Initial Evidence for the Efficacy of Naporafenib in Combination With Trametinib in NRAS-Mutant Melanoma: Results From the Expansion Arm of a Phase Ib, Open-Label Study

被引:25
作者
de Braud, Filippo [1 ,2 ]
Dooms, Christophe [3 ]
Heist, Rebecca S. [4 ]
Lebbe, Celeste [5 ]
Wermke, Martin [6 ]
Gazzah, Anas [7 ]
Schadendorf, Dirk [8 ,9 ]
Rutkowski, Piotr [10 ]
Wolf, Juergen [11 ]
Ascierto, Paolo A.
Gil-Bazo, Ignacio
Kato, Shumei
Wolodarski, Maria
McKean, Meredith
Couselo, Eva Munoz
Sebastian, Martin
Santoro, Armando
Cooke, Vesselina
Manganelli, Luca
Wan, Kitty
Gaur, Anil
Kim, Jaeyeon
Caponigro, Giordano
Couillebault, Xuan-Mai
Evans, Helen
Campbell, Catarina D.
Basu, Sumit
Moschetta, Michele
Daud, Adil [30 ,12 ]
机构
[1] Univ Milan, Dept Oncol & Hematol Oncol, Milan, Italy
[2] Ist Nazl Tumori, Med Oncol & Hematol Dept, Milan, Italy
[3] Univ Hosp Leuven, Leuven, Belgium
[4] Massachusetts Gen Hosp, Canc Ctr, Boston, MA USA
[5] Univ Paris Cite, Hop St Louis, AP HP, Dept Dermato Oncol & CIC,Inserm U976, Paris, France
[6] Tech Univ Dresden, NCT UCC Early Clin Trial Unit, Dresden, Germany
[7] Gustave Roussy Canc Inst, Dept Med Oncol, Thorac Canc Grp, Villejuif, France
[8] Univ Hosp Essen, Dept Dermatol, Partner Site Essen, Essen, Germany
[9] German Canc Consortium, Partner Site Essen, Essen, Germany
[10] Mar Sklodowska Curie Natl Res Inst Oncol, Warsaw, Poland
[11] Univ Hosp Cologne, Ctr Integrated Oncol, Dept Internal Med, Cologne, Germany
[12] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
关键词
INHIBITOR; BRAF; LXH254;
D O I
10.1200/JCO.22.02018
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
PURPOSE No approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS)-mutant melanoma is currently available. PATIENTS AND METHODS In this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF-mutant non-small-cell lung cancer (escalation arm) or NRAS-mutant melanoma (escalation and expansion arms). RESULTS Thirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade $3 dose-limiting toxicities, including dermatitis acneiform (n 5 2), maculopapular rash (n 5 2), increased lipase (n 5 1), and Stevens-Johnson syndrome (n 5 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n524), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n 5 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. CONCLUSION Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.
引用
收藏
页码:2651 / +
页数:12
相关论文
共 15 条
[1]   A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer [J].
Braicu, Cornelia ;
Buse, Mihail ;
Busuioc, Constantin ;
Drula, Rares ;
Gulei, Diana ;
Raduly, Lajos ;
Rusu, Alexandru ;
Irimie, Alexandru ;
Atanasov, Atanas G. ;
Slaby, Ondrej ;
Ionescu, Calin ;
Berindan-Neagoe, Ioana .
CANCERS, 2019, 11 (10)
[2]   Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i [J].
Dummer, Reinhard ;
Lebbe, Celeste ;
Atkinson, Victoria ;
Mandala, Mario ;
Nathan, Paul D. ;
Arance, Ana ;
Richtig, Erika ;
Yamazaki, Naoya ;
Robert, Caroline ;
Schadendorf, Dirk ;
Tawbi, Hussein A. ;
Ascierto, Paolo A. ;
Ribas, Antoni ;
Flaherty, Keith T. ;
Pakhle, Neha ;
Campbell, Catarina D. ;
Gusenleitner, Daniel ;
Masood, Aisha ;
Brase, Jan C. ;
Gasal, Eduard ;
Long, Georgina, V .
NATURE MEDICINE, 2020, 26 (10) :1557-+
[3]   Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial [J].
Dummer, Reinhard ;
Schadendorf, Dirk ;
Ascierto, Paolo A. ;
Arance, Ana ;
Dutriaux, Caroline ;
Di Giacomo, Anna Maria ;
Rutkowski, Piotr ;
Del Vecchio, Michele ;
Gutzmer, Ralf ;
Mandala, Mario ;
Thomas, Luc ;
Demidov, Lev ;
Garbe, Claus ;
Hogg, David ;
Liszkay, Gabriella ;
Queirolo, Paola ;
Wasserman, Ernesto ;
Ford, James ;
Weill, Marine ;
Sirulnik, L. Andres ;
Jehl, Valentine ;
Bozon, Viviana ;
Long, Georgina V. ;
Flaherty, Keith .
LANCET ONCOLOGY, 2017, 18 (04) :435-445
[4]   New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) [J].
Eisenhauer, E. A. ;
Therasse, P. ;
Bogaerts, J. ;
Schwartz, L. H. ;
Sargent, D. ;
Ford, R. ;
Dancey, J. ;
Arbuck, S. ;
Gwyther, S. ;
Mooney, M. ;
Rubinstein, L. ;
Shankar, L. ;
Dodd, L. ;
Kaplan, R. ;
Lacombe, D. ;
Verweij, J. .
EUROPEAN JOURNAL OF CANCER, 2009, 45 (02) :228-247
[5]   Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial [J].
Falchook, Gerald S. ;
Lewis, Karl D. ;
Infante, Jeffrey R. ;
Gordon, Michael S. ;
Vogelzang, Nicholas J. ;
DeMarini, Douglas J. ;
Sun, Peng ;
Moy, Christopher ;
Szabo, Stephen A. ;
Roadcap, Lori T. ;
Peddareddigari, Vijay G. R. ;
Lebowitz, Peter F. ;
Le, Ngocdiep T. ;
Burris, Howard A., III ;
Messersmith, Wells A. ;
O'Dwyer, Peter J. ;
Kim, Kevin B. ;
Flaherty, Keith ;
Bendell, Johanna C. ;
Gonzalez, Rene ;
Kurzrock, Razelle ;
Fecher, Leslie A. .
LANCET ONCOLOGY, 2012, 13 (08) :782-789
[6]   Prognostic significance of BRAF and NRAS mutations in melanoma: a German study from routine care [J].
Heppt, Markus V. ;
Siepmann, Timo ;
Engel, Jutta ;
Schubert-Fritschle, Gabriele ;
Eckel, Renate ;
Mirlach, Laura ;
Kirchner, Thomas ;
Jung, Andreas ;
Gesierich, Anja ;
Ruzicka, Thomas ;
Flaig, Michael J. ;
Berking, Carola .
BMC CANCER, 2017, 17 :536
[7]   A phase I study of LXH254 in patients (pts) with advanced solid tumors harboring MAPK pathway alterations. [J].
Janku, Filip ;
Iyer, Gopa ;
Spreafico, Anna ;
Yamamoto, Noboru ;
Bang, Yung-Jue ;
Elez, Elena ;
De Jonge, Maja J. ;
Groen, Harry J. M. ;
Marme, Frederik ;
Gollmer, Kathrin ;
St-Pierre, Annie ;
Melendez, Maritza ;
Mais, Anna ;
Nauwelaertsx, Heidi ;
Nauwelaerts, Heidi ;
Stammberger, Uz M. ;
Dummer, Reinhard .
JOURNAL OF CLINICAL ONCOLOGY, 2018, 36 (15)
[8]  
Lebbe C., PHASE 2 STUDY MULTIP
[9]   Pimasertib Versus Dacarbazine in Patients With UnresectableNRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover [J].
Lebbe, Celeste ;
Dutriaux, Caroline ;
Lesimple, Thierry ;
Kruit, Willem ;
Kerger, Joseph ;
Thomas, Luc ;
Guillot, Bernard ;
de Braud, Filippo ;
Garbe, Claus ;
Grob, Jean-Jacques ;
Loquai, Carmen ;
Ferraresi, Virginia ;
Robert, Caroline ;
Vasey, Paul ;
Conry, Robert ;
Isaacs, Richard ;
Espinosa, Enrique ;
Schueler, Armin ;
Massimini, Giorgio ;
Dreno, Brigitte .
CANCERS, 2020, 12 (07) :1-11
[10]   LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors [J].
Monaco, Kelli-Ann ;
Delach, Scott ;
Yuan, Jing ;
Mishina, Yuji ;
Fordjour, Paul ;
Labrot, Emma ;
McKay, Daniel ;
Guo, Ribo ;
Higgins, Stacy ;
Wang, Hui Qin ;
Liang, Jinsheng ;
Bui, Karen ;
Green, John ;
Aspesi, Peter ;
Ambrose, Jessi ;
Mapa, Felipa ;
Griner, Lesley ;
Jaskelioff, Mariela ;
Fuller, John ;
Crawford, Kenneth ;
Pardee, Gwynn ;
Widger, Stephania ;
Hammerman, Peter S. ;
Engelman, Jeffrey A. ;
Stuart, Darrin D. ;
Cooke, Vesselina G. ;
Caponigro, Giordano .
CLINICAL CANCER RESEARCH, 2021, 27 (07) :2061-2073