab (P) will produce a durable anti-tumor response to BTC, especially in patients with HR-DDR mutations. Methods: Consent for participation was obtained. Eligibility criteria included age > 18 years with an ECOG score of ≤1 and a histologic diagnosis of advanced or metastatic BTC with progression of disease (PD) on prior first-line therapy. Treatment featured oral O (300 mg twice daily) plus intravenous P (200 mg every 3 weeks). Response was measured radiographically using RECIST 1.1 guidelines. The primary endpoint was overall response rate (ORR), with the alternative hypothesis that O + P would improve ORR compared to historical controls (versus the null hypothesis of no improvement). Type I and II error rates were set at 5% and 15%, respectively. Simon’s optimal two-stage design was used. Planned sample size was 13 patients in the first stage. Continuation to the second stage would only occur if ≥3 patients demonstrated response. The second stage was planned to include 20 additional patients (N = 33 total), which was based on the number needed to demonstrate an improvement in ORR from 17.5% in historical controls to at least 35.0%. Results: Of 21 eligible patients, 14 were accrued between June 2020 and March 2022, and 13 were evaluable for efficacy. Patients had a median age of 63 years, were primarily female (71%), Caucasian (50%), and with metastatic disease (93%). Patients received a mean of 6.5 cycles of therapy. Best treatment response included partial response (N = 2), stable disease (N = 5), and PD (N = 6). The ORR was 15.3% (95% CI = 0.02-0.45). Of the partial responders, 1 patient achieved a duration of response of 8 months (mos), and 1 has ongoing response at 24 mos. Median (med) time to progression was 7.7 mos (95% CI = 1.2-9.3), med progression free survival was 5.5 mos (95% CI = 1.2-7.7), and med overall survival was 11.9 mos (95% CI = 5.5-15.4). Most patients (64%) developed at least one treatment-related adverse event (trAE). Grade 3 trAEs were experienced in 5 patients (36%) and included anemia (N = 3), diarrhea (N = 1), and transaminitis (N = 1). Conclusions: While O + P has acceptable safety and toxicity, the study did not achieve significant improvement in the primary endpoint. However, the two patients who demonstrated durable treatment response were found to have HR-DDR tumor mutations (including RAD51, ATM, and BRCA2), necessitating further research into the efficacy of O + P for patients with similar tumor genomes. Clinical trial information: NCT04306367 .

Association of vitamin D and polymorphisms of its receptor with antiviral therapy in pregnant women with hepatitis B.

The interruption of mother-to-child transmission (MTCT) is considered important to decrease the individual and population morbidity of hepatitis B virus (HBV) infection as well as the global burden of hepatitis B. Serum vitamin D (VD) is associated with hepatitis B. To assess whether baseline VD levels and single nucleotide polymorphisms of the VD receptor gene (VDR SNPs) are associated with the efficacy of tenofovir disoproxil fumarate (TDF) in the prevention of MTCT in pregnant women with high HBV viral loads. Thirty-eight pregnant women who were at high risk for MTCT of HBV (those with an HBV DNA level ≥ 2 × 105 IU/mL during 12-24 wk of gestation) receiving antiviral therapy of TDF between June 1, 2019 and June 30, 2021 in Mianyang were included in this retrospective study. The women received 300 mg TDF once daily from gestational weeks 24-28 until 3 mo after delivery. To further characterize the clinical relevance of maternal serum HBV DNA levels, we stratified patients according to HBV DNA level as follows: Those with levels < 2 × 105 (full responder group) vs those levels ≥ 2 × 105 IU/mL (partial responder group) at delivery. Serum levels of 25-hydroxyvitamin D [25(OH)D], liver function markers, virological parameters, VDR SNPs and other clinical parameters were collected to analyze their association with the efficacy of TDF. The Mann-Whitney U test or t test was used to analyze the serum levels of 25(OH)D in different groups. Multiple linear regressions were utilized to analyze the determinants of the maternal HBV DNA level at delivery. Univariate and multivariate logistic regression analyses were employed to explore the association of targeted antiviral effects with various characteristics at baseline and delivery. A total of 38 pregnant women in Mianyang City at high risk for MTCT of HBV were enrolled in the study. The MTCT rate was 0%. No mother achieved hepatitis B e antigen or hepatitis B surface antigen (HBsAg) clearance at delivery. Twenty-three (60.5%) participants were full responders, and 15 (39.5%) participants were partial responders according to antiviral efficacy. The present study showed that a high percentage (76.3%) of pregnant women with high HBV viral loads had deficient (< 20 ng/mL) or insufficient (≥ 20 but < 31 ng/mL) VD levels. Serum 25(OH)D levels in partial responders appeared to be significantly lower than those in full responders both at baseline (25.44 ± 9.42 vs 17.66 ± 5.34 ng/mL, P = 0.006) and delivery (26.76 ± 8.59 vs 21.24 ± 6.88 ng/mL, P = 0.044). Serum 25(OH)D levels were negatively correlated with maternal HBV DNA levels [log(10) IU/mL] at delivery after TDF therapy (r = -0.345, P = 0.034). In a multiple linear regression analysis, maternal HBV DNA levels were associated with baseline maternal serum 25(OH)D levels (P < 0.0001, β = -0.446), BMI (P = 0.03, β = -0.245), baseline maternal log10 HBsAg levels (P = 0.05, β = 0.285) and cholesterol levels at delivery (P = 0.015, β = 0.341). Multivariate logistic regression analysis showed that baseline serum 25(OH)D levels (OR = 1.23, 95%CI: 1.04-1.44), maternal VDR Cdx2 TT (OR = 0.09, 95%CI: 0.01-0.88) and cholesterol levels at delivery (OR = 0.39, 95%CI: 0.17-0.87) were associated with targeted antiviral effects (maternal HBV DNA levels < 2 × 105 at delivery). Maternal VD levels and VDR SNPs may be associated with the efficacy of antiviral therapy in pregnant women with high HBV viral loads. Future studies to evaluate the therapeutic value of VD and its analogs in reducing the MTCT of HBV may be justified.

Type I and Type IIb Autoimmunity in Chronic Spontaneous Urticaria Patients: Evaluating the Clinical Response to Omalizumab

This study aimed to evaluate the clinical response to omalizumab in patients with Type 1 and Type IIb autoimmunity suffering from chronic spontaneous urticaria (CSU) and to compare the difference in laboratory data. A retrospective study was conducted from September 2019 to December 2022 in the Center of Allergy and Immunology in Tbilisi, Georgia, involving 39 patients (95% females, 5% males, average age 35.82 years). Total IgE and ANA antibodies were taken as markers of autoimmunity. The study included patients who still had high disease activity despite using a fourfold dose of non-sedating antihistamines. Patients were prescribed omalizumab according to international guidelines with an interval of 4 weeks for at least 3 months. Disease activity was determined using the urticaria activity score (UAS7), and patients were divided into three groups according to CSU activity: low, moderate, and high disease activity. Response to omalizumab was assessed as non-responders, partial responders, and complete responders. The results showed that Type I autoimmunity had a higher percentage of complete responders than Type IIb (55.5% vs. 18.3%). Non-responder rates were higher in Type IIb than in Type I (72.7% vs. 18.5%). The median total IgE levels were significantly higher in Type I than in Type IIb (138 vs. 23.95 kU/I). The median duration of the disease was significantly shorter in Type I than in Type IIb (9 vs. 27 months). No significant differences were found between the two groups regarding age, angioedema, CRP levels, H. pylori infection rates, anti-TPO IgG levels, eosinopenia, and basopenia. In conclusion, this study suggests that the clinical response to omalizumab differs depending on the type of autoimmunity. Type I autoimmunity patients had a better response to omalizumab than Type IIb. The median duration of the disease was significantly shorter in Type I than in Type IIb. Further studies are needed to evaluate the mechanism underlying the difference in response to omalizumab and the use of different treatment options for patients with different types of autoimmunity.

Assessment of Transarterial Chemoembolization Using Super-resolution Ultrasound Imaging and a Rat Model of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly prevalent form of liver cancer diagnosed annually in 600,000 people worldwide. A common treatment is transarterial chemoembolization (TACE), which interrupts the blood supply of oxygen and nutrients to the tumor mass. The need for repeat TACE treatments may be assessed in the weeks after therapy with contrast-enhanced ultrasound (CEUS) imaging. Although the spatial resolution of traditional CEUS has been restricted by the diffraction limit of ultrasound (US), this physical barrier has been overcome by a recent innovation known as super-resolution US (SRUS) imaging. In short, SRUS enhances the visible details of smaller microvascular structures on the 10 to 100 µm scale, which unlocks a host of new clinical opportunities for US. In this study, a rat model of orthotopic HCC is introduced and TACE treatment response (to a doxorubicin-lipiodol emulsion) is assessed using longitudinal SRUS and magnetic resonance imaging (MRI) performed at 0, 7 and 14 d. Animals were euthanized at 14 d for histological analysis of excised tumor tissue and determination of TACE response, that is, control, partial response or complete response. CEUS imaging was performed using a pre-clinical US system (Vevo 3100, FUJIFILM VisualSonics Inc.) equipped with an MX201 linear array transducer. After administration of a microbubble contrast agent (Definity, Lantheus Medical Imaging), a series of CEUS images were collected at each tissue cross-section as the transducer was mechanically stepped at 100 μm increments. SRUS images were formed at each spatial position, and a microvascular density metric was calculated. Microscale computed tomography (microCT, OI/CT, MILabs) was used to confirm TACE procedure success, and tumor size was monitored using a small animal MRI system (BioSpec 3T, Bruker Corp.). Although there were no differences at baseline (p > 0.15), both microvascular density levels and tumor size measures from the complete responder cases at 14 d were considerably lower and smaller, respectively, than those in the partial responder or control group animals. Histological analysis revealed tumor-to-necrosis levels of 8.4%, 51.1% and 100%, for the control, partial responder and complete responder groups, respectively (p < 0.005). SRUS imaging is a promising modality for assessing early changes in microvascular networks in response to tissue perfusion-altering interventions such as TACE treatment of HCC.

Methylomic biomarkers of lithium response in bipolar disorder: a clinical utility study

BackgroundResponse to lithium (Li) is highly variable in bipolar disorders (BD). Despite decades of research, no clinical predictor(s) of response to Li prophylaxis have been consistently identified. Recently, we developed epigenetic Methylation Specific High-Resolution Melting (MS-HRM) assays able to discriminate good responders (GR) from non-responders (NR) to Li in individuals with BD type 1 (BD-I). This study examined whether a combination of clinical and epigenetic markers can distinguish NR from other types of Li responders.MethodsWe recorded clinical variables that are potentially associated with Li response in 64 individuals with BD-I. MS-HRM assays were performed on DNA isolated from peripheral blood. We used backward stepwise logistic regression analyses, followed by receiver operating characteristic (ROC) curve analysis to estimate the performance of the clinical variables, alone then in combination with the epigenetic biomarkers, to identify GR and partial responders (PaR) vs NR.ResultsPolarity at onset, psychotic symptoms at onset and family history of BD classified correctly 70% of individuals according to their Li response (PaR + GR = 86%; NR = 35%). When combined with the epigenetic biomarkers, these three clinical variables plus alcohol misuse (and one DMR: Differentially Methylated Region) correctly classified 86% of individuals, improving the prediction of PaR + GR (93%) and of NR (70%). The ROC analysis demonstrated an improvement in the area under the curve from 0.75 (clinical variables alone) to 0.87 (combination of clinical and epigenetic markers).ConclusionsCombining clinical predictors and DNA methylation markers of Li response may have greater utility in clinical practice than relying on clinical characteristics alone.

No virologic resistance to bulevirtide monotherapy detected in patients through 24 weeks treatment in phase II and III clinical trials for chronic hepatitis delta

Bulevirtide (BLV) is a hepatitis D virus (HDV)/hepatitis B virus (HBV) entry inhibitor that has shown virologic response (responder, HDV-RNA undetectable or ≥2 log10 IU/mL decrease from baseline) in >50% of patients after 24-week treatment. However, some patients achieve <1 log10 IU/mL decline in HDV-RNA through 24-week treatment (non-responder). Here we report viral resistance analyses for BLV monotreated participants who were non-responders or experienced virologic breakthrough (VB, 2 consecutive increases in HDV-RNA of ≥1 log10 IU/mL from nadir or 2 consecutive HDV-RNA detectable if previously undetectable) in phase II study MYR202 and phase III study MYR301. Deep-sequencing of BLV-corresponding region in HBV PreS1 and HDV HDAg gene and in vitro phenotypic testing were performed for the participant with VB (n=1) and non-responders (n=20) at baseline (BL) and Week 24 (WK24). No amino acid exchanges within the BLV-corresponding region and HDAg associated with reduced susceptibility to BLV were identified in isolates from any of the 21 participants at BL and WK24. Although variants (HBV n=1; HDV n=13) were detected at BL in some non-responders or the participant with VB, none were associated with reduced sensitivity to BLV in vitro. Furthermore, the same variant was found in virologic responders. A comprehensive phenotypic analysis demonstrated that the BLV EC50 values from 116 BL samples were similar across non-responders, partial responders (HDV RNA decline ≥1 but <2 log10 IU/mL), and responders regardless of the presence of HBV and/or HDV polymorphisms. No amino acid substitutions associated with reduced sensitivity to BLV monotherapy were detected at BL or WK24 in non-responders or the participant with VB after 24-week BLV treatment.

Prognostic value of [18F]FDG PET/CT on treatment response and progression-free survival of gastroesophageal cancer patients undergoing perioperative FLOT chemotherapy

PurposeTo evaluate the prognostic role of [18F]FDG PET/CT metabolic parameters in gastric cancer (GC) and gastroesophageal adenocarcinoma (GEJAC) patients receiving neoadjuvant chemotherapy. MethodIn this retrospective study, 31 patients with biopsy-proven GC or GEJAC were included between August 2016 and March 2020. [18F]FDG PET/CT was performed before the neoadjuvant chemotherapy. Primary tumours’ semi-quantitative metabolic parameters were extracted. All patients received a perioperative FLOT regimen thereafter. Post-chemotherapy [18F]FDG PET/CT was performed in most patients (17/31). All patients underwent surgical resection. Histopathology response to treatment and progression-free survival (PFS) were evaluated. Two-sided p-values < 0.05 were considered statistically significant. ResultsThirty-one patients (mean age = 62 ± 8), including 21 GC and 10 GEJAC patients, were evaluated. 20/31(65%) patients were histopathology responders to neoadjuvant chemotherapy, including twelve complete and eight partial responders. During the median follow-up of 42.0 months, nine patients experienced recurrence. The median PFS was 60(95% CI:32.9–87.1) months. Pre-neoadjuvant chemotherapy SULpeak was significantly correlated with pathological response to treatment (p-value = 0.03;odds ratio = 16.75). In survival analysis, SUVmax (p-value = 0.01;hazard ratio[HR] = 1.55), SUVmean (p-value = 0.04;HR = 2.73), SULpeak (p-value < 0.001;HR = 1.91) and SULmean (p-value = 0.04;HR = 4.22) in the post-neoadjuvant chemotherapy pre-operative [18F]FDG PET/CT showed significant correlation with PFS. Additionally, aspects of staging were significantly correlated with PFS (p-value = 0.01;HR = 2.21). ConclusionsPre-neoadjuvant chemotherapy [18F]FDG PET/CT parameters, especially SULpeak, could predict the pathological response to treatment in GC and GEJAC patients. Additionally, in survival analysis, post-chemotherapy metabolic parameters significantly correlated with PFS. Thus, performing [18F]FDG PET/CT before chemotherapy may help to identify patients at risk for inadequate response to perioperative FLOT and, after chemotherapy, may predict clinical outcomes.

Thyroid Autoimmunity in CSU: A Potential Marker of Omalizumab Response?

The response of severe chronic spontaneous urticaria (CSU) to omalizumab largely depends on the autoimmune or autoallergic endotype of the disease. Whether thyroid autoimmunity may predict omalizumab response along with total IgE in CSU is still unclear. Three hundred and eighty-five patients (M/F 123/262; mean age 49.5 years; range 12-87 years) with severe CSU were studied. Total IgE levels and thyroid autoimmunity (levels of anti-thyroid peroxidase [TPO] IgG) were measured before omalizumab treatment. Based on the clinical response, patients were divided into early (ER), late (LR), partial (PR) and non (NR) responders to omalizumab. Thyroid autoimmunity was detected in 92/385 (24%) patients. Altogether, 52%, 22%, 16% and 10% of patients were ER, LR, PR and NR to omalizumab, respectively. Response to omalizumab was not associated with thyroid autoimmunity (p = 0.77). Conversely, we found a strongly positive association between IgE levels and omalizumab response (p < 0.0001); this association was largely driven by early response (OR = 5.46; 95% CI: 2.23-13.3). Moreover, the predicted probabilities of early response strongly increased with increasing IgE levels. Thyroid autoimmunity alone cannot be used as a clinical predictor of omalizumab response. Total IgE levels remain the only and most reliable prognostic marker for omalizumab response in patients with severe CSU.

Abstract 5174: PEGylated liposomal doxorubicin improves oral cancer response to radio-immunotherapy

Abstract Introduction: The immunosuppressive tumor microenvironment (TME) in oral cancer inhibits response to conventional treatment (surgery +/- chemoradiotherapy) and check-point inhibitor (αPD1) immunotherapy. The chemotherapeutic agent doxorubicin and its PEGylated liposomal nanoparticle formulation (PLD) have been shown to target myeloid derived suppressor cells (MDSCs) in the TME. In this preclinical work, we investigated whether PLD improves response to radio-immunotherapy in a highly aggressive and immunologically ‘cold’ oral cancer model. Experimental Procedure: Studies were performed in the MOC2 syngeneic mouse model of oral cancer. Mice were randomized to one of seven treatment groups: αPD1, Radiation (XRT), αPD1+XRT, PLD, PLD+αPD1, PLD+XRT, PLD+αPD1+XRT. High-resolution nanoparticle contrast-enhanced computed tomography (nCECT) imaging was performed, and whole-body T2-weighted magnetic resonance imaging (MRI) used to monitor primary tumor response and development of metastases. Response evaluation criteria in solid tumors (RECIST) were used to evaluate treatment outcomes. Results: Tumors in all non-PLD groups were treatment resistant and grew progressively, consistent with the immunologically ‘cold’ MOC2 model. In contrast, all PLD groups showed tumor regression with 25-38% complete responders (CR) and 12-88% partial responders (PR) while all animals in non-PLD groups showed progressive disease (PD). MR imaging identified a high incidence of regional and distant metastases in the non-PLD groups while the PLD groups showed decreased regional and no distant metastases (Table 1). Presence of metastases was confirmed by nCECT imaging and histopathological analysis. Conclusion: PLD improved response to radio-immunotherapy in a highly aggressive immunologically ‘cold’ mouse model of oral cancer while simultaneously preventing disease progression and metastasis. Citation Format: Laxman Devkota, Rohan Bhavane, Andrew Badachhape, Ratna Veeramachaneni, Renuka Menon, Prajwal Bhandari, Sofia Cortes, Fabio Henrique Brasil Da Costa, Ketan Ghaghada, Simon Young, Andrew G. Sikora, Ananth V. Annapragada. PEGylated liposomal doxorubicin improves oral cancer response to radio-immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5174.

Abstract 1604: Preclinical development of ADCT-211, a novel pyrrolobenzodiazepine dimer-based antibody-drug conjugate targeting solid tumors expressing IL13RA2

Abstract Interleukin 13 receptor subunit alpha 2 (IL13RA2) is one of the two major receptors for the cytokine interleukin 13 (IL-13). While IL13RA1 has low affinity for IL-13 and it is expressed ubiquitously in humans, IL13RA2 has high binding affinity to IL-13 and its expression in normal tissues is mainly restricted to the testes. IL13RA2 was initially regarded as a decoy receptor because it has a short cytoplasmic tail with no known signaling motifs, and its binding to IL-13 does not lead to activation of the JAK/STAT6 pathway. However, recent studies demonstrated that IL-13-mediated IL13RA2 signaling occurs via STAT6-independent pathways. IL13RA2 is reported to be expressed at a high frequency in glioblastoma multiforme (GBM) as well as in other solid tumors including melanoma, renal cell carcinoma and adrenocortical carcinoma and is correlated with poor prognosis. ADCT-211 is an antibody-drug conjugate composed of HuCl47, a humanized IgG1 antibody directed against human IL13RA2, site-specifically conjugated using GlycoConnectTM technology to PL1801, which contains HydraspaceTM, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG2000 (drug to antibody ratio ~ 1.8). The purpose of this study was to characterize the in vitro and in vivo anti-tumor activity of ADCT-211 in human cancer cell lines and xenograft models, to determine its safety, tolerability and pharmacokinetic (PK) in the rat and to measure IL13RA2 expression by immunohistochemistry (IHC) in human tumor specimens. HuCl47 showed specific binding to recombinant IL13RA2, while it did not bind to IL13RA1. In vitro, ADCT-211 had highly potent and targeted cytotoxicity against various IL13RA2-expressing solid cancer cell lines. In vivo, a single dose of ADCT-211 at 10 mg/kg was able to completely eradicate tumors in the subcutaneous (sc) A375 human melanoma xenograft model and resulted in 8/8 tumor-free survivors (TFS) at the end of the study on day 57. In the sc U251 human glioblastoma xenograft model, a single dose of ADCT-211 at 3.75 mg/kg showed potent and durable antitumor activity and it resulted in 5/10 partial responders and 5/10 complete responders, 2 of which were TFS at the end of the study on day 51. In an MTD study in male rats, ADCT-211 was stable and tolerated up to 24 mg/kg single dose, with exposure data being indicative of a linear PK profile with a half-life of 12-19 days. Expression of membranous IL13RA2 was confirmed by IHC in a panel of primary and refractory GBM samples and malignant melanoma, highlighting them as potential indications for the clinical development of ADCT-211. In conclusion, ADCT-211 demonstrated potent and specific in vitro and in vivo anti-tumor activity and it was stable and well tolerated in the rat, warranting further development of ADCT-211 into the clinic in IL13RA2-expressing cancers. Citation Format: Francesca Zammarchi, Karin Havenith, Ben Leatherdale, Britanny Roberts, Lara Montolio, Afroze Patel, Narinder Janghra, Pedro Alves, Kristina Zaitseva, Cecile Oblette, Ian Kirby, Lolke de Haan, Patrick H van Berkel. Preclinical development of ADCT-211, a novel pyrrolobenzodiazepine dimer-based antibody-drug conjugate targeting solid tumors expressing IL13RA2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1604.

Abstract 2278: Dissecting immuno-genomic pathways of response and resistance to immunotherapy in metastatic urothelial carcinoma in a real-world cohort

Abstract Background: While Immune Checkpoint Inhibitors (ICI) are widely used for the treatment (tx) of patients (pts) with metastatic urothelial carcinoma (mUC), response rates are only around 20%. There is an unmet need to develop biomarkers of response and resistance to avoid unnecessary treatment in the majority of pts who will not respond to ICI, to spare toxicity from ICI as well as mitigate the financial burden. Here we report tumor immune-genomic characteristics associated with response and resistance to ICI in a real-world cohort of mUC pts at the Cleveland Clinic. Methods: We selected 61 mUC pts who received at least 2 cycles of ICI (atezolizumab or pembrolizumab) between 2015-2020 and had pre-tx archival fresh frozen paraffin-embedded (FFPE) tissues available. Pts were categorized by their response to ICI as complete responders (CR; N=8), partial responders (PR; N=14), stable disease (SD; N=9), and progressive disease (PD; N=30). Tumor was macrodissected from 2-5 FFPE slides guided by an H&amp;E stained section of tumor. RNA extraction was done using Qiagen Rneasy FFPE kit. 100ng of RNA was used for transcriptomic analysis using the 770-gene Nanostring PanCancer IO 360 panel. Data normalization and analysis was carried out using nSolver 4.0. Results: Using unsupervised hierarchical clustering, when comparing molecular signatures of pts with CR vs PD respectively, we saw upregulation of exhausted CD8 (log fold change (FC) = 0.7287, p= 0.03289) and IFN downstream (logFC = 0.5929, p = 0.04986). Notably, the molecular signatures upregulated between SD vs PD respectively were IFN Gamma (logFC = 1.503, p = 0.0044), PD-L1 (logFC = 1.136, p = 0.0123), Antigen-presenting machinery (APM) (logFC = 1.103, p = 0.0006), Immunoproteasome (logFC = 0.984, p = 0.00096) and Tumor inflammatory score (logFC = 0.947, p = 0.032). Furthermore, molecular signatures were not differently upregulated between pts with PR vs PD. In our cohort, the proportion of pts who were alive at 35.9 months (median follow-up) was 62.5% for CR (5 of 8), 28.5% for PR (4 of 14), 22.2% for SD (2 of 9) and 6.2% for PD (2 of 30) even though the median overall survival was not significantly different between the groups. Conclusion: In our cohort of ICI-treated mUC pts, we found an association between existing T-cell effector function, particularly IFN-gamma responses, and response to ICI. Signatures associated with T cell exhaustion were also upregulated among pts with CR indicating ongoing anti-tumor activity. These findings need to be further validated in prospective trials. Ongoing genomic and immunologic correlative studies in our cohort will further help understand comprehensive biomarkers of response and resistance to ICI in pts with mUC are currently underway. Citation Format: Nikhil Pramod, Paul Pavicic, Scott Dawsey, Alan Shen, Roshan Lodha, Moshe Ornstein, Omar Mian, Timothy Gilligan, Christopher Wee, Amanda Nizam, Jane Nguyen, C. Marcela Diaz-Montero, Shilpa Gupta. Dissecting immuno-genomic pathways of response and resistance to immunotherapy in metastatic urothelial carcinoma in a real-world cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2278.

MP64-17 THE ROLE OF 18-FDG PET/CT SCAN IN EARLY RESPONSE TO SYSTEMIC THERAPY FOR METASTATIC RENAL CELL CARCINOMA: BEYOND SUV max

You have accessJournal of UrologyCME1 Apr 2023MP64-17 THE ROLE OF 18-FDG PET/CT SCAN IN EARLY RESPONSE TO SYSTEMIC THERAPY FOR METASTATIC RENAL CELL CARCINOMA: BEYOND SUVmax Sanjoy Kumar Sureka, Sumit Mandal, and Uday Pratap Singh Sanjoy Kumar SurekaSanjoy Kumar Sureka More articles by this author , Sumit MandalSumit Mandal More articles by this author , and Uday Pratap SinghUday Pratap Singh More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003322.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In metastatic renal cell carcinoma (RCC), the CECT scan evaluates lesions in their anatomic context while FDG-PET/CT scan demonstrates metabolic component. Often the size of the lesion may take time to respond and metabolic activity changes first. We evaluated the role of FDG PET/CT scan in this setting with an objective to evaluate the role of FDG-PET/CT as a monitoring tool for early response to systemic therapy in metastatic RCC. METHODS: From January 2017 to Dec 2021, 48 patients with synchronous and metachronous metastatic RCC with ECOG <2 underwent a baseline 18-FDG/PET-CT scan followed by repeat scan for response assessment 3 months later. Pregnant and nursing mothers, hypothyroid, diabetics and those with brain metastasis or another malignancy were excluded. Response evaluation was done with both RECIST version 1.1 (for CECT) and PERCIST (for PET-CT) criteria. Also, total lesion glycolysis (TLG), and metabolic tumour volume (MTV) were assessed. Interrater agreement was done using Cohen’s kappa between the scores. RESULTS: Mean age of 48 patients was 55.3±5.6 years and 28(58.3%) were males. Clear cell histology was present in 44 patients. Sunitinib, Pazopanib, Everolimus and Axitinib were given to 12, 22, 6 and 8 patients respectively. Out of 22 patients with partial response (PR) in RECIST, 8 patients were upgraded to Stable disease (SD) in 2 and Progressive disease (PD) in 6 as per PERCIST, subsequently leading to a change in their management. All 14 patients with PR in PERCIST had better long-term survival as compared to the rest upgraded 8. There was a significant decline in median SUVmax, MTV and TLG after 3 months in these patients. CONCLUSIONS: 18-FDG PET/CT scan is useful for monitoring the early response to systemic therapy in metastatic RCC based on 18-FDG avidity including TLG & MTV and correctly identifying partial responders. Changes in the metabolic parameters detect response to therapy earlier and guide subsequent changes in therapy. Source of Funding: None. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e887 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sanjoy Kumar Sureka More articles by this author Sumit Mandal More articles by this author Uday Pratap Singh More articles by this author Expand All Advertisement PDF downloadLoading ...

Retrospective Study of the Efficacy and Safety of Laser and Oral Combination Therapy for Non-responders to Neodymium-doped Yttrium Aluminum Garnet Laser: A Review of 20 Patients with Onychomycosis

Background: Oral antifungal drugs are the primary treatment for onychomycosis. However, there are few studies on the effectiveness and safety of oral combination therapy after laser treatment. Objective: We sought to contrast the efficacy and safety of laser and oral combination therapy with that of oral monotherapy for non-responders to laser treatment. Methods: We retrospectively evaluated the medical charts and photographs of 20 patients who received four sessions of Nd:YAG laser. Among these patients, 11 were "laser non-responders" and 9 were "laser partial responders". Afterward, 10 patients received oral drugs in addition to laser treatment (combination therapy) and the other 10 were completely altered to oral drugs, with no laser treatment (oral monotherapy). Clinical evaluation was conducted at baseline and 3 months after treatment. Recurrence was evaluated 3 months after the final evaluation. Results: Clinical evaluation revealed that combining or switching to oral antifungal drugs was substantially effective in the laser non-responder group (Z = -2.481, p = 0.013). Combination therapy was more effective than oral monotherapy (Z = -1.324, p = 0.247). Furthermore, positive baseline mycological results demonstrated a higher possibility of laser monotherapy failure (χ2 = -5.089, p = 0.024). There were two cases of recurrence in the oral monotherapy group and no adverse effect was discovered in any patient. Conclusion: This study highlighted that the combination of oral drugs with laser therapy could be beneficial regarding efficacy, recurrence, and safety in the treatment of patients who are refractory to laser therapy.

Evaluation of the Clinical Features and Laboratory Data of Patients with Severe Eosinophilic Asthma Classified as Super-Responders, Partial Responders, or Nonresponders to Mepolizumab Treatment: A Real-Life Study

Introduction: Mepolizumab is a treatment option in patients with severe eosinophilic asthma, which inhibits interleukin-5. The aim of this study was to evaluate the clinical features and laboratory data of patients with severe eosinophilic asthma who were classified as super-responders, partial responders, or nonresponders to mepolizumab treatment. Methods: In this retrospective real-life study, the clinical features and laboratory data were compared between groups of patients with severe eosinophilic asthma who were classified as super-responders, partial responders, or nonresponders to mepolizumab treatment. Results: Evaluation was made of a total of 55 patients, comprising 17 (30.9%) males and 38 (69.1%) females with a mean age of 51.28 ± 14.32 years. All the patients were receiving mepolizumab treatment for severe eosinophilic asthma, with 17 (30.9%) patients evaluated as super-responders, 26 (47.3%) as partial responders, and 12 (21.8%) as nonresponders. After mepolizumab treatment, there was a statistically significant decrease in asthma exacerbations, the number of oral corticosteroids (OCSs) used, the rate of hospitalization due to asthma attacks, and the eosinophil count (cells/µL) (p < 0.001, p < 0.001, p < 0.001, and <0.001, respectively). A statistically significant increase was determined in the forced expiratory volume in 1 s (FEV1) value (p = 0.010) and asthma control test (ACT) score (p < 0.001) after mepolizumab treatment. The baseline eosinophil count, eosinophil/lymphocyte ratio and FEV1 (%) values were significantly higher in the super-responder and partial responder groups (p < 0.001, p = 0.002, and p = 0.002, respectively). The baseline ACT score and the rate of chronic sinusitis with nasal polyps were significantly higher in the partial responder group (p = 0.004, p = 0.015, respectively). The rate of regular OCS use before mepolizumab treatment was significantly higher in the nonresponder group (p = 0.049). As a result of the receiver operating characteristics curve analysis, the blood eosinophil count (area under the curve [AUC]: 0.967, p < 0.001), eosinophil/lymphocyte ratio (AUC: 0.921, p < 0.001), and FEV1 (%) (AUC: 0.828, p = 0.002) were found to have diagnostic value in predicting the response to mepolizumab treatment in patients with severe eosinophilic asthma. Conclusion: Baseline eosinophil count, eosinophil/lymphocyte ratio, and FEV1 (%) were found to be important predictors of response to mepolizumab treatment. Further studies are needed to define the characterization of mepolizumab responders in the real world.

Maintained improvement in physician- and patient-reported outcomes with baricitinib in adults with moderate-to-severe atopic dermatitis who were treated for up to 104 weeks in a randomized trial

BackgroundPatients who completed the originating studies, BREEZE-AD1 (NCT03334396), BREEZE-AD2(NCT03334422), and BREEZE-AD7 (NCT03733301), were eligible for enrollment in the multicenter,phase-3, long-term extension study BREEZE-AD3 (NCT03334435).MethodsAt week 52, responders and partial responders to baricitinib 4 mg were re-randomized (1:1) into the sub-study to dose continuation (4 mg, N = 84), or dose down-titration (2 mg, N = 84). Maintenance of response was assessed from week 52 to 104 of BREEZE-AD3. Physician-rated outcomes included vIGA-AD (0,1), EASI75, and mean change from baseline in EASI. Patient-reported outcomes included DLQI, P OEM total score, HADS, and from baseline: WPAI (presenteeism, absenteeism, overall work impairment, daily activity impairment) and change from baseline in SCORAD itch and sleep loss.ResultsWith continuous treatment with baricitinib 4 mg, efficacy was maintained up to week 104 in vIGA-AD (0,1), EASI75, EASI mean change from baseline, SCORAD itch, SCORAD sleep loss, DLQI, P OEM, HADS, and WPAI (all scores). Patients down-titrated to 2 mg maintained most of their improvements in each of these measures.ConclusionThe sub-study of BREEZE AD3 supports flexibility in baricitinib dosing regimens. Patients who continued treatment with baricitinib 4 mg and down-titrated to 2 mg maintained improvements in skin, itch, sleep, and quality of life for up to 104 weeks.

The role of adjuvant pharmacotherapy with liraglutide for patients with inadequate weight loss following bariatric surgery

PurposeDespite the benefits of bariatric surgery for many patients, there are a proportion of patients who do not achieve adequate weight loss. We evaluate the role of liraglutide as adjuvant pharmacotherapy in those who respond poorly to weight loss surgery.Materials and MethodsA non-controlled, prospective, open-label cohort study in which participants are prescribed liraglutide following inadequate response to weight loss surgery. The efficacy and tolerability of liraglutide was measured through measurement of BMI and monitoring of side effect profile.ResultsA total of 68 partial responders to bariatric surgery were included in the study, 2 participants were lost to follow-up. Overall 89.7% lost weight on liraglutide, with 22.1% showing a good response (>10% total body weight loss). There were 41 patients who discontinued liraglutide mainly due to cost.ConclusionLiraglutide is efficacious in achieving weight loss and reasonably well tolerated in patients who have inadequate weight loss post-bariatric surgery.