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1. A targetable type III immune response with increase of IL-17A expressing CD4+ T cells is associated with immunotherapy-induced toxicity in melanoma

Author

Dimitriou, Florentia, Cheng, Phil F., Saltari, Annalisa, Schaper-Gerhardt, Katrin, Staeger, Ramon, Haunerdinger, Veronika, Sella, Federica, Tastanova, Aizhan, Urban, Christian, Dettwiler, Susanne, Mihic-Probst, Daniela, Matter, Christian M., Michielin, Olivier, Gutzmer, Ralf, Long, Georgina V., Becher, Burkhard, Levesque, Mitchell P., and Dummer, Reinhard

Published
2024
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2. Efficacy and Safety of the Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter Phase 3 Study

Author

Zager, Jonathan S., Orloff, Marlana, Ferrucci, Pier Francesco, Choi, Junsung, Eschelman, David J., Glazer, Evan S., Ejaz, Aslam, Howard, J. Harrison, Richtig, Erika, Ochsenreither, Sebastian, Reddy, Sunil A., Lowe, Michael C., Beasley, Georgia M., Gesierich, Anja, Bender, Armin, Gschnell, Martin, Dummer, Reinhard, Rivoire, Michel, Arance, Ana, Fenwick, Stephen William, Sacco, Joseph J., Haferkamp, Sebastian, Weishaupt, Carsten, John, Johnny, Wheater, Matthew, and Ottensmeier, Christian H.

Published
2024
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3. The genetic evolution of acral melanoma

Author

Wang, Meng, Fukushima, Satoshi, Sheen, Yi-Shuan, Ramelyte, Egle, Cruz-Pacheco, Noel, Shi, Chenxu, Liu, Shanshan, Banik, Ishani, Aquino, Jamie D, Sangueza Acosta, Martin, Levesque, Mitchell, Dummer, Reinhard, Liau, Jau-Yu, Chu, Chia-Yu, Shain, A Hunter, Yeh, Iwei, and Bastian, Boris C

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Human Genome, Cancer, Biotechnology, Clinical Research, Cancer Genomics, 2.1 Biological and endogenous factors, Humans, Melanoma, Skin Neoplasms, Mutation, Telomerase, DNA Copy Number Variations, Evolution, Molecular, Male, Exome Sequencing, Female, MAP Kinase Signaling System
Abstract

Acral melanoma is an aggressive type of melanoma with unknown origins. It is the most common type of melanoma in individuals with dark skin and is notoriously challenging to treat. We examine exome sequencing data of 139 tissue samples, spanning different progression stages, from 37 patients. We find that 78.4% of the melanomas display clustered copy number transitions with focal amplifications, recurring predominantly on chromosomes 5, 11, 12, and 22. These complex genomic aberrations are typically shared across all progression stages of individual patients. TERT activating alterations also arise early, whereas MAP-kinase pathway mutations appear later, an inverted order compared to the canonical evolution. The punctuated formation of complex aberrations and early TERT activation suggest a unique mutational mechanism that initiates acral melanoma. The marked intratumoral heterogeneity, especially concerning MAP-kinase pathway mutations, may partly explain the limited success of therapies for this melanoma subtype.

Published
2024

4. Three-Year Overall Survival with Tebentafusp in Metastatic Uveal Melanoma.

Author

Hassel, Jessica, Piperno-Neumann, Sophie, Rutkowski, Piotr, Baurain, Jean-Francois, Schlaak, Max, Butler, Marcus, Sullivan, Ryan, Dummer, Reinhard, Kirkwood, John, Orloff, Marlana, Sacco, Joseph, Ochsenreither, Sebastian, Joshua, Anthony, Gastaud, Lauris, Curti, Brendan, Piulats, Josep, Salama, April, Shoushtari, Alexander, Demidov, Lev, Milhem, Mohammed, Chmielowski, Bartosz, Kim, Kevin, Carvajal, Richard, Hamid, Omid, Collins, Laura, Ranade, Koustubh, Holland, Chris, Pfeiffer, Constance, and Nathan, Paul

Subjects
Adult, Humans, Antineoplastic Combined Chemotherapy Protocols, HLA-A Antigens, Melanoma, Uveal Neoplasms, Recombinant Fusion Proteins
Abstract

BACKGROUND: Tebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have unresectable or metastatic uveal melanoma. The primary analysis in the present phase 3 trial supported a long-term survival benefit associated with the drug. METHODS: We report the 3-year efficacy and safety results from our open-label, phase 3 trial in which HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma were randomly assigned in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigators choice of therapy with pembrolizumab, ipilimumab, or dacarbazine (control group), with randomization stratified according to the lactate dehydrogenase level. The primary end point was overall survival. RESULTS: At a minimum follow-up of 36 months, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (hazard ratio for death, 0.68; 95% confidence interval, 0.54 to 0.87). The estimated percentage of patients surviving at 3 years was 27% in the tebentafusp group and 18% in the control group. The most common treatment-related adverse events of any grade in the tebentafusp group were rash (83%), pyrexia (76%), pruritus (70%), and hypotension (38%). Most tebentafusp-related adverse events occurred early during treatment, and no new adverse events were observed with long-term administration. The percentage of patients who discontinued treatment because of adverse events continued to be low in both treatment groups (2% in the tebentafusp group and 5% in the control group). No treatment-related deaths occurred. CONCLUSIONS: This 3-year analysis supported a continued long-term benefit of tebentafusp for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. (Funded by Immunocore; IMCgp100-202 ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).

Published
2023

5. Correction: Efficacy and Safety of the Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter Phase 3 Study

Author

Zager, Jonathan S., Orloff, Marlana, Ferrucci, Pier Francesco, Choi, Junsung, Eschelman, David J., Glazer, Evan S., Ejaz, Aslam, Howard, J. Harrison, Richtig, Erika, Ochsenreither, Sebastian, Reddy, Sunil A., Lowe, Michael C., Beasley, Georgia M., Gesierich, Anja, Bender, Armin, Gschnell, Martin, Dummer, Reinhard, Rivoire, Michel, Arance, Ana, Fenwick, Stephen William, Sacco, Joseph J., Haferkamp, Sebastian, Weishaupt, Carsten, John, Johnny, Wheater, Matthew, and Ottensmeier, Christian H.

Published
2024
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8. Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial

Author

Ascierto, Paolo A., Casula, Milena, Bulgarelli, Jenny, Pisano, Marina, Piccinini, Claudia, Piccin, Luisa, Cossu, Antonio, Mandalà, Mario, Ferrucci, Pier Francesco, Guidoboni, Massimo, Rutkowski, Piotr, Ferraresi, Virginia, Arance, Ana, Guida, Michele, Maiello, Evaristo, Gogas, Helen, Richtig, Erika, Fierro, Maria Teresa, Lebbe, Celeste, Helgadottir, Hildur, Queirolo, Paola, Spagnolo, Francesco, Tucci, Marco, Del Vecchio, Michele, Cao, Maria Gonzales, Minisini, Alessandro Marco, De Placido, Sabino, Sanmamed, Miguel F., Mallardo, Domenico, Paone, Miriam, Vitale, Maria Grazia, Melero, Ignacio, Grimaldi, Antonio M., Giannarelli, Diana, Dummer, Reinhard, Sileni, Vanna Chiarion, and Palmieri, Giuseppe

Published
2024
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9. ASO Visual Abstract: Efficacy and Safety of Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter, Phase 3 Study

Author

Zager, Jonathan S., Orloff, Marlana, Ferrucci, Pier Francesco, Choi, Junsung, Eschelman, David J., Glazer, Evan S., Ejaz, Aslam, Howard, J. Harrison, Richtig, Erika, Ochsenreither, Sebastian, Reddy, Sunil A., Lowe, Michael C., Beasley, Georgia M., Gesierich, Anja, Bender, Armin, Gschnell, Martin, Dummer, Reinhard, Rivoire, Michel, Arance, Ana, Fenwick, Stephen William, Sacco, Joseph J., Haferkamp, Sebastian, Weishaupt, Carsten, John, Johnny, Wheater, Matthew, and Ottensmeier, Christian H.

Published
2024
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10. Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma

Author

Chesney, Jason A, Ribas, Antoni, Long, Georgina V, Kirkwood, John M, Dummer, Reinhard, Puzanov, Igor, Hoeller, Christoph, Gajewski, Thomas F, Gutzmer, Ralf, Rutkowski, Piotr, Demidov, Lev, Arenberger, Petr, Shin, Sang Joon, Ferrucci, Pier Francesco, Haydon, Andrew, Hyngstrom, John, van Thienen, Johannes V, Haferkamp, Sebastian, Guilera, Josep Malvehy, Rapoport, Bernardo Leon, VanderWalde, Ari, Diede, Scott J, Anderson, James R, Treichel, Sheryl, Chan, Edward L, Bhatta, Sumita, Gansert, Jennifer, Hodi, Frank Stephen, and Gogas, Helen

Subjects
Patient Safety, Clinical Research, Cancer, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Humans, Melanoma, Oncolytic Virotherapy, Herpesvirus 1, Human, Double-Blind Method, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeThe combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma.MethodsPatients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 106 plaque-forming unit (PFU) followed by ≤ 4 × 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis.ResultsOverall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm.ConclusionT-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.

Published
2023

12. Nature and management of melanoma recurrences following adjuvant anti-PD-1 based therapy

Author

Woodford, Rachel, McKeown, Janet, Hoeijmakers, Lotte L., Mangana, Johanna, Dimitriou, Florentia, Allayous, Clara, Zaman, Farzana, Aya, Francisco, Marsiglio, John, Goodman, Rachel, Rayson, Victoria, Placzke, Joanna, Kessels, Jolien, Ramalyte, Egle, Haque, Waqas, Wilson, Isabella, Trojaniello, Claudia, Benannoune, Naima, Roberts-Thomson, Rachel, Robert, Caroline, Blank, Christian U., Dummer, Reinhard, Lebbe, Celeste, Haydon, Andrew, Arance, Ana, Hu-Lieskovan, Siwen, Johnson, Douglas B., Mcarthur, Grant A., Rutkowski, Piotr, Neyns, Bart, Sullivan, Ryan J., Weber, Jeffrey, Carlino, Matteo S., Ascierto, Paolo A., Lo, Serigne, Long, Georgina V., and Menzies, Alexander M.

Published
2024
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15. Approach to Mycosis Fungoides in children: Consensus-based recommendations

Author

Zvulunov, Alex, Neale, Holly, Stern, Jonah, Santaguida, Pasqualina, Stein, Amy Buros, Koh, Mark, Eichenfield, Lawrence F., Guitart, Joan, Goebeler, Matthias, Scarisbrick, Julia, Willemze, Rein, Coughlin, Carrie C., George, Renu, Brazzelli, Valeria, Marschalkó, Márta, Belousova, Irena, Querfeld, Christiane, Bagot, Martine, Szepietowski, Jacek C., Papadavid, Evangelina, Quaglino, Pietro, Hoeger, Peter, Ortiz-Romero, Pablo L., Nikolaou, Vasiliki, Dummer, Reinhard, Aung, Phyu P., Lawley, Leslie, Morel, Kimberly D., Ngan, Bo, Wain, Mary, Gameiro, Ana, Lacy-Niebla, Rosa María, and Pope, Elena

Published
2024
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16. Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with BRAF V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i)

Author

Tawbi, Hussein A, Robert, Caroline, Brase, Jan C, Gusenleitner, Daniel, Gasal, Eduard, Garrett, James, Savchenko, Alexander, Görgün, Güllü, Flaherty, Keith T, Ribas, Antoni, Dummer, Reinhard, Schadendorf, Dirk, Long, Georgina V, Nathan, Paul D, and Ascierto, Paolo A

Subjects
Genetics, Cancer, Clinical Trials and Supportive Activities, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Good Health and Well Being, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, B7-H1 Antigen, Biomarkers, Tumor, Clinical Trials, Phase III as Topic, Humans, Imidazoles, Melanoma, Oximes, Proto-Oncogene Proteins B-raf, Pyridones, Pyrimidinones, Randomized Controlled Trials as Topic, Skin Neoplasms, Drug Therapy, Combination, Tumor Biomarkers
Abstract

BackgroundThe randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic BRAF V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram.MethodsIn COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; BRAF V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4+/CD8+ T-cell ratio via immunophenotyping.ResultsExtensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by BRAF V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4+/CD8+ ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4+/CD8+ ratio was strongly predictive (interaction p=0.0131).ConclusionsThese results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4+/CD8+ T-cell ratio was significantly predictive of PFS benefit with sparta-DabTram but requires further validation as a biomarker in melanoma. Taken together with previous observations, further study of checkpoint inhibitor plus targeted therapy combination in patients with higher disease burden may be warranted.Trial registration numberNCT02967692.

Published
2022

18. Myeloid-T cell interplay and cell state transitions associated with checkpoint inhibitor response in melanoma

Author

Schlenker, Ramona, Schwalie, Petra C., Dettling, Steffen, Huesser, Tamara, Irmisch, Anja, Mariani, Marisa, Martínez Gómez, Julia M., Ribeiro, Alison, Limani, Florian, Herter, Sylvia, Yángüez, Emilio, Hoves, Sabine, Somandin, Jitka, Siebourg-Polster, Juliane, Kam-Thong, Tony, de Matos, Ines Grazina, Umana, Pablo, Dummer, Reinhard, Levesque, Mitchell P., and Bacac, Marina

Published
2024
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19. COLUMBUS 7-year update: A randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600E/K-mutant melanoma

Author

Schadendorf, Dirk, Dummer, Reinhard, Flaherty, Keith T., Robert, Caroline, Arance, Ana, de Groot, Jan Willem B., Garbe, Claus, Gogas, Helen J., Gutzmer, Ralf, Krajsová, Ivana, Liszkay, Gabriella, Loquai, Carmen, Mandalà, Mario, Yamazaki, Naoya, Queirolo, Paola, Guenzel, Carolin, Polli, Anna, Thakur, Mahgull, di Pietro, Alessandra, and Ascierto, Paolo A.

Published
2024
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20. Checkpoint inhibitor–induced lichen planus differs from spontaneous lichen planus on the clinical, histological, and gene expression level

Author

Meier-Schiesser, Barbara, Zecha, Christine, Zierold, Sarah, Kolm, Isabel, Röckel, Magdalena, Fröhlich, Waltraud, Mittag, Nora, Schmitt, Christina, Kumbrink, Joerg, Hassel, Jessica C., Berking, Carola, Nashan, Dorothee, French, Lars Einar, Vera-González, Julio, Dummer, Reinhard, Kerl-French, Katrin, and Heinzerling, Lucie

Published
2024
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21. The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab

Author

Mallardo, Domenico, Woodford, Rachel, Menzies, Alexander M., Zimmer, Lisa, williamson, Andrew, Ramelyte, Egle, Dimitriou, Florentia, Wicky, Alexandre, Wallace, Roslyn, Mallardo, Mario, Cortellini, Alessio, Budillon, Alfredo, Atkinson, Victoria, Sandhu, Shahneen, Olivier, Michielin, Dummer, Reinhard, Lorigan, Paul, Schadendorf, Dirk, Long, Georgina V., Simeone, Ester, and Ascierto, Paolo A.

Published
2023
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23. Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment

Author

Haake, Markus, Haack, Beatrice, Schäfer, Tina, Harter, Patrick N., Mattavelli, Greta, Eiring, Patrick, Vashist, Neha, Wedekink, Florian, Genssler, Sabrina, Fischer, Birgitt, Dahlhoff, Julia, Mokhtari, Fatemeh, Kuzkina, Anastasia, Welters, Marij J. P., Benz, Tamara M., Sorger, Lena, Thiemann, Vincent, Almanzar, Giovanni, Selle, Martina, Thein, Klara, Späth, Jacob, Gonzalez, Maria Cecilia, Reitinger, Carmen, Ipsen-Escobedo, Andrea, Wistuba-Hamprecht, Kilian, Eichler, Kristin, Filipski, Katharina, Zeiner, Pia S., Beschorner, Rudi, Goedemans, Renske, Gogolla, Falk Hagen, Hackl, Hubert, Rooswinkel, Rogier W., Thiem, Alexander, Roche, Paula Romer, Joshi, Hemant, Pühringer, Dirk, Wöckel, Achim, Diessner, Joachim E., Rüdiger, Manfred, Leo, Eugen, Cheng, Phil F., Levesque, Mitchell P., Goebeler, Matthias, Sauer, Markus, Nimmerjahn, Falk, Schuberth-Wagner, Christine, von Felten, Stefanie, Mittelbronn, Michel, Mehling, Matthias, Beilhack, Andreas, van der Burg, Sjoerd H., Riedel, Angela, Weide, Benjamin, Dummer, Reinhard, and Wischhusen, Jörg

Published
2023
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24. Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600–Mutant Unresectable or Metastatic Melanoma

Author

Dummer, Reinhard, Long, Georgina V, Robert, Caroline, Tawbi, Hussein A, Flaherty, Keith T, Ascierto, Paolo A, Nathan, Paul D, Rutkowski, Piotr, Leonov, Oleg, Dutriaux, Caroline, Mandalà, Mario, Lorigan, Paul, Ferrucci, Pier Francesco, Grob, Jean Jacques, Meyer, Nicolas, Gogas, Helen, Stroyakovskiy, Daniil, Arance, Ana, Brase, Jan C, Green, Steven, Haas, Tomas, Masood, Aisha, Gasal, Eduard, Ribas, Antoni, and Schadendorf, Dirk

Subjects
Clinical Research, Genetics, Cancer, Clinical Trials and Supportive Activities, Human Genome, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adolescent, Adult, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Humans, Imidazoles, Melanoma, Mutation, Neoplasms, Second Primary, Oximes, Proto-Oncogene Proteins B-raf, Pyridones, Pyrimidinones, Receptors, Death Domain, Skin Neoplasms, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposePreclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600-mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti-programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600-mutant unresectable or metastatic melanoma.MethodsPatients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic BRAF V600-mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692).ResultsAt data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm.ConclusionThe study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.

Published
2022

27. Anti-PD-(L)1 plus BRAF/MEK inhibitors (triplet therapy) after failure of immune checkpoint inhibition and targeted therapy in patients with advanced melanoma

Author

Albrecht, Lea Jessica, Dimitriou, Florentia, Grover, Piyush, Hassel, Jessica C., Erdmann, Michael, Forschner, Andrea, Johnson, Douglas B., Váraljai, Renáta, Lodde, Georg, Placke, Jan Malte, Krefting, Frederik, Zaremba, Anne, Ugurel, Selma, Roesch, Alexander, Schulz, Carsten, Berking, Carola, Pöttgen, Christoph, Menzies, Alexander M., Long, Georgina V., Dummer, Reinhard, Livingstone, Elisabeth, Schadendorf, Dirk, and Zimmer, Lisa

Published
2024
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28. Efficacy and safety of ‘Second Adjuvant’ therapy with BRAF/MEK inhibitors after local therapy for recurrent melanoma following adjuvant PD-1 based immunotherapy

Author

Taylor, Amelia M., McKeown, Janet, Dimitriou, Florentia, Jacques, Sarah K., Zimmer, Lisa, Allayous, Clara, Yeoh, Hui-Ling, Haydon, Andrew, Ressler, Julia M., Galea, Claire, Woodford, Rachel, Kahler, Katharina, Hauschild, Axel, Festino, Lucia, Hoeller, Christoph, Schwarze, Julia K., Neyns, Bart, Wicky, Alexandre, Michielin, Olivier, Placzke, Joanna, Rutkowski, Piotr, Johnson, Douglas B., Lebbe, Celeste, Dummer, Reinhard, Ascierto, Paolo A., Lo, Serigne, Long, Georgina V., Carlino, Matteo S., and Menzies, Alexander M.

Published
2024
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29. The side effect registry immuno-oncology (SERIO) – A tool for systematic analysis of immunotherapy-induced side effects

Author

Ertl, Carolin, Ruf, Theresa, Mentzer, Dirk, Kong, Mingzi, Kramer, Rafaela, Bergwelt-Baildon, Michael von, Subklewe, Marion, Tomsitz, Dirk, Ascierto, Paolo A., Dummer, Reinhard, Gogas, Helen, Lebbé, Celeste, Long, Georgina V., McArthur, Grant, Neilan, Tomas G., Ribas, Antoni, Robert, Caroline, Schadendorf, Dirk, Zimmer, Lisa, Eigentler, Thomas, Grabbe, Stephan, Forschner, Andrea, Kähler, Katharina C., Milani, Valeria, Pföhler, Claudia, Hassel, Jessica, Gutzmer, Ralf, Loquai, Carmen, Routy, Bertrand, Furness, Andrew J.S., Blank, Christian, Wolchok, Jedd D., French, Lars E., Hauschild, Axel, and Heinzerling, Lucie

Published
2024
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32. Real-World efficiency of pembrolizumab in metastatic melanoma patients following adjuvant anti-PD1 treatment

Author

Weichenthal, Michael, Svane, Inge Marie, Mangana, Johanna, Leiter, Ulrike, Meier, Friedegund, Ruhlmann, Christina, Ziogas, Dimitrios, Dummer, Reinhard, Cerenzuela, Pablo, Manzano, Jose Luis, Bender, Marc, Jiang, Shan, Ascierto, Paolo Antonio, Gavrilova, Iva, Kandolf, Lidija, Gogas, Helen, Mohr, Peter, Schadendorf, Dirk, and Ellebaek, Eva

Published
2024
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35. First-in-human study of naporafenib (LXH254) with or without spartalizumab in adult patients with advanced solid tumors harboring MAPK signaling pathway alterations

Author

Janku, Filip, Kim, Tae Min, Iyer, Gopakumar, Spreafico, Anna, Elez, Elena, de Jonge, Maja, Yamamoto, Noboru, van der Wekken, Anthonie J., Ascierto, Paolo Antonio, Maur, Michela, Marmé, Frederik, Kiladjian, Jean-Jacques, Basu, Sumit, Baffert, Fabienne, Buigues, Amparo, Chen, Chi, Cooke, Vesselina, Giorgetti, Elisa, Kim, Jaeyeon, McCarthy, Fiona, Moschetta, Michele, and Dummer, Reinhard

Published
2024
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38. Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study

Author

Dummer, Reinhard, Queirolo, Paola, Gerard Duhard, Pauline, Hu, Youyou, Wang, Dao, de Azevedo, Sergio Jobim, Robert, Caroline, Ascierto, Paolo Antonio, Chiarion-Sileni, Vanna, Pronzato, Paolo, Spagnolo, Francesco, Mujika Eizmendi, Karmele, Liszkay, Gabriella, de la Cruz Merino, Luis, and Tawbi, Hussein

Published
2023
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39. EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – Update 2023

Author

Latzka, Johanna, Assaf, Chalid, Bagot, Martine, Cozzio, Antonio, Dummer, Reinhard, Guenova, Emmanuella, Gniadecki, Robert, Hodak, Emmilia, Jonak, Constanze, Klemke, Claus-Detlev, Knobler, Robert, Morrris, Stephen, Nicolay, Jan P., Ortiz-Romero, Pablo L., Papadavid, Evangelia, Pimpinelli, Nicola, Quaglino, Pietro, Ranki, Annamari, Scarisbrick, Julia, Stadler, Rudolf, Väkevä, Liisa, Vermeer, Maarten H., Wehkamp, Ulrike, Whittaker, Sean, Willemze, Rein, and Trautinger, Franz

Published
2023
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40. Neoadjuvant immunotherapy for melanoma is now ready for clinical practice

Author

Garbe, Claus, Dummer, Reinhard, Amaral, Teresa, Amaria, Rodabe N., Ascierto, Paolo A., Burton, Elizabeth M., Dreno, Brigitte, Eggermont, Alexander M. M., Hauschild, Axel, Hoeller, Christoph, Kaufmann, Roland, Lebbe, Celeste, Mandala, Mario, Menzies, Alexander M., Moreno, David, Michielin, Olivier, Nathan, Paul, Patel, Sapna P., Robert, Caroline, Schadendorf, Dirk, Lorigan, Paul C., Scolyer, Richard A., Tawbi, Hussein A., van de Wiel, Bart A., Blank, Christian, and Long, Georgina V.

Published
2023
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41. Response to brentuximab vedotin versus physician’s choice by CD30 expression and large cell transformation status in patients with mycosis fungoides: An ALCANZA sub-analysis

Author

Kim, Youn H, Prince, H Miles, Whittaker, Sean, Horwitz, Steven M, Duvic, Madeleine, Bechter, Oliver, Sanches, Jose A, Stadler, Rudolf, Scarisbrick, Julia, Quaglino, Pietro, Zinzani, Pier Luigi, Wolter, Pascal, Eradat, Herbert, Pinter-Brown, Lauren C, Ortiz-Romero, Pablo L, Akilov, Oleg E, Trotman, Judith, Taylor, Kerry, Weichenthal, Michael, Walewski, Jan, Fisher, David, McNeeley, Marise, Gru, Alejandro A, Brown, Lisa, Palanca-Wessels, M Corinna, Lisano, Julie, Onsum, Matthew, Bunn, Veronica, Little, Meredith, Trepicchio, William L, and Dummer, Reinhard

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Lymphoma, Clinical Research, Hematology, Orphan Drug, Cancer, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological, Brentuximab Vedotin, Choice Behavior, Decision Support Techniques, Female, Follow-Up Studies, Humans, International Agencies, Ki-1 Antigen, Male, Middle Aged, Mycosis Fungoides, Physicians, Prognosis, Retrospective Studies, Survival Rate, Young Adult, Antibody-drug conjugate, Brentuximab vedotin, CD30, Cutaneous T-cell lymphoma, Efficacy, Large-cell transformation, Mycosis fungoides, Objective response, Progression-free survival, Safety, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

IntroductionMycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, can lead to disfiguring lesions, debilitating pruritus and frequent skin infections. This study assessed response to brentuximab vedotin in patients with MF in the phase III ALCANZA study.MethodsBaseline CD30 levels and large-cell transformation (LCT) status were centrally reviewed in patients with previously-treated CD30-positive MF using ≥2 skin biopsies obtained at screening; eligible patients required ≥1 biopsy with ≥10% CD30 expression. Patients were categorised as CD30min

Published
2021

42. European consensus-based interdisciplinary guideline for invasive cutaneous squamous cell carcinoma: Part 2. Treatment–Update 2023

Author

Stratigos, Alexander J., Garbe, Claus, Dessinioti, Clio, Lebbe, Celeste, van Akkooi, Alexander, Bataille, Veronique, Bastholt, Lars, Dreno, Brigitte, Dummer, Reinhard, Fargnoli, Maria Concetta, Forsea, Ana Maria, Harwood, Catherine A., Hauschild, Axel, Hoeller, Christoph, Kandolf-Sekulovic, Lidija, Kaufmann, Roland, Kelleners-Smeets, Nicole WJ, Lallas, Aimilios, Leiter, Ulrike, Malvehy, Josep, del Marmol, Veronique, Moreno-Ramirez, David, Pellacani, Giovanni, Peris, Ketty, Saiag, Philippe, Tagliaferri, Luca, Trakatelli, Myrto, Ioannides, Dimitrios, Vieira, Ricardo, Zalaudek, Iris, Arenberger, Petr, Eggermont, Alexander M.M., Röcken, Martin, Grob, Jean-Jacques, and Lorigan, Paul

Published
2023
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43. European consensus-based interdisciplinary guideline for invasive cutaneous squamous cell carcinoma. Part 1: Diagnostics and prevention–Update 2023

Author

Stratigos, Alexander J., Garbe, Claus, Dessinioti, Clio, Lebbe, Celeste, van Akkooi, Alexander, Bataille, Veronique, Bastholt, Lars, Dreno, Brigitte, Dummer, Reinhard, Fargnoli, Maria Concetta, Forsea, Ana Maria, Harwood, Catherine A., Hauschild, Axel, Hoeller, Christoph, Kandolf-Sekulovic, Lidija, Kaufmann, Roland, Kelleners-Smeets, Nicole WJ, Lallas, Aimilios, Leiter, Ulrike, Malvehy, Josep, del Marmol, Veronique, Moreno-Ramirez, David, Pellacani, Giovanni, Peris, Ketty, Saiag, Philippe, Tagliaferri, Luca, Trakatelli, Myrto, Ioannides, Dimitrios, Vieira, Ricardo, Zalaudek, Iris, Arenberger, Petr, Eggermont, Alexander M.M., Röcken, Martin, Grob, Jean-Jacques, and Lorigan, Paul

Published
2023
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44. European consensus-based interdisciplinary guideline for diagnosis and treatment of basal cell carcinoma—update 2023

Author

Peris, Ketty, Fargnoli, Maria Concetta, Kaufmann, Roland, Arenberger, Petr, Bastholt, Lars, Seguin, Nicole Basset, Bataille, Veronique, Brochez, Lieve, del Marmol, Veronique, Dummer, Reinhard, Forsea, Ana-Marie, Gaudy-Marqueste, Caroline, Harwood, Catherine A., Hauschild, Axel, Höller, Christoph, Kandolf, Lidija, Kellerners-Smeets, Nicole W.J., Lallas, Aimilios, Leiter, Ulrike, Malvehy, Josep, Marinović, Branka, Mijuskovic, Zeljko, Moreno-Ramirez, David, Nagore, Eduardo, Nathan, Paul, Stratigos, Alexander J., Stockfleth, Eggert, Tagliaferri, Luca, Trakatelli, Myrto, Vieira, Ricardo, Zalaudek, Iris, and Garbe, Claus

Published
2023
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46. Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma

Author

Robert, Caroline, Hwu, Wen-Jen, Hamid, Omid, Ribas, Antoni, Weber, Jeffrey S, Daud, Adil I, Hodi, F Stephen, Wolchok, Jedd D, Mitchell, Tara C, Hersey, Peter, Dronca, Roxana, Joseph, Richard W, Boutros, Celine, Min, Le, Long, Georgina V, Schachter, Jacob, Puzanov, Igor, Dummer, Reinhard, Lin, Jianxin, Ibrahim, Nageatte, Diede, Scott J, Carlino, Matteo S, and Joshua, Anthony M

Subjects
Cancer, Vaccine Related, Immunization, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, Clinical Trials as Topic, Drug-Related Side Effects and Adverse Reactions, Female, Follow-Up Studies, Humans, Male, Melanoma, Meta-Analysis as Topic, Middle Aged, Prognosis, Young Adult, Pembrolizumab, Advanced melanoma, Immune-related adverse events, Immune-checkpoint inhibitors, PD-1 inhibitors, Immunomodulating drugs, Corticosteroid use, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

ObjectiveLong-term safety of pembrolizumab in melanoma was analyzed in KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006.Patients and methodsAnalysis involved patients who received ≥1 pembrolizumab dose. Lead-time bias was addressed via landmark analyses in patients who were progression-free before day 147.ResultsAdverse events (AEs) were analyzed for 1567 patients (median follow-up, 42.4 months). Most AEs were mild/moderate; grade 3/4 treatment-related AEs occurred in 17.7% of patients. Two pembrolizumab-related deaths occurred. Any-grade immune-mediated AEs (imAEs) occurred in 23.0%, most commonly hypothyroidism (9.1%), pneumonitis (3.3%), and hyperthyroidism (3.0%); grade 3/4 imAEs occurred in 6.9% of patients. Most imAEs occurred within 16 weeks of treatment. In landmark analysis, patients who did (n = 79) versus did not (n = 384) develop imAEs had similar objective response rates (ORRs) (64.6% versus 63.0%); median time to response (TTR), 5.6 months for both; median duration of response (DOR), 20.0 versus 25.3 months; median progression-free survival (PFS), 17.0 versus 17.7 months; median overall survival (OS), not reached (NR) versus 43 months (p = 0.1104). Patients who did (n = 17) versus did not (n = 62) receive systemic corticosteroids had similar ORRs (70.6% vs. 62.9%) and median TTR (6.4 vs. 5.6 months) but numerically shorter median PFS (9.9 vs. 17.0 months); median DOR, 14.2 months versus NR; median OS, NR for both.ConclusionsThese results enhance the knowledge base for pembrolizumab in advanced melanoma, with no new toxicity signals after lengthy follow-up of a large population. In landmark analyses, pembrolizumab efficacy was similar regardless of imAEs or systemic corticosteroid use.Clinical trial registryNCT01295827, NCT01704287, NCT01866319.

Published
2021

48. Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors

Author

Nuñez, Nicolas Gonzalo, Berner, Fiamma, Friebel, Ekaterina, Unger, Susanne, Wyss, Nina, Gomez, Julia Martinez, Purde, Mette-Triin, Niederer, Rebekka, Porsch, Maximilian, Lichtensteiger, Christa, Kramer, Rafaela, Erdmann, Michael, Schmitt, Christina, Heinzerling, Lucie, Abdou, Marie-Therese, Karbach, Julia, Schadendorf, Dirk, Zimmer, Lisa, Ugurel, Selma, Klümper, Niklas, Hölzel, Michael, Power, Laura, Kreutmair, Stefanie, Capone, Mariaelena, Madonna, Gabriele, Cevhertas, Lacin, Heider, Anja, Amaral, Teresa, Hasan Ali, Omar, Bomze, David, Dimitriou, Florentia, Diem, Stefan, Ascierto, Paolo Antonio, Dummer, Reinhard, Jäger, Elke, Driessen, Christoph, Levesque, Mitchell Paul, van de Veen, Willem, Joerger, Markus, Früh, Martin, Becher, Burkhard, and Flatz, Lukas

Published
2023
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49. Stringent monitoring can decrease mortality of immune checkpoint inhibitor induced cardiotoxicity

Author

Wang, Ying, primary, Ertl, Carolin, additional, Schmitt, Christina, additional, Hammann, Linda, additional, Kramer, Rafaela, additional, Grabmaier, Ulrich, additional, Schöberl, Florian, additional, Anz, David, additional, Piseddu, Ignazio, additional, Pesch, Giulia, additional, Vera, Julio, additional, Froehlich, Waltraud, additional, Weckbach, Ludwig, additional, Tomsitz, Dirk, additional, Loquai, Carmen, additional, Zimmer, Lisa, additional, Mangana, Johanna, additional, Dummer, Reinhard, additional, Gutzmer, Ralf, additional, Klespe, Kai-Christian, additional, Stege, Henner, additional, Meiss, Frank, additional, Thoms, Kai-Martin, additional, Terheyden, Patrick, additional, Bröckelmann, Paul J., additional, Johnson, Douglas B., additional, French, Lars E., additional, and Heinzerling, Lucie, additional

Published
2024
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50. A phase 3 trial of IMC-F106C (PRAME x CD3) plus nivolumab versus standard nivolumab regimens in HLA-A*02:01+ patients with previously untreated advanced melanoma (PRISM-MEL-301).

Author

Long, Georgina V., primary, Atkinson, Victoria, additional, Ascierto, Paolo Antonio, additional, Davar, Diwakar, additional, Hamid, Omid, additional, Robert, Caroline, additional, Butler, Marcus O., additional, Dummer, Reinhard, additional, Hafner, Christine, additional, Khattak, Muhammad Adnan, additional, Larkin, James, additional, Lorigan, Paul, additional, McKean, Meredith, additional, Seedor, Rino S., additional, Shaw, Heather May, additional, Stephenson, Joe, additional, Yuan, Yuan, additional, Patel, Roma, additional, Thiyagarajah, Piruntha, additional, and Schadendorf, Dirk, additional

Published
2024
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