المؤلفون: Ribas, Antoni, Puzanov, Igor, Dummer, Reinhard, Schadendorf, Dirk, Hamid, Omid, Robert, Caroline, Hodi, F Stephen, Schachter, Jacob, Pavlick, Anna C, Lewis, Karl D, Cranmer, Lee D, Blank, Christian U, O'Day, Steven J, Ascierto, Paolo A, Salama, April KS, Margolin, Kim A, Loquai, Carmen, Eigentler, Thomas K, Gangadhar, Tara C, Carlino, Matteo S, Agarwala, Sanjiv S, Moschos, Stergios J, Sosman, Jeffrey A, Goldinger, Simone M, Shapira-Frommer, Ronnie, Gonzalez, Rene, Kirkwood, John M, Wolchok, Jedd D, Eggermont, Alexander, Li, Xiaoyun Nicole, Zhou, Wei, Zernhelt, Adriane M, Lis, Joy, Ebbinghaus, Scot, Kang, S Peter, Daud, Adil

المصدر: The Lancet Oncology. 16(8)

مصطلحات موضوعية: Clinical Trials and Supportive Activities, Cancer, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Disease Progression, Disease-Free Survival, Drug Resistance, Neoplasm, Female, Humans, Intention to Treat Analysis, Ipilimumab, Kaplan-Meier Estimate, Male, Melanoma, Middle Aged, Skin Neoplasms, Time Factors, Treatment Outcome, Young Adult, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: BackgroundPatients with melanoma that progresses on ipilimumab and, if BRAF(V600) mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma.MethodsWe carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF(V600) mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF(V600) mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients.FindingsBetween Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45-0·73; p

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8j23r3pnTest

المؤلفون: Sarnaik Amod A., Hamid Omid, Khushalani Nikhil I., Lewis Karl D., Medina Theresa, Kluger Harriet M., Sajeve Thomas S., Evidio Domingo-Musibay, Pavlick Anna C., Whitman Eric D., Salvador Martin-Algarra, Pippa Corrie, Curti Brendan D., Oláh Judit Magdolna, Lutzky Jose

مصطلحات موضوعية: 03.02. Klinikai orvostan

وصف الملف: text

العلاقة: http://publicatio.bibl.u-szeged.hu/21420/1/jco.21.00612.pdfTest; Sarnaik Amod A.; Hamid Omid; Khushalani Nikhil I.; Lewis Karl D.; Medina Theresa; Kluger Harriet M.; Sajeve Thomas S.; Evidio Domingo-Musibay; Pavlick Anna C.; Whitman Eric D.; Salvador Martin-Algarra; Pippa Corrie; Curti Brendan D.; Oláh Judit Magdolna; Lutzky Jose: Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. JOURNAL OF CLINICAL ONCOLOGY, 39 (24). p. 2656. ISSN 0732-183X (2021)

الإتاحة: https://doi.org/10.1200/JCO.21.00612Test
http://publicatio.bibl.u-szeged.hu/21420Test/
http://publicatio.bibl.u-szeged.hu/21420/1/jco.21.00612.pdfTest

المؤلفون: Rabinowits, Guilherme, Migden, Michael R., Schlesinger, Todd E., Ferris, Robert L., Freeman, Morganna, Guild, Valerie, Koyfman, Shlomo, Pavlick, Anna C., Swanson, Neil, Wolf, Gregory T., Dinehart, Scott M.

المصدر: JID Innovations ; volume 1, issue 4, page 100045 ; ISSN 2667-0267

الإتاحة: https://doi.org/10.1016/j.xjidi.2021.100045Test
https://api.elsevier.com/content/article/PII:S2667026721000461?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2667026721000461?httpAccept=text/plainTest

المؤلفون: Pavlick, Anna C, Zhao, Ruizhi, Lee, Cho-Han, Ritchings, Corey, Rao, Sumati

المساهمون: Bristol Myers Squibb

المصدر: Future Oncology ; volume 17, issue 6, page 689-699 ; ISSN 1479-6694 1744-8301

الإتاحة: https://doi.org/10.2217/fon-2020-0643Test

المؤلفون: Wilken, Reason, Criscito, Maressa, Pavlick, Anna C., Stevenson, Mary L., Carucci, John A.

المصدر: Facial Plastic Surgery ; volume 36, issue 02, page 200-210 ; ISSN 0736-6825 1098-8793

الوصف: There have been several significant advances in cancer treatment in the last decade that are applicable to the treatment of melanoma and advanced nonmelanoma skin cancers. Among these are the development of immune checkpoint inhibitors targeting the programmed death protein-1 (PD-1)/programmed death legand-1 (PDL-1) axis, as well as targeted inhibitors of the BRAF/MEK signaling cascade in melanoma, and the hedgehog signaling pathway in basal cell carcinoma (BCC). These immune-based and targeted therapies have dramatically changed the treatment options for locally advanced and metastatic melanoma, Merkel's cell carcinoma, cutaneous squamous cell carcinoma (cSCC), and BCC. In this article, we will briefly review the currently approved targeted and immunotherapy-based treatments for locally advanced and metastatic melanoma, Merkel's cell carcinoma, and cSCC and discuss various combinations of approved therapies, as well as emerging therapeutic candidates that are currently in clinical trials, including novel checkpoint inhibitors in development, intratumoral oncolytic agents (viral and nonviral), and various immune-based therapies such as toll-like receptor (TLR) agonists, adoptive T-cell therapy, T-cell costimulation, and innate immune cell therapy. For advanced BCC, we will discuss trials investigating the currently approved smoothened (SMO) inhibitors for neoadjuvant use, emerging SMO inhibitors in development, topical SMO inhibitors, alternative targets in the hedgehog signaling pathway, and the use of anti-PD-1 agents for advanced BCC both alone and in combination with SMO inhibitors.

الإتاحة: https://doi.org/10.1055/s-0040-1709118Test

المؤلفون: Frazzette, Nicholas, Khodadadi-Jamayran, Alireza, Doudican, Nicole, Santana, Alexis, Felsen, Diane, Pavlick, Anna C., Tsirigos, Aristotelis, Carucci, John A.

المساهمون: Regeneron Pharmaceuticals

المصدر: npj Precision Oncology ; volume 4, issue 1 ; ISSN 2397-768X

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: T-cell landscape differences between cutaneous squamous cell carcinoma (cSCC) tumors in immune competent (SCC in IC) and immunocompromised organ transplant recipients (TSCC in OTR) are unclear. We developed an analytical method to define tumor infiltrating lymphocyte (TIL) phenotype in cSCC from immune competent and immune suppressed patients using single-cell TCR sequencing and gene expression data. TSCC exhibits reduced proportions of cytotoxic and naïve TILs and similar numbers of regulatory TILs. Fewer, more heterogeneous TCR clonotypes are observed in TIL from OTR. Most TCR sequences for top ten clonotypes correspond to known antigens, while 24% correspond to putative neoantigens. OTR show increased cSCC events over 12 months possibly due to reduced cytotoxic T-cells. Our novel method of barcoding CD8+ T-cells is the first providing gene expression and TCR sequences in cSCC. Knowledge regarding putative antigens recognized by TCRs with phenotypic function of T-cells bearing those TCRs could facilitate personalized cSCC treatments.

الإتاحة: https://doi.org/10.1038/s41698-020-0119-9Test
https://www.nature.com/articles/s41698-020-0119-9.pdfTest
https://www.nature.com/articles/s41698-020-0119-9Test

المؤلفون: Boland, Patrick, Pavlick, Anna C, Weber, Jeffrey, Sandigursky, Sabina

المصدر: Journal for ImmunoTherapy of Cancer ; volume 8, issue 1, page e000356 ; ISSN 2051-1426

الوصف: In the past 10 years, immune checkpoint inhibitors (ICIs) have become an additional pillar of cancer therapy by activating the immune system to treat a number of different malignancies. Many patients receiving ICIs develop immune-related adverse events (irAEs) that mimic some features of classical autoimmune diseases. Unfortunately, patients with underlying autoimmune conditions, many of whom have an increased risk for malignancy, have been excluded from clinical trials of ICIs due to a concern that they will have an increased risk of irAEs. Retrospective data from patients with autoimmune diseases and concomitant malignancy treated with ICIs are encouraging and suggest that ICIs may be tolerated safely in patients with specific autoimmune diseases, but there are no prospective data to guide management. In this manuscript, we review the relationship between pre-existing autoimmune disease and irAEs from checkpoint inhibitors. In addition, we assess the likelihood of autoimmune disease exacerbations in patients with pre-existing autoimmunity receiving ICI.

الإتاحة: https://doi.org/10.1136/jitc-2019-000356Test

المؤلفون: Rischin, Danny, Migden, Michael R, Lim, Annette M, Schmults, Chrysalyne D, Khushalani, Nikhil I, Hughes, Brett G M, Schadendorf, Dirk, Dunn, Lara A, Hernandez-Aya, Leonel, Chang, Anne Lynn S, Modi, Badri, Hauschild, Axel, Ulrich, Claas, Eigentler, Thomas, Stein, Brian, Pavlick, Anna C, Geiger, Jessica L, Gutzmer, Ralf, Alam, Murad, Okoye, Emmanuel, Mathias, Melissa, Jankovic, Vladimir, Stankevich, Elizabeth, Booth, Jocelyn, Li, Siyu, Lowy, Israel, Fury, Matthew G, Guminski, Alexander

المساهمون: Sanofi, Regeneron Pharmaceuticals

المصدر: Journal for ImmunoTherapy of Cancer ; volume 8, issue 1, page e000775 ; ISSN 2051-1426

الوصف: Background Cemiplimab, a high-affinity, potent human immunoglobulin G4 monoclonal antibody to programmed cell death-1 demonstrated antitumor activity in a Phase 1 advanced cutaneous squamous cell carcinoma (CSCC) expansion cohort ( NCT02383212 ) and the pivotal Phase 2 study ( NCT02760498 ). Here we report the primary analysis of fixed dose cemiplimab 350 mg intravenously every 3 weeks (Q3W) (Group 3) and provide a longer-term update after the primary analysis of weight-based cemiplimab 3 mg/kg intravenously every 2 weeks (Q2W) (Group 1) among metastatic CSCC (mCSCC) patients in the pivotal study ( NCT02760498 ). Methods The primary objective for each group was objective response rate (ORR) per independent central review (ICR). Secondary endpoints included ORR by investigator review (INV), duration of response (DOR) per ICR and INV, and safety and tolerability. Results For Group 3 (n=56) and Group 1 (n=59), median follow-up was 8.1 (range, 0.6 to 14.1) and 16.5 (range, 1.1 to 26.6) months, respectively. ORR per ICR was 41.1% (95% CI, 28.1% to 55.0%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 45.2% (95% CI, 35.9% to 54.8%) in both groups combined. Per ICR, Kaplan–Meier estimate for DOR at 8 months was 95.0% (95% CI, 69.5% to 99. 3%) in responding patients in Group 3, and at 12 months was 88.9% (95% CI, 69.3% to 96.3%) in responding patients in Group 1. Per INV, ORR was 51.8% (95% CI, 38.0% to 65.3%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 50.4% (95% CI, 41.0% to 59.9%) in both groups combined. Overall, the most common adverse events regardless of attribution were fatigue (27.0%) and diarrhea (23.5%). Conclusion In patients with mCSCC, cemiplimab 350 mg intravenously Q3W produced substantial antitumor activity with durable response and an acceptable safety profile. Follow-up data of cemiplimab 3 mg/kg intravenously Q2W demonstrate ongoing durability of responses. Trial registration number Clinicaltrials.gov, NCT02760498 . Registered May 3, 2016, ...

الإتاحة: https://doi.org/10.1136/jitc-2020-000775Test

المؤلفون: Rasco, Drew W., Medina, Theresa, Corrie, Pippa, Pavlick, Anna C., Middleton, Mark R., Lorigan, Paul, Hebert, Chris, Plummer, Ruth, Larkin, James, Agarwala, Sanjiv S., Daud, Adil I., Qiu, Jiaheng, Bozon, Viviana, Kneissl, Michelle, Barry, Elly, Olszanski, Anthony J.

مصطلحات موضوعية: Phase 1, Pan-RAF inhibitor, Melanoma, BRAF, Tovorafenib

الوصف: Acknowledgements: Medical writing support was provided by Sandya Govinda Raju of Day One Biopharmaceuticals and Jim Heighway of Cancer Communications and Consultancy Ltd (Plumley, UK), with funding from Day One. ; Funder: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited ; Purpose: Genomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib. Methods: This two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics. Results: Tovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in ...

وصف الملف: application/pdf; application/zip; text/xml

العلاقة: https://www.repository.cam.ac.uk/handle/1810/361733Test

الإتاحة: https://www.repository.cam.ac.uk/handle/1810/361733Test

المؤلفون: Ott, Patrick A., Pavlick, Anna C., Johnson, Douglas B., Hart, Lowell L., Infante, Jeffrey R., Luke, Jason J., Lutzky, Jose, Rothschild, Neal E., Spitler, Lynn E., Cowey, C. Lance, Alizadeh, Aaron R., Salama, April K., He, Yi, Hawthorne, Thomas R., Bagley, Rebecca G., Zhang, Joshua, Turner, Christopher D., Hamid, Omid

المساهمون: Celldex Therapeutics

المصدر: Cancer ; volume 125, issue 7, page 1113-1123 ; ISSN 0008-543X 1097-0142

الوصف: Background Glembatumumab vedotin is an antibody‐drug conjugate that produced preliminary clinical activity against advanced melanoma in a phase 1 dose‐escalation trial. The objective of the current study was to investigate further the antitumor activity of glembatumumab vedotin at the recommended phase 2 dose in heavily pretreated patients with melanoma. Methods This single‐arm, phase 2 study enrolled patients with stage IV melanoma who were refractory to checkpoint inhibition and to B‐raf proto‐oncogene, serine/threonine kinase (BRAF)/mitogen‐activated protein kinase kinase (MEK) inhibition (in the presence of a BRAF valine mutation at codon 600). Patients received 1.9 mg/kg glembatumumab vedotin intravenously every 3 weeks until they developed disease progression or intolerance. The primary endpoint was objective response rate (ORR), which was determined according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression‐free survival (PFS), duration of response, overall survival (OS), safety, and clinical efficacy versus tumor glycoprotein NMB (gpNMB) expression. Tumor expression of gpNMB was assessed using immunohistochemistry. Results In total, 62 patients received treatment. The ORR was 11% and the median response duration was 6.0 months (95% confidence interval [CI], 4.1 months to not reached). The median PFS was 4.4 months (95% CI, 2.6‐5.5 months), and the median OS was 9.0 months (95% CI, 6.1‐11.7 months). For patients who developed rash during the first cycle versus those who did not, the ORR was 21% versus 7%, respectively, and there was an overall improvement in PFS (hazard ratio, 0.43; P = .013) and OS (hazard ratio, 0.43; P = .017). The most frequent adverse events were alopecia, neuropathy, rash, fatigue, and neutropenia. With one exception, all evaluable tumors were positive for gpNMB, and 46 of 59 tumors (76%) had 100% gpNMB‐positive epithelial cells. Conclusions Glembatumumab vedotin had modest activity and an acceptable safety profile in patients ...

الإتاحة: https://doi.org/10.1002/cncr.31892Test