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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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4. Interim analysis of the multinational, post-authorization safety study (NISSO) to assess the long-term safety of sonidegib in patients with locally advanced basal cell carcinoma

Author

Gutzmer, Ralf, Leiter, Ulrike, Mohr, Peter, Kähler, Katharina C., Ascierto, Paolo Antonio, Scalvenzi, Massimiliano, Peris, Ketty, Pérez-Pastor, Gemma María, Fernández-de-Misa, Ricardo, Botella-Estrada, Rafael, Hunger, Robert E., Martelli, Serena, Güneli, Nur, Arntz, Ramon, and Hauschild, Axel

Published
2024
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7. 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

8. Preferences of physicians for treatment-related toxicity vs. recurrence in melanoma (GERMELATOX-A): the doctors’ perspective

Author

Kähler, Katharina C., Gutzmer, Ralf, Angela, Yenny, Livingstone, Elisabeth, Lodde, Georg, Meiss, Frank, Rafei-Shamsabadi, David A., Weyer-Fahlbusch, Sera S., Nashan, Dorothée, Loquai, Carmen, Hassel, Jessica C., Sachse, Michael M. M., Maul, Lara V., Heinzerling, Lucie, Heppt, Markus V., Colapietro, Chiara, Rusch, Judith, and Blome, Christine

Published
2024
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10. Seven-year analysis of adjuvant pembrolizumab versus placebo in stage III melanoma in the EORTC1325 / KEYNOTE-054 trial

Author

Eggermont, Alexander MM, Kicinski, Michal, Blank, Christian U., Mandala, Mario, Long, Georgina V., Atkinson, Victoria, Dalle, Stéphane, Haydon, Andrew, Meshcheryakov, Andrey, Khattak, Adnan, Carlino, Matteo S., Sandhu, Shahneen, Larkin, James, Puig, Susana, Ascierto, Paolo A., Rutkowski, Piotr, Schadendorf, Dirk, Boers-Sonderen, Marye, Di Giacomo, Anna Maria, van den Eertwegh, Alfonsus JM, Grob, Jean-Jacques, Gutzmer, Ralf, Jamal, Rahima, van Akkooi, Alexander C.J., Lorigan, Paul, Grebennik, Dmitri, Kreplere, Clemens, Marreaud, Sandrine, Suciu, Stefan, and Robert, Caroline

Published
2024
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11. Early versus late response to PD-1-based immunotherapy in metastatic melanoma

Author

Lodde, Georg C., Zhao, Fang, Herbst, Rudolf, Terheyden, Patrick, Utikal, Jochen, Pföhler, Claudia, Ulrich, Jens, Kreuter, Alexander, Mohr, Peter, Gutzmer, Ralf, Meier, Friedegund, Dippel, Edgar, Weichenthal, Michael, Jansen, Philipp, Kowall, Bernd, Galetzka, Wolfgang, Hörst, Fabian, Kleesiek, Jens, Hellwig, Birte, Rahnenführer, Jörg, Rajcsanyi, Luisa, Peters, Triinu, Hinney, Anke, Placke, Jan-Malte, Sucker, Antje, Paschen, Annette, Becker, Jürgen C., Livingstone, Elisabeth, Zimmer, Lisa, Tasdogan, Alpaslan, Roesch, Alexander, Hadaschik, Eva, Schadendorf, Dirk, Griewank, Klaus, and Ugurel, Selma

Published
2024
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12. Improved survival of advanced melanoma patients receiving immunotherapy with concomitant antithrombotic therapy – A multicenter study on 2419 patients from the prospective skin cancer registry ADOReg

Author

Kött, Julian, Zell, Tim, Zimmermann, Noah, Rünger, Alessandra, Smit, Daniel J., Abeck, Finn, Geidel, Glenn, Hansen-Abeck, Inga, Heidrich, Isabel, Weichenthal, Michael, Ugurel, Selma, Leiter, Ulrike, Berking, Carola, Gutzmer, Ralf, Schadendorf, Dirk, Zimmer, Lisa, Livingstone, Elisabeth, Wasielewski, Imke von, Mohr, Peter, Meier, Friedegund, Haferkamp, Sebastian, Drexler, Konstantin, Herbst, Rudolf, Kellner, Ivonne, Utikal, Jochen, Wohlfeil, Sebastian A., Pföhler, Claudia, Adam, Leonie, Terheyden, Patrick, Ulrich, Jens, Meiss, Frank, Möbes, Monica, Welzel, Julia, Schilling, Bastian, Ziller, Fabian, Kaatz, Martin, Kreuter, Alexander, Sindrilaru, Anca, Dippel, Edgar, Sachse, Michael, Weishaupt, Carsten, Hüning, Svea, Heinzerling, Lucie, Loquai, Carmen, Schley, Gaston, Gambichler, Thilo, Löffler, Harald, Grabbe, Stephan, Schultz, Erwin, Devereux, Nina, Hassel, Jesscia C., Simon, Jan-Ch., Raap, Ulrike, Assaf, Chalid, Klemke, Claus-Detlev, Sunderkötter, Cord, Hofmann, Silke C., Wenk, Saskia, Tronnier, Michael, Thies, Silke, Heppt, Markus V., Eggermont, Alexander, Schulze, Hans-Joachim, Zouboulis, Christos C., Tüting, Thomas, Bauer, Alexander T., Schneider, Stefan W., and Gebhardt, Christoffer

Published
2025
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13. Health-Related Quality of Life with Pembrolizumab in Patients with Locally Advanced or Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma: KEYNOTE-629

Author

Bratland, Åse, Munoz-Couselo, Eva, Mortier, Laurent, Roshdy, Osama, González, Rene, Schachter, Jacob, Arance, Ana M., Grange, Florent, Meyer, Nicolas, Joshi, Abhishek Jagdish, Billan, Salem, Hughes, Brett G. M., Grob, Jean-Jacques, Ramakrishnan, Karthik, Ge, Joy, Gumuscu, Burak, Swaby, Ramona F., and Gutzmer, Ralf

Published
2023
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14. Liver-directed treatment is associated with improved survival and increased response to immune checkpoint blockade in metastatic uveal melanoma: results from a retrospective multicenter trial

Author

Koch, Elias A. T., Petzold, Anne, Wessely, Anja, Dippel, Edgar, Eckstein, Markus, Gesierich, Anja, Gutzmer, Ralf, Hassel, Jessica C., Knorr, Harald, Kreuzberg, Nicole, Leiter, Ulrike, Loquai, Carmen, Meier, Friedegund, Meissner, Markus, Mohr, Peter, Pföhler, Claudia, Rahimi, Farnaz, Schadendorf, Dirk, Schlaak, Max, Thoms, Kai-Martin, Ugurel, Selma, Utikal, Jochen, Weichenthal, Michael, Schuler-Thurner, Beatrice, Berking, Carola, and Heppt, Markus V.

Published
2023
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15. Shortened progression free and overall survival to immune-checkpoint inhibitors in BRAF-, RAS- and NF1- (“Triple”) wild type melanomas

Author

Jansen, Philipp, Galetzka, Wolfgang, Lodde, Georg C., Standl, Fabian, Zaremba, Anne, Herbst, Rudolf, Terheyden, Patrick, Utikal, Jochen, Pföhler, Claudia, Ulrich, Jens, Kreuter, Alexander, Mohr, Peter, Gutzmer, Ralf, Meier, Friedegund, Dippel, Edgar, Weichenthal, Michael, Placke, Jan-Malte, Landsberg, Jennifer, Möller, Inga, Sucker, Antje, Paschen, Annette, Hadaschik, Eva, Zimmer, Lisa, Livingstone, Elisabeth, Schadendorf, Dirk, Ugurel, Selma, Stang, Andreas, and Griewank, Klaus G.

Published
2024
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16. Anti-PD-1 alone or in combination with anti-CTLA-4 for advanced melanoma patients with liver metastases

Author

Pires da Silva, Ines, Li, Isabel, Ugurel, Selma, Serra-Bellver, Patricio, Andhale, Avanti, Burnette, Hannah, Aya, Francisco, Conway, Jordan W., Braden, Jorja, Carlino, Matteo S., Menzies, Alexander M., Weichenthal, Michael, Mohr, Peter, Gutzmer, Ralf, Arance, Ana M., Johnson, Douglas B., Lorigan, Paul, Schadendorf, Dirk, Lo, Serigne N., and Long, Georgina V.

Published
2024
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18. 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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19. Second-line therapies for steroid-refractory immune-related adverse events in patients treated with immune checkpoint inhibitors

Author

Ruf, Theresa, Kramer, Rafaela, Forschner, Andrea, Leiter, Ulrike, Meier, Friedegund, Reinhardt, Lydia, Dücker, Pia, Ertl, Carolin, Tomsitz, Dirk, Tietze, Julia K., Gutzmer, Ralf, Dabrowski, Evelyn, Zimmer, Lisa, Gesierich, Anja, Zierold, Sarah, French, Lars E., Eigentler, Thomas, Amaral, Teresa, and Heinzerling, Lucie

Published
2024
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21. Prognostic and predictive value of non-steroidal anti-inflammatory drugs in the EORTC 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma

Author

Kennedy, Oliver John, Glassee, Nina, Kicinski, Michal, Blank, Christian U., Long, Georgina V., Atkinson, Victoria G., Dalle, Stéphane, Haydon, Andrew M., Meshcheryakov, Andrey, Khattak, Adnan, Carlino, Matteo S., Sandhu, Shahneen, Larkin, James, Puig, Susana, Ascierto, Paolo A., Rutkowski, Piotr, Schadendorf, Dirk, Boers-Sonderen, Marye, Giacomo, Anna Maria Di, van den Eertwegh, Alfonsus J.M., Grob, Jean-Jacques, Gutzmer, Ralf, Jamal, Rahima, van Akkooi, Alexander C.J., Gandini, Sara, Buhrer, Emanuel, Suciu, Stefan, Robert, Caroline, Eggermont, Alexander M.M., Mandala, Mario, Lorigan, Paul, and Valpione, Sara

Published
2024
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22. 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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23. Association of antibiotic treatment with survival outcomes in treatment-naïve melanoma patients receiving immune checkpoint blockade

Author

Chorti, Eleftheria, Kowall, Bernd, Hassel, Jessica C., Schilling, Bastian, Sachse, Michael, Gutzmer, Ralf, Loquai, Carmen, Kähler, Katharina C., Hüsing, Anika, Gilde, Catharina, Thielmann, Carl M., Zaremba-Montenari, Anne, Placke, Jan-Malte, Gratsias, Emmanouil, Martaki, Anna, Roesch, Alexander, Ugurel, Selma, Schadendorf, Dirk, Livingstone, Elisabeth, Stang, Andreas, and Zimmer, Lisa

Published
2024
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24. Effects of an immunosuppressive therapy on the efficacy of immune checkpoint inhibition in metastatic melanoma – An analysis of the prospective skin cancer registry ADOREG

Author

Kochanek, Corinna, Gilde, Catharina, Zimmer, Lisa, Ugurel, Selma, Meier, Friedegund, Utikal, Jochen, Pföhler, Claudia, Herbst, Rudolf, Haferkamp, Sebastian, Welzel, Julia, Dücker, Pia, Leiter, Ulrike, Weichenthal, Michael, von Wasielewski, Imke, Angela, Yenny, and Gutzmer, Ralf

Published
2024
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26. 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, Jan-Malte, Kimmig, Mona, Griewank, Klaus, Herbst, Rudolf, Terheyden, Patrick, Utikal, Jochen, Pföhler, Claudia, Ulrich, Jens, Kreuter, Alexander, Mohr, Peter, Gutzmer, Ralf, Meier, Friedegund, Dippel, Edgar, Welzel, Julia, Engel, Daniel Robert, Kreft, Sophia, Sucker, Antje, Lodde, Georg, Krefting, Frederik, Stoffels, Ingo, Klode, Joachim, Roesch, Alexander, Zimmer, Lisa, Livingstone, Elisabeth, Hadaschik, Eva, Becker, Jürgen C., Weichenthal, Michael, Tasdogan, Alpaslan, Schadendorf, Dirk, and Ugurel, Selma

Published
2023
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27. Adjuvant immunotherapy with nivolumab versus observation in completely resected Merkel cell carcinoma (ADMEC-O): disease-free survival results from a randomised, open-label, phase 2 trial

Author

van Akkooi, Alexander, van Houdt, Winan, Wilhelm, Tabea, Farmer, Kimberley, Ulrich, Claas, Gambichler, Thilo, Bluhm, Leonie, Schinagl, Heidemarie, Kellner, Ivonne, Herbst, Rudolf, Meiß, Frank, Rafei-Shamsabadi, David, Sell, Sabine, Kaatz, Martin, Wulfken, Lena, Hartmann, Martin, Kähler, Katharina, Ziemer, Mirjana, Simon, Jan, Terheyden, Patrick, Thaci, Diamant, Loquai, Carmen, Mitzel-Rink, Heidrun, Grabbe, Stephan, Stege, Henner, Gaiser, Maria, Utikal, Jochen, Berking, Carola, Heinzerling, Lucie, Schlaak, Max, Tomsitz, Dirk, Dyballa, Jörg, Magnolo, Nina, Weishaupt, Carsten, Berneburg, Mark, Garbe, Claus, Flatz, Lukas, Gesierich, Anja, Schilling, Bastian, Becker, Jürgen C, Ugurel, Selma, Leiter, Ulrike, Meier, Friedegund, Gutzmer, Ralf, Haferkamp, Sebastian, Zimmer, Lisa, Livingstone, Elisabeth, Eigentler, Thomas K, Hauschild, Axel, Kiecker, Felix, Hassel, Jessica C, Mohr, Peter, Fluck, Michael, Thomas, Ioannis, Garzarolli, Marlene, Grimmelmann, Imke, Drexler, Konstantin, Spillner, Alexandra N, Eckhardt, Sebastian, and Schadendorf, Dirk

Published
2023
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29. Adjuvant treatment and outcome of stage III melanoma patients: Results of a multicenter real-world German Dermatologic Cooperative Oncology Group (DeCOG) study

Author

Lodde, Georg C., Hassel, Jessica, Wulfken, Lena M., Meier, Friedegund, Mohr, Peter, Kähler, Katharina, Hauschild, Axel, Schilling, Bastian, Loquai, Carmen, Berking, Carola, Hüning, Svea, Eckardt, Julia, Gutzmer, Ralf, Reinhardt, Lydia, Glutsch, Valerie, Nikfarjam, Ulrike, Erdmann, Michael, Beckmann, Catharina L., Stang, Andreas, Kowall, Bernd, Galetzka, Wolfgang, Roesch, Alexander, Ugurel, Selma, Zimmer, Lisa, Schadendorf, Dirk, Forschner, Andrea, and Livingstone, Elisabeth

Published
2023
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30. Prognostic and predictive value of metformin in the European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma

Author

Kennedy, Oliver John, Kicinski, Michal, Valpione, Sara, Gandini, Sara, Suciu, Stefan, Blank, Christian U., Long, Georgina V., Atkinson, Victoria G., Dalle, Stéphane, Haydon, Andrew M., Meshcheryakov, Andrey, Khattak, Adnan, Carlino, Matteo S., Sandhu, Shahneen, Larkin, James, Puig, Susana, Ascierto, Paolo A., Rutkowski, Piotr, Schadendorf, Dirk, Boers-Sonderen, Marye, Di Giacomo, Anna Maria, van den Eertwegh, Alfonsus J.M., Grob, Jean-Jacques, Gutzmer, Ralf, Jamal, Rahima, van Akkooi, Alexander C.J., Robert, Caroline, Eggermont, Alexander M.M., Lorigan, Paul, and Mandala, Mario

Published
2023
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31. Immune checkpoint inhibition in patients with NRAS mutated and NRAS wild type melanoma: a multicenter Dermatologic Cooperative Oncology Group study on 637 patients from the prospective skin cancer registry ADOREG

Author

Zaremba, Anne, Mohr, Peter, Gutzmer, Ralf, Meier, Friedegund, Pföhler, Claudia, Weichenthal, Michael, Terheyden, Patrick, Forschner, Andrea, Leiter, Ulrike, Ulrich, Jens, Utikal, Jochen, Welzel, Julia, Kaatz, Martin, Gebhardt, Christoffer, Herbst, Rudolf, Sindrilaru, Anca, Dippel, Edgar, Sachse, Michael, Meiss, Frank, Heinzerling, Lucie, Haferkamp, Sebastian, Weishaupt, Carsten, Löffler, Harald, Kreft, Sophia, Griewank, Klaus, Livingstone, Elisabeth, Schadendorf, Dirk, Ugurel, Selma, and Zimmer, Lisa

Published
2023
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32. Association of baseline systemic corticosteroid use with overall survival and time to next treatment in patients receiving immune checkpoint inhibitor therapy in real-world US oncology practice for advanced non-small cell lung cancer, melanoma, or urothelial carcinoma.

Author

Drakaki, Alexandra, Dhillon, Preet, Wakelee, Heather, Chui, Stephen, Shim, Jinjoo, Kent, Matthew, Degaonkar, Viraj, Hoang, Tien, McNally, Virginia, Luhn, Patricia, and Gutzmer, Ralf

Subjects
Checkpoint inhibitors, corticosteroids, melanoma, non-small cell lung cancer, urothelial cancer, Adrenal Cortex Hormones, Adult, Carcinoma, Non-Small-Cell Lung, Carcinoma, Transitional Cell, Humans, Immune Checkpoint Inhibitors, Lung Neoplasms, Melanoma, Retrospective Studies, Urinary Bladder Neoplasms
Abstract

Immune checkpoint inhibitors (CPIs) have expanded treatment options for patients with solid tumors. Systemic corticosteroids (CSs) have an indispensable role in cancer care, but CS-related immunosuppression may counteract the CPI-driven antitumor immune response. This retrospective study investigated the association between baseline CS use (bCS; ≤14 days before, ≤30 days after CPI initiation) and clinical outcomes in patients with advanced non-small cell lung cancer (aNSCLC), melanoma (aMel), or urothelial carcinoma (aUC). We analyzed data from the Flatiron Health electronic health record-derived de-identified database for adults diagnosed with aNSCLC, aMel, or aUC between January 2011 and June 2017 who received ≥1 CPI monotherapy in any treatment line. Associations of bCS use with overall survival (OS) and time to next treatment (TTNT) were estimated using multivariable Cox proportional hazards models adjusting for demographic and clinical characteristics (i.e., ECOG performance status, site of metastases). In total, 2,213 patients were diagnosed with aNSCLC (n = 862), aMel (n = 742), or aUC (n = 609) and received ≥1 CPI administration. Most patients (67%-95%) received CSs, many during the baseline period (19%-30%). Patients with bCS use had shorter median OS than those with no bCS use for aNSCLC (6.6 vs 10.6 months; P= .00018), aMel (16.4 vs 21.5; P= .095), and aUC (4.1 vs 7.7; P= .0012). bCS use was associated with shorter OS (not significant for aMel) and TTNT in adjusted multivariable analyses, and clinical outcomes were not explained by prior CS use or other measured confounders. These findings suggest a potential association between bCS use and decreased CPI effectiveness, warranting further investigation.

Published
2020

33. Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib monotherapy: Analysis from phase 2 and 3 clinical trials

Author

Hauschild, Axel, Ascierto, Paolo A, Schadendorf, Dirk, Grob, Jean Jacques, Ribas, Antoni, Kiecker, Felix, Dutriaux, Caroline, Demidov, Lev V, Lebbé, Céleste, Rutkowski, Piotr, Blank, Christian U, Gutzmer, Ralf, Millward, Michael, Kefford, Richard, Haas, Tomas, D'Amelio, Anthony, Gasal, Eduard, Mookerjee, Bijoyesh, and Chapman, Paul B

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Clinical Research, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Dacarbazine, Disease Progression, Female, Follow-Up Studies, Humans, Imidazoles, Male, Melanoma, Middle Aged, Oximes, Patient Selection, Progression-Free Survival, Proto-Oncogene Proteins B-raf, Skin Neoplasms, Time Factors, Young Adult, BRAF, Dabrafenib, Metastatic, Long-term outcomes, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundPrevious analyses of BREAK-2 and BREAK-3 showed that durable outcomes lasting ≥3 years are achievable with dabrafenib in some patients with BRAF V600-mutant metastatic melanoma (MM); however, additional follow-up is needed to fully characterise the long-term impact of dabrafenib in these patients.MethodsBREAK-2 was a single-arm phase 2 study evaluating dabrafenib in treatment-naive or previously treated BRAF V600E/K-mutant MM. BREAK-3, a randomised (3:1) phase 3 study, assessed dabrafenib versus dacarbazine in previously untreated unresectable or metastatic BRAF V600E-mutant melanoma. Five-year analyses were performed.ResultsAll BREAK-2 patients (N = 92 [V600E, n = 76; V600K, n = 16]) discontinued treatment by the data cutoff. Median follow-up was 13.0 months. In BRAF V600E patients, 5-year progression-free survival (PFS) and overall survival (OS) were 11% and 20%, respectively. Subsequent immunotherapy was received by 22% of patients. In BREAK-3, median follow-up was 17.0 and 12.0 months in the dabrafenib (n = 187) and dacarbazine (n = 63) arms, respectively. Thirty-seven patients (59%) receiving dacarbazine crossed over to dabrafenib following disease progression as per protocol. Five-year PFS was 12% in the dabrafenib arm; all dacarbazine-arm patients progressed or were censored by 5 years. Dabrafenib improved PFS versus dacarbazine, regardless of baseline lactate dehydrogenase levels. Five-year OS rates were 24% and 22% in the dabrafenib and dacarbazine arms, respectively. Subsequent therapy in each arm included anti-CTLA-4 (dabrafenib [24%] and dacarbazine [24%]) and/or anti-PD-1 (8% and 2%) treatment. No new safety signals were observed.Conclusions and relevanceThese data, representing extended follow-up for dabrafenib monotherapy, demonstrate that durable benefit lasting ≥5 years is achievable in a subset of patients.Trial registrationClinicalTrials.gov (BREAK-2, NCT01153763; BREAK-3, NCT01227889).

Published
2020

34. Characterisation and outcome of RAC1 mutated melanoma

Author

Lodde, Georg C., Jansen, Philipp, Herbst, Rudolf, Terheyden, Patrick, Utikal, Jochen, Pföhler, Claudia, Ulrich, Jens, Kreuter, Alexander, Mohr, Peter, Gutzmer, Ralf, Meier, Friedegund, Dippel, Edgar, Weichenthal, Michael, Sucker, Antje, Placke, Jan-Malte, Zaremba, Anne, Albrecht, Lea Jessica, Kowall, Bernd, Galetzka, Wolfgang, Becker, Jürgen C., Tasdogan, Alpaslan, Zimmer, Lisa, Livingstone, Elisabeth, Hadaschik, Eva, Schadendorf, Dirk, Ugurel, Selma, and Griewank, Klaus

Published
2023
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35. German S3 guideline “actinic keratosis and cutaneous squamous cell carcinoma” – Long version of the update 2023

Author

Leiter, Ulrike, Heppt, Markus V., Steeb, Theresa, Alter, Mareike, Amaral, Teresa, Bauer, Andrea, Bechara, Falk G., Becker, Jürgen C., Breitbart, Eckhard W., Breuninger, Helmut, Diepgen, Thomas, Dirschka, Thomas, Eigentler, Thomas, El Gammal, A.K. Stephan, Felcht, Moritz, Flaig, Michael J., Follmann, Markus, Fritz, Klaus, Grabbe, Stephan, Greinert, Rüdiger, Gutzmer, Ralf, Hauschild, Axel, Hillen, Uwe, Ihrler, Stephan, John, Swen Malte, Kofler, Lukas, Koelbl, Oliver, Krause-Bergmann, Albrecht, Kraywinkel, Klaus, Krohn, Steffen, Langer, Thomas, Loquai, Carmen, Löser, Christoph R., Mohr, Peter, Nashan, Dorothée, Nothacker, Monika, Pfannenberg, Christina, Salavastru, Carmen, Schmitz, Lutz, Stockfleth, Eggert, Szeimies, Rolf-Markus, Ulrich, Claas, Voelter-Mahlknecht, Susanne, Vordermark, Dirk, Weichenthal, Michael, Welzel, Julia, Wermker, Kai, Wiegand, Susanne, Garbe, Claus, and Berking, Carola

Published
2023
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36. Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study

Author

Ascierto, Paolo A, Stroyakovskiy, Daniil, Gogas, Helen, Robert, Caroline, Lewis, Karl, Protsenko, Svetlana, Pereira, Rodrigo P, Eigentler, Thomas, Rutkowski, Piotr, Demidov, Lev, Zhukova, Natalia, Schachter, Jacob, Yan, Yibing, Caro, Ivor, Hertig, Christian, Xue, Cloris, Kusters, Lieke, McArthur, Grant A, and Gutzmer, Ralf

Published
2023
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37. Adjuvant nivolumab plus ipilimumab or nivolumab alone versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): final results of a randomised, double-blind, phase 2 trial

Author

Livingstone, Elisabeth, Zimmer, Lisa, Hassel, Jessica C, Fluck, Michael, Eigentler, Thomas K, Loquai, Carmen, Haferkamp, Sebastian, Gutzmer, Ralf, Meier, Friedegund, Mohr, Peter, Hauschild, Axel, Schilling, Bastian, Menzer, Christian, Kiecker, Felix, Dippel, Edgar, Roesch, Alexander, Ziemer, Mirjana, Conrad, Beate, Körner, Silvia, Simon, Jan-Christoph, Herbst, Rudolf A, Berking, Carola, Utikal, Jochen, Sell, Sabine, Martens, Uwe M, Terheyden, Patrick, Stadler, Rudolf, Windemuth-Kieselbach, Christine, Schwarz, Leonora, Garbe, Claus, Becker, Jürgen C, and Schadendorf, Dirk

Published
2022
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39. Influence of adjuvant therapies on organ‐specific recurrence of cutaneous melanoma: A multicenter study on 1383 patients of the prospective DeCOG registry ADOReg.

Author

Wohlfeil, Sebastian A., Kranzmann, Leonie, Weiß, Christel, von Wasielewski, Imke, Klespe, Kai C., Kähler, Katharina C., Weichenthal, Michael, Schadendorf, Dirk, Zimmer, Lisa, Mohr, Peter, Meier, Friedegund, Pfoehler, Claudia, Berking, Carola, Heppt, Markus V., Herbst, Rudolf, Kreuter, Alexander, Gutzmer, Ralf, Ulrich, Jens, Meiss, Frank, and Gebhardt, Christoffer

Subjects
IMMUNE checkpoint inhibitors, SKIN cancer, IMMUNOLOGICAL adjuvants, OVERALL survival, NIVOLUMAB
Abstract

This study investigated whether adjuvant treatments in stage III cutaneous melanoma (CM) influenced patterns of recurrence. Patients with primary (n = 1033) or relapsed CM (n = 350) who received adjuvant therapies with Nivolumab (N), Pembrolizumab (P), or Dabrafenib and Trametinib (D + T) were extracted from the prospective multicenter real‐world skin cancer registry ADOReg. Endpoints were progression‐free survival (PFS), distant metastasis‐free survival (DMFS), organ‐specific DMFS, and overall survival (OS). For primary cases, D + T indicated an improved PFS (1‐ and 2‐year PFS: 90.9%; 82.7%) as compared to P (81.0%, 73.9%; p =.0208), or N (83.8%, 75.2%; p =.0539). BRAF‐mutated(mut) CM demonstrated significantly lower PFS (p =.0022) and decreased DMFS (p =.0580) when treated with immune checkpoint inhibitor (ICI) instead of D + T. Besides, NRAS‐mut CM tended to perform worse than wt CM upon ICI (PFS: p =.1349; DMFS: p =.0540). OS was similar between the groups. Relapsed cases showed decreased PFS, DMFS, and OS in comparison to primary (all: p <.001), without significant differences between the subgroups. Organ‐specific DMFS was significantly altered for primary cases with bone (p =.0367) or brain metastases (p =.0202). In relapsed CM, the frequency of liver (D + T: 1.5%; P: 12%; N: 9%) and LN metastases (D + T: 1.5%; P: 12%; N: 10.2%) was significantly lower with adjuvant D + T than ICI. NRAS‐mut CM showed increased recurrence in primary and relapsed cases. These data show that adjuvant D + T is superior to ICI in primary BRAF‐mut CM. [ABSTRACT FROM AUTHOR]

Published
2024
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40. Histamine and Th2 cytokines independently and synergistically upregulate MMP12 expression in human M2 macrophages.

Author

da Fonseca, Alice Pereira, Traidl, Stephan, Gutzmer, Ralf, Schaper-Gerhardt, Katrin, Werfel, Thomas, and Mommert, Susanne

Subjects
TH2 cells, MATRIX metalloproteinases, GENE expression, ATOPIC dermatitis, RNA sequencing
Abstract

Beyond Th2 cells and various immune cells, M2 macrophages have been identified in lesional skin of atopic dermatitis (AD) indicating their involvement in the disease's underlying mechanisms. MMP12, a matrix-degrading enzyme, which is predominantly produced by macrophages, is increased in skin lesions of AD patients. In this study we investigated the expression of MMP12 mRNA in lesional AD skin at single cell level through RNA sequencing (scRNA-seq) and the expression of MMP12 in M2 macrophages from healthy individuals and AD patients in response to Th2 cytokines and histamine using quantitative PCR and ELISA. Additionally, we analyzed macrophages from dupilumab-treated AD patients using the same methods to assess the influence of Th2 cytokines on MMP12 expression ex-vivo. ScRNA-seq identified macrophages as the primary producers of MMP12 in lesional AD skin. In-vitro, both MMP12 mRNA and protein expression were significantly increased in monocytes during differentiation to M2 macrophages in the presence of histamine, of Th2 cytokines or of Th2 cytokines in combination with histamine. In M2 macrophages obtained from dupilumabtreated AD patients, the upregulation of MMP12 expression by IL-4 and IL-13 was attenuated. Our findings unveil a novel mechanism whereby Th2 cytokines and histamine regulate MMP12 expression, potentially impacting skin barrier homeostasis in AD. [ABSTRACT FROM AUTHOR]

Published
2024
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41. Nanopore Sequencing for T-Cell Receptor Rearrangement Analysis in Cutaneous T-Cell Lymphoma.

Author

Cieslak, Cassandra, Hain, Carsten, Rückert-Reed, Christian, Busche, Tobias, Klages, Levin Joe, Schaper-Gerhardt, Katrin, Gutzmer, Ralf, Kalinowski, Jörn, and Stadler, Rudolf

Subjects
T-cell lymphoma, T cells, GENOMICS, DESCRIPTIVE statistics, MYCOSIS fungoides, SEZARY syndrome, CUTANEOUS T-cell lymphoma, BIOINFORMATICS, SEQUENCE analysis
Abstract

Simple Summary: Precise analysis of T-cell receptor clonality is essential in lymphoma diagnostics, particularly for cutaneous T-cell lymphomas like Mycosis fungoides (MF) and Sézary Syndrome (SS). The current gold standard, based on next generation sequencing (NGS), is precise and accurate but time- and cost-intensive. This study established a workflow for the analysis of the T-cell receptor repertoire using third generation nanopore sequencing. Results are similarly accurate to NGS for cutaneous T-cell lymphoma, but less time-consuming and cost-intensive. Background: Analysis of T-cell receptor (TCR) clonality is a major diagnostic tool for lymphomas, particularly for cutaneous T-cell lymphomas (CTCL) like Mycosis fungoides and Sézary syndrome. However, a fast and cost-effective workflow is needed to enable widespread use of this method. Methods: We established a procedure for TCR rearrangement analysis via Oxford Nanopore Technology (ONT) sequencing. TCR receptor rearrangements (TCR-gamma and TCR-beta chains) were analyzed in samples from 45 patients with various diagnoses: Mycosis fungoides (37/45), Sézary Syndrome (2/45), folliculotropic CTCL (1/45), and non-CTCL diagnoses as polyclonal controls (5/45). Sample types included formalin-fixed paraffin-embedded (FFPE) samples (27/45), fresh frozen samples (9/45), and CD3-isolated cells (9/45). In addition, DNA of a Jurkat cell line was used as a monoclonal control. TCR amplicons were generated employing an optimized version of the protocol from the Euro Clonality consortium. Sequencing was conducted on the ONT GridION and Illumina MiSeq platforms, followed by similar bioinformatic analysis protocols. The tumor clone frequency (TCF), a crucial prognostic factor for CTCL patients, was used for method comparison. Results: The use of an optimized amplicon protocol and adapted bioinformatic tools demonstrated a strong correlation in TCF values between both sequencing methods across all sample types (range R: 0.992–0.996; range r2: 0.984–0.991). Conclusions: In summary, ONT sequencing was able to detect TCR clonality comparable to NGS, indicating its potential as a faster and more cost-effective option for routine diagnostic use. [ABSTRACT FROM AUTHOR]

Published
2024
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42. Situation klinischer Studien in Deutschland – ein interdisziplinäres Positionspapier

Author

Grünwald, Viktor, Bethge, Wolfgang, Blohmer, Jens-Uwe, Burkhardt, Birgit, Dirksen, Uta, Ebert, Matthias, Gschwend, Jürgen, Gutzmer, Ralf, Henn, Doris, Hermann, Ken, Isbary, Georg, Klußmann, Jens Peter, Knauf, Wolfgang, Krause, Mechthild, Luntz, Steffen, Paradies, Kerstin, Piso, Pompiliu, Ryll, Bettina, Schmidt, Georg, Sinn, Marianne, Stintzing, Sebastian, Wedding, Ulrich, Wesselmann, Simone, and Reinacher-Schick, Anke

Published
2022
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43. Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator’s Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial

Author

Larkin, James, Minor, David, D'Angelo, Sandra, Neyns, Bart, Smylie, Michael, Miller, Wilson H, Gutzmer, Ralf, Linette, Gerald, Chmielowski, Bartosz, Lao, Christopher D, Lorigan, Paul, Grossmann, Kenneth, Hassel, Jessica C, Sznol, Mario, Daud, Adil, Sosman, Jeffrey, Khushalani, Nikhil, Schadendorf, Dirk, Hoeller, Christoph, Walker, Dana, Kong, George, Horak, Christine, and Weber, Jeffrey

Subjects
Clinical Trials and Supportive Activities, Cancer, Patient Safety, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Administration, Intravenous, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological, Antineoplastic Combined Chemotherapy Protocols, Carboplatin, Dacarbazine, Disease Progression, Drug Administration Schedule, Female, Humans, Male, Melanoma, Middle Aged, Nivolumab, Paclitaxel, Progression-Free Survival, Skin Neoplasms, Time Factors, Young Adult, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Purpose Until recently, limited options existed for patients with advanced melanoma who experienced disease progression while receiving treatment with ipilimumab. Here, we report the coprimary overall survival (OS) end point of CheckMate 037, which has previously shown that nivolumab resulted in more patients achieving an objective response compared with chemotherapy regimens in ipilimumab-refractory patients with advanced melanoma. Patients and Methods Patients were stratified by programmed death-ligand 1 expression, BRAF status, and best prior cytotoxic T-lymphocyte antigen-4 therapy response, then randomly assigned 2:1 to nivolumab 3 mg/kg intravenously every 2 weeks or investigator's choice chemotherapy (ICC; dacarbazine 1,000 mg/m2 every 3 weeks or carboplatin area under the curve 6 plus paclitaxel 175 mg/m2 every 3 weeks). Patients were treated until they experienced progression or unacceptable toxicity, with follow-up of approximately 2 years. Results Two hundred seventy-two patients were randomly assigned to nivolumab (99% treated) and 133 to ICC (77% treated). More nivolumab-treated patients had brain metastases (20% v 14%) and increased lactate dehydrogenase levels (52% v 38%) at baseline; 41% of patients treated with ICC versus 11% of patients treated with nivolumab received anti-programmed death 1 agents after randomly assigned therapy. Median OS was 16 months for nivolumab versus 14 months for ICC (hazard ratio, 0.95; 95.54% CI, 0.73 to 1.24); median progression-free survival was 3.1 months versus 3.7 months, respectively (hazard ratio, 1.0; 95.1% CI, 0.78 to 1.436). Overall response rate (27% v 10%) and median duration of response (32 months v 13 months) were notably higher for nivolumab versus ICC. Fewer grade 3 and 4 treatment-related adverse events were observed in patients on nivolumab (14% v 34%). Conclusion Nivolumab demonstrated higher, more durable responses but no difference in survival compared with ICC. OS should be interpreted with caution as it was likely impacted by an increased dropout rate before treatment, which led to crossover therapy in the ICC group, and by an increased proportion of patients in the nivolumab group with poor prognostic factors.

Published
2018

45. Optimizing immune checkpoint blockade in metastatic uveal melanoma: exploring the association of overall survival and the occurrence of adverse events

Author

Koch, Elias A. T., primary, Petzold, Anne, additional, Dippel, Edgar, additional, Erdmann, Michael, additional, Gesierich, Anja, additional, Gutzmer, Ralf, additional, Hassel, Jessica C., additional, Haferkamp, Sebastian, additional, Kähler, Katharina C., additional, Kreuzberg, Nicole, additional, Leiter, Ulrike, additional, Loquai, Carmen, additional, Meier, Friedegund, additional, Meissner, Markus, additional, Mohr, Peter, additional, Pföhler, Claudia, additional, Rahimi, Farnaz, additional, Schell, Beatrice, additional, Terheyden, Patrick, additional, Thoms, Kai-Martin, additional, Ugurel, Selma, additional, Ulrich, Jens, additional, Utikal, Jochen, additional, Weichenthal, Michael, additional, Ziller, Fabian, additional, Berking, Carola, additional, and Heppt, Markus V., additional

Published
2024
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46. 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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47. Characteristics of hospital admission during checkpoint-inhibition therapy.

Author

Fröhlich, Tabea Constanze, primary, Wiegmann, Jonas Paul, additional, Möhn, Nora, additional, Mahjoub, Susann, additional, Duzzi, Laura, additional, Narte, Emily, additional, Aurich, Johanna, additional, Berliner, Dominik, additional, Wirth, Thomas, additional, Golpon, Heiko, additional, von Wasielewski, Imke, additional, Heidel, Florian, additional, Skripuletz, Thomas, additional, Gutzmer, Ralf, additional, Beutel, Gernot, additional, and Ivanyi, Philipp, additional

Published
2024
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48. Anti-PD-1 alone or in combination with anti-CTLA-4 for advanced melanoma patients with liver metastases.

Author

da Silva, Ines Pires, primary, Li, Isabel, additional, Ugurel, Selma, additional, Serra-Bellver, Patricio, additional, Andhale, Avanti, additional, Burnette, Hannah, additional, Aya, Francisco, additional, Conway, Jordan W., additional, Braden, Jorja, additional, Carlino, Matteo S., additional, Menzies, Alexander M., additional, Weichenthal, Michael, additional, Mohr, Peter, additional, Gutzmer, Ralf, additional, Arance, Ana M., additional, Johnson, Douglas B., additional, Lorigan, Paul, additional, Schadendorf, Dirk, additional, Lo, Serigne N, additional, and Long, Georgina V., additional

Published
2024
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