المؤلفون: Xiaoyun Li, Cathy Anne Pinto, Emilie Scherrer, Mizuho Kalabis, Xinyue Liu

المصدر: Journal for ImmunoTherapy of Cancer, Vol 8, Iss Suppl 3 (2020)

مصطلحات موضوعية: medicine.medical_specialty, Chemotherapy, Combination therapy, business.industry, medicine.medical_treatment, Medical record, Disease progression, Pembrolizumab, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, Stable Disease, Internal medicine, medicine, Nivolumab, business, Social Security Death Index

الوصف: Background Immuno-oncology (I-O) plays a major role in the treatment of advanced melanoma (aMel); however, resistance to therapy remains an important clinical problem. This study examined treatment patterns and overall survival (OS) for aMel patients who progressed on anti-programmed death ligand 1 (anti-PD-1) therapy in a real-world clinical setting. Methods A retrospective database study of Flatiron electronic medical records (EMR) was conducted with 304 aMel patients who progressed on first or second line anti-PD1 (baseline) therapy with pembrolizumab or nivolumab and received subsequent (index) therapy with ≥3 months of potential follow-up. Patients who discontinued treatment for reasons other than progression (primarily toxicity) were excluded. The primary outcome was OS, defined using EMR data linked to external mortality sources (e.g. Social Security Death Index). OS analysis was stratified by several factors (e.g. age, ECOG, BRAF, LDH, type of index therapy, and best overall response [BOR] to baseline anti-PD-1 therapy). BOR defined as response, stable disease, or disease progression was based on clinician assessment following radiographic imaging. Descriptive and log-rank test statistics for OS were used. Results Among patients receiving index therapy (n=304), 50% received I-O (n=91/151 combination therapy), 36% received BRAFi/MEKi (n=102/109 combination therapy) and 14% received other therapies (n=34/44 chemotherapy). Median (range) age was 67 (23–85) years, with 65% male, 62% ECOG≤1, 33% elevated LDH, and 51% with BRAF mutations. Most patients received baseline anti-PD1 monotherapy (77%) as first line therapy. Median OS (95%CI) was 7.2 (6.4, 8.8) months, with a significant OS association with ECOG≤1 (p Conclusions Suboptimal OS in patients who progress on anti-PD-1 therapy in a real-world clinical setting, with predictors of enhanced survival, highlights the need for further research to inform optimal treatment strategies. Acknowledgements The authors would like to acknowledge the contributions of Bo Zheng, Clemens Krepler, Diana Malandrucollo, and Shelby Marx of Merck & Co, Inc.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::67a08aa4a18c0690b927dab1976b7af3Test
https://doaj.org/article/1bfc61267f7a45059e87b4fee703575bTest

المؤلفون: Daniela E. Myers, Lawrence F. Eichenfield, Mizuho Kalabis, Linda Stein Gold, Paul Sanders, Chuanbo Zang, Gil Yosipovitch, Joseph C. Cappelleri, Andrew G. Bushmakin, Melissa Olivadoti, Amy S. Paller, Bonnie Vlahos

المصدر: Pediatric Dermatology

مصطلحات موضوعية: Boron Compounds, medicine.medical_specialty, Adolescent, Dermatology, Severity of Illness Index, Dermatitis, Atopic, Ointments, 030207 dermatology & venereal diseases, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Disease severity, Double-Blind Method, Phosphodiesterase 4 Inhibitor, Internal medicine, Post-hoc analysis, medicine, Humans, Child, Nonsteroidal, atopic dermatitis, business.industry, Pruritus, therapy‐topical, Crisaborole, Atopic dermatitis, Original Articles, medicine.disease, Bridged Bicyclo Compounds, Heterocyclic, Treatment Outcome, chemistry, 030220 oncology & carcinogenesis, Child, Preschool, Pediatrics, Perinatology and Child Health, Original Article, business

الوصف: Background/Objectives Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild‐to‐moderate atopic dermatitis (AD). This pooled post hoc analysis of two phase 3 trials (NCT02118766, NCT02118792) assessed improvement and time to improvement in Investigator's Static Global Assessment (ISGA) and Severity of Pruritus Scale (SPS) outcomes in pediatric patients with mild‐to‐moderate AD. Methods Patients aged ≥2 years were randomly assigned 2:1 to receive twice‐daily crisaborole or vehicle for 28 days. Patients aged 2‐17 years were pooled for this analysis. Proportions of patients and time to achieving ISGA success (clear [0] or almost clear [1] with ≥2‐grade improvement from baseline), ISGA clear/almost clear, ≥1‐grade improvement in ISGA, SPS success (SPS score ≤1 with ≥1‐grade improvement), or ≥1‐grade improvement in SPS score were analyzed and stratified by baseline ISGA. Results At first postbaseline assessment (day 8), significantly higher proportions of crisaborole‐ than vehicle‐treated patients achieved ISGA success, ISGA clear/almost clear, ≥1‐grade ISGA improvement, SPS success, or ≥1‐grade improvement in SPS regardless of baseline ISGA. Differences were significantly greater over time for all outcomes for patients with moderate baseline ISGA and numerically greater for those with mild baseline ISGA. Median times to ISGA and SPS outcomes were shorter for crisaborole versus vehicle. Conclusion Improvement in ISGA and SPS outcomes were observed with crisaborole in pediatric patients with mild‐to‐moderate baseline AD.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::952ff611dd5cbeb0967aa859501efed0Test
https://pubmed.ncbi.nlm.nih.gov/32981097Test

المؤلفون: Evan J. Lipson, Ragini R. Kudchadkar, Sunil Reddy, Tomoko Akaike, Thomas Olencki, William H. Sharfman, Philip Friedlander, Steven P. Fling, Mizuho Kalabis, Candice D. Church, Kari Kendra, Michi M. Shinohara, Adil Daud, Adam I. Riker, Harriet M. Kluger, Elad Sharon, Melissa Amber Burgess, Janis M. Taube, Paul Nghiem, Brent A. Hanks, Suzanne L. Topalian, Blanca Homet Moreno, Andrew S. Brohl, Brian C. Boulmay, Martin A. Cheever, Bob Salim, Erin Jensen, Shailender Bhatia, Nirasha Ramchurren

المصدر: Journal for ImmunoTherapy of Cancer, Vol 9, Iss 4 (2021)
Journal for immunotherapy of cancer, vol 9, iss 4
Journal for Immunotherapy of Cancer

مصطلحات موضوعية: Male, 0301 basic medicine, Oncology, Cancer Research, Skin Neoplasms, Time Factors, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Pembrolizumab, 0302 clinical medicine, Stable Disease, Cancer immunotherapy, Monoclonal, 80 and over, Immunology and Allergy, Humanized, Immune Checkpoint Inhibitors, 6.2 Cellular and gene therapies, RC254-282, Cancer, Aged, 80 and over, Clinical/Translational Cancer Immunotherapy, Merkel cell carcinoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Middle Aged, Progression-Free Survival, 6.1 Pharmaceuticals, 030220 oncology & carcinogenesis, Disease Progression, Molecular Medicine, Female, immunotherapy, medicine.medical_specialty, Clinical Trials and Supportive Activities, Immunology, Antibodies, Monoclonal, Humanized, Antibodies, 03 medical and health sciences, Clinical Research, Internal medicine, medicine, Humans, Neoplasm Staging, Aged, Salvage Therapy, Pharmacology, Chemotherapy, business.industry, Carcinoma, Evaluation of treatments and therapeutic interventions, Immunotherapy, medicine.disease, Carcinoma, Merkel Cell, 030104 developmental biology, Tumor progression, Merkel Cell, Skin cancer, business

الوصف: BackgroundMerkel cell carcinoma (MCC) is an aggressive skin cancer associated with poor survival. Programmed cell death-1 (PD-1) pathway inhibitors have shown high rates of durable tumor regression compared with chemotherapy for MCC. The current study was undertaken to assess baseline and on-treatment factors associated with MCC regression and 3-year survival, and to explore the effects of salvage therapies in patients experiencing initial non-response or tumor progression after response or stable disease following first-line pembrolizumab therapy on Cancer Immunotherapy Trials Network-09/KEYNOTE-017.MethodsIn this multicenter phase II trial, 50 patients with advanced unresectable MCC received pembrolizumab 2 mg/kg every 3 weeks for ≤2 years. Patients were followed for a median of 31.8 months.ResultsOverall response rate to pembrolizumab was 58% (complete response 30%+partial response 28%; 95% CI 43.2 to 71.8). Among 29 responders, the median response duration was not reached (NR) at 3 years (range 1.0+ to 51.8+ months). Median progression-free survival (PFS) was 16.8 months (95% CI 4.6 to 43.4) and the 3-year PFS was 39.1%. Median OS was NR; the 3-year OS was 59.4% for all patients and 89.5% for responders. Baseline Eastern Cooperative Oncology Group performance status of 0, greater per cent tumor reduction, completion of 2 years of treatment and low neutrophil-to-lymphocyte ratio were associated with response and longer survival. Among patients with initial disease progression or those who developed progression after response or stable disease, some had extended survival with subsequent treatments including chemotherapies and immunotherapies.ConclusionsThis study represents the longest available follow-up from any first-line anti-programmed death-(ligand) 1 (anti-PD-(L)1) therapy in MCC, confirming durable PFS and OS in a proportion of patients. After initial tumor progression or relapse following response, some patients receiving salvage therapies survived. Improving the management of anti-PD-(L)1-refractory MCC remains a challenge and a high priority.Trial registration numberNCT02267603.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::272adca2addf0d58650483b69b745a95Test
https://doi.org/10.1136/jitc-2021-002478Test

المؤلفون: Elliot Chartash, Lokesh Jain, Dinesh P. de Alwis, Mallika Lala, Shu-Chih Su, Omobolaji Oyekunle Akala, Mizuho Kalabis, Vikram Sinha

المصدر: Cancer Research. 80:CT042-CT042

مصطلحات موضوعية: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, business.industry, Pembrolizumab, Clinical trial, 03 medical and health sciences, Regimen, 030104 developmental biology, 0302 clinical medicine, Pharmacokinetics, 030220 oncology & carcinogenesis, Internal medicine, Cohort, medicine, Every Three Weeks, media_common.cataloged_instance, Dosing, European union, business, media_common

الوصف: Background: Pembrolizumab is approved globally in multiple cancer indications at a dose of 200 mg or 2 mg/kg every three weeks (Q3W). An alternative dosing regimen of 400 mg every six weeks (Q6W), which provides convenience and flexibility to patients and prescribers, is also approved in markets including the European Union (EU), Australia and New Zealand based on pharmacokinetic (PK) modeling and simulation. KEYNOTE-555 Cohort B is an open-label, clinical study in patients with metastatic melanoma designed evaluate the Q6W dosing. The preliminary PK data to validate the model-based assessments as well as efficacy and safety of the Q6W regimen compared to historical data will be described. Methods: A total of 101 patients are enrolled in this study; complete cycle 1 PK data from 37 patients are available. Observed concentration-time profiles from cycle 1 were compared with predictions from the model, which is based on 2993 patients from 5 clinical trials across tumor types. The associated efficacy and safety from these patients will be reviewed and compared to previous clinical trials in advanced melanoma. Results: The demographics from KN-555 Cohort B were similar to previous trials of pembrolizumab in metastatic melanoma, with mean age: 62 years, mean body weight: 85 kg, and 34% female patients. The observed concentrations for 400 mg Q6W were well within the 90% prediction intervals of simulated concentrations using the model. The geometric mean (GM) of observed trough concentration at six weeks (Ctrough) at 400 mg Q6W is 14.5 ug/mL, which is 18% lower than at 200 mg Q3W (18.1 ug/mL) and 11% higher than at 2 mg/kg Q3W (13.4 ug/mL). The GM of observed peak concentration at the end of infusion at 400 mg Q6W is 136 ug/mL, which is below (38% lower) that at the highest clinically tested dose of 10 mg/kg Q2W (220 ug/mL). The ORR in KN-555 Cohort B is comparable to the ORR in previous pembrolizumab studies in metastatic melanoma, indicating similarity of efficacy between the Q6W and Q3W regimens. The safety of the Q6W regimen is comparable to the extensive pembrolizumab safety profile that has been demonstrated in over twelve tumor types. Conclusion: The preliminary PK, efficacy and safety analyzed from KN-555 Cohort B validates the findings from the model-based assessment, of a consistent benefit-risk profile for a 400 mg Q6W regimen as compared to the 200 mg (or 2 mg/kg) Q3W regimen. The study supports that pembrolizumab Q6W is a safe and effective dosing regimen and offers a more convenient option for patients and physicians. Citation Format: Mallika Lala, Omobolaji Akala, Elliot Chartash, Mizuho Kalabis, Shu-Chih Su, Dinesh de Alwis, Vikram Sinha, Lokesh Jain. Pembrolizumab 400 mg Q6W dosing: First clinical outcomes data from Keynote-555 cohort B in metastatic melanoma patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT042.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::1d8ef5ccc60934dcfca3fe1cc81b3fcfTest
https://doi.org/10.1158/1538-7445.am2020-ct042Test

المؤلفون: Nicholas J. Petrelli, Michela Perego, Marilda Beqiri, Mizuho Kalabis, Denitsa Hristova, Rajasekharan Somasundaram, Min Xiao, Clemens Krepler, Meenhard Herlyn

المصدر: Clinical Cancer Research. 22:PR02-PR02

مصطلحات موضوعية: Genetically modified mouse, Cancer Research, biology, business.industry, Melanoma, medicine.disease, Immune checkpoint, Immune system, Oncology, Antigen, Immunology, Humanized mouse, biology.protein, Medicine, Antibody, business, Immunodeficient Mouse

الوصف: Melanoma patients develop resistance to both chemo- and targeted-therapy drugs. Promising pre-clinical and clinical results with immune checkpoint inhibitors using antibodies directed against CTLA4 and PD1 have re-energized the field of immune-based therapies in melanoma. However, similar to chemo- or targeted-therapies only subsets of melanoma patients respond to immune checkpoint blockade. Currently available immunodeficient mouse xenograft and transgenic mouse melanoma models have a number of short comings and are unable to address the basis of drug resistance and immune non-responsiveness frequently observed in melanoma patients treated either with chemo- and targeted-therapy drugs or immune checkpoint inhibitors. Thus there is an urgent need to establish a mouse model with an immune microenvironment that can address the above issues encountered in melanoma patients. For this, our laboratory has developed a humanized mouse melanoma model using patient-derived xenograft (PDX). Immunodeficient (NOD/Shi-SCID/IL-2Rgnull [NOG; Taconic]/ NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ [NSG; Jackson Laboratory]) mice were reconstituted with human CD34+ cells and after 12 weeks, mature human CD45+ cells are observed in mouse peripheral blood and in the lymphoid organs. Humanized mice with optimum number of mature human CD45+ cells in peripheral blood were challenged with HLA-matched melanoma PDX and the immune response to melanoma associated antigens were monitored. Lymphoid cells derived from humanized mice that are challenged with human leukocyte antigen (HLA) matched melanoma cells in vivo showed enhanced cytokine expression to in vitro stimulation with peptides derived from melanoma antigens. In addition, cytotoxic T-cells were able to functionally lyse tumor cells in vitro, infiltrate and restrict in vivo tumor growth. We are currently refining our model to establish an autologous mouse melanoma model. Our innovative humanized mouse melanoma model will enable one to understand the causes of therapy resistance and immune non-responsiveness in patients. This abstract is also being presented as Poster B33. Citation Format: Clemens Krepler, Michela Perego, Mizuho Kalabis, Marilda Beqiri, Denitsa Hristova, Min Xiao, Nicholas J. Petrelli, Rajasekharan Somasundaram, Meenhard Herlyn. Humanized mouse melanoma model using patient-derived xenografts. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr PR02.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::8d0506b5ced6fd89f03d0cb8c5ceeff4Test
https://doi.org/10.1158/1557-3265.pdx16-pr02Test