136 results on '"R. Gutzmer"'
Search Results
2. Key Clinical Adverse Events in Patients with Advanced Basal Cell Carcinoma Treated with Sonidegib or Vismodegib: A Post Hoc Analysis
- Author
-
R. Gutzmer, Karl D. Lewis, Serena Martelli, Brigitte Dréno, Carmen Loquai, Meenal Kheterpal, Ramon Arntz, Nicholas Squittieri, Caroline Robert, and Alexander Guminski
- Subjects
medicine.medical_specialty ,Vismodegib ,Nausea ,Dermatology ,Gastroenterology ,Sonidegib ,chemistry.chemical_compound ,Internal medicine ,Post-hoc analysis ,medicine ,Basal cell carcinoma ,Adverse effect ,business.industry ,Brief Report ,Common Terminology Criteria for Adverse Events ,medicine.disease ,Adverse event onset ,Dysgeusia ,Hedgehog inhibitors ,chemistry ,medicine.symptom ,business ,medicine.drug - Abstract
Introduction Sonidegib is approved to treat locally advanced basal cell carcinoma (laBCC) in the USA, EU, Switzerland, and Australia and metastatic basal cell carcinoma (mBCC) in Switzerland and Australia in patients not amenable to surgery or radiotherapy. Vismodegib is approved to treat patients with mBCC, recurrent laBCC, or those not candidates for surgery or radiation. There is no head-to-head trial comparing Hedgehog inhibitors. We describe time to onset and severity of adverse events (AEs) in two studies reporting cumulative AE incidence every treatment cycle: the sonidegib phase 2 BOLT study and the expanded-access, open-label vismodegib study. Methods This analysis included patients with histologically confirmed laBCC or mBCC from BOLT who received sonidegib 200 mg once daily (QD) and patients from the vismodegib study who received vismodegib 150 mg QD. Cumulative occurrence of AEs and median time to AE onset were calculated on 30-day cycles for sonidegib and 28-day cycles for vismodegib. AEs were graded for severity using the Common Terminology Criteria for Adverse Events. Only common (at least 15% incidence) AEs were analyzed in this study. Results Over 18 treatment cycles, the most common all-grade AEs for sonidegib and vismodegib were muscle spasm (54.4% vs 70.6%; P = 0.0236), alopecia (49.4% vs 58.0%; no significant difference [NS]), and dysgeusia (43.0% vs 70.6%; P = 0.0003); incidences of diarrhea, nausea, fatigue, and weight decrease were 31.6% vs 25.2% (NS), 39.2% vs 19.3% (P = 0.0032), 32.9% vs 19.3% (P = 0.0429), and 30.4% vs 16.0% (P = 0.0217), respectively. Sonidegib-treated patients had more delayed median time to onset for all AEs than vismodegib-treated patients, except fatigue and weight decrease (NS). Most AEs reported were grade ≤ 2. Conclusion This post hoc analysis suggests lower overall incidence and slower onset of certain AEs in patients treated with sonidegib compared with vismodegib. In the absence of head-to-head comparisons, the relevance of these findings needs further studies to provide conclusive evidence.
- Published
- 2021
3. 813P Time to development of central nervous system (CNS) metastases (mets) with atezolizumab (A) or placebo (P) combined with vemurafenib (V) + cobimetinib (C): Updated results from the phase III IMspire150 study
- Author
-
K. Lewis, C. Robert, R. Ramella Munhoz, G. Liszkay, L. de la Cruz Merino, J. Olah, P. Queirolo, J. Mackiewicz, H. Li, Q. Zhu, C. Hertig, N. Paranthaman, E.F. McKenna, R. Gutzmer, G. McArthur, and P.A. Ascierto
- Subjects
Oncology ,Hematology - Published
- 2022
4. Assessment of various efficacy outcomes using ERIVANCE-like criteria in patients with locally advanced basal cell carcinoma receiving sonidegib: results from a preplanned sensitivity analysis
- Author
-
Ramon Arntz, Serena Martelli, R. Gutzmer, Nicholas Squittieri, Dirk Schadendorf, Caroline Robert, Carmen Loquai, Reinhard Dummer, University of Zurich, and Gutzmer, Ralf
- Subjects
Adult ,Cancer Research ,Skin Neoplasms ,Pyridines ,medicine.medical_treatment ,Medizin ,Tumor outcome ,Vismodegib ,610 Medicine & health ,mRECIST ,Drug Administration Schedule ,Hedgehog pathway inhibitor ,Sonidegib ,chemistry.chemical_compound ,Double-Blind Method ,1311 Genetics ,Confidence Intervals ,Genetics ,Humans ,Medicine ,Anilides ,Basal cell carcinoma ,1306 Cancer Research ,Response Evaluation Criteria in Solid Tumors ,RC254-282 ,medicine.diagnostic_test ,business.industry ,Research ,Biphenyl Compounds ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,10177 Dermatology Clinic ,Magnetic resonance imaging ,medicine.disease ,Confidence interval ,Radiation therapy ,Treatment Outcome ,chemistry ,Oncology ,Carcinoma, Basal Cell ,Disease Progression ,2730 Oncology ,business ,Nuclear medicine ,Progressive disease ,medicine.drug - Abstract
Background The BOLT study for sonidegib, a Hedgehog pathway inhibitor (HHI) approved for patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy, used modified Response Evaluation Criteria in Solid Tumors (mRECIST) for laBCC tumor evaluation. The ERIVANCE study for vismodegib, another HHI, used a composite RECIST endpoint of ≥30% reduction in externally visible tumor or radiographic dimension, or complete ulceration resolution. This preplanned sensitivity BOLT analysis evaluated efficacy outcomes using ERIVANCE-like criteria in patients with laBCC who received sonidegib 200 mg once daily. Methods This phase 2, double-blind study randomized patients 1:2 to sonidegib 200:800 mg daily, respectively. Key endpoints included objective response rate (ORR), duration of response (DOR), complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). laBCC tumors were assessed by both mRECIST and ERIVANCE-like criteria. Per mRECIST, an overall response of CR was based on negative histology; photographic assessment of CR, PR (scar/fibrosis only), SD (scar/fibrosis only), or not available (NA); and a magnetic resonance imaging response of CR or NA. An overall response of CR was primarily based on negative histology using ERIVANCE-like criteria. Results Per mRECIST criteria, ORR (95% confidence interval [CI]) by central and investigator review for patients with laBCC (n = 66) was 56.1% (43.3–68.3%) and 71.2% (58.7–81.7%), respectively. CR per central review was achieved in 3 (4.5%) patients and PR, SD, and PD occurred in 34 (51.5%), 23 (34.8%), and 1 (1.5%) patient, respectively. Median (95% CI) DOR was 26.1 months (not estimable [NE]). Using ERIVANCE-like criteria, efficacy outcomes per central and investigator review were higher, with an ORR (95% CI) of 60.6% (47.8–72.4%) and 74.2% (62.0–84.2%), respectively. CR per central review was reached in 14 (21.2%) patients and PR, SD, and PD occurred in 26 (39.4%), 20 (30.3%), and 1 (1.5%) patient, respectively. DOR was unchanged with a median (95% CI) of 26.1 months (NE). Conclusions Overall, applying ERIVANCE-like criteria to patients with laBCC receiving sonidegib 200 mg daily yielded higher response rates vs mRECIST criteria. Trial registration BOLT registration: ClinicalTrials.gov (NCT01327053) on March 30, 2011.
- Published
- 2021
5. Histamine Increases Th2 Cytokine-Induced CCL18 Expression in Human M2 Macrophages
- Author
-
Thomas Werfel, R. Gutzmer, Susanne Mommert, Katrin Schaper-Gerhardt, and Judith Tabea Schaper
- Subjects
Agonist ,Chemokine ,medicine.drug_class ,QH301-705.5 ,Stimulation ,Histamine H1 receptor ,Catalysis ,Article ,Dermatitis, Atopic ,Inorganic Chemistry ,chemistry.chemical_compound ,Histamine receptor ,Th2 Cells ,Downregulation and upregulation ,medicine ,CCL18 ,Humans ,Physical and Theoretical Chemistry ,Biology (General) ,Molecular Biology ,QD1-999 ,Cells, Cultured ,Spectroscopy ,Inflammation ,Interleukin-13 ,biology ,atopic dermatitis ,Chemistry ,Organic Chemistry ,General Medicine ,Macrophage Activation ,histamine ,Interleukin-10 ,Up-Regulation ,Computer Science Applications ,macrophages ,Chemokines, CC ,Immunology ,biology.protein ,Interleukin-4 ,Histamine - Abstract
The chemokine CCL18 is produced in cells of the myelomonocytic lineage and represents one of the most highly expressed chemokines in lesional skin and serum of atopic dermatitis patients. We investigated the role of histamine in CCL18 production in human monocyte-derived M2 macrophages differentiated in the presence of M-CSF and activated with IL-4, IL-13 or with IL-10. Since expression and regulation of histamine H1 receptor (H1R), H2R and H4R by IL-4 and IL-13 on human M2 macrophages were described, we analyzed expression of the histamine receptors in response to IL-10 stimulation by quantitative RT-PCR. IL-10 upregulated H2R and downregulated H4R mRNA expression by trend in M2 macrophages. IL-10, but in a more pronounced manner, IL-4 and IL-13, also upregulated CCL18. Histamine increased the cytokine-induced upregulation of CCL18 mRNA expression by stimulating the H2R. This effect was stronger in IL-10-stimulated M2 macrophages where the upregulation of CCL18 was confirmed at the protein level by ELISA using selective histamine receptor agonist and antagonists. The histamine-induced CCL18 upregulation in IL-10-activated M2 macrophages was almost similar in cells obtained from atopic dermatitis patients compared to cells from healthy control persons. In summary, our data stress a new function of histamine showing upregulation of the Th2 cells attracting chemokine CCL18 in human, activated M2 macrophages. This may have an impact on the course of atopic dermatitis and for the development of new therapeutic interventions.
- Published
- 2021
6. Biomarkers of treatment benefit with atezolizumab plus vemurafenib plus cobimetinib in BRAF
- Author
-
C, Robert, K D, Lewis, R, Gutzmer, D, Stroyakovskiy, H, Gogas, S, Protsenko, R P, Pereira, T, Eigentler, P, Rutkowski, L, Demidov, I, Caro, H, Forbes, K, Shah, Y, Yan, H, Li, G A, McArthur, and P A, Ascierto
- Subjects
Proto-Oncogene Proteins B-raf ,Piperidines ,Vemurafenib ,Antineoplastic Combined Chemotherapy Protocols ,Mutation ,Biomarkers, Tumor ,Azetidines ,Humans ,Antibodies, Monoclonal, Humanized ,Melanoma ,B7-H1 Antigen - Abstract
The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAFFive hundred fourteen patients were randomized to atezolizumab (n = 256) or control (n = 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers.PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.52-1.02; P = 0.067] versus low TMB (10 mutations/Mb; HR 0.92; 95% CI 0.65-1.30; P = 0.64) and similar between patients with strong IFN-γ (≥median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-γ (median; HR 0.79; 95% CI 0.58-1.08). In patients with elevated LDH, PFS benefit for atezolizumab versus control was greater in the PD-L1- subgroup (HR 0.53; 95% CI 0.29-0.95; P = 0.032) than in the PD-L1+ subgroup (HR 1.16; 95% CI 0.75-1.80; P = 0.51). Recursive partitioning analysis showed that IFN-γ discriminated PFS outcomes in patients with normal LDH, whereas TMB discriminated outcomes in patients with elevated LDH in the atezolizumab group. Neither IFN-γ nor TMB discriminated PFS outcomes in the control group.Treatment benefits in the atezolizumab group seemed to be most evident in patients with elevated LDH and PD-L1- tumors. LDH remains the primary predictor of outcomes regardless of treatment. IFN-γ and TMB further differentiate outcomes for patients treated with atezolizumab, vemurafenib, and cobimetinib.
- Published
- 2021
7. 828P Effectiveness and safety of dabrafenib and trametinib in patients with BRAFV600 mutated metastatic melanoma in the real-world setting: Final results of the non-interventional COMBI-r study
- Author
-
C. Berking, E. Livingstone, M. Weichenthal, U. Leiter-Stoppke, J. Remy, T. Eigentler, P. Mohr, F. Kiecker, C. Loquai, D. Debus, and R. Gutzmer
- Subjects
Oncology ,Hematology - Published
- 2022
8. 786O Tumor biomarker analysis from COLUMBUS part 1: Encorafenib + binimetinib for BRAF V600E/K-mutant advanced or metastatic melanoma
- Author
-
R. Dummer, N. Pathan, S. Deng, C. Robert, A.M. Arance Fernandez, J.W.B. de Groot, C. Garbe, H.J. Gogas, R. Gutzmer, I. Krajsova, G. Liszkay, C. Loquai, M. Mandala, D. Schadendorf, N. Yamazaki, A. di Pietro, T. Xie, P.A. Ascierto, and K. Flaherty
- Subjects
Oncology ,Hematology - Published
- 2022
9. 787O Adjuvant immunotherapy with nivolumab (NIVO) versus observation in completely resected Merkel cell carcinoma (MCC): Disease-free survival (DFS) results from ADMEC-O, a randomized, open-label phase II trial
- Author
-
J.C. Becker, S. Ugurel, U. Leiter-Stoppke, F. Meier, R. Gutzmer, S. Haferkamp, L. Zimmer, E. Livingstone, T. Eigentler, A. Hauschild, F. Kiecker, J.C. Hassel, P. Mohr, M. Fluck, I. Thomas, M. Garzarolli, I. Grimmelmann, K. Drexler, S. Eckhardt, and D. Schadendorf
- Subjects
Oncology ,Hematology - Published
- 2022
10. Corrigendum to ‘Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial
- Author
-
B.G.M. Hughes, E. Munoz-Couselo, L. Mortier, Å. Bratland, R. Gutzmer, O. Roshdy, R. González Mendoza, J. Schachter, A. Arance, F. Grange, N. Meyer, A. Joshi, S. Billan, P. Zhang, B. Gumuscu, R.F. Swaby, and J.-J. Grob
- Subjects
Oncology ,Hematology - Published
- 2022
11. Expression of histamine receptors H2R and H4R are predominantly regulated via the IL-4/IL-13 receptor type II on human M2 macrophages
- Author
-
Susanne Mommert, Thomas Werfel, Martin Jahn, R. Gutzmer, and Katrin Schaper-Gerhardt
- Subjects
Macrophages ,Immunology ,Receptors, Interleukin-13 ,Atopic dermatitis ,Receptor type ,medicine.disease ,Molecular biology ,Receptors, G-Protein-Coupled ,Histamine receptor ,chemistry.chemical_compound ,chemistry ,Interleukin 13 ,medicine ,Immunology and Allergy ,Humans ,Receptors, Histamine ,Interleukin-4 ,Receptors, Histamine H1 ,Histamine ,Interleukin 4 ,Receptors, Histamine H4 - Published
- 2021
12. Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial
- Author
-
Eva Muñoz-Couselo, Osama Roshdy, Salem Billan, Nicolas Meyer, P. Zhang, Abhishek Joshi, Florent Grange, R. Gonzalez Mendoza, Laurent Mortier, J.-J. Grob, A. Arance, Burak Gumuscu, Brett G.M. Hughes, R. Gutzmer, Jacob Schachter, Åse Bratland, and Ramona F. Swaby
- Subjects
medicine.medical_specialty ,Skin Neoplasms ,business.industry ,Hematology ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,Confidence interval ,Antineoplastic Agents, Immunological ,Oncology ,Tolerability ,Interquartile range ,Response Evaluation Criteria in Solid Tumors ,Internal medicine ,Cohort ,Clinical endpoint ,medicine ,Carcinoma, Squamous Cell ,Humans ,Neoplasm Recurrence, Local ,Adverse effect ,business - Abstract
Background Pembrolizumab demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile in recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). Patients and methods KEYNOTE-629 was a global, open-label, nonrandomized, phase II trial of patients with locally advanced (LA) or R/M cSCC conducted at 59 centers. Eligible patients received intravenous pembrolizumab 200 mg every 3 weeks for up to 35 cycles. Primary endpoint was objective response rate (ORR), defined as the percentage of patients with a complete (CR) or partial response (PR), by blinded independent central review as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included duration of response (DOR), disease control rate, progression-free survival, overall survival, and safety and tolerability. Efficacy and safety were analyzed in patients who were treated with at least one dose of pembrolizumab. Results Between 29 November 2017 and 25 September 2019, 159 patients were enrolled and treated with pembrolizumab (LA cohort, n = 54; R/M cohort, n = 105). The median time from the first dose to data cut-off date (29 July 2020) was 14.9 [interquartile range (IQR), 12.6-17.2] months for the LA cohort and 27.2 (IQR, 25.6-29.2) months for the R/M cohort. In the LA cohort, ORR was 50.0% [95% confidence interval (CI), 36.1% to 63.9%], including 16.7% of patients with a CR and 33.3% with a PR. In the R/M cohort, ORR was 35.2% (95% CI, 26.2% to 45.2%), including 10.5% of patients with a CR and 24.8% with a PR. Median DOR was not reached in either cohort. Grade 3-5 treatment-related adverse events occurred in 11.9% of patients. Conclusions The robust antitumor activity of pembrolizumab in both LA and R/M cSCC was confirmed and demonstrated to be durable without unexpected safety signals. Our findings establish pembrolizumab as a promising treatment option for cSCC.
- Published
- 2021
13. 149P KEYNOTE-629: Efficacy of pembrolizumab (Pembro) per immune-related RECIST (irRECIST) in locally advanced (LA) and recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC)
- Author
-
E. Munoz Couselo, B.G.M. Hughes, Å. Bratland, R. Gutzmer, O. Roshdy, R. González Mendoza, J. Schachter, A.M. Arance Fernandez, F. Grange, N. Meyer, A.J. Joshi, S. Billan, J.J. Grob, P. Zhang, B. Gumuscu, R. Swaby, and L. Mortier
- Subjects
Oncology ,Hematology - Published
- 2021
14. 1041MO 5-year update on COLUMBUS: A randomized phase III trial of encorafenib (enco) + binimetinib (bini) versus enco or vemurafenib (vem) in patients (pts) with BRAF V600-mutant melanoma
- Author
-
Carmen Loquai, Dirk Schadendorf, P.A. Ascierto, R. Gutzmer, Naoya Yamazaki, C. Robert, Michelle L. Edwards, A. Arance, Fabian Zohren, Keith T. Flaherty, Ivana Krajsová, Mario Mandalà, Helen Gogas, G. Liszkay, R. Dummer, J.W.B. de Groot, and Claus Garbe
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Melanoma ,Mutant ,Binimetinib ,Hematology ,medicine.disease ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Encorafenib ,medicine ,In patient ,Vemurafenib ,business ,medicine.drug - Published
- 2021
15. IgE blockade in the management of eosinophil-associated recalcitrant pruritus due to medical tumor therapy
- Author
-
V. Sibaud, R. Gutzmer, and Jessica C. Hassel
- Subjects
biology ,business.industry ,Pruritus ,Immune checkpoint inhibitors ,Tumor therapy ,Omalizumab ,Hematology ,Immunoglobulin E ,Eosinophil ,Blockade ,Eosinophils ,medicine.anatomical_structure ,Oncology ,Neoplasms ,Immunology ,medicine ,biology.protein ,Humans ,business ,Immune Checkpoint Inhibitors ,medicine.drug - Published
- 2021
16. Corrigendum to ‘IgE blockade in the management of eosinophil-associated recalcitrant pruritus due to medical tumor therapy’
- Author
-
Jessica C. Hassel, V. Sibaud, and R. Gutzmer
- Subjects
Oncology ,medicine.medical_specialty ,biology ,business.industry ,Tumor therapy ,Hematology ,Eosinophil ,Immunoglobulin E ,Blockade ,medicine.anatomical_structure ,Internal medicine ,biology.protein ,Medicine ,business - Published
- 2021
17. Aktueller Stand bei nichtmelanozytären Hauttumoren
- Author
-
Dirk Vordermark, R. Gutzmer, C. Rose, and H. Schmidberger
- Subjects
Radiation therapy ,medicine.medical_specialty ,Oncology ,Surgical oncology ,business.industry ,medicine.medical_treatment ,General surgery ,medicine ,Hematology ,business - Published
- 2021
18. 1104P Nivolumab (NIVO) monotherapy or combination therapy with ipilimumab (NIVO+IPI) in advanced melanoma patients with brain metastases: Real-world evidence from the German non-interventional study NICO
- Author
-
Patrick Terheyden, Katharina C. Kähler, T. Sickmann, Christoffer Gebhardt, Friedegund Meier, Daniela Göppner, A. Sindrilaru, Sebastian Haferkamp, Jens Ulrich, J. Utikal, Imke Satzger, Thomas Eigentler, Carsten Weishaupt, Peter Mohr, Michael Weichenthal, Selma Ugurel, R. Gutzmer, Claudia Pföhler, Dirk Schadendorf, and P. Dücker
- Subjects
Oncology ,medicine.medical_specialty ,Combination therapy ,business.industry ,Ipilimumab ,Hematology ,Real world evidence ,language.human_language ,German ,Internal medicine ,Non interventional ,medicine ,language ,Nivolumab ,business ,Advanced melanoma ,medicine.drug - Published
- 2020
19. 1127P Correlation of BRAF mutation status in circulating tumour DNA (ctDNA) with tumour biopsy and clinical outcomes in COLUMBUS
- Author
-
Caroline Robert, Claus Garbe, E. Kiprilov, J.W.B. de Groot, G. Liszkay, Michael D Pickard, Keith T. Flaherty, Helen Gogas, A.M. Arance Fernandez, Ivana Krajsová, Reinhard Dummer, C. Dutriaux, P.A. Ascierto, R. Gutzmer, J. Cantey-Kiser, Dirk Schadendorf, A. Harney, Mario Mandalà, and Carmen Loquai
- Subjects
chemistry.chemical_compound ,Oncology ,medicine.diagnostic_test ,chemistry ,business.industry ,Mutation (genetic algorithm) ,Biopsy ,Cancer research ,Medicine ,Hematology ,business ,DNA - Published
- 2020
20. PCN40 Healthcare Resource Utilization in Patients Treated with Encorafenib PLUS Binimetinib for BRAF-Mutant Metastatic Melanoma: DATA from Columbus, a Phase 3 Trial in BRAF-Mutant Melanoma
- Author
-
A. Tadmouri, P.A. Ascierto, Ashwin Gollerkeri, R. Gutzmer, Keith T. Flaherty, Ivana Krajsová, Dirk Schadendorf, Michael D Pickard, Mario Mandalà, C. Dutriaux, A. Arance, Carmen Loquai, G. Liszkay, Claus Garbe, R. Dummer, V. Chiarion Sileni, Helen Gogas, and C. Robert
- Subjects
Metastatic melanoma ,business.industry ,Health Policy ,Melanoma ,Mutant ,Public Health, Environmental and Occupational Health ,Binimetinib ,medicine.disease ,chemistry.chemical_compound ,chemistry ,Encorafenib ,Cancer research ,medicine ,In patient ,business ,Resource utilization - Published
- 2020
21. 1137P Incidence and time course of adverse events (AEs) with atezolizumab (A) in combination with vemurafenib (V) and cobimetinib (C) in the phase III IMspire150 study
- Author
-
L. de la Cruz Merino, Judit Oláh, V. McNally, P.A. Ascierto, Haocheng Li, C. Robert, Karl D. Lewis, Q. Zhu, Jacek Mackiewicz, Grant A. McArthur, Rodrigo Ramella Munhoz, Edward McKenna, R. Gutzmer, Paola Queirolo, and G. Liszkay
- Subjects
Oncology ,Cobimetinib ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Hematology ,chemistry.chemical_compound ,chemistry ,Atezolizumab ,Internal medicine ,Time course ,medicine ,Vemurafenib ,Adverse effect ,business ,medicine.drug - Published
- 2020
22. Contents Vol. 227, 2013
- Author
-
R. Gutzmer, Yu-Mei Han, Maria Sole Chimenti, Bruno E. Paredes, Sonja Ständer, S. Fukushima, Davor Rimac, Alessandra Ventura, Werner Kempf, Veda Marija Varnai, Sonja Ostheeren, Andrea Chiricozzi, M. Jinnin, T. Makino, M. Alter, Z. Kang, Marjam J. Barysch, A. Mattern, Chunmei Ma, Sanja Kežić, Li Xia, Mi Ryung Roh, Matthias Braeutigam, Nan Yu, Lian-Jun Chen, In Kyung Jeon, Dmitry V. Kazakov, Y. Inoue, Qin-Ping Yang, Druck Reinhardt Druck Basel, F. Xu, Dorothee Siepmann, Aixia Duan, Sung Eun Chang, Hubert R. Laeng, Thomas A. Luger, Min Liu, Trude Butterfass-Bahloul, Christine Blome, Gyeong-Hun Park, Ye Guo, Fred Rincon, X. Guo, Q. Yang, Tobias Lotts, Gabriele Palmedo, Roberto Perricone, Severin Läuchli, Vaneeta M. Sheth, H. Ihn, Jürg Hafner, Carlo Chiaramonte, Matthias Augustin, Ngoc Quan Phan, Jelena Macan, Rosita Saraceno, Dieter Mayer, R. Hu, Xia Dou, Miriam Teoli, Xinhong Ge, A. Kapp, Lars E. French, Sergio Chimenti, Y. Han, Erine A Kupetsky, Abrar A. Qureshi, Annunziata Dattola, S. Qi, Heinz Kutzner, I. Satzger, K. Sakai, Y. Sheng, Xiaoming Zhang, Huijuan Shi, S. Yamada, Jingxia Wang, Y. Miao, and Satz Mengensatzproduktion
- Subjects
Dermatology - Published
- 2013
23. Adjuvant low-dose interferon α2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis
- Author
-
Michael Weichenthal, Thomas Eigentler, Ruthild Linse, R. Gutzmer, U. Ellwanger, Claus Garbe, Rudolf Stadler, Peter Radny, Reinhard Dummer, Axel Hauschild, and Jens Ulrich
- Subjects
Adult ,Male ,medicine.medical_specialty ,Skin Neoplasms ,Adolescent ,Dacarbazine ,Antineoplastic Agents ,Interferon alpha-2 ,Humans ,Medicine ,Prospective Studies ,Child ,Prospective cohort study ,Melanoma ,Lymph node ,Survival rate ,Survival analysis ,Intention-to-treat analysis ,business.industry ,Infant, Newborn ,Infant ,Interferon-alpha ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,Recombinant Proteins ,Surgery ,medicine.anatomical_structure ,Oncology ,Child, Preschool ,Lymphatic Metastasis ,Quality of Life ,Lymph Node Excision ,Female ,Lymph Nodes ,Lymph ,business ,medicine.drug - Abstract
BACKGROUND: More than half of patients with melanoma that has spread to regional lymph nodes develop recurrent disease within the first 3 years after surgery. The aim of the study was to improve disease-free survival (DFS) and overall survival (OS) with interferon (IFN) alpha2a with or without dacarbazine (DTIC) compared with observation alone. PATIENTS AND METHODS: A total of 444 patients from 42 centers of the German Dermatologic Cooperative Oncology Group who had received a complete lymph node dissection for pathologically proven regional node involvement were randomized to receive either 3 MU s.c. of IFNalpha2a three times a week for 2 years (Arm A) or combined treatment with same doses of IFNalpha2a plus DTIC 850 mg/m(2) every 4-8 weeks for 2 years (Arm B) or to observation alone (Arm C). Treatment was discontinued at first sign of relapse. RESULTS: A total of 441 patients were eligible for intention-to-treat analysis. Kaplan-Meier 4-year OS rate of those who had received IFNalpha2a was 59%. For those with surgery alone, survival was 42% (A versus C, P = 0.0045). No improvement of survival was found for the combined treatment Arm B with 45% survival rate (B versus C, P = 0.76). Similarly, DFS rates showed significant benefit for Arm A, and not for Arm B. Multivariate Cox model confirmed that Arm A has an impact on OS (P = 0.005) but not Arm B (P = 0.34). CONCLUSIONS: 3 MU interferon alpha2a given s.c. three times a week for 2 years significantly improved OS and DFS in patients with melanoma that had spread to the regional lymph nodes. Interestingly, the addition of DTIC reversed the beneficial effect of adjuvant interferon alpha2a therapy.
- Published
- 2008
24. Dermatoonkologie
- Author
-
C. Ulrich, U. Hillen, and R. Gutzmer
- Subjects
Medizin ,Dermatology - Published
- 2014
25. Malignes Melanom
- Author
-
R. Gutzmer and F. Meier
- Subjects
business.industry ,Melanoma ,Cancer research ,medicine ,Dermatology ,medicine.disease ,business - Published
- 2016
26. Hospitalization Rates in COLUMBUS Part 1: A Phase 3 Trial of Encorafenib (ENCO) Plus Binimetinib (BINI) Versus Vemurafenib (VEM) or ENCO in BRAF-Mutant Melanoma
- Author
-
L.A. de Parseval, Naoya Yamazaki, P.A. Ascierto, R. Gutzmer, V. Sandor, Dirk Schadendorf, Gabriella Liszkay, C. Dutriaux, Carmen Loquai, Mario Mandalà, J.W.B. de Groot, V. Chiarion Sileni, Michael D Pickard, Claus Garbe, Helen Gogas, C. Robert, Ana Arance, Keith T. Flaherty, Ivana Krajsová, and R. Dummer
- Subjects
medicine.medical_specialty ,business.industry ,Melanoma ,Mutant ,Binimetinib ,Hematology ,medicine.disease ,Dermatology ,030207 dermatology & venereal diseases ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Encorafenib ,medicine ,Cancer research ,Vemurafenib ,business ,medicine.drug
27. Adjuvant low-dose interferon {alpha}2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis.
- Author
-
C. Garbe, P. Radny, R. Linse, R. Dummer, R. Gutzmer, J. Ulrich, R. Stadler, M. Weichenthal, TK. Eigentler, U. Ellwanger, and A. Hauschild
- Subjects
- *
MELANOMA , *LYMPH nodes , *INTERFERONS , *ANTIVIRAL agents , *NEUROENDOCRINE tumors , *IMMUNOLOGICAL adjuvants - Abstract
Background: More than half of patients with melanoma that has spread to regional lymph nodes develop recurrent disease within the first 3 years after surgery. The aim of the study was to improve disease-free survival (DFS) and overall survival (OS) with interferon (IFN) a2a with or without dacarbazine (DTIC) compared with observation alone. Patients and methods: A total of 444 patients from 42 centers of the German Dermatologic Cooperative Oncology Group who had received a complete lymph node dissection for pathologically proven regional node involvement were randomized to receive either 3 MU s.c. of IFNa2a three times a week for 2 years (Arm A) or combined treatment with same doses of IFNa2a plus DTIC 850 mg/m2 every 4â8 weeks for 2 years (Arm B) or to observation alone (Arm C). Treatment was discontinued at first sign of relapse. Results: A total of 441 patients were eligible for intention-to-treat analysis. KaplanâMeier 4-year OS rate of those who had received IFNa2a was 59%. For those with surgery alone, survival was 42% (A versus C, P?=?0.0045). No improvement of survival was found for the combined treatment Arm B with 45% survival rate (B versus C, P?=?0.76). Similarly, DFS rates showed significant benefit for Arm A, and not for Arm B. Multivariate Cox model confirmed that Arm A has an impact on OS (P?=?0.005) but not Arm B (P?=?0.34). Conclusions: 3 MU interferon a2a given s.c. three times a week for 2 years significantly improved OS and DFS in patients with melanoma that had spread to the regional lymph nodes. Interestingly, the addition of DTIC reversed the beneficial effect of adjuvant interferon a2a therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
28. Optimizing immune checkpoint blockade in metastatic uveal melanoma: exploring the association of overall survival and the occurrence of adverse events.
- Author
-
Koch EAT, Petzold A, Dippel E, Erdmann M, Gesierich A, Gutzmer R, Hassel JC, Haferkamp S, Kähler KC, Kreuzberg N, Leiter U, Loquai C, Meier F, Meissner M, Mohr P, Pföhler C, Rahimi F, Schell B, Terheyden P, Thoms KM, Ugurel S, Ulrich J, Utikal J, Weichenthal M, Ziller F, Berking C, and Heppt MV
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Adult, Aged, 80 and over, Neoplasm Metastasis, Uveal Neoplasms mortality, Uveal Neoplasms drug therapy, Uveal Neoplasms immunology, Uveal Neoplasms pathology, Melanoma drug therapy, Melanoma mortality, Melanoma immunology, Immune Checkpoint Inhibitors adverse effects, Immune Checkpoint Inhibitors therapeutic use
- Abstract
Introduction: Despite recent advancements in the treatment of metastatic uveal melanoma (UM), the availability of further treatment options remains limited and the prognosis continues to be poor in many cases. In addition to tebentafusp, immune checkpoint blockade (ICB, PD-1 (+/-) CTLA-4 antibodies) is commonly used for metastatic UM, in particular in HLA-A 02:01-negative patients. However, ICB comes at the cost of potentially severe immune-related adverse events (irAE). Thus, the selection of patient groups that are more likely to benefit from ICB is desirable., Methods: In this analysis, 194 patients with metastatic UM undergoing ICB were included. Patients were recruited from German skin cancer sites and the ADOReg registry. To investigate the association of irAE occurrence with treatment response, progression-free survival (PFS), and overall survival (OS) two cohorts were compared: patients without irAE or grade 1/2 irAE (n=137) and patients with grade 3/4 irAE (n=57)., Results: In the entire population, the median OS was 16.4 months, and the median PFS was 2.8 months. Patients with grade 3/4 irAE showed more favorable survival than patients without or grade 1/2 irAE (p=0.0071). IrAE occurred in 44.7% (87/194), and severe irAE in 29.4% (57/194) of patients. Interestingly, irColitis and irHepatitis were significantly associated with longer OS (p=0.0031 and p=0.011, respectively)., Conclusions: This data may indicate an association between irAE and favorable survival outcomes in patients with metastatic UM undergoing ICB treatment and suggests that a reduced tolerance to tumor antigens could be linked to reduced tolerance to self-antigens., Competing Interests: AG speaker´s honoraria from Allmirall, Amgen, Bristol-Myers Squibb, Immunocore, MSD Sharp & Dohme and Roche; intermittent advisory board relationships with Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel and congress fee support from Bristol-Myers Squibb, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, Bristol-Myers Squibb, Delcath Systems Inc, GSK, Novartis, MSD Sharp & Dohme, Pfizer, and Roche. CB declares speaker´s and/or consultancy honoraria from Almirall, Bristol-Myers Squibb, Delcath, Immunocore, Leo Pharma, Miltenyi, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals, Regeneron, and Sanofi-Aventis outside the submitted work. CP received honoraria speaker honoraria or honoraria as a consultant and travel support from Novartis, Bristol-Myers Squibb, Roche, Merck Serono, MSD Sharp & Dohme, Celgene, AbbVie, Sun Pharma, UCB, Allergy Therapeutics, and LEO. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, Bristol-Myers Squibb, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Sanofi, and Immunocore and research funding from Novartis and Roche. FZ declares speakers and advisory board honoraria and/or travel support from Bristol-Myers Squibb, MSD Sharp & Dohme, Roche, Novartis, Pierre Fabre Pharmaceuticals, and Sanofi-Aventis outside the submitted work. JCH declares research support from Bristol Myers Squibb, Sanofi, and Sunpharma, advisory board honoraria from GSK, Pierre Fabre Pharmaceuticals, Sun Pharma, speaker honoraria from Amgen, Bristol-Myers Squibb, Delcath, GSK, Immuno core, MSD Sharp & Dohme, Novartis, Sanofi and Sun Pharma and travel support from Bristol-Myers Squibb, Iovance and Sun Pharma. SH declares speakers and advisory board honoraria from Merck Sharp & Dohme, Bristol-Myers Squibb, Novartis, Sanofi, Sun Pharma, and Pierre Fabre Pharmaceuticals. JUl: Speakers and advisory board honoraria from Bristol-Myers Squibb, Kyowa-Kirin, Merck Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Sanofi, and travel support from Pierre Fabre Pharmaceuticals. JUt is on the advisory board or has received honoraria and travel support from Amgen, Bristol-Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre Pharmaceuticals, Roche, Sanofi outside the submitted work. KCK serves as a consultant to Philogen, Bristol-Myers Squibb, MSD Sharp & Dohme, Sanofi Aventis, and Immunocore and received travel grants and speaker fees from Philogen, Pierre Fabre Pharmaceuticals, Bristol-Myers Squibb, MSD Sharp & Dohme, Sun Pharma, Sanofi Aventis, Novartis, Medac and has received research support by Novartis. K-MT received speaker or consultant honoraria and travel support from Bristol-Myers Squibb, MSD Sharp & Dohme, Roche, Novartis, Pierre Fabre Pharmaceuticals, Sanofi Genzyme, Sun Pharma, Amgen, LEO Pharma, Galderma, Almirall, and Candela. ME declares honoraria and travel support from Bristol-Myers Squibb, Immunocore, Novartis, Pierre Fabre Pharmaceuticals, and Sanofi, outside the submitted work. MVH: Honoraria from MSD Sharp & Dohme, Bristol-Myers Squibb, Roche, Novartis, Sun Pharma, Sanofi, Almirall, Biofrontera, Galderma. PM Research support: Novartis, Bristol-Myers Squibb, MSD Sharp & Dohme. Honoraria for lectures: Roche, Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, Merck-Serono, Pierre Fabre Pharmaceuticals, Sanofi, Sun Pharma, Baiersdorf; Honoraria for advisory boards: Roche Pharma, Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, Pierre Fabre Pharmaceuticals, MSD Sharp & Dohme, Immunocore, Sun Pharma, Sanofi. PT: Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, CureVac, Roche, Kyowa Kirin, Biofrontera, Invited Speaker, Personal BMS, Novartis, Pierre Fabre Pharmaceuticals, Merck Serono, Sanofi, Roche, Kyowa Kirin, Advisory Board, Personal BMS, Pierre Fabre Pharmaceuticals, Other, Personal, Travel support. RG Research support: Amgen, MSD Sharp & Dohme, Sun Pharma, Sanofi/Regeneron, Almirall, Kyowa Kirin. Honoraria for lectures: Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, MSD Sharp & Dohme, Sun, Pierre Fabre Pharmaceuticals, Sanofi/Regeneron, Sun Pharma Honoraria for advisory boards: Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, Pierre Fabre Pharmaceuticals, MSD Sharp & Dohme, 4SC, Immunocore, Sun Pharma, Sanofi/Regeneron, Delcath. SU declares research support from Bristol-Myers Squibb and MSD Sharp & Dohme; speakers and advisory board honoraria from Bristol-Myers Squibb, MSD Sharp & Dohme, Merck Serono, Novartis, and Roche, and travel support from Bristol-Myers Squibb, and MSD Sharp & Dohme. UL declares research support from MSD Sharp & Dohme; speakers and advisory board honoraria from MSD Sharp & Dohme, Novartis, Sanofi, and Sun Pharma, and travel support from Pierre Fabre Pharmaceuticals and Sun Pharma. BS Speakers honoria and/or travel support from Amgen, Bristol-Myers Squibb, MSD Sharp & Dohme, Jansen, Novartis, Roche, Sun Pharma, abbvie, Sanofi, Pierre Fabre Pharmaceuticals, Boehringer Ingelheim and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AT declared a past co-authorship with the author RG, JH, SH, KCK, CL, FM, MM, PT, K-MT, FZ, and MVH to the handling editor., (Copyright © 2024 Koch, Petzold, Dippel, Erdmann, Gesierich, Gutzmer, Hassel, Haferkamp, Kähler, Kreuzberg, Leiter, Loquai, Meier, Meissner, Mohr, Pföhler, Rahimi, Schell, Terheyden, Thoms, Ugurel, Ulrich, Utikal, Weichenthal, Ziller, Berking and Heppt.)
- Published
- 2024
- Full Text
- View/download PDF
29. Stringent monitoring can decrease mortality of immune checkpoint inhibitor induced cardiotoxicity.
- Author
-
Wang Y, Ertl C, Schmitt C, Hammann L, Kramer R, Grabmaier U, Schöberl F, Anz D, Piseddu I, Pesch G, Vera J, Froehlich W, Weckbach L, Tomsitz D, Loquai C, Zimmer L, Mangana J, Dummer R, Gutzmer R, Klespe KC, Stege H, Meiss F, Thoms KM, Terheyden P, Bröckelmann PJ, Johnson DB, French LE, and Heinzerling L
- Abstract
Background: Immune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%-46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management., Methods: Patients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases ( n = 12) were analyzed by Nanostring and compared to healthy heart muscle ( n = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients ( n = 4 baseline and n = 8 during irAE) in comparison to patients without toxicity under ICI-therapy ( n = 4 baseline and n = 7 during ICI-therapy) using flow cytometry., Results: A total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and -if required-second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4-1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis., Conclusion: Interestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity., Competing Interests: LH received speaker and consultancy fees from BiomeDx, BMS, Immunocore, Kyowa Kirin, Merck, MSD, Myoncare, Novartis, Pieris, Pierre-Fabre, Roche, Sanofi, Stemline Therapeutics, SUN and Therakos. The LMU received research grants or clinical study grants from Agenus, AstraZeneca Inc., BMS, Hoffmann-La Roche AG, Huya Bioscience, Immunocore, IO Biotech, Merck, Merck Sharp & Dome GmbH, Miltenyi Biomedicine GmbH, Novartis, Pfizer, Pierre Fabre, Regeneron, Replimune, and Sanofi Aventis. CE reports on speaker fees from BristolMyers Squibb, GSK, Immunocore, Kyowa Kirin, MSD CL received honoraria (lectures, presentations, speakers bureaus, manuscript writing or educational events) and travel support from: BMS, MSD Merck, Pierre-Fabre, Biontech, Almirall Hermal, Sun Pharma, KyowaKirin, Immunocore, Sanofi, Novartis. DT reports consultancy, speaker fees or travel grants: BMS, Roche, Novartis, Sanofi, Recordati, Kyowa Kirin, Sun Pharma and Pierre Fabre. LZ served as consultant and has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work. PJB reports research funding (inst) by BeiGene, BMS, MSD and Takeda; an advisory role to BeiGene, BMS, MSD, Need Inc., Stemline and Takeda; honoraria from BeiGene, BMS, Celgene, MSD, Need Inc., Stemline and Takeda and stock options from Need Inc. RG received honoraria for advice and lectures from BristolMyers Squibb, Roche Pharma, MerckSharpDohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/Regeneron. Ralf Gutzmer received travel support from SUN Pharma, Boehringer Ingelheim and PierreFabre. Ralf Gutzmer received research grants from Novartis, Sanofi/Regeneron, Merck Serono, Amgen, SUN Pharma, KyowaKirin, Admiral Hermal. RD has intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and touchIME outside the submitted work. All remaining authors have declared no conflicts of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Wang, Ertl, Schmitt, Hammann, Kramer, Grabmaier, Schöberl, Anz, Piseddu, Pesch, Vera, Froehlich, Weckbach, Tomsitz, Loquai, Zimmer, Mangana, Dummer, Gutzmer, Klespe, Stege, Meiss, Thoms, Terheyden, Bröckelmann, Johnson, French and Heinzerling.)
- Published
- 2024
- Full Text
- View/download PDF
30. Health-Related Quality of Life with Pembrolizumab in Patients with Locally Advanced or Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma: KEYNOTE-629.
- Author
-
Bratland Å, Munoz-Couselo E, Mortier L, Roshdy O, González R, Schachter J, Arance AM, Grange F, Meyer N, Joshi AJ, Billan S, Hughes BGM, Grob JJ, Ramakrishnan K, Ge J, Gumuscu B, Swaby RF, and Gutzmer R
- Abstract
Introduction: At first interim analysis of KEYNOTE-629, health-related quality of life (HRQoL) with pembrolizumab was stable or improved over 48 weeks in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). HRQoL results from the second interim analysis in R/M or locally advanced (LA) cSCC are presented., Methods: Patients received pembrolizumab 200 mg every 3 weeks for ≤ 2 years. Change in EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EQ-5D-5L scores were exploratory end points. Primary analysis was performed at week 12 to ensure adequate completion/compliance. Descriptive analyses were also conducted through weeks 48 and 75 for the LA and R/M cohorts, respectively., Results: At data cutoff (29 July 2020), mean scores in the LA cohort (n = 47) were stable from baseline to week 12 for EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) (-0.27 points [95% confidence interval (CI) -10.93 to 10.39]), physical functioning (-1.29 points [95% CI -8.77 to 6.19]), and EQ-5D-5L visual analog scale (2.06 [95% CI -7.70 to 11.82]). HRQoL remained stable through week 48 in the LA cohort; 76.6% and 74.5% of patients had improved or stable GHS/QoL and physical functioning scores, respectively. HRQoL continued to show stability or improvement through week 75 in the R/M cohort (n = 99); 71.7% and 64.6% of patients had improved or stable GHS/QoL and physical functioning scores, respectively., Conclusions: Pembrolizumab has demonstrated antitumor activity and manageable safety. The current analysis shows pembrolizumab treatment preserved HRQoL. Collectively, these results support pembrolizumab as standard of care for LA or R/M cSCC., Trial Registration: ClinicalTrials.gov, NCT03284424-September 15, 2017., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
31. Use of Pegylated Interferon Alpha-2a in Cutaneous T-cell Lymphoma: A Retrospective Case Collection.
- Author
-
Gosmann J, Stadler R, Quint KD, Gutzmer R, and Vermeer MH
- Subjects
- Humans, Interferon-alpha adverse effects, Polyethylene Glycols adverse effects, Retrospective Studies, Lymphoma, T-Cell, Cutaneous drug therapy, Skin Neoplasms drug therapy
- Abstract
Mycosis fungoides and Sézary syndrome are rare and largely incurable types of cutaneous T-cell lymphoma with limited therapeutic options. In 1984 Bunn et al. reported that interferon alpha is an efficient monotherapy in cutaneous T-cell lymphoma and 14 years later it was shown in a prospective, randomized trial that a combination of interferon alpha and psoralen plus ultraviolet A therapy (PUVA) is most efficient in the treatment of cutaneous T-cell lymphoma. Since then interferon alpha as single agent or, most often, in combination with phototherapy and/or retinoids has been integrated as standard of care in cutaneous T-cell lymphoma guidelines worldwide. However, production of interferon alpha was discontinued recently worldwide and pegylated interferon alpha-2a (PEG-IFNα) has been used as an alternative therapy. In contrast to numerous interferon alpha studies, only a few studies focusing on PEG-IFNα are available. Therefore, the aim of this study was to conduct a retrospective data collection to report on the efficacy, adverse events and therapy regimens of PEG-IFNα in cutaneous T-cell lymphoma. In 28 patients with cutaneous T-cell lymphoma treated in Germany and in the Netherlands, 36% of patients achieved complete remission, 36% partial remission and 29% stable disease. Eighteen percent of patients developed adverse events during therapy, which led to the discontinuation of PEG-IFNα therapy in 2 patients. The most common concomittant therapies were oral PUVA phototherapy and local radiotherapy. In conclusion, PEG-IFNα, especially in combination with skin-directed therapies, is an effective treatment option for cutaneous T-cell lymphoma in clinical practice.
- Published
- 2023
- Full Text
- View/download PDF
32. Correlation of tumor PD-L1 expression in different tissue types and outcome of PD-1-based immunotherapy in metastatic melanoma - analysis of the DeCOG prospective multicenter cohort study ADOREG/TRIM.
- Author
-
Placke JM, Kimmig M, Griewank K, Herbst R, Terheyden P, Utikal J, Pföhler C, Ulrich J, Kreuter A, Mohr P, Gutzmer R, Meier F, Dippel E, Welzel J, Engel DR, Kreft S, Sucker A, Lodde G, Krefting F, Stoffels I, Klode J, Roesch A, Zimmer L, Livingstone E, Hadaschik E, Becker JC, Weichenthal M, Tasdogan A, Schadendorf D, and Ugurel S
- Subjects
- Humans, B7-H1 Antigen metabolism, Cohort Studies, Immunotherapy, Prognosis, Programmed Cell Death 1 Receptor, Prospective Studies, Melanoma immunology, Melanoma therapy, Skin Neoplasms immunology, Skin Neoplasms therapy, Immune Checkpoint Inhibitors therapeutic use
- Abstract
Background: PD-1-based immune checkpoint inhibition (ICI) is the major backbone of current melanoma therapy. Tumor PD-L1 expression represents one of few biomarkers predicting ICI therapy outcome. The objective of the present study was to systematically investigate whether the type of tumor tissue examined for PD-L1 expression has an impact on the correlation with ICI therapy outcome., Methods: Pre-treatment tumor tissue was collected within the prospective DeCOG cohort study ADOREG/TRIM (CA209-578; NCT05750511) between February 2014 and May 2020 from 448 consecutive patients who received PD-1-based ICI for non-resectable metastatic melanoma. The primary study endpoint was best overall response (BOR), secondary endpoints were progression-free (PFS) and overall survival (OS). All endpoints were correlated with tumor PD-L1 expression (quantified with clone 28-8; cutoff ≥5%) and stratified by tissue type., Findings: Tumor PD-L1 was determined in 95 primary tumors (PT; 36.8% positivity), 153 skin/subcutaneous (34.0% positivity), 115 lymph node (LN; 50.4% positivity), and 85 organ (40.8% positivity) metastases. Tumor PD-L1 correlated with BOR if determined in LN (OR = 0.319; 95% CI = 0.138-0.762; P = 0.010), but not in skin/subcutaneous metastases (OR = 0.656; 95% CI = 0.311-1.341; P = 0.26). PD-L1 positivity determined on LN metastases was associated with favorable survival (PFS, HR = 0.490; 95% CI = 0.310-0.775; P = 0.002; OS, HR = 0.519; 95% CI = 0.307-0.880; P = 0.014). PD-L1 positivity determined in PT (PFS, HR = 0.757; 95% CI = 0.467-1.226; P = 0.27; OS; HR = 0.528; 95% CI = 0.305-0.913; P = 0.032) was correlated with survival to a lesser extent. No relevant survival differences were detected by PD-L1 determined in skin/subcutaneous metastases (PFS, HR = 0.825; 95% CI = 0.555-1.226; P = 0.35; OS, HR = 1.083; 95% CI = 0.698-1.681; P = 0.72)., Interpretation: For PD-1-based immunotherapy in melanoma, tumor PD-L1 determined in LN metastases was stronger correlated with therapy outcome than that assessed in PT or organ metastases. PD-L1 determined in skin/subcutaneous metastases showed no outcome correlation and therefore should be used with caution for clinical decision making., Funding: Bristol-Myers Squibb (ADOREG/TRIM, NCT05750511); German Research Foundation (DFG; Clinician Scientist Program UMEA); Else Kröner-Fresenius-Stiftung (EKFS; Medical Scientist Academy UMESciA)., Competing Interests: Declaration of interests Jürgen C. Becker is receiving speaker's bureau honoraria from Amgen, Pfizer, Recordati and Sanofi, and is a paid consultant/advisory board member/DSMB member for Almirall, Boehringer Ingelheim, InProTher, ICON, MerckSerono, Pfizer, 4SC, and Sanofi/Regeneron. His group received research grants from Bristol-Myers Squibb, Merck Serono, HTG, IQVIA, and Alcedis. Ralf Gutzmer reported Personal Honoraria from Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall, SUN, Sanofi, Pierre-Fabre; Consultant or Advisory Role (personal) for BMS, Roche, Novartis, Almirall, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, Immunocore; Research Funding (to institution) from Novartis, Pfizer, Amgen, Merck-Serono, SUN, KyowaKirin, Almirall; and Travel, Accommodations, Expenses from SUN, Pierre-Fabre, Boehringer-Ingelheim; outside the submitted work. Rudolf Herbst is employee of Helios Klinikum Erfurt GmbH. Joachim Klode reported grants and or personal fees from Novartis, LaVision Bio Tec and Sastomed. Sophia Kreft has received honoraria from Sun Pharma and reports travel support from Sanofi Genzyme. Frederik Krefting received travel support for participation in congresses and/or (speaker) honoraria from Novartis, Almirall and Boehringer Ingelheim outside the submitted work. Elisabeth Livingstone received honoraria from Novartis, Medac, Bristol Myers Squibb, Sanofi, Sun Pharma, and Pierre Fabre, reports consulting/advisory roles with Bristol Myers Squibb, Pierre Fabre and Novartis; and received travel/accommodations/expenses from Pierre Fabre, Bristol Myers Squibb, Medac, and Sun Pharma. Georg Lodde received travel support from Sun Pharma. Friedegund Meier has received travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD, Pierre Fabre, Sanofi and Immunocore and research funding from Novartis and Roche. Peter Mohr declares research support from Bristol Myers Squibb, Merck Sharp & Dohme and Novartis; speakers and advisory board honoraria from Bristol Myers Squibb, Beiersdorf, Merck Sharp & Dohme, Pierre Fabre, Sun Pharma, Immunocore, Sanofi and Novartis, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi, Sun Pharma, and Pierre Fabre, outside the submitted work. Claudia Pföhler received honoraria (speaker honoraria or honoraria as a consultant) and travel support from Novartis, BMS, MSD, Merck Serono, MSD, Celgene, AbbVie, Sunpharma, Pierre Fabre, UCB, Nutricia Milupa, Janssen and LEO, outside the submitted work. Jan-Malte Placke served as consultant and/or has received honoraria from Bristol-Myers Squibb, Novartis, Sanofi and received travel support from Bristol-Myers Squibb, Novartis, Pierre Fabre and Therakos. Alexander Roesch reported grants from Novartis, Bristol Myers Squibb, and Adtec; personal fees from Merck Sharp & Dohme; and nonfinancial support from Amgen, Roche, Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, and Teva. Dirk Schadendorf reports partial financial support from Bristol Myers Squibb for the conduct of this study and drug supply (nivolumab and ipilimumab) support; grants (or contracts) from Amgen, Array/Pfizer, Bristol-Myers Squibb, MSD, Novartis and Roche; consulting fees from 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Haystick, Immunocore, InFlarX, Innocent, LabCorp, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, Sun Pharma; honoraria from Bristol-Myers Squibb, MSD/Merck, Merck Serono, Novartis, Roche, Sanofi and Sun Pharma; support for attendings meetings or travel support from Bristol-Myers Squibb, MSD, Merck Serono, Novartis, Pierre Fabre and Sanofi; participation on drug safety monitoring or advisory boards for 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Immunocore, InFlarX, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron and SunPharma; leadership roles for DeCOG, German Cancer Society, Hiege-Stiftung, Deutsche Hautkrebsstiftung, NVKH e.V. and EuMelaReg. Patrick Terheyden has received honoraria from Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre Fabre, CureVac, Merck Serono, Sanofi, Roche, Kyowa Kirin and Biofrontera and travel support from Bristol-Myers Squibb and Pierre Fabre. Selma Ugurel declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, and Novartis, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. Jens Ulrich received honoraria (speaker honoraria or honoraria as a consultant) and travel support from Bristol-Myers Squibb, Kyowa Kirin, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi/Regeneron, Sunpharma outside the submitted work. Jochen Utikal is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. Michael Weichenthal received grants from Bristol-Myers Squibb and Merck Sharp & Dohme, consulting fees from Merck Sharp & Dohme, Immunocore and Novartis, lecture honoraria from Bristol-Myers Squibb and Merck Sharp & Dohme and Pierre-Fabre, and advisory board honoraria from Merck Sharp & Dohme. Julia Welzel received travel grants from Bristol-Myers Squibb and Almriall as well as lecture honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and Almirall. Lisa Zimmer declares speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sunpharma, research support from Novartis and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma and Novartis; outside the submitted work. The other authors did not report conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
33. COMBI-r: A Prospective, Non-Interventional Study of Dabrafenib Plus Trametinib in Unselected Patients with Unresectable or Metastatic BRAF V600-Mutant Melanoma.
- Author
-
Berking C, Livingstone E, Debus D, Loquai C, Weichenthal M, Leiter U, Kiecker F, Mohr P, Eigentler TK, Remy J, Schober K, Heppt MV, von Wasielewski I, Schadendorf D, and Gutzmer R
- Abstract
Combined BRAF/MEK-inhibition constitutes a relevant treatment option for BRAF -mutated advanced melanoma. The prospective, non-interventional COMBI-r study assessed the effectiveness and tolerability of the BRAF-inhibitor dabrafenib combined with the MEK-inhibitor trametinib in patients with advanced melanoma under routine clinical conditions. Progression-free survival (PFS) was the primary objective, and secondary objectives included overall survival (OS), disease control rate, duration of therapy, and the frequency and severity of adverse events. This study enrolled 472 patients at 55 German sites. The median PFS was 8.3 months (95%CI 7.1-9.3) and the median OS was 18.3 months (14.9-21.3), both tending to be longer in pre-treated patients. In the 147 patients with CNS metastases, PFS was similar in those requiring corticosteroids (probably representing symptomatic patients, 5.6 months (3.9-7.2)) compared with those not requiring corticosteroids (5.9 months (4.8-6.9)); however, OS was shorter in patients with brain metastases who received corticosteroids (7.8 (6.3-11.6)) compared to those who did not (11.9 months (9.6-19.5)). The integrated subjective assessment of tumor growth dynamics proved helpful to predict outcome: investigators' upfront categorization correlated well with time-to-event outcomes. Taken together, COMBI-r mirrored PFS outcomes from other prospective, observational studies and confirmed efficacy and safety findings from the pivotal phase III COMBI-d/-v and COMBI-mb trials.
- Published
- 2023
- Full Text
- View/download PDF
34. Long-term strategies for management of advanced basal cell carcinoma with hedgehog inhibitors.
- Author
-
Bossi P, Ascierto PA, Basset-Seguin N, Dreno B, Dummer R, Hauschild A, Mohr P, Kaufmann R, Pellacani G, Puig S, Moreno-Ramírez D, Robert C, Stratigos A, Gutzmer R, Queirolo P, Quaglino P, and Peris K
- Abstract
Basal cell carcinoma (BCC), the most common type of skin cancer, is characterized by aberrant activation of the hedgehog molecular pathway. Systemic therapy is indicated when local approaches, such as surgery and radiation, are inappropriate. In this article, a group of clinical experts recommends the long-term management strategy for advanced BCC patients treated with systemic therapy. The hedgehog inhibitors sonidegib and vismodegib are first-line treatments for advanced BCC with a long-lasting response, but long-term treatment with hedgehog inhibitors is often challenged by tolerability issues. However, several strategies for adverse effect management are available, such as dose interruptions, on-label alternate-day dosing and supportive medications. In conclusion, although BCC shows a high tumor mutational burden that favors a response to immunotherapy, experts recommend keeping patients on hedgehog inhibitors limiting immunotherapy to those who developed resistance during hedgehog inhibitor therapy or in case of persisting toxicity despite long-term management of adverse events., Competing Interests: Declaration of Competing Interest The authors declare the following conflicts of interest. Pietro Quaglino: advisory boards and speaker fees from Sanofi, SUNPharma, Roche. Ralf Gutzmer: research support to Pfizer, Johnson&Johnson, Novartis, Amgen, Sanofi, Merck-Serono, Kyowa-Kirin, Almirall; honoraria for lectures from Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck-Serono, Bayer, SUN, Pierre-Fabre, Sanofi; honoraria for advice from Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre-Fabre, Merck-Serono, 4SC, SUN, Sanofi, Immunocore; support for participation in meetings from Roche Pharma, Bristol-MyersSquibb, Pierre-Fabre, Merck-Serono, SUN, Merck-Serono. Brigitte Dreno: personal fees for board meetings from Roche, Regeneron and Sun Pharma. Paolo Ascierto: consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. Roland Kaufmann: institutional grants outside the submitted talk and entirely linked to clinical trials from Novartis and Roche, and grants from AbbVie, Amgen, Astra Zeneca, Biontech, BMS, Celgene, Galderma, Incyte, Janssen, Leo, Lilly., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
35. Treatment management for BRAF -mutant melanoma patients with tumor recurrence on adjuvant therapy: a multicenter study from the prospective skin cancer registry ADOREG.
- Author
-
Haist M, Stege H, Rogall F, Tan Y, von Wasielewski I, Klespe KC, Meier F, Mohr P, Kähler KC, Weichenthal M, Hauschild A, Schadendorf D, Ugurel S, Lodde G, Zimmer L, Gutzmer R, Debus D, Schilling B, Kreuter A, Ulrich J, Meiss F, Herbst R, Forschner A, Leiter U, Pfoehler C, Kaatz M, Ziller F, Hassel JC, Tronnier M, Sachse M, Dippel E, Terheyden P, Berking C, Heppt MV, Kiecker F, Haferkamp S, Gebhardt C, Simon JC, Grabbe S, and Loquai C
- Subjects
- Humans, Proto-Oncogene Proteins B-raf genetics, Cohort Studies, Neoplasm Recurrence, Local genetics, Prospective Studies, Registries, Adjuvants, Immunologic, Skin Neoplasms drug therapy, Skin Neoplasms genetics, Melanoma drug therapy, Melanoma genetics
- Abstract
Background: Adjuvant therapy with immune-checkpoint inhibitors (CPI) or BRAF/MEK-directed targeted therapy (TT) improves recurrence-free survival (RFS) for patients with advanced, BRAF V600-mutant ( BRAF mut) resected melanoma. However, 40% of these patients will develop distant metastases (DM) within 5 years, which require systemic therapy. Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM. This study evaluated the efficacy of subsequent treatments following tumor recurrence upon upfront adjuvant therapy., Methods: For this multicenter cohort study, we identified 515 BRAF mut patients with resected stage III melanoma who were treated with PD-1 inhibitors (anti-PD1) or TT in the adjuvant setting. Disease characteristics, treatment regimens, details on tumor recurrence, subsequent treatment management, and survival outcomes were collected within the prospective, real-world skin cancer registry ADOReg. Primary endpoints included progression-free survival (PFS) following DM and best tumor response to first-line (1L) treatments., Results: Among 515 eligible patients, 273 patients received adjuvant anti-PD1 and 242 adjuvant TT. At a median follow-up of 21 months, 54.6% of anti-PD1 patients and 36.4% of TT patients recurred, while 39.6% (anti-PD1) and 29.3% (TT) developed DM. Risk of recurrence was significantly reduced in patients treated with TT compared with anti-PD1 (adjusted HR 0.52; 95% CI 0.40 to 0.68, p<0.001). Likewise, median RFS was significantly longer in TT-treated patients (31 vs 17 months, p<0.001). Patients who received TT as second adjuvant treatment upon locoregional recurrence had a longer RFS2 as compared with adjuvant CPI (41 vs 6 months, p=0.009). Patients who recurred at distant sites following adjuvant TT showed favorable response rates (42.9%) after switching to 1L ipilimumab+nivolumab (ipi+nivo). Patients with DM during adjuvant anti-PD1 achieved response rates of 58.7% after switching to 1L TT and 35.3% for 1L ipi+nivo. Overall, median PFS was significantly longer in patients who switched treatments for stage IV disease (median PFS 9 vs 5 months, p=0.004)., Conclusions: BRAF mut melanoma patients who developed DM upon upfront adjuvant therapy achieve favorable tumor control and prolonged PFS after switching treatment modalities in the first-line setting of stage IV disease. Patients with locoregional recurrence benefit from complete resection of recurrence followed by a second adjuvant treatment with TT., Competing Interests: Competing interests: All authors declare no conflicts of interest affecting this study. Conflicts of interest outside the submitted work are: PM declares research support from Bristol Myers Squibb, Novartis and Merck Sharp & Dome; speakers and advisory board honoraria from Almirall Hermal, Beiersdorf, Bristol Myers Squibb, Merck Sharp & Dome, Immunocore, Merck Serono, Medac, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre. KCK declareds speakers and advisory board Honoria from Novartis and BMS, as well as travel support from Novartis, Pierre Fabre, Kyowa Kirin and Sun Pharma. FMeier has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. GL has received travel support for congress participation by Sun Pharma, Pierre-Fabre and research funding from Novartis. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. LZ served as consultant and/or has received honoraria from Roche, BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. RG served as consultant or/and has received Honoria from Roche Pharma, Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, Almirall-Hermal, Amgen, Pierre Fabre, Merck-Serono, Sun Pharma, Sanofi/Regeneron, Immunocore, 4SC, Delcath, received travel support from Sun Pharma, Pierre Fabre, and Boehringer-Ingelheim. AH received consultancy and advisory board fees from Agenus Bio, Almirall Hermal, Amgen, Beiersdorf, BMS, Dermagnostix, Eisai, Highlight Therapeutics, Incyte, IO Biotech, Immunocore, MSD/Merck, MerckPfizer, NeraCare, Novartis, Philogen, Pierre Fabre, Regeneron, Replimune, Roche, Sanofi-Genzyme, Seagen and Xenthera. UL served as consultant to Roche, Novartis, MSD, Almirall Hermal, Sanofi and Sun Pharma; received travel support from Sun Pharma and Pierre-Fabre, received speaker fees from Roche, Novartis, MSD, Sun Pharma and Sanofi, outside the submitted work. She reports institutional research grants from MSD. KCK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. DD has been on the advisory board or has received honoraria from BMS, MSD, Novartis, Pierre Fabre. IvW declares speakers and advisory board honoraria from Almirall Hermal, Bristol Myers Squibb, Merck Sharp & Dome, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche. RH reports speakers and advisory board honoraria from Bristol-Myers Squibb (BMS), Immunocore, Novartis, Pierre-Fabre, Roche and SUN pharma outside the submitted work. JCH received research grants from BMS, Sanofi and Sunpharma and served as a consultant and/or received honoria from Amgen, BMS, GSK, Immunocore, MSD, Novartis, Onkowissen, Pierre Fabre, Sanofi and Sunpharma, outside of the submitted work. MVH reports honoraria from MSD, BMS, Roche, Novartis, Sun Pharma, Sanofi, Almirall, Biofrontera, Galderma, Pierre Fabre, Immunocore. BS is on the advisory board or has received honoraria from Immunocore, Almirall, Pfizer, Sanofi, Novartis, Roche, BMS and MSD, research funding from Novartis and Pierre Fabre Pharmaceuticals, and travel support from Novartis, Roche, Bristol-Myers Squibb and Pierre Fabre Pharma, outside the submitted work. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, SUNPHARMA, UCB, Allergy Therapeutics, Pierre Fabre, Kyowa Kirin and LEO. KCK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. PT served as consultant and/or received honoraria form Almirall, Bristol Myers Squibb, Biofrontera, Curevac, Kyowa Kirin, Merck, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Roche, Sanofi, 4SC, and travel support from Bristol Myers Squibb outside the submitted work. FZ served as consultant and/or has received honoria from BMS, MSD, Novartis, Pierre-Fabre, Sanofi, Sun Pharma. AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD and CeGaT, outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie. FMeiss served as a consultant and/or has received honoraria from Novartis, BMS, MSD, Pierre Fabre, Sanofi Genzyme, Sun Pharma and travel support from Novartis, Sun Pharma, Roche, Pierre Fabre and MSD. SG declares honoraria for advisory boards, oral presentations, and travel expenses from Roche, Novartis, MSD, and BMS outside the submitted work. CL declares speakers, advisory board honoraria, and travel support from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis, Roche, Pierre Fabre, Sun Pharma, Kiowa Kirin, Sanofi, Biontech, and Almirall Hermal outside the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
- Full Text
- View/download PDF
36. Medical Needs and Therapeutic Options for Melanoma Patients Resistant to Anti-PD-1-Directed Immune Checkpoint Inhibition.
- Author
-
Hassel JC, Zimmer L, Sickmann T, Eigentler TK, Meier F, Mohr P, Pukrop T, Roesch A, Vordermark D, Wendl C, and Gutzmer R
- Abstract
Available 4- and 5-year updates for progression-free and for overall survival demonstrate a lasting clinical benefit for melanoma patients receiving anti-PD-directed immune checkpoint inhibitor therapy. However, at least one-half of the patients either do not respond to therapy or relapse early or late following the initial response to therapy. Little is known about the reasons for primary and/or secondary resistance to immunotherapy and the patterns of relapse. This review, prepared by an interdisciplinary expert panel, describes the assessment of the response and classification of resistance to PD-1 therapy, briefly summarizes the potential mechanisms of resistance, and analyzes the medical needs of and therapeutic options for melanoma patients resistant to immune checkpoint inhibitors. We appraised clinical data from trials in the metastatic, adjuvant and neo-adjuvant settings to tabulate frequencies of resistance. For these three settings, the role of predictive biomarkers for resistance is critically discussed, as well as are multimodal therapeutic options or novel immunotherapeutic approaches which may help patients overcome resistance to immune checkpoint therapy. The lack of suitable biomarkers and the currently modest outcomes of novel therapeutic regimens for overcoming resistance, most of them with a PD-1 backbone, support our recommendation to include as many patients as possible in novel or ongoing clinical trials.
- Published
- 2023
- Full Text
- View/download PDF
37. COLUMBUS 5-year update: a randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF.
- Author
-
Dummer R, Flaherty KT, Robert C, Arance A, B de Groot JW, Garbe C, Gogas HJ, Gutzmer R, Krajsová I, Liszkay G, Loquai C, Mandalà M, Schadendorf D, Yamazaki N, Pietro AD, Cantey-Kiser J, Edwards M, and Ascierto PA
- Subjects
- Humans, Antineoplastic Combined Chemotherapy Protocols adverse effects, Mutation, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins B-raf genetics, Vemurafenib adverse effects, Drug-Related Side Effects and Adverse Reactions etiology, Melanoma drug therapy, Melanoma genetics, Melanoma pathology, Skin Neoplasms drug therapy, Skin Neoplasms genetics, Skin Neoplasms pathology
- Abstract
What Is This Summary About?: Here, we summarize the 5-year results from part 1 of the COLUMBUS clinical study, which looked at the combination treatment of encorafenib plus binimetinib in people with a specific type of skin cancer called melanoma. Encorafenib (BRAFTOVI
® ) and binimetinib (MEKTOVI® ) are medicines used to treat a type of melanoma that has a change in the BRAF gene, called advanced or metastatic BRAF V600-mutant melanoma. Participants with advanced or metastatic BRAF V600-mutant melanoma took either encorafenib plus binimetinib together (COMBO group), compared with encorafenib alone (ENCO group) or vemurafenib (ZELBORAF® ) alone (VEMU group)., What Were the Results?: In this 5-year update, more participants in the COMBO group were alive for longer without their disease getting worse after 5 years than those in the VEMU and ENCO groups. Patients in the COMBO group were alive for longer without their disease getting worse when they: Had less advanced cancer Were able to do more daily activities Had normal lactate dehydrogenase (LDH) levels Had fewer organs with tumors before treatment After treatment, fewer participants in the COMBO group received additional anticancer treatment than participants in the VEMU and ENCO groups. The number of participants who reported severe side effects was similar for each treatment. The side effects caused by the drugs in the COMBO group decreased over time., What Do the Results Mean?: Overall, this 5-year update confirmed that people with BRAF V600-mutant melanoma that has spread to other parts of the body and who took encorafenib plus binimetinib were alive for longer without their disease getting worse than those who took vemurafenib or encorafenib alone. Clinical Trial Registration: NCT01909453 (ClinicalTrials.gov).- Published
- 2023
- Full Text
- View/download PDF
38. Monocyte chemoattractant protein 1 as a potential biomarker for immune checkpoint inhibitor-associated neurotoxicity.
- Author
-
Möhn N, Mahjoub S, Duzzi L, Narten E, Grote-Levi L, Körner G, Seeliger T, Beutel G, Bollmann BA, Wirth T, Huss A, Tumani H, Grimmelmann I, Gutzmer R, Ivanyi P, and Skripuletz T
- Subjects
- Humans, Chemokine CCL2, Biomarkers, Cytokines, Immune Checkpoint Inhibitors adverse effects, Brain-Derived Neurotrophic Factor
- Abstract
Background: Oncological patients can benefit substantially from treatment with immune checkpoint inhibitors (ICI). However, there is a growing awareness of immune-related adverse events (irAE). Especially ICI-mediated neurological adverse events (nAE(+)), are tough to diagnose and biomarkers to identify patients at risk are missing., Methods: A prospective register with prespecified examinations was established for ICI treated patients in December 2019. At the time of data cut-off, 110 patients were enrolled and completed the clinical protocol. Herein, cytokines and serum neurofilament light chain (sNFL) from 21 patients were analyzed., Results: nAE of any grade were observed in 31% of the patients (n = 34/110). In nAE(+) patients a significant increase in sNFL concentrations over time was observed. Patients with higher-grade nAE had significantly elevated serum-concentrations of monocyte chemoattractant protein 1 (MCP-1) and brain-derived neurotrophic factor (BDNF) at baseline compared to individuals without any nAE (p < 0.01 and p < 0.05)., Conclusion: Here, we identified nAE to occur more frequently than previously reported. Increase of sNFL during nAE confirms the clinical diagnosis of neurotoxicity and might be a suitable marker for neuronal damage associated with ICI therapy. Furthermore, MCP-1 and BDNF are potentially the first clinical-class nAE predictors for patients under ICI therapy., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
39. Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG.
- Author
-
Franklin C, Mohr P, Bluhm L, Meier F, Garzarolli M, Weichenthal M, Kähler K, Grimmelmann I, Gutzmer R, Utikal J, Terheyden P, Herbst R, Haferkamp S, Pfoehler C, Forschner A, Leiter U, Ziller F, Meiss F, Ulrich J, Kreuter A, Gebhardt C, Welzel J, Schilling B, Kaatz M, Scharfetter-Kochanek K, Dippel E, Nashan D, Sachse M, Weishaupt C, Löffler H, Gambichler T, Loquai C, Heinzerling L, Grabbe S, Debus D, Schley G, Hassel JC, Weyandt G, Trommer M, Lodde G, Placke JM, Zimmer L, Livingstone E, Becker JC, Horn S, Schadendorf D, and Ugurel S
- Subjects
- Humans, CTLA-4 Antigen, Proto-Oncogene Proteins B-raf genetics, Programmed Cell Death 1 Receptor, Prospective Studies, Registries, Mitogen-Activated Protein Kinase Kinases, Brain pathology, Melanoma pathology, Skin Neoplasms drug therapy, Brain Neoplasms pathology
- Abstract
Background: Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy., Methods: Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC-V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS)., Results: Of 1704 patients, 916 were BRAF wild-type (BRAF wt ) and 788 were BRAF V600 mutant (BRAF mut ). Median follow-up time after start of 1L-therapy was 40.4 months. BRAF wt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAF mut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAF mut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAF mut patients. In BRAF wt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAF wt patients. For BRAF mut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK., Conclusions: In BRAF mut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAF wt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1., Competing Interests: Competing interests: All authors declare no conflicts of interest affecting this study. Conflicts of interest outside the submitted work are as following: CF has been on the advisory board or has received honoraria from Bristol Myers Squibb, Immunocore and Novartis and received travel grants from Bristol Myers Squibb, Novartis and Pierre Fabre. PM declares research support from Bristol Myers Squibb, Novartis and Merck Sharp & Dome; speakers and advisory board honoraria from Almirall Hermal, Beiersdorf, Bristol Myers Squibb, Merck Sharp & Dome, Immunocore, Merck Serono, Medac, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre. LB received honoraria from Amgen, Bristol-Myers Squibb and Sun Pharma. FriM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. KK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. IG declares speakers and advisory board honoraria from Almirall Hermal, Bristol Myers Squibb, Merck Sharp & Dome, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche. RG: Invited speaker: Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre. Advisory board: BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, Bayer, MerckSerono, Pfizer, Immunocore. Research grants: Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi. Travel/meeting support: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre. JU is on the advisory board or has received travel support from: Amgen, BMS, GSK, Immunocore, Leo Pharma, MSD, Novartis, Pierre Fabre, Sanofi, Roche. JU has received research support from Novartis; speakers and advisory board honoraria. PT has been on the advisory board or has received honoraria from Almirall, Bristol-Myers Squibb, Novartis, Pierre-Fabre, Merck Serono, Sanofi, Roche, Kyowa Kirin, Biofrontera, and 4SC and received travel grants from Bristol Myers Squibb, and Pierre Fabre. RH reports speakers and advisory board honoraria from Bristol-Myers Squibb (BMS), Immunocore, Novartis, Pierre-Fabre, Roche and SUN pharma outside the submitted work. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, SUNPHARMA, UCB, Allergy Therapeutics, Pierre Fabre, Kyowa Kirin and LEO. AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD and CeGaT, outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie. FZ declares speakers and advisory board honoraria and/or travel support from BMS, MSD, Roche, Novartis, Pierre Fabre and Sanofi Aventis. FraM (Frank Meiss) served as a consultant and/or has received honoraria from Novartis, BMS, MSD, Pierre Fabre, Sanofi Genzyme, Sun Pharma and travel support from Novartis, Sun Pharma, Roche, Pierre Fabre and MSD. BS is on the advisory board or has received honoraria from Immunocore, Almirall, Pfizer, Sanofi, Novartis, Roche, BMS and MSD, research funding from Novartis and Pierre Fabre and travel support from Novartis, Roche, BMS and Pierre Fabre. AK reports receiving lecture fees and fees for serving on advisory boards from MSD Sharp & Dohme, Almirall, Infectopharm, and Boehringer Ingelheim. JW has been on the advisory board, received honoraria and/or travel grants from Bristol Myers Squibb, Novartis, MSD, and Pierre Fabre. TG has received speakers and/or advisory board honoraria and travel support from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, Merck-Serono. CL has received speaker’s fees, advisory board honoraria and travel reimbursements from Merck, MSD, Roche, Almirall Hermal, Biontech, Sanofi, Sun Pharma, Kyowa Kirin, Immonocore, BMS, Pierre Fabre, Novartis. LH has received consultancy and speaker fees from Amgen, Biome Dx, BMS, Curevac, Merck, MSD, Myoncare, Novartis, Pierre-Fabre, Roche, Sanofi and SUN. SG has been on the advisory board and/or has received travel support from Bristol Myers Squibb, MSD, Sun Pharma and Novartis and received research support from Novartis and Pierre Fabre. DD has been on the advisory board or has received honoraria from BMS, Kyowa Kirin, MSD, Novartis, Pierre Fabre, Sanofi and received travel grants from Boehringer, Mylan, Pfizer. GS has received honoraria from BMS. GL has received travel support from Sun Pharma. LZ served as consultant and/or has received honoraria from Roche, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Amgen, Pierre Fabre, Sunpharma, Sanofi and Novartis. EL served as consultant and/or has received honoraria from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Sanofi, Sunpharma and travel support from Medac, Bristol-Myers Squibb, Pierre Fabre, Sunpharma and Novartis. JCB received speaker’s bureau honoraria from Amgen, Pfizer, Recordati and Sanofi, and is a paid consultant/advisory board/DSMB member for Almirall, Boehringer Ingelheim, InProTher, ICON, MerckSerono, Pfizer, 4SC, and Sanofi/Regeneron. His group received research grants from Bristol-Myers Squibb, Merck Serono, HTG, IQVIA, and Alcedis. DS declares relevant financial activities (Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Sanofi, Regeneron, Array, Pierre Fabre, 4SC, Helsinn, Philogen, InFlarX, Merck-Serono, SunPharma, Ultimovacs, Sandoz). SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
- Full Text
- View/download PDF
40. Tolerability of BRAF and MEK Inhibitors for Metastasized Melanoma after Intra-Class Switch: A Multicenter, Retrospective Study.
- Author
-
Salzmann M, Wald A, Stege H, Loquai C, Zimmer L, Hayani KM, Heinzerling L, Gutzmer R, Enk AH, and Hassel JC
- Abstract
Targeted therapy with BRAF and MEK inhibitors (BRAFi, MEKi) is one of the mainstays of melanoma treatment. When dose-limiting toxicity (DLT) is observed, an option represents the intra-class switch to a different BRAFi+MEKi combination. Currently, there is scarce evidence for this procedure. This is a multicenter, retrospective analysis from six German skin cancer centers of patients who received two different combinations of BRAFi and MEKi. In total, 94 patients were included: 38 patients (40%) were re-exposed with a different combination because of previous unacceptable toxicity, 51 (54%) were re-exposed after progression, and 5 (5%) were included for other reasons. Of the 44 patients with a DLT during their first BRAFi+MEKi combination, only five (11%) experienced the same DLT during their second combination. A new DLT was experienced by 13 patients (30%). Six patients (14%) had to discontinue the second BRAFi treatment due to its toxicity. Compound-specific adverse events were avoided in the majority of patients by switching to a different combination. Efficacy data were similar to historical cohorts of BRAFi+MEKi rechallenge, with an overall response rate of 31% for patients who had previously progressed to treatment. We conclude that switching to a different BRAFi+MEKi combination if dose-limiting toxicity occurs is a feasible and rational approach in patients with metastatic melanoma.
- Published
- 2023
- Full Text
- View/download PDF
41. Response to First-Line Treatment with Immune-Checkpoint Inhibitors in Patients with Advanced Cutaneous Squamous Cell Carcinoma: A Multicenter, Retrospective Analysis from the German ADOReg Registry.
- Author
-
Haist M, Stege H, Lang BM, Tsochataridou A, Salzmann M, Mohr P, Schadendorf D, Ugurel S, Placke JM, Weichenthal M, Gutzmer R, Leiter U, Kaatz M, Haferkamp S, Berking C, Heppt M, Tschechne B, Schummer P, Gebhardt C, Grabbe S, and Loquai C
- Abstract
Cutaneous squamous cell carcinoma (cSCC) is a common malignancy of the skin and has an overall favorable outcome, except for patients with an advanced stage of the disease. The efficacy of checkpoint inhibitors (CPI) for advanced cSCC has been demonstrated in recent clinical studies, but data from real-world cohorts and trial-ineligible cSCC patients are limited. We retrospectively investigated patients with advanced cSCC who have been treated with CPI in a first-line setting at eight German skin cancer centers registered within the multicenter registry ADOReg. Clinical outcome parameters including response, progression-free (PFS) and overall survival (OS), time-to-next-treatment (TTNT), and toxicity were analyzed and have been stratified by the individual immune status. Among 39 evaluable patients, the tumor response rate (rwTRR) was 48.6%, the median PFS was 29.0 months, and the median OS was not reached. In addition, 9 patients showed an impaired immune status due to immunosuppressive medication or hematological diseases. Our data demonstrated that CPI also evoked tumor responses among immunocompromised patients (rwTRR: 48.1 vs. 50.0%), although these responses less often resulted in durable remissions. In line with this, the median PFS (11 vs. 40 months, p = 0.059), TTNT (12 months vs. NR, p = 0.016), and OS (29 months vs. NR, p < 0.001) were significantly shorter for this patient cohort. CPI therapy was well tolerated in both subcohorts with 15% discontinuing therapy due to toxicity. Our real-world data show that first-line CPI therapy produced strong and durable responses among patients with advanced cSCC. Immunocompromised patients were less likely to achieve long-term benefit from anti-PD1 treatment, despite similar tumor response rates.
- Published
- 2022
- Full Text
- View/download PDF
42. Triple Combination of Immune Checkpoint Inhibitors and BRAF/MEK Inhibitors in BRAF V600 Melanoma: Current Status and Future Perspectives.
- Author
-
Welti M, Dimitriou F, Gutzmer R, and Dummer R
- Abstract
Immune checkpoint inhibitors (ICIs), namely programmed cell death 1 (PD-1) or cytotoxic t-lymphocyte antigen 4 (CTLA-4) inhibitors, are currently the standard of care for the treatment of advanced melanoma, with robust and durable responses in a subset of patients. For BRAFV600-mutant melanoma, treatment with BRAF and MEK inhibitors has resulted in high objective response rates, but most responses are short-lived. Preclinical data suggest that BRAF and MEK inhibitors result in immunomodulatory changes in the tumor microenvironment; early data in murine models further suggest that these changes could enhance sensitivity to ICIs. Subsequently, the notion of combining the two therapy modalities for a more effective response was further evolved in early phase clinical trials. In this review, we analyzed the results of recent phase 2 and 3 clinical trials investigating the combination of ICIs with targeted therapy in BRAFV600-mutated advanced melanoma. Furthermore, we evaluated the results of recent studies investigating the first-line treatment sequencing of ipilimumab/nivolumab and BRAF/MEK inhibitors in these patients. We discussed the study limitations and interpreted how these recent advances could be incorporated into the treatment landscape of advanced BRAFV600-mutant melanoma.
- Published
- 2022
- Full Text
- View/download PDF
43. Reinduction of Hedgehog Inhibitors after Checkpoint Inhibition in Advanced Basal Cell Carcinoma: A Series of 12 Patients.
- Author
-
DeTemple VK, Hassel JC, Sachse MM, Grimmelmann I, Leiter U, Gebhardt C, Eckardt J, Pföhler C, Angela Y, Hübbe H, and Gutzmer R
- Abstract
For patients with advanced basal cell carcinoma (aBCC) first-line treatment with hedgehog inhibitors (HHIs) and second-line treatment with PD1 inhibitors (PD1i) is available, offering combination and sequencing options. Here, we focus on the efficacy and safety of HHI reinduction after PD1i failure. Retrospective data analysis was performed with 12 patients with aBCC (locally advanced (n = 8)/metastatic (n = 4)). These patients (male:female 6:6, median age 68 years) initially received HHIs, leading to complete/partial response (66%) or stable disease (33%). Median treatment duration was 20.8 (2-64.5) months until discontinuation due to progression (n = 8), adverse events (n = 3), or patient request (n = 1). Subsequent PD1 inhibition (pembrolizumab 42%, cemiplimab 58%) yielded a partial response (8%), stable disease (33%), or progression (59%). Median treatment duration was 4.1 (0.8-16.3) months until discontinuation due to progression (n = 9), adverse events (n = 1), patient request (n = 1), or missing drug approval (n = 1). HHI reinduction resulted in complete/partial response (33%), stable disease (50%), or progression (17%). Median treatment duration was 3.6 (1-29) months. Response duration in the four responding patients was 2-29+ months. Thus, a subgroup of patients with aBCC responded to reinduction of HHI following PD1i failure. Therefore, this sequential treatment represents a feasible treatment option.
- Published
- 2022
- Full Text
- View/download PDF
44. Long-Term Management of Advanced Basal Cell Carcinoma: Current Challenges and Future Perspectives.
- Author
-
Heppt MV, Gebhardt C, Hassel JC, Alter M, Gutzmer R, Leiter U, and Berking C
- Abstract
The first-line therapy for locally advanced basal cell carcinoma (laBCC) is Hedgehog pathway inhibitors (HHIs), as they achieve good efficacy and duration of response. However, toxicity in the course of long-term treatment may lead to a decrease in the quality of life, and consequently to interruption or even discontinuation of therapy. As HHI therapy is a balancing act between effectiveness, adverse events, quality of life, and adherence, numerous successful treatment strategies have evolved, such as dose reduction and dose interruptions with on-off treatment schedules or interruptions with re-challenge after progression. As a small percentage of patients show primary or acquired resistance to HHIs, the inhibition of programmed cell death protein 1 (PD-1) has been approved as a second-line therapy, which may also be accompanied by immune-related toxicities and non-response. Thus, optimization of current treatment schedules, novel agents, and combination strategies are urgently needed for laBCC. Here, we narratively model the treatment sequence for patients with laBCC and summarize the current state of approved treatment regimens and therapeutic strategies to optimize the long-term management of laBCC.
- Published
- 2022
- Full Text
- View/download PDF
45. Histamine Activates Human Eosinophils via H 2 R and H 4 R Predominantly in Atopic Dermatitis Patients.
- Author
-
Beyer L, Kabatas AS, Mommert S, Stark H, Werfel T, Gutzmer R, and Schaper-Gerhardt K
- Subjects
- Eosinophils metabolism, Humans, Interleukin-18 genetics, Interleukin-5, RNA, Messenger metabolism, Receptors, G-Protein-Coupled metabolism, Receptors, Histamine genetics, Receptors, Histamine metabolism, Receptors, Histamine H4, Receptors, Interleukin-18, Dermatitis, Atopic metabolism, Histamine metabolism, Histamine pharmacology
- Abstract
Atopic dermatitis (AD) is maintained by a variety of cells and inflammatory mediators, including eosinophils and histamine. We recently reported that eosinophils from AD patients highly express the H
4 R. However, its immunomodulatory function in eosinophils is still largely unexplored. In this study, transcriptome analysis of blood eosinophils from AD patients stimulated with histamine and the H4 R agonist ST-1006 revealed several regulated genes (e.g., IL-18R, IL-1RL1, PDE4B, CXCR4) involved in inflammation. Subsequently, the impact of histamine on one of the strongly regulated genes, the IL-18 receptor (IL-18Rα), was investigated in detail. Stimulation with histamine induced the upregulation of IL-18Rα at mRNA and at the protein level in human eosinophils, which was more pronounced in cells from AD patients than in cells from healthy controls. IL-18 was upregulated via histamine as well. After pre-incubation with histamine and IFN-γ, subsequent stimulation with IL-18 resulted in an increased ECP mRNA expression. The activation of eosinophils by histamine, in combination with IFN-γ and IL-5, was also accompanied by an upregulation of CD69. Thus, our results indicate a crucial role of histamine in the upregulation of the IL-18/IL-18R axis and in the activation of human eosinophils from AD patients.- Published
- 2022
- Full Text
- View/download PDF
46. Corrigendum to 'Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial: [Annals of Oncology Volume 32, Issue 10, October 2021, Pages 1276-1285].
- Author
-
Hughes BGM, Munoz-Couselo E, Mortier L, Bratland Å, Gutzmer R, Roshdy O, González Mendoza R, Schachter J, Arance A, Grange F, Meyer N, Joshi A, Billan S, Zhang P, Gumuscu B, Swaby RF, and Grob JJ
- Published
- 2022
- Full Text
- View/download PDF
47. Impact of radiotherapy and sequencing of systemic therapy on survival outcomes in melanoma patients with previously untreated brain metastasis: a multicenter DeCOG study on 450 patients from the prospective skin cancer registry ADOREG.
- Author
-
Franklin C, Mohr P, Bluhm L, Grimmelmann I, Gutzmer R, Meier F, Garzarolli M, Weichenthal M, Pfoehler C, Herbst R, Terheyden P, Utikal J, Ulrich J, Debus D, Haferkamp S, Kaatz M, Forschner A, Leiter U, Nashan D, Kreuter A, Sachse M, Welzel J, Heinzerling L, Meiss F, Weishaupt C, Gambichler T, Weyandt G, Dippel E, Schatton K, Celik E, Trommer M, Helfrich I, Roesch A, Zimmer L, Livingstone E, Schadendorf D, Horn S, and Ugurel S
- Subjects
- Aged, CTLA-4 Antigen therapeutic use, Humans, Mitogen-Activated Protein Kinase Kinases therapeutic use, Programmed Cell Death 1 Receptor therapeutic use, Prospective Studies, Proto-Oncogene Proteins B-raf, Registries, Brain Neoplasms drug therapy, Brain Neoplasms radiotherapy, Melanoma drug therapy, Melanoma pathology, Skin Neoplasms drug therapy
- Abstract
Background: Despite of various therapeutic strategies, treatment of patients with melanoma brain metastasis (MBM) still is a major challenge. This study aimed at investigating the impact of type and sequence of immune checkpoint blockade (ICB) and targeted therapy (TT), radiotherapy, and surgery on the survival outcome of patients with MBM., Method: We assessed data of 450 patients collected within the prospective multicenter real-world skin cancer registry ADOREG who were diagnosed with MBM before start of the first non-adjuvant systemic therapy. Study endpoints were progression-free survival (PFS) and overall survival (OS)., Results: Of 450 MBM patients, 175 (38.9%) received CTLA-4+PD-1 ICB, 161 (35.8%) PD-1 ICB, and 114 (25.3%) BRAF+MEK TT as first-line treatment. Additional to systemic therapy, 67.3% of the patients received radiotherapy (stereotactic radiosurgery (SRS); conventional radiotherapy (CRT)) and 24.4% had surgery of MBM. 199 patients (42.2%) received a second-line systemic therapy. Multivariate Cox regression analysis revealed the application of radiotherapy (HR for SRS: 0.213, 95% CI 0.094 to 0.485, p<0.001; HR for CRT: 0.424, 95% CI 0.210 to 0.855, p=0.016), maximal size of brain metastases (HR for MBM >1 cm: 1.977, 95% CI 1.117 to 3.500, p=0.019), age (HR for age >65 years: 1.802, 95% CI 1.016 to 3.197, p=0.044), and ECOG performance status (HR for ECOG ≥2: HR: 2.615, 95% CI 1.024 to 6.676, p=0.044) as independent prognostic factors of OS on first-line therapy. The type of first-line therapy (ICB vs TT) was not independently prognostic. As second-line therapy BRAF+MEK showed the best survival outcome compared with ICB and other therapies (HR for CTLA-4+PD-1 compared with BRAF+MEK: 13.964, 95% CI 3.6 to 54.4, p<0.001; for PD-1 vs BRAF+MEK: 4.587 95% CI 1.3 to 16.8, p=0.022 for OS). Regarding therapy sequencing, patients treated with ICB as first-line therapy and BRAF+MEK as second-line therapy showed an improved OS (HR for CTLA-4+PD-1 followed by BRAF+MEK: 0.370, 95% CI 0.157 to 0.934, p=0.035; HR for PD-1 followed by BRAF+MEK: 0.290, 95% CI 0.092 to 0.918, p=0.035) compared with patients starting with BRAF+MEK in first-line therapy. There was no significant survival difference when comparing first-line therapy with CTLA-4+PD-1 ICB with PD-1 ICB., Conclusions: In patients with MBM, the addition of radiotherapy resulted in a favorable OS on systemic therapy. In BRAF-mutated MBM patients, ICB as first-line therapy and BRAF+MEK as second-line therapy were associated with a significantly prolonged OS., Competing Interests: Competing interests: The authors declare no competing interests in reference to this work. For conflicts of interest outside the submitted work see list: CF has been on the advisory board or has received honoraria from Bristol Myers Squibb, Immunocore and Novartis and received travel grants from Bristol Myers Squibb, Novartis and Pierre Fabre. PM declares research support from Bristol Myers Squibb, Novartis and Merck Sharp & Dome; speakers and advisory board honoraria from Almirall Hermal, Beiersdorf, Bristol Myers Squibb, Merck Sharp & Dome, Immunocore, Merck Serono, Medac, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre. LB received honoraria from Amgen, Bristol Myers Squibb and Sun Pharma. IG declares speakers and advisory board honoraria from Almirall Hermal, Bristol Myers Squibb, Merck Sharp & Dome, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. RH reports speakers and advisory board honoraria from Bristol Myers Squibb (BMS), Immunocore, Novartis, Pierre-Fabre, Roche and SUN pharma. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, SUNPHARMA, UCB, Allergy Therapeutics, Pierre Fabre, Kyowa Kirin and LEO. JUl has received research support from Novartis; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Pierre Fabre, and travel support from Bristol Myers Squibb and medac. PT declares speakers and advisory board honoraria from Almirall, Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre-Fabre, CureVac, Merck Serono, Sanofi, Roche, Kyowa Kirin, Biofrontera and 4SC; travel support from Bristol Myers Squibb and Pierre-Fabre. DN has received advisory and speaker honoraria from Merck Sharp & Dome, Bristol Myers Squibb, Novartis, Almirall and Sanofi. AF Advisory Board: Roche, Novartis, MSD, BMS, Pierre-Fabre; support for congress participation: Roche, Novartis, BMS, Pierre-Fabre; speaker honoraria: Roche, Novartis, BMS, MSD, CeGaT; institutional research support BMS Stiftung Immunonkologie. JUt is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche and Sanofi. TG has received speakers and/or advisory board honoraria and travel support from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, and Merck-Serono. FM served as consultant and/or has received honoraria from Novartis, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi Genzyme and travel support from Novartis, Sunpharma and Bristol Myers Squibb. JW received honoraria from Pierre Fabre, Novartis and Merck Sharp & Dohme. KS has been on the advisory board or has received honoraria from Bristol Myers Squibb, Roche, Merck Sharp & Dome, Pierre Fabre, Novartis and received travel grants from Bristol Myers Squibb, Novartis and Pierre Fabre. IH has been on the advisory board of Ymmunobio. AR reported grants from Novartis, Bristol Myers Squibb, and Adtec; personal fees from Merck Sharp & Dohme; and non-financial support from Amgen, Roche, Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, and Teva. LZ served as consultant and/or has received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sunpharma and Sanofi; research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Pierre-Fabre, Sunpharma, Sanofi and Novartis. EL served as consultant and/or has received honoraria from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Sanofi, Sunpharma and travel support from Medac, Bristol Myers Squibb, Pierre Fabre, Sunpharma and Novartis. DS: relevant financial activities (Roche, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi, Regeneron, Array, Pierre Fabre, 4SC, Helsinn, Philogen, InFlarX, Merck-Serono, SunPharma, Ultimovacs, and Sandoz). SU declares research support from Bristol Myers Squibb and Merck Serona; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dome, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme and Pierre Fabre. All other authors have no conflict of interest to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
- Full Text
- View/download PDF
48. Biomarkers of treatment benefit with atezolizumab plus vemurafenib plus cobimetinib in BRAF V600 mutation-positive melanoma.
- Author
-
Robert C, Lewis KD, Gutzmer R, Stroyakovskiy D, Gogas H, Protsenko S, Pereira RP, Eigentler T, Rutkowski P, Demidov L, Caro I, Forbes H, Shah K, Yan Y, Li H, McArthur GA, and Ascierto PA
- Subjects
- Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Azetidines, B7-H1 Antigen genetics, B7-H1 Antigen therapeutic use, Biomarkers, Tumor genetics, Humans, Mutation, Piperidines, Vemurafenib, Melanoma drug therapy, Melanoma genetics, Melanoma pathology, Proto-Oncogene Proteins B-raf genetics
- Abstract
Background: The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAF
V600 -mutated advanced melanoma. We report exploratory biomarker analyses to optimize targeting of patients who are more likely to benefit from triplet combination therapy., Patients and Methods: Five hundred fourteen patients were randomized to atezolizumab (n = 256) or control (n = 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers., Results: PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.52-1.02; P = 0.067] versus low TMB (<10 mutations/Mb; HR 0.92; 95% CI 0.65-1.30; P = 0.64) and similar between patients with strong IFN-γ (≥median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-γ (- Published
- 2022
- Full Text
- View/download PDF
49. Effectiveness, Safety and Utilization of Vismodegib for Locally Advanced Basal Cell Carcinoma Under Real-world Conditions: Non-interventional Cohort Study JONAS.
- Author
-
Kaatz M, Mohr P, Livingstone E, Weichenthal M, Kreuter A, Pföhler C, Leiter U, Ulrich J, Utikal JS, Gutzmer R, Herbst R, and Schadendorf D
- Subjects
- Anilides adverse effects, Cohort Studies, Hedgehog Proteins metabolism, Hedgehog Proteins therapeutic use, Humans, Pyridines, Antineoplastic Agents adverse effects, Carcinoma, Basal Cell drug therapy, Carcinoma, Basal Cell pathology, Skin Neoplasms pathology
- Abstract
Most patients with advanced basal cell carcinomas (BCCs) may not benefit sufficiently from standard treatment comprising surgery and radiation. Vismodegib, an oral selective hedgehog pathway inhibitor, is approved for treatment of patients with locally advanced BCC inappropriate for surgery or radiotherapy, or for patients with symptomatic metastatic BCC. In order to enhance understanding of the effectiveness, safety and utilization of vismodegib in clinical practice in Germany, a non-interventional study, JONAS, was conducted. A total of 53 patients with locally advanced BCC who initiated treatment with vismodegib between 2016 and 2018 were included in the study, which was embedded in the German ADOReg skin cancer registry. Duration of response, the primary endpoint, was 12.4 months, progression-free survival 32.2 months and overall response rate 77.4%. Most adverse events were mild to moderate. Overall, results confirmed previous findings, demonstrating favourable responses and manageable safety of vismodegib in patients with locally advanced BCC in clinical practice.
- Published
- 2022
- Full Text
- View/download PDF
50. Real-World Therapy with Pembrolizumab: Outcomes and Surrogate Endpoints for Predicting Survival in Advanced Melanoma Patients in Germany.
- Author
-
Mohr P, Scherrer E, Assaf C, Bender M, Berking C, Chandwani S, Eigentler T, Grimmelmann I, Gutzmer R, Haferkamp S, Hassel JC, Hauschild A, Herbst R, Jiang R, Kähler KC, Krepler C, Kreuter A, Leiter U, Loquai C, Meier F, Pföhler C, Rudolph A, Schadendorf D, Schiavone M, Schley G, Terheyden P, Ugurel S, Ulrich J, Utikal J, Weishaupt C, Welzel J, and Weichenthal M
- Abstract
Knowledge on the real-world characteristics and outcomes of pembrolizumab-treated advanced melanoma patients in Germany and on the value of different real-world endpoints as surrogates for overall survival (OS) is limited. A sample of 664 pembrolizumab-treated patients with advanced melanoma from the German registry ADOReg was used. We examined OS, real-world progression-free survival (rwPFS), real-world time to next treatment (rwTtNT), and real-world time on treatment (rwToT). Spearman's rank and iterative multiple imputation (IMI)-based correlation coefficients were computed between the OS and the rwPFS, rwTtNT, and rwToT and reported for the first line of therapy and the overall sample. The median OS was 30.5 (95%CI 25.0-35.4) months, the rwPFS was 3.9 months (95%CI 3.5-4.9), the rwTtNT was 10.7 months (95%CI 9.0-12.9), and the rwToT was 6.2 months (95%CI 5.1-6.8). The rwTtNT showed the highest correlation with the OS based on the IMI (rIMI = 0.83), Spearman rank correlations (rs = 0.74), followed by the rwToT (rIMI = 0.74 and rs = 0.65) and rwPFS (rIMI = 0.69 and rs = 0.56). The estimates for the outcomes and correlations were similar for the overall sample and those in first-line therapy. The median OS was higher compared to recent real-world studies, supporting the effectiveness of pembrolizumab in regular clinical practice. The rwTtNT may be a valuable OS surrogate, considering the highest correlation was observed with the OS among the investigated real-world endpoints.
- Published
- 2022
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.