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1. 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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2. 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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3. 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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4. 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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5. 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

6. 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

8. Nivolumab plus ipilimumab in melanoma patients with asymptomatic brain metastases: 7-year outcomes and quality of life from the multicenter phase III NIBIT-M2 trial

Author

Di Giacomo, Anna Maria, Chiarion-Sileni, Vanna, Del Vecchio, Michele, Ferrucci, Pier Francesco, Guida, Michele, Quaglino, Pietro, Guidoboni, Massimo, Marchetti, Paolo, Simonetti, Elena, Santangelo, Federica, Amato, Giovanni, Covre, Alessia, Camerini, Roberto, Valente, Monica, Mandalà, Mario, Giannarelli, Diana, Calabrò, Luana, and Maio, Michele

Published
2024
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10. KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma

Author

Ferrucci, Pier Francesco, Di Giacomo, Anna Maria, Del Vecchio, Michele, Atkinson, Victoria, Schmidt, Henrik, Schachter, Jacob, Queirolo, Paola, Long, Georgina V, Stephens, Rosalie, Svane, Inge Marie, Lotem, Michal, Abu-Amna, Mahmoud, Gasal, Eduard, Ghori, Razi, Diede, Scott J, Croydon, Elizabeth S, Ribas, Antoni, and Ascierto, Paolo Antonio

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Trials and Supportive Activities, Clinical Research, Cancer, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Double-Blind Method, Female, Humans, Imidazoles, Male, Melanoma, Oximes, Pyridones, Pyrimidinones, Survival Analysis, drug therapy, combination, immunotherapy, melanoma, programmed cell death 1 receptor, KEYNOTE-022 international team, Immunology, Oncology and carcinogenesis
Abstract

In the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progression-free survival (PFS) versus placebo with dabrafenib and trametinib (doublet) without reaching statistical significance. Mature results on PFS, duration of response (DOR), and overall survival (OS) are reported. The double-blind, phase 2 part of KEYNOTE-022 enrolled patients with previously untreated BRAFV600E/K-mutated advanced melanoma from 22 sites in seven countries. Patients were randomly assigned 1:1 to intravenous pembrolizumab (200 mg every 3 weeks) or placebo plus dabrafenib (150 mg orally two times per day) and trametinib (2 mg orally one time a day). Primary endpoint was PFS. Secondary endpoints were objective response rate, DOR, and OS. Efficacy was assessed in the intention-to-treat population, and safety was assessed in all patients who received at least one dose of study drug. This analysis was not specified in the protocol. Between November 30, 2015 and April 24, 2017, 120 patients were randomly assigned to triplet (n=60) or doublet (n=60) therapy. With 36.6 months of follow-up, median PFS was 16.9 months (95% CI 11.3 to 27.9) with triplet and 10.7 months (95% CI 7.2 to 16.8) with doublet (HR 0.53; 95% CI 0.34 to 0.83). With triplet and doublet, respectively, PFS at 24 months was 41.0% (95% CI 27.4% to 54.2%) and 16.3% (95% CI 8.1% to 27.1%); median DOR was 25.1 months (95% CI 14.1 to not reached) and 12.1 months (95% CI 6.0 to 15.7), respectively. Median OS was not reached with triplet and was 26.3 months with doublet (HR 0.64; 95% CI 0.38 to 1.06). With triplet and doublet, respectively, OS at 24 months was 63.0% (95% CI 49.4% to 73.9%) and 51.7% (95% CI 38.4% to 63.4%). Grade 3-5 treatment-related adverse events (TRAEs) occurred in 35 patients (58%, including one death) receiving triplet and 15 patients (25%) receiving doublet. In BRAFV600E/K-mutant advanced melanoma, pembrolizumab plus dabrafenib and trametinib substantially improved PFS, DOR, and OS with a higher incidence of TRAEs. Interpretation of these results is limited by the post hoc nature of the analysis.

Published
2020

12. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial

Author

Lesimple, Thierry, Maio, Michele, Linette, Gerald, Mortier, Laurent, Svane, Inge Marie, Schachter, Jacob, Brown, Michael, Hersey, Peter, Barrow, Catherine, Kudchadkar, Ragini, Dutriaux, Caroline, Song, Xinni, Quaglino, Pietro, Queirolo, Paola, Meier, Friedegund, Stroyakovskiy, Daniil, Guillot, Bernard, Romero, Pablo Luis Ortiz, Bastholt, Lars, Garbe, Claus, Grange, Florent, Mohr, Peter, Algazi, Alain, Bechter, Oliver, Hernberg, Micaela, Loquai, Carmen, Meiss, Frank, Chiarion Sileni, Vanna, Bar-Sela, Gil, Fitzharris, Bernard, Saiag, Philippe, Arnault, Jean-Philippe, Simon, Jan-Christoph, Stephens, Rosalie, Baurain, Jean-Francois, Lebbe, Célèste, Combemale, Patrick, Dummer, Reinhard, Hauschild, Axel, Parente, Phillip, Yamazaki, Naoya, Milhem, Mohammed, Leccia, Marie-Thérèse, Geoffrois, Lionel, Kretschmer, Lutz, Dunwoodie, Elaine, Walker, John, Lotem, Michal, Hendler, Daniel, Mackiewicz, Andrzej, Sekulovic, Lidija, Dzienis, Marcin, Hospers, Geke A.P., Siano, Marco, Hassel, Jessica, Corrie, Philippa, Passos, Maria-Jose, Levin, Max, Hoeller, Christoph, Machet, Laurent, Hallmeyer, Sigrun, Waterston, Ashita, Descamps, Vincent, Kiecker, Felix, Aarts, Maureen, Schmidt, Henrik, Raimundo, Ana, Nyakas, Marta, Lacour, Jean-Philippe, Berking, Carola, Ferrucci, Pier Francesco, Jameson, Michael, Kim, Kevin, Yokota, Kenji, Kerger, Joseph, Aubin, François, Groenewegen, Gerard, Kapiteijn, Helena, Boehncke, Wolf-Henning, Utikal, Jochen, Casasola, Richard, Marshall, Ernest, Ferraresi, Virginia, Richtig, Erika, Matkovic, Suzana, Inozume, Takashi, Crook, Timothy, McNeil, Catriona, Kiyohara, Yoshio, Avril, Marie-Francoise, Hein, Rüdiger, Terheyden, Patrick, Nathan, Paul, Aoi, Jun, Skytta, Tanja, Jouary, Thomas, Takenouchi, Tatsuya, Straume, Oddbjorn, Martins, César, Mukhametshina, Guzel, Bottomley, Andrew, Coens, Corneel, Mierzynska, Justyna, Blank, Christian U, Mandalà, Mario, Long, Georgina V, Atkinson, Victoria G, Dalle, Stéphane, Haydon, Andrew M, Meshcheryakov, Andrey, Khattak, Adnan, Carlino, Matteo S, Sandhu, Shahneen, Puig, Susana, Ascierto, Paolo A, Larkin, James, Lorigan, Paul C, Rutkowski, Piotr, Schadendorf, Dirk, Koornstra, Rutger, Hernandez-Aya, Leonel, Di Giacomo, Anna Maria, van den Eertwegh, Alfonsus J M, Grob, Jean-Jacques, Gutzmer, Ralf, Jamal, Rahima, van Akkooi, Alexander C J, Krepler, Clemens, Ibrahim, Nageatte, Marreaud, Sandrine, Kicinski, Michal, Suciu, Stefan, Robert, Caroline, and Eggermont, Alexander M M

Published
2021
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13. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial

Author

Menzies, Alex, Lesimple, Thierry, Maio, Michele, Linette, Gerald, Brown, Michael, Hersey, Peter, Svane, Inge Marie, Mortier, Laurent, Schachter, Jacob, Barrow, Catherine, Kudchadkar, Ragini, Song, Xinni, Dutriaux, Caroline, Quaglino, Pietro, Meier, Friedegund, Queirolo, Paola, Stroyakovskiy, Daniil, Bastholt, Lars, Guillot, Bernard, Garbe, Claus, Ortiz Romero, Pablo Luis, Grange, Florent, Mohr, Peter, Algazi, Alain, Bechter, Oliver, Hernberg, Micaela, Arnault, Jean-Philippe, Saiag, Philippe, Loquai, Carmen, Meiss, Frank, Simon, Jan-Christoph, Bar-Sela, Gil, Chiarion Sileni, Vanna, Fitzharris, Bernard, McCrystal, Mike, Parente, Phillip, Baurain, Jean-Francois, Combemale, Patrick, Lebbe, Célèste, Hauschild, Axel, Yamazaki, Naoya, Dummer, Reinhard, Milhem, Mohammed, Dzienis, Marcin, Walker, John, Geoffrois, Lionel, Leccia, Marie-Thérèse, Kretschmer, Lutz, Hendler, Daniel, Lotem, Michal, Mackiewicz, Andrzej, Sekulovic, Lidija, Dunwoodie, Elaine, Hoeller, Christoph, Machet, Laurent, Hassel, Jessica, Hospers, Geke A.P., Passos, Maria-Jose, Levin, Max, Fehr, Martin, Corrie, Philippa, Waterston, Ashita, Hallmeyer, Sigrun, Schmidt, Henrik, Descamps, Vincent, Lacour, Jean-Philippe, Berking, Carola, Kiecker, Felix, Ferrucci, Pier Francesco, Yokota, Kenji, Aarts, Maureen, Jameson, Michael, Winge-Main, Anna Katharina, Ferreira, Paula, Kim, Kevin, McNeil, Catriona, Hofmann-Wellenhof, Reiner, Kerger, Joseph, Aubin, François, Utikal, Jochen, Ferraresi, Virginia, Inozume, Takashi, Kiyohara, Yoshio, Groenewegen, Gerard, Kapiteijn, Helena, Matkovic, Suzana, Boehncke, Wolf-Henning, Casasola, Richard, Crook, Timothy, Marshall, Ernest, Skytta, Tanja, Avril, Marie-Francoise, Jouary, Thomas, Hein, Rüdiger, Terheyden, Patrick, Aoi, Jun, Takenouchi, Tatsuya, Straume, Oddbjorn, Martins, César, Mukhametshina, Guzel, Nathan, Paul, Eggermont, Alexander M M, Blank, Christian U, Mandalà, Mario, 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, Koornstra, Rutger, Hernandez-Aya, Leonel, Di Giacomo, Anna Maria, van den Eertwegh, Alfonsus J M, Grob, Jean-Jacques, Gutzmer, Ralf, Jamal, Rahima, Lorigan, Paul C, van Akkooi, Alexander C J, Krepler, Clemens, Ibrahim, Nageatte, Marreaud, Sandrine, Kicinski, Michal, Suciu, Stefan, and Robert, Caroline

Published
2021
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14. 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; https://orcid.org/0000-0002-8322-475X, Casula, Milena, Bulgarelli, Jenny; https://orcid.org/0000-0002-6551-0189, Pisano, Marina, Piccinini, Claudia, Piccin, Luisa, Cossu, Antonio, Mandalà, Mario; https://orcid.org/0000-0001-8846-8959, Ferrucci, Pier Francesco; https://orcid.org/0000-0001-6255-5851, Guidoboni, Massimo; https://orcid.org/0000-0001-7703-790X, Rutkowski, Piotr; https://orcid.org/0000-0002-8920-5429, Ferraresi, Virginia, Arance, Ana; https://orcid.org/0000-0003-2896-1957, Guida, Michele, Maiello, Evaristo, Gogas, Helen; https://orcid.org/0000-0002-0451-2885, Richtig, Erika; https://orcid.org/0000-0002-5505-6103, Fierro, Maria Teresa, Lebbe, Celeste; https://orcid.org/0000-0002-5854-7290, Helgadottir, Hildur, Queirolo, Paola, Spagnolo, Francesco, Tucci, Marco, Del Vecchio, Michele, Cao, Maria Gonzales; https://orcid.org/0000-0003-3791-540X, Minisini, Alessandro Marco, De Placido, Sabino, Sanmamed, Miguel F; https://orcid.org/0000-0002-7295-6074, Mallardo, Domenico; https://orcid.org/0000-0002-1081-5313, Dummer, Reinhard; https://orcid.org/0000-0002-2279-6906, et al, Ascierto, Paolo A; https://orcid.org/0000-0002-8322-475X, Casula, Milena, Bulgarelli, Jenny; https://orcid.org/0000-0002-6551-0189, Pisano, Marina, Piccinini, Claudia, Piccin, Luisa, Cossu, Antonio, Mandalà, Mario; https://orcid.org/0000-0001-8846-8959, Ferrucci, Pier Francesco; https://orcid.org/0000-0001-6255-5851, Guidoboni, Massimo; https://orcid.org/0000-0001-7703-790X, Rutkowski, Piotr; https://orcid.org/0000-0002-8920-5429, Ferraresi, Virginia, Arance, Ana; https://orcid.org/0000-0003-2896-1957, Guida, Michele, Maiello, Evaristo, Gogas, Helen; https://orcid.org/0000-0002-0451-2885, Richtig, Erika; https://orcid.org/0000-0002-5505-6103, Fierro, Maria Teresa, Lebbe, Celeste; https://orcid.org/0000-0002-5854-7290, Helgadottir, Hildur, Queirolo, Paola, Spagnolo, Francesco, Tucci, Marco, Del Vecchio, Michele, Cao, Maria Gonzales; https://orcid.org/0000-0003-3791-540X, Minisini, Alessandro Marco, De Placido, Sabino, Sanmamed, Miguel F; https://orcid.org/0000-0002-7295-6074, Mallardo, Domenico; https://orcid.org/0000-0002-1081-5313, Dummer, Reinhard; https://orcid.org/0000-0002-2279-6906, and et al

Abstract

No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy.

Published
2024

17. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma

Author

Ascierto, Paolo Antonio, Ferrucci, Pier Francesco, Fisher, Rosalie, Del Vecchio, Michele, Atkinson, Victoria, Schmidt, Henrik, and Schachter, Jacob

Subjects
Drug therapy, Combination -- Testing, Melanoma -- Drug therapy, Biological sciences, Health
Abstract

Blocking programmed death 1 (PD-1) may enhance the durability of anti-tumor responses that are induced by the combined inhibition of BRAF and MEK.sup.1. Here we performed a randomized phase 2 trial ((https://clinicaltrials.gov/ct2/show/NCT02130466)), in which patients with treatment-naive BRAF.sup.V600E/K-mutant, advanced melanoma received the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib together with the PD-1-blocking antibody pembrolizumab (triplet; n = 60) or placebo (doublet; n = 60). The primary end point of progression-free survival was numerically improved in the triplet group--16.0 months--compared with 10.3 months in the doublet group (hazard ratio, 0.66; P = 0.043); however, the trial did not reach the planned benefit for a statistically significant improvement. Median duration of response was 18.7 months (95% confidence interval, 10.1-22.1) and 12.5 months (95% confidence interval, 6.0-14.1); 59.8 and 27.8% of responses were estimated to have lasted for more than 18 months for triplet and doublet treatment, respectively. Grade 3-5 treatment-related adverse events occurred in 58.3 and 26.7% of patients treated with triplet and doublet therapies, respectively, which were most commonly fever, increased transaminase levels and rash. One patient who received triplet therapy died of pneumonitis. In summary, triplet therapy with dabrafenib, trametinib and pembrolizumab conferred numerically longer progression-free survival and duration of response with a higher rate of grade 3/4 adverse events compared with the doublet therapy of dabrafenib, trametinib and placebo. A randomized phase 2 trial testing triple combination of BRAF, MEK and PD-1 inhibition as first-line therapy in patients with BRAF-mutant melanoma shows durable responses and encouraging progression-free survival., Author(s): Paolo Antonio Ascierto [sup.1] , Pier Francesco Ferrucci [sup.2] , Rosalie Fisher [sup.3] , Michele Del Vecchio [sup.4] , Victoria Atkinson [sup.5] , Henrik Schmidt [sup.6] , Jacob Schachter [...]

Published
2019
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18. Percutaneous hepatic perfusion (chemosaturation) with melphalan in patients with intrahepatic cholangiocarcinoma: European multicentre study on safety, short-term effects and survival

Author

Marquardt, Steffen, Kirstein, Martha M., Brüning, Roland, Zeile, Martin, Ferrucci, Pier Francesco, Prevoo, Warner, Radeleff, Boris, Trillaud, Hervé, Tselikas, Lambros, Vicente, Emilio, Wiggermann, Philipp, Manns, Michael P., Vogel, Arndt, and Wacker, Frank K.

Published
2019
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19. Soluble CTLA-4 as a favorable predictive biomarker in metastatic melanoma patients treated with ipilimumab: an Italian melanoma intergroup study

Author

Pistillo, Maria Pia, Fontana, Vincenzo, Morabito, Anna, Dozin, Beatrice, Laurent, Stefania, Carosio, Roberta, Banelli, Barbara, Ferrero, Francesca, Spano, Laura, Tanda, Enrica, Ferrucci, Pier Francesco, Martinoli, Chiara, Cocorocchio, Emilia, Guida, Michele, Tommasi, Stefania, De Galitiis, Federica, Pagani, Elena, Antonini Cappellini, Gian Carlo, Marchetti, Paolo, Quaglino, Pietro, Fava, Paolo, Osella-Abate, Simona, Ascierto, Paolo Antonio, Capone, Mariaelena, Simeone, Ester, Romani, Massimo, Spagnolo, Francesco, Queirolo, Paola, and On behalf of the Italian Melanoma Intergroup (IMI)

Published
2019
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20. Corrigendum to “Nivolumab plus ipilimumab in melanoma patients with asymptomatic brain metastases: 7-year outcomes and quality of life from the multicenter phase III NIBIT-M2 trial” [Eur J Cancer 199 (2024) 113531]

Author

Di Giacomo, Anna Maria, Chiarion-Sileni, Vanna, Del Vecchio, Michele, Ferrucci, Pier Francesco, Guida, Michele, Quaglino, Pietro, Guidoboni, Massimo, Marchetti, Paolo, Simonetti, Elena, Santangelo, Federica, Amato, Giovanni, Covre, Alessia, Camerini, Roberto, Valente, Monica, Mandalà, Mario, Giannarelli, Diana, Calabrò, Luana, and Maio, Michele

Published
2024
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21. First-Line, Fixed-Duration Nivolumab Plus Ipilimumab Followed by Nivolumab in Clinically Diverse Patient Populations With Unresectable Stage III or IV Melanoma: CheckMate 401

Author

Dummer, Reinhard, primary, Corrie, Pippa, additional, Gutzmer, Ralf, additional, Meniawy, Tarek M., additional, Del Vecchio, Michele, additional, Lebbé, Céleste, additional, Guida, Michele, additional, Dutriaux, Caroline, additional, Dreno, Brigitte, additional, Meyer, Nicolas, additional, Ferrucci, Pier Francesco, additional, Dalle, Stéphane, additional, Khattak, Muhammad Adnan, additional, Grob, Jean-Jacques, additional, Briscoe, Karen, additional, Larkin, James, additional, Mansard, Sandrine, additional, Lesimple, Thierry, additional, Guidoboni, Massimo, additional, Sabatini, Silvia, additional, Richtig, Erika, additional, Herbst, Rudolf, additional, Lobo, Maurice, additional, Askelson, Margarita, additional, Ascierto, Paolo A., additional, and Maio, Michele, additional

Published
2023
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22. Health-related quality of life results from the phase III CheckMate 067 study

Author

Schadendorf, Dirk, Larkin, James, Wolchok, Jedd, Hodi, F. Stephen, Chiarion-Sileni, Vanna, Gonzalez, Rene, Rutkowski, Piotr, Grob, Jean-Jacques, Cowey, C. Lance, Lao, Christopher, Wagstaff, John, Callahan, Margaret K., Postow, Michael A., Smylie, Michael, Ferrucci, Pier Francesco, Dummer, Reinhard, Hill, Andrew, Taylor, Fiona, Sabater, Javier, Walker, Dana, Kotapati, Srividya, Abernethy, Amy, and Long, Georgina V.

Published
2017
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27. First-Line, Fixed-Duration Nivolumab Plus Ipilimumab Followed by Nivolumab in Clinically Diverse Patient Populations With Unresectable Stage III or IV Melanoma: CheckMate 401

Author

Dummer, Reinhard; https://orcid.org/0000-0002-2279-6906, Corrie, Pippa; https://orcid.org/0000-0003-4875-7021, Gutzmer, Ralf; https://orcid.org/0000-0001-7921-2820, Meniawy, Tarek M; https://orcid.org/0000-0002-1457-6137, Del Vecchio, Michele, Lebbé, Céleste; https://orcid.org/0000-0002-5854-7290, Guida, Michele, Dutriaux, Caroline, Dreno, Brigitte; https://orcid.org/0000-0001-5574-5825, Meyer, Nicolas, Ferrucci, Pier Francesco; https://orcid.org/0000-0001-6255-5851, Dalle, Stéphane, Khattak, Muhammad Adnan, Grob, Jean-Jacques; https://orcid.org/0000-0002-0667-153X, Briscoe, Karen, Larkin, James; https://orcid.org/0000-0001-5569-9523, Mansard, Sandrine; https://orcid.org/0000-0002-8064-5399, Lesimple, Thierry, Guidoboni, Massimo; https://orcid.org/0000-0001-7703-790X, Sabatini, Silvia, Richtig, Erika; https://orcid.org/0000-0002-5505-6103, Herbst, Rudolf; https://orcid.org/0000-0002-4238-9486, Lobo, Maurice; https://orcid.org/0009-0008-4674-6744, Askelson, Margarita, Ascierto, Paolo A; https://orcid.org/0000-0002-8322-475X, Maio, Michele; https://orcid.org/0000-0002-0323-6321, Dummer, Reinhard; https://orcid.org/0000-0002-2279-6906, Corrie, Pippa; https://orcid.org/0000-0003-4875-7021, Gutzmer, Ralf; https://orcid.org/0000-0001-7921-2820, Meniawy, Tarek M; https://orcid.org/0000-0002-1457-6137, Del Vecchio, Michele, Lebbé, Céleste; https://orcid.org/0000-0002-5854-7290, Guida, Michele, Dutriaux, Caroline, Dreno, Brigitte; https://orcid.org/0000-0001-5574-5825, Meyer, Nicolas, Ferrucci, Pier Francesco; https://orcid.org/0000-0001-6255-5851, Dalle, Stéphane, Khattak, Muhammad Adnan, Grob, Jean-Jacques; https://orcid.org/0000-0002-0667-153X, Briscoe, Karen, Larkin, James; https://orcid.org/0000-0001-5569-9523, Mansard, Sandrine; https://orcid.org/0000-0002-8064-5399, Lesimple, Thierry, Guidoboni, Massimo; https://orcid.org/0000-0001-7703-790X, Sabatini, Silvia, Richtig, Erika; https://orcid.org/0000-0002-5505-6103, Herbst, Rudolf; https://orcid.org/0000-0002-4238-9486, Lobo, Maurice; https://orcid.org/0009-0008-4674-6744, Askelson, Margarita, Ascierto, Paolo A; https://orcid.org/0000-0002-8322-475X, and Maio, Michele; https://orcid.org/0000-0002-0323-6321

Abstract

PURPOSE To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma. METHODS Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype. RESULTS In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months' median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup. CONCLUSION Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients.

Published
2023

28. First-Line, Fixed-Duration Nivolumab Plus Ipilimumab Followed by Nivolumab in Clinically Diverse Patient Populations With Unresectable Stage III or IV Melanoma: CheckMate 401

Author

Dummer, Reinhard, Corrie, Pippa, Gutzmer, Ralf, Meniawy, Tarek M, Del Vecchio, Michele, Lebbé, Céleste, Guida, Michele, Dutriaux, Caroline, Dreno, Brigitte, Meyer, Nicolas, Ferrucci, Pier Francesco, Dalle, Stéphane, Khattak, Muhammad Adnan, Grob, Jean-Jacques, Briscoe, Karen, Larkin, James, Mansard, Sandrine, Lesimple, Thierry, Guidoboni, Massimo, Sabatini, Silvia, Richtig, Erika, Herbst, Rudolf, Lobo, Maurice, Askelson, Margarita, Ascierto, Paolo A, Maio, Michele, and University of Zurich

Subjects
Cancer Research, Oncology, 10177 Dermatology Clinic, 610 Medicine & health
Published
2023

29. Effectiveness of dabrafenib in the treatment of patients with BRAF V600–mutated metastatic melanoma in a Named Patient Program

Author

Martin-Algarra, Salvador, Hinshelwood, Rebecca, Mesnage, Soizick, Cebon, Jonathan, Ferrucci, Pier Francesco, Aglietta, Massimo, Neyns, Bart, Chiarion-Sileni, Vanna, Lindsay, Colin R., Del Vecchio, Michele, Linardou, Helen, Merelli, Barbara, Tonini, Giuseppe, Atkinson, Victoria, Freivogel, Klaus, Stein, Dara, Dalland, Lindi, Lau, Mike, Legenne, Philippe, Queirolo, Paola, and Millward, Michael

Published
2019
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30. Supplementary methods from Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion

Author

Conforti, Fabio, primary, Pala, Laura, primary, Pagan, Eleonora, primary, Bagnardi, Vincenzo, primary, De Pas, Tommaso, primary, Queirolo, Paola, primary, Pennacchioli, Elisabetta, primary, Catania, Chiara, primary, Cocorocchio, Emilia, primary, Ferrucci, Pier Francesco, primary, Saponara, Maristella, primary, Orsolini, Gianmarco, primary, Zagami, Paola, primary, Nicoló, Eleonora, primary, De Marinis, Filippo, primary, Tortora, Giampaolo, primary, Bria, Emilio, primary, Minucci, Saverio, primary, Joffe, Hadine, primary, Veronesi, Paolo, primary, Wargo, Jennifer, primary, Rosenthal, Rachel, primary, Swanton, Charles, primary, Mantovani, Alberto, primary, Gelber, Richard D., primary, Viale, Giuseppe, primary, Goldhirsch, Aron, primary, and Giaccone, Giuseppe, primary

Published
2023
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31. Table S1 from Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases

Author

Di Giacomo, Anna Maria, primary, Chiarion-Sileni, Vanna, primary, Del Vecchio, Michele, primary, Ferrucci, Pier Francesco, primary, Guida, Michele, primary, Quaglino, Pietro, primary, Guidoboni, Massimo, primary, Marchetti, Paolo, primary, Cutaia, Ornella, primary, Amato, Giovanni, primary, Covre, Alessia, primary, Camerini, Roberto, primary, Calabrò, Luana, primary, Valente, Monica, primary, Giannarelli, Diana, primary, Mandalà, Mario, primary, and Maio, Michele, primary

Published
2023
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32. Table S2 from Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion

Author

Conforti, Fabio, primary, Pala, Laura, primary, Pagan, Eleonora, primary, Bagnardi, Vincenzo, primary, De Pas, Tommaso, primary, Queirolo, Paola, primary, Pennacchioli, Elisabetta, primary, Catania, Chiara, primary, Cocorocchio, Emilia, primary, Ferrucci, Pier Francesco, primary, Saponara, Maristella, primary, Orsolini, Gianmarco, primary, Zagami, Paola, primary, Nicoló, Eleonora, primary, De Marinis, Filippo, primary, Tortora, Giampaolo, primary, Bria, Emilio, primary, Minucci, Saverio, primary, Joffe, Hadine, primary, Veronesi, Paolo, primary, Wargo, Jennifer, primary, Rosenthal, Rachel, primary, Swanton, Charles, primary, Mantovani, Alberto, primary, Gelber, Richard D., primary, Viale, Giuseppe, primary, Goldhirsch, Aron, primary, and Giaccone, Giuseppe, primary

Published
2023
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33. Figure S1 from Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion

Author

Conforti, Fabio, primary, Pala, Laura, primary, Pagan, Eleonora, primary, Bagnardi, Vincenzo, primary, De Pas, Tommaso, primary, Queirolo, Paola, primary, Pennacchioli, Elisabetta, primary, Catania, Chiara, primary, Cocorocchio, Emilia, primary, Ferrucci, Pier Francesco, primary, Saponara, Maristella, primary, Orsolini, Gianmarco, primary, Zagami, Paola, primary, Nicoló, Eleonora, primary, De Marinis, Filippo, primary, Tortora, Giampaolo, primary, Bria, Emilio, primary, Minucci, Saverio, primary, Joffe, Hadine, primary, Veronesi, Paolo, primary, Wargo, Jennifer, primary, Rosenthal, Rachel, primary, Swanton, Charles, primary, Mantovani, Alberto, primary, Gelber, Richard D., primary, Viale, Giuseppe, primary, Goldhirsch, Aron, primary, and Giaccone, Giuseppe, primary

Published
2023
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34. Fig.S1 from Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases

Author

Di Giacomo, Anna Maria, primary, Chiarion-Sileni, Vanna, primary, Del Vecchio, Michele, primary, Ferrucci, Pier Francesco, primary, Guida, Michele, primary, Quaglino, Pietro, primary, Guidoboni, Massimo, primary, Marchetti, Paolo, primary, Cutaia, Ornella, primary, Amato, Giovanni, primary, Covre, Alessia, primary, Camerini, Roberto, primary, Calabrò, Luana, primary, Valente, Monica, primary, Giannarelli, Diana, primary, Mandalà, Mario, primary, and Maio, Michele, primary

Published
2023
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35. Fig S2 from Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases

Author

Di Giacomo, Anna Maria, primary, Chiarion-Sileni, Vanna, primary, Del Vecchio, Michele, primary, Ferrucci, Pier Francesco, primary, Guida, Michele, primary, Quaglino, Pietro, primary, Guidoboni, Massimo, primary, Marchetti, Paolo, primary, Cutaia, Ornella, primary, Amato, Giovanni, primary, Covre, Alessia, primary, Camerini, Roberto, primary, Calabrò, Luana, primary, Valente, Monica, primary, Giannarelli, Diana, primary, Mandalà, Mario, primary, and Maio, Michele, primary

Published
2023
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36. Legends of supplementary figure 1 and 2 from Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion

Author

Conforti, Fabio, primary, Pala, Laura, primary, Pagan, Eleonora, primary, Bagnardi, Vincenzo, primary, De Pas, Tommaso, primary, Queirolo, Paola, primary, Pennacchioli, Elisabetta, primary, Catania, Chiara, primary, Cocorocchio, Emilia, primary, Ferrucci, Pier Francesco, primary, Saponara, Maristella, primary, Orsolini, Gianmarco, primary, Zagami, Paola, primary, Nicoló, Eleonora, primary, De Marinis, Filippo, primary, Tortora, Giampaolo, primary, Bria, Emilio, primary, Minucci, Saverio, primary, Joffe, Hadine, primary, Veronesi, Paolo, primary, Wargo, Jennifer, primary, Rosenthal, Rachel, primary, Swanton, Charles, primary, Mantovani, Alberto, primary, Gelber, Richard D., primary, Viale, Giuseppe, primary, Goldhirsch, Aron, primary, and Giaccone, Giuseppe, primary

Published
2023
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40. Differential activity of avapritinib in patients with metastases from mucosal melanoma and thymic carcinoma harbouring KIT exon 17 mutations: Initial experience from a Compassionate Use Program in Italy

Author

Corti, Chiara, primary, Conforti, Fabio, additional, Pala, Laura, additional, Catania, Chiara, additional, Cocorocchio, Emilia, additional, Ferrucci, Pier Francesco, additional, Curigliano, Giuseppe, additional, Queirolo, Paola, additional, and de Pas, Tommaso, additional

Published
2022
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41. KEYNOTE - D36: Personalized immunotherapy with a neoepitope vaccine, EVX-01 and pembrolizumab in advanced melanoma

Author

Long, Georgina V., Ferrucci, Pier Francesco, Khattak, Adnan, Meniawy, Tarek M., Ott, Patrick Alexander, Chisamore, Michael, Trolle, Thomas, Hyseni, Agon, Heegaard, Erik, Long, Georgina V., Ferrucci, Pier Francesco, Khattak, Adnan, Meniawy, Tarek M., Ott, Patrick Alexander, Chisamore, Michael, Trolle, Thomas, Hyseni, Agon, and Heegaard, Erik

Abstract

Despite improvements made with checkpoint inhibitor (CPI) therapy, a need for new approaches to improve outcomes for patients with unresectable or metastatic melanoma remains. EVX-01, a personalized neoepitope vaccine, combined with pembrolizumab treatment, holds the potential to fulfill this need. Here we present the rationale and novel design behind the KEYNOTE - D36 trial: an open label, single arm, phase II trial aiming to establish the clinical proof of concept and evaluate the safety of EVX-01 in combination with pembrolizumab in CPI naive patients with unresectable or metastatic melanoma. The primary objective is to evaluate if EVX-01 improves best overall response after initial stable disease or partial response to pembrolizumab treatment, in patients with advanced melanoma. The novel end points ensure a decisive readout which may prove helpful before making major investments in phase III trials with limited phase I data. Clinical Trial Registration: NCT05309421 (ClinicalTrials.gov).

Published
2022

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

Author

Dummer, Reinhard; https://orcid.org/0000-0002-2279-6906, Long, Georgina V; https://orcid.org/0000-0001-8894-3545, Robert, Caroline; https://orcid.org/0000-0002-9493-0238, Tawbi, Hussein A; https://orcid.org/0000-0003-1942-851X, Flaherty, Keith T; https://orcid.org/0000-0002-3402-0478, Ascierto, Paolo A; https://orcid.org/0000-0002-8322-475X, Nathan, Paul D; https://orcid.org/0000-0002-2327-3250, Rutkowski, Piotr; https://orcid.org/0000-0002-8920-5429, Leonov, Oleg; https://orcid.org/0000-0001-6667-7135, Dutriaux, Caroline, Mandalà, Mario, Lorigan, Paul; https://orcid.org/0000-0002-8875-2164, Ferrucci, Pier Francesco; https://orcid.org/0000-0001-6255-5851, Grob, Jean Jacques; https://orcid.org/0000-0002-0667-153X, Meyer, Nicolas, Gogas, Helen; https://orcid.org/0000-0002-0451-2885, Stroyakovskiy, Daniil, Arance, Ana; https://orcid.org/0000-0003-2896-1957, Brase, Jan C; https://orcid.org/0000-0002-1325-2528, Green, Steven, Haas, Tomas; https://orcid.org/0000-0003-0407-1079, Masood, Aisha, Gasal, Eduard, Ribas, Antoni; https://orcid.org/0000-0003-3669-8458, Schadendorf, Dirk; https://orcid.org/0000-0003-3524-7858, Dummer, Reinhard; https://orcid.org/0000-0002-2279-6906, Long, Georgina V; https://orcid.org/0000-0001-8894-3545, Robert, Caroline; https://orcid.org/0000-0002-9493-0238, Tawbi, Hussein A; https://orcid.org/0000-0003-1942-851X, Flaherty, Keith T; https://orcid.org/0000-0002-3402-0478, Ascierto, Paolo A; https://orcid.org/0000-0002-8322-475X, Nathan, Paul D; https://orcid.org/0000-0002-2327-3250, Rutkowski, Piotr; https://orcid.org/0000-0002-8920-5429, Leonov, Oleg; https://orcid.org/0000-0001-6667-7135, Dutriaux, Caroline, Mandalà, Mario, Lorigan, Paul; https://orcid.org/0000-0002-8875-2164, Ferrucci, Pier Francesco; https://orcid.org/0000-0001-6255-5851, Grob, Jean Jacques; https://orcid.org/0000-0002-0667-153X, Meyer, Nicolas, Gogas, Helen; https://orcid.org/0000-0002-0451-2885, Stroyakovskiy, Daniil, Arance, Ana; https://orcid.org/0000-0003-2896-1957, Brase, Jan C; https://orcid.org/0000-0002-1325-2528, Green, Steven, Haas, Tomas; https://orcid.org/0000-0003-0407-1079, Masood, Aisha, Gasal, Eduard, Ribas, Antoni; https://orcid.org/0000-0003-3669-8458, and Schadendorf, Dirk; https://orcid.org/0000-0003-3524-7858

Abstract

PURPOSE Preclinical 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. METHODS Patients 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 ). RESULTS At 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. CONCLUSION The 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 the

Published
2022

43. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma

Author

Wolchok, Jedd D; https://orcid.org/0000-0001-6718-2222, Chiarion-Sileni, Vanna; https://orcid.org/0000-0001-9191-9124, Gonzalez, Rene, Grob, Jean-Jacques; https://orcid.org/0000-0002-0667-153X, Rutkowski, Piotr; https://orcid.org/0000-0002-8920-5429, Lao, Christopher D, Cowey, C Lance, Schadendorf, Dirk; https://orcid.org/0000-0003-3524-7858, Wagstaff, John; https://orcid.org/0000-0002-1140-5981, Dummer, Reinhard; https://orcid.org/0000-0002-2279-6906, Ferrucci, Pier Francesco; https://orcid.org/0000-0001-6255-5851, Smylie, Michael, Butler, Marcus O; https://orcid.org/0000-0002-9840-7057, Hill, Andrew, Márquez-Rodas, Ivan; https://orcid.org/0000-0002-2476-668X, Haanen, John B A G; https://orcid.org/0000-0001-5884-7704, Guidoboni, Massimo, Maio, Michele; https://orcid.org/0000-0002-0323-6321, Schöffski, Patrick; https://orcid.org/0000-0001-5980-030X, Carlino, Matteo S, Lebbé, Céleste; https://orcid.org/0000-0002-5854-7290, McArthur, Grant; https://orcid.org/0000-0001-8908-6071, Ascierto, Paolo A; https://orcid.org/0000-0002-8322-475X, Daniels, Gregory A; https://orcid.org/0000-0001-9087-8009, Long, Georgina V; https://orcid.org/0000-0001-8894-3545, Bas, Tuba, Ritchings, Corey; https://orcid.org/0000-0002-9240-9211, Larkin, James; https://orcid.org/0000-0001-5569-9523, Hodi, F Stephen; https://orcid.org/0000-0001-6825-091X, Wolchok, Jedd D; https://orcid.org/0000-0001-6718-2222, Chiarion-Sileni, Vanna; https://orcid.org/0000-0001-9191-9124, Gonzalez, Rene, Grob, Jean-Jacques; https://orcid.org/0000-0002-0667-153X, Rutkowski, Piotr; https://orcid.org/0000-0002-8920-5429, Lao, Christopher D, Cowey, C Lance, Schadendorf, Dirk; https://orcid.org/0000-0003-3524-7858, Wagstaff, John; https://orcid.org/0000-0002-1140-5981, Dummer, Reinhard; https://orcid.org/0000-0002-2279-6906, Ferrucci, Pier Francesco; https://orcid.org/0000-0001-6255-5851, Smylie, Michael, Butler, Marcus O; https://orcid.org/0000-0002-9840-7057, Hill, Andrew, Márquez-Rodas, Ivan; https://orcid.org/0000-0002-2476-668X, Haanen, John B A G; https://orcid.org/0000-0001-5884-7704, Guidoboni, Massimo, Maio, Michele; https://orcid.org/0000-0002-0323-6321, Schöffski, Patrick; https://orcid.org/0000-0001-5980-030X, Carlino, Matteo S, Lebbé, Céleste; https://orcid.org/0000-0002-5854-7290, McArthur, Grant; https://orcid.org/0000-0001-8908-6071, Ascierto, Paolo A; https://orcid.org/0000-0002-8322-475X, Daniels, Gregory A; https://orcid.org/0000-0001-9087-8009, Long, Georgina V; https://orcid.org/0000-0001-8894-3545, Bas, Tuba, Ritchings, Corey; https://orcid.org/0000-0002-9240-9211, Larkin, James; https://orcid.org/0000-0001-5569-9523, and Hodi, F Stephen; https://orcid.org/0000-0001-6825-091X

Abstract

PURPOSE In the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes. PATIENTS AND METHODS Patients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks (n = 314), nivolumab 3 mg/kg once every 2 weeks (n = 316), or ipilimumab 3 mg/kg once every 3 weeks (four doses; n = 315). Coprimary end points were progression-free survival and overall survival (OS) with nivolumab plus ipilimumab or nivolumab versus ipilimumab. Secondary end points included objective response rate, descriptive efficacy assessments of nivolumab plus ipilimumab versus nivolumab alone, and safety. Melanoma-specific survival (MSS; descriptive analysis), which excludes deaths unrelated to melanoma, was also evaluated. RESULTS Median OS (minimum follow-up, 6.5 years) was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median MSS was not reached, 58.7, and 21.9 months, respectively; 6.5-year OS rates were 57%, 43%, and 25% in patients with BRAF-mutant tumors and 46%, 42%, and 22% in those with BRAF-wild-type tumors, respectively. In patients who discontinued treatment, the median treatment-free interval was 27.6, 2.3, and 1.9 months, respectively. Since the 5-year analysis, no new safety signals were observed. CONCLUSION These 6.5-year CheckMate 067 results, which include the longest median OS in a phase III melanoma trial reported to date and the first report of MSS, showed durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and, in descriptive analyses, with the combination over nivolumab monotherapy.

Published
2022

45. Abstract CT167: Neoadjuvant ipilimumab/nivolumab in locally advanced or oligometastatic melanoma: An open label, single arm, multi-institutional clinical study with molecular and immunological biomarker’s analysis

Author

Ferrucci, Pier Francesco, primary, Duso, Bruno Achutti, additional, Nezi, Luigi, additional, Mazzarella, Luca, additional, Lotti, Fiorenza, additional, Gandini, Sara, additional, Orsolini, Gianmarco, additional, Pennacchioli, Elisabetta, additional, Gnagnarella, Patrizia, additional, Manzo, Teresa, additional, Ribero, Simone, additional, Fierro, Maria Teresa, additional, Senetta, Rebecca, additional, Riviello, Concetta, additional, Caliendo, Virginia, additional, Quaglino, Pietro, additional, Barberis, Massino, additional, Bonizzi, Giuseppina, additional, and Cocorocchio, Emilia, additional

Published
2022
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47. Dabrafenib (D) and trametinib (T) plus spartalizumab (S) in patients (pts) with previously untreated BRAF V600–mutant unresectable or metastatic melanoma: Three-year overall survival (OS) data from the randomized part 3 of the phase III COMBI-i trial.

Author

Dummer, Reinhard, primary, Long, Georgina V., additional, Tawbi, Hussein A., additional, Flaherty, Keith, additional, Ascierto, Paolo Antonio, additional, Nathan, Paul D., additional, Rutkowski, Piotr, additional, Leonov, Oleg, additional, Mandalà, Mario, additional, Lorigan, Paul, additional, Ferrucci, Pier Francesco, additional, Grob, Jean-Jacques, additional, Meyer, Nicolas, additional, Gogas, Helen, additional, Stroyakovskiy, Daniil, additional, Arance, Ana Maria, additional, Pakhle, Neha, additional, Waters, Sorcha, additional, Ribas, Antoni, additional, and Schadendorf, Dirk, additional

Published
2022
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48. Primary ipilimumab/nivolumab followed by adjuvant nivolumab in patients with locally advanced or oligometastatic melanoma: Update on outcome.

Author

Cocorocchio, Emilia, primary, Gandini, Sara, additional, Nezi, Luigi, additional, Manzo, Teresa, additional, Mazzarella, Luca, additional, Barberis, Massimo, additional, Lanfrancone, Luisa, additional, Pala, Laura, additional, Conforti, Fabio, additional, Pennacchioli, Elisabetta, additional, Orsolini, Gianmarco, additional, Fierro, Maria Teresa, additional, Quaglino, Pietro, additional, Senetta, Rebecca, additional, Caliendo, Virginia, additional, Riviello, Concetta, additional, Stucchi, Sara, additional, Macandog, Angeli Dominique, additional, Frige, Gianmaria, additional, and Ferrucci, Pier Francesco, additional

Published
2022
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49. FOCUS phase 3 trial results: Percutaneous hepatic perfusion (PHP) with melphalan for patients with ocular melanoma liver metastases (PHP-OCM-301/301A).

Author

Zager, Jonathan S., primary, Orloff, Marlana M., additional, Ferrucci, Pier Francesco, additional, Glazer, Evan Scott, additional, Ejaz, Aslam, additional, Richtig, Erika, additional, Ochsenreither, Sebastian, additional, Lowe, Michael C., additional, Reddy, Sunil A., additional, Beasley, Georgia, additional, Gesierich, Anja, additional, Dummer, Reinhard, additional, Arance, Ana Maria, additional, Fenwick, Stephen William, additional, Wheater, Matthew, additional, and Ottensmeier, Christian, additional

Published
2022
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50. Phase II study SECOMBIT (sequential combo immuno and target therapy study): A subgroup analysis with a longer follow-up.

Author

Ascierto, Paolo Antonio, primary, Mandalà, Mario, additional, Ferrucci, Pier Francesco, additional, Guidoboni, Massimo, additional, Rutkowski, Piotr, additional, Ferraresi, Virginia, additional, Arance, Ana Maria, additional, Guida, Michele, additional, Maiello, Evaristo, additional, Gogas, Helen, additional, Richtig, Erika, additional, Fierro, Maria Teresa, additional, Lebbe, Celeste, additional, Helgadottir, Hildur, additional, Melero Bermejo, Ignacio, additional, Palmieri, Giuseppe, additional, Giannarelli, Diana, additional, Grimaldi, Antonio Maria, additional, Dummer, Reinhard, additional, and Chiarion-Sileni, Vanna, additional

Published
2022
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