Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial

James Larkin; Richard Marais; Nuria Porta; David Gonzalez de Castro; Lisa Parsons; Christina Messiou; Gordon Stamp; Lisa Thompson; Kim Edmonds; Sarah Sarker; Jane Banerji; Paul Lorigan; Thomas R Jeffry Evans; Pippa Corrie; Ernest Marshall; Mark R Middleton; Paul Nathan; Steve Nicholson; Christian Ottensmeier; Ruth Plummer; Judith Bliss; Sara Valpione; Samra Turajlic

doi:10.1016/j.xcrm.2024.101435

Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial

James Larkin, Richard Marais, Nuria Porta, David Gonzalez de Castro, Lisa Parsons, Christina Messiou, Gordon Stamp, Lisa Thompson, Kim Edmonds, Sarah Sarker, Jane Banerji, Paul Lorigan, Thomas R Jeffry Evans, Pippa Corrie, Ernest Marshall, Mark R Middleton, Paul Nathan, Steve Nicholson, Christian Ottensmeier, Ruth PlummerJudith Bliss, Sara Valpione, Samra Turajlic

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Abstract

Mucosal (MM) and acral melanomas (AM) are rare melanoma subtypes of unmet clinical need; 15%-20% harbor KIT mutations potentially targeted by small-molecule inhibitors, but none yet approved in melanoma. This multicenter, single-arm Phase II trial (NICAM) investigates nilotinib safety and activity in KIT mutated metastatic MM and AM. KIT mutations are identified in 39/219 screened patients (18%); of 29/39 treated, 26 are evaluable for primary analysis. Six patients were alive and progression free at 6 months (local radiology review, 25%); 5/26 (19%) had objective response at 12 weeks; median OS was 7.7 months; ddPCR assay correctly identifies KIT alterations in circulating tumor DNA (ctDNA) in 16/17 patients. Nilotinib is active in KIT-mutant AM and MM, comparable to other KIT inhibitors, with demonstrable activity in nonhotspot KIT mutations, supporting broadening of KIT evaluation in AM and MM. Our results endorse further investigations of nilotinib for the treatment of KIT-mutated melanoma. This clinical trial was registered with ISRCTN (ISRCTN39058880) and EudraCT (2009-012945-49).

Original language	English
Article number	101435
Number of pages	16
Journal	Cell Reports Medicine
Volume	5
Issue number	3
Early online date	19 Mar 2024
DOIs	https://doi.org/10.1016/j.xcrm.2024.101435
Publication status	Published - 21 Mar 2024
Externally published	Yes

Keywords

Humans
Melanoma/drug therapy
Antineoplastic Agents/adverse effects
Proto-Oncogene Proteins c-kit/genetics
Skin Neoplasms/drug therapy
Pyrimidines/adverse effects

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10.1016/j.xcrm.2024.101435Licence: CC BY

Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial
Copyright 2024 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 3.27 MBLicence: CC BY

Cite this

Larkin, J., Marais, R., Porta, N., Gonzalez de Castro, D., Parsons, L., Messiou, C., Stamp, G., Thompson, L., Edmonds, K., Sarker, S., Banerji, J., Lorigan, P., Evans, T. R. J., Corrie, P., Marshall, E., Middleton, M. R., Nathan, P., Nicholson, S., Ottensmeier, C., ... Turajlic, S. (2024). Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial. Cell Reports Medicine, 5(3), Article 101435. https://doi.org/10.1016/j.xcrm.2024.101435

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title = "Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial",

abstract = "Mucosal (MM) and acral melanomas (AM) are rare melanoma subtypes of unmet clinical need; 15%-20% harbor KIT mutations potentially targeted by small-molecule inhibitors, but none yet approved in melanoma. This multicenter, single-arm Phase II trial (NICAM) investigates nilotinib safety and activity in KIT mutated metastatic MM and AM. KIT mutations are identified in 39/219 screened patients (18%); of 29/39 treated, 26 are evaluable for primary analysis. Six patients were alive and progression free at 6 months (local radiology review, 25%); 5/26 (19%) had objective response at 12 weeks; median OS was 7.7 months; ddPCR assay correctly identifies KIT alterations in circulating tumor DNA (ctDNA) in 16/17 patients. Nilotinib is active in KIT-mutant AM and MM, comparable to other KIT inhibitors, with demonstrable activity in nonhotspot KIT mutations, supporting broadening of KIT evaluation in AM and MM. Our results endorse further investigations of nilotinib for the treatment of KIT-mutated melanoma. This clinical trial was registered with ISRCTN (ISRCTN39058880) and EudraCT (2009-012945-49).",

keywords = "Humans, Melanoma/drug therapy, Antineoplastic Agents/adverse effects, Proto-Oncogene Proteins c-kit/genetics, Skin Neoplasms/drug therapy, Pyrimidines/adverse effects",

author = "James Larkin and Richard Marais and Nuria Porta and {Gonzalez de Castro}, David and Lisa Parsons and Christina Messiou and Gordon Stamp and Lisa Thompson and Kim Edmonds and Sarah Sarker and Jane Banerji and Paul Lorigan and Evans, {Thomas R Jeffry} and Pippa Corrie and Ernest Marshall and Middleton, {Mark R} and Paul Nathan and Steve Nicholson and Christian Ottensmeier and Ruth Plummer and Judith Bliss and Sara Valpione and Samra Turajlic",

year = "2024",

month = mar,

day = "21",

doi = "10.1016/j.xcrm.2024.101435",

language = "English",

volume = "5",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "3",

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Larkin, J, Marais, R, Porta, N, Gonzalez de Castro, D, Parsons, L, Messiou, C, Stamp, G, Thompson, L, Edmonds, K, Sarker, S, Banerji, J, Lorigan, P, Evans, TRJ, Corrie, P, Marshall, E, Middleton, MR, Nathan, P, Nicholson, S, Ottensmeier, C, Plummer, R, Bliss, J, Valpione, S & Turajlic, S 2024, 'Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial', Cell Reports Medicine, vol. 5, no. 3, 101435. https://doi.org/10.1016/j.xcrm.2024.101435

TY - JOUR

T1 - Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial

AU - Larkin, James

AU - Marais, Richard

AU - Porta, Nuria

AU - Gonzalez de Castro, David

AU - Parsons, Lisa

AU - Messiou, Christina

AU - Stamp, Gordon

AU - Thompson, Lisa

AU - Edmonds, Kim

AU - Sarker, Sarah

AU - Banerji, Jane

AU - Lorigan, Paul

AU - Evans, Thomas R Jeffry

AU - Corrie, Pippa

AU - Marshall, Ernest

AU - Middleton, Mark R

AU - Nathan, Paul

AU - Nicholson, Steve

AU - Ottensmeier, Christian

AU - Plummer, Ruth

AU - Bliss, Judith

AU - Valpione, Sara

AU - Turajlic, Samra

PY - 2024/3/21

Y1 - 2024/3/21

N2 - Mucosal (MM) and acral melanomas (AM) are rare melanoma subtypes of unmet clinical need; 15%-20% harbor KIT mutations potentially targeted by small-molecule inhibitors, but none yet approved in melanoma. This multicenter, single-arm Phase II trial (NICAM) investigates nilotinib safety and activity in KIT mutated metastatic MM and AM. KIT mutations are identified in 39/219 screened patients (18%); of 29/39 treated, 26 are evaluable for primary analysis. Six patients were alive and progression free at 6 months (local radiology review, 25%); 5/26 (19%) had objective response at 12 weeks; median OS was 7.7 months; ddPCR assay correctly identifies KIT alterations in circulating tumor DNA (ctDNA) in 16/17 patients. Nilotinib is active in KIT-mutant AM and MM, comparable to other KIT inhibitors, with demonstrable activity in nonhotspot KIT mutations, supporting broadening of KIT evaluation in AM and MM. Our results endorse further investigations of nilotinib for the treatment of KIT-mutated melanoma. This clinical trial was registered with ISRCTN (ISRCTN39058880) and EudraCT (2009-012945-49).

AB - Mucosal (MM) and acral melanomas (AM) are rare melanoma subtypes of unmet clinical need; 15%-20% harbor KIT mutations potentially targeted by small-molecule inhibitors, but none yet approved in melanoma. This multicenter, single-arm Phase II trial (NICAM) investigates nilotinib safety and activity in KIT mutated metastatic MM and AM. KIT mutations are identified in 39/219 screened patients (18%); of 29/39 treated, 26 are evaluable for primary analysis. Six patients were alive and progression free at 6 months (local radiology review, 25%); 5/26 (19%) had objective response at 12 weeks; median OS was 7.7 months; ddPCR assay correctly identifies KIT alterations in circulating tumor DNA (ctDNA) in 16/17 patients. Nilotinib is active in KIT-mutant AM and MM, comparable to other KIT inhibitors, with demonstrable activity in nonhotspot KIT mutations, supporting broadening of KIT evaluation in AM and MM. Our results endorse further investigations of nilotinib for the treatment of KIT-mutated melanoma. This clinical trial was registered with ISRCTN (ISRCTN39058880) and EudraCT (2009-012945-49).

KW - Humans

KW - Melanoma/drug therapy

KW - Antineoplastic Agents/adverse effects

KW - Proto-Oncogene Proteins c-kit/genetics

KW - Skin Neoplasms/drug therapy

KW - Pyrimidines/adverse effects

U2 - 10.1016/j.xcrm.2024.101435

DO - 10.1016/j.xcrm.2024.101435

M3 - Article

C2 - 38417447

SN - 2666-3791

VL - 5

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 3

M1 - 101435

ER -

Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial

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Keywords

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