Clinical Trial

. 2024 Mar 19;5(3):101435.

doi: 10.1016/j.xcrm.2024.101435. Epub 2024 Feb 27.

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

James Larkin¹, Richard Marais², Nuria Porta³, David Gonzalez de Castro⁴, Lisa Parsons⁵, Christina Messiou⁶, Gordon Stamp⁷, Lisa Thompson⁸, Kim Edmonds⁹, Sarah Sarker⁹, Jane Banerji³, Paul Lorigan¹⁰, Thomas R Jeffry Evans¹¹, Pippa Corrie¹², Ernest Marshall¹³, Mark R Middleton¹⁴, Paul Nathan¹⁵, Steve Nicholson¹⁶, Christian Ottensmeier¹⁷, Ruth Plummer¹⁸, Judith Bliss³, Sara Valpione¹⁹, Samra Turajlic²⁰

Affiliations

¹ Skin and Renal Units, The Royal Marsden Hospital NHS Foundation Trust, London, UK; Melanoma and Kidney Cancer Team, The Institute of Cancer Research, London, UK.
² Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK.
³ Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK.
⁴ Molecular Diagnostics, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK.
⁵ University of Edinburgh, Edinburgh, UK; PDD - Thermo Fisher Scientific, Bend, Oregon, USA.
⁶ Department of Radiology, The Royal Marsden Hospital NHS Foundation Trust, London, UK.
⁷ Department of Histopathology, The Royal Marsden Hospital NHS Foundation Trust, London, UK.
⁸ Centre for Molecular Pathology, The Royal Marsden Hospital NHS Foundation Trust, London, UK.
⁹ Skin and Renal Units, The Royal Marsden Hospital NHS Foundation Trust, London, UK.
¹⁰ Division of Cancer Sciences, Unviersity of Manchester, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK.
¹¹ Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
¹² Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹³ The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK.
¹⁴ Department of Oncology, University of Oxford, Oxford, UK.
¹⁵ Mount Vernon Cancer Centre, East & North Herts NHS Trust, Northwood, UK.
¹⁶ University Hospitals of Leicester NHS Foundation Trust, Leicester, UK.
¹⁷ University Hospitals Southampton NHS Foundation Trust, Southampton, UK.
¹⁸ Newcastle University and Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK.
¹⁹ Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK. Electronic address: sara.valpione@cruk.manchester.ac.uk.
²⁰ Skin and Renal Units, The Royal Marsden Hospital NHS Foundation Trust, London, UK; Melanoma and Kidney Cancer Team, The Institute of Cancer Research, London, UK; Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK. Electronic address: samra.turajlic@crick.ac.uk.

PMID: 38417447
PMCID: PMC10982988
DOI: 10.1016/j.xcrm.2024.101435

Clinical Trial

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

James Larkin et al. Cell Rep Med. 2024.

. 2024 Mar 19;5(3):101435.

doi: 10.1016/j.xcrm.2024.101435. Epub 2024 Feb 27.

Authors

Affiliations

¹ Skin and Renal Units, The Royal Marsden Hospital NHS Foundation Trust, London, UK; Melanoma and Kidney Cancer Team, The Institute of Cancer Research, London, UK.
² Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK.
³ Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK.
⁴ Molecular Diagnostics, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK.
⁵ University of Edinburgh, Edinburgh, UK; PDD - Thermo Fisher Scientific, Bend, Oregon, USA.
⁶ Department of Radiology, The Royal Marsden Hospital NHS Foundation Trust, London, UK.
⁷ Department of Histopathology, The Royal Marsden Hospital NHS Foundation Trust, London, UK.
⁸ Centre for Molecular Pathology, The Royal Marsden Hospital NHS Foundation Trust, London, UK.
⁹ Skin and Renal Units, The Royal Marsden Hospital NHS Foundation Trust, London, UK.
¹⁰ Division of Cancer Sciences, Unviersity of Manchester, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK.
¹¹ Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
¹² Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹³ The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK.
¹⁴ Department of Oncology, University of Oxford, Oxford, UK.
¹⁵ Mount Vernon Cancer Centre, East & North Herts NHS Trust, Northwood, UK.
¹⁶ University Hospitals of Leicester NHS Foundation Trust, Leicester, UK.
¹⁷ University Hospitals Southampton NHS Foundation Trust, Southampton, UK.
¹⁸ Newcastle University and Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK.
¹⁹ Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK. Electronic address: sara.valpione@cruk.manchester.ac.uk.
²⁰ Skin and Renal Units, The Royal Marsden Hospital NHS Foundation Trust, London, UK; Melanoma and Kidney Cancer Team, The Institute of Cancer Research, London, UK; Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK. Electronic address: samra.turajlic@crick.ac.uk.

PMID: 38417447
PMCID: PMC10982988
DOI: 10.1016/j.xcrm.2024.101435

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: KIT mutation; acral; liquid biopsy; melanoma; mucosal; tyrosine kinase inhibitor.

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Conflict of interest statement

Declaration of interests J.L. declares the following: honoraria: Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, BMS, Immatics, Insighter, and GCO; consultancy: iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, Incyte, Pfizer, and Novartis; speaker’s fees: Pierre Fabre, BMS, Ipsen, Roche, EUSA Pharma, Novartis, Aptitude, AstraZeneca, GSK, Eisai, Calithera, Ultimovacs, Seagen, Merck, eCancer, Inselgruppe, Pfizer, Goldman Sachs, MSD, Regional British Society of Gastroenterology, and Agence Unik; institutional research support: BMS, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, and Aveo; grants: Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo, and Pharmacyclics. R.M. is an expert witness for Pfizer and may benefit financially from commercialized programs. P.L. declares the following: honoraria: Novartis, PierreFabre, Merck, BMS, MSD, NeraCare GmbH, Amgen, Roche, OncologyEducation Canada, and Nektar; consultancy: Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre Fabre, Novartis, Nektar, and NeraCare GmbH; speakers’ bureaus: Merck Sharp & Dohme, Novartis, Bristol-Myers Squibb, and Pierre Fabre; institutional research funding: BMS and Pierre Fabre; travel, accommodations, expenses: Merck Sharp & Dohme and Bristol-Myers Squibb. T.R.J.E. reported the following competing interests: honoraria (payable to employing institution): Ascelia, AstraZeneca, Bicycle Therapeutics, BMS, Eisai, Medivir, MSD, Nucana, Roche/Genentech, and Seagen; advisory/consulting (payable to employing institution): Karus Therapeutics; speakers’ bureaus (payable to employing institution): AstraZeneca, BMS, Eisai, Medivir, MSD, Nucana, Roche/Genentech, and United Medical; research funding (payable to employing institution): Adaptimmune, Astellas Pharma, AstraZeneca, Athenex, Avacta, Basilea, Bayer, Beigene, Berg Pharma, Bicycle Therapeutics, BiolineRx, Boehringer Ingelheim, BMS, Celgene, Clovis Oncology, Codiak, CytomX Therapeutics, Eisai, GlaxoSmithKline, Halozyme, Immunocore, iOnctura, Iovance Biotherapeutics, Janssen, Johnson & Johnson, Lilly, Medivir, Merck Serono, MSD, MiNA Therapeutics, Modulate Pharma, Novartis, Nucana, Nurix, Plexxikon, Roche/Genentech, Sanofi/Aventis, Sapience Therapeutics, Seagen, Seattle Genetics, Sierra Pharma, Starpharma, T3P, UCB, Verastem, and Vertex; expert testimony (payable to employing institution): Medivir; support to attend international conferences (personal): BMS, Celgene, Eisai, MSD, Nucana, Pierre Fabre, and Roche; other relationship (payable to employing institution): Genmab. M.R.M. is supported by the NIHR Biomedical Research Center in Oxford and reports grants from Roche, AstraZeneca, GSK, GRAIL (outside the submitted work), grants and other from Immunocore, and other from Novartis, BMS, Pfizer, Merck/MSD, Regeneron, BiolineRx, and Replimune. P.N. reported having received funding for advisory boards and/or speakers’ bureau from the following sources: AstraZeneca, BMS, Esai, Ideaya, Immunocore, Ipsen, Medicenna, MSD, Merck, Novartis, and Pfizer. R.P. reported, in the last 4 years, having received honoraria for attending advisory boards from Pierre Faber, Bayer, Novartis, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Immunocore, Genmab, Astex Therapeutics, Medivir, and Sanofi Aventis; honoraria as an IDMC member for Alligator Biosciences, GSK, Onxeo, SOTIO Biotech AG, and AstraZeneca; having been paid for delivery of educational talks or chairing educational meetings by AstraZeneca, Novartis, Bayer, MSD, and BMS; and received funds to support attendance at conferences from MSD and BMS. J. Bliss reported receiving grants to ICR-CTSU from AstraZeneca, Merck Sharp & Dohme, Puma Biotechnology, Pfizer, Roche, Novartis (previously GlaxoSmithKline), Eli Lilly, Janssen-Cilag, Clovis Oncology, and Cancer Research UK; and nonfinancial support from the National Institute for Health Research. S.V. is a recipient of a research grant from Amgen. S.T. is funded by CRUK (grant no. A29911), the Francis Crick Institute, which receives its core funding from CRUK (FC10988), the UK Medical Research Council (FC10988), the Wellcome Trust (FC10988), the National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital and Institute of Cancer Research (grant no. A109), the Royal Marsden Cancer Charity, The Rosetrees Trust (grant no. A2204), Ventana Medical Systems (grant nos. 10467 and 10530), the National Institutes of Health (U01 CA247439), and the Melanoma Research Alliance (Award Ref no 686061). S.T. has received speaking fees from Roche, Astra Zeneca, Novartis, and Ipsen. S.T. has filed the following patents: Indel mutations as a therapeutic target and predictive biomarker PCTGB2018/051892 and PCTGB2018/051893 and P113326GB.

Figures

**Figure 1**
Patient flowchart in the NICAM trial

**Figure 2**
c-*KIT* molecular characterization in the NICAM trial The chart shows the individual c-*KIT* mutation characterization in the 29 trial patients who were enrolled in the molecular profiling. The gene fragment affected by mutations spanned from exons 9 to 17, comprising the immunoglobulin-like-C2 type 5 domain (green), a junction domain (pink), and the protein kinase domain (light blue). Each lollipop anchor corresponds to individual mutation sites (complex mutations are in purple and missense single-nucleotide mutations are in blue), and the height of the lollipop is indicative of the mutation frequency in the trial population.

**Figure 3**
Time on treatment for all entered NICAM patients, by cKIT mutation exon Bar length indicate months on treatment; objective disease progression and death are indicated in the figure. Patients were allowed to continue treatment as long as clinically indicated by the treating physician.

**Figure 4**
Association of mutation with outcome data (A) Percentage change from baseline at 12 weeks in sum of target lesions as per RECIST 1.1 by exon where *KIT* mutation was detected. (B) OS by exon where *KIT* mutation was detected. (C) Percentage change from baseline at 12 weeks in sum of target lesions as per RECIST 1.1 by type of *KIT* mutation. (D) OS by type of *KIT* mutation. For the waterfall plots (A) and (C), only evaluable patients with data at the 12-week scan since start of nilotinib are included.

See this image and copyright information in PMC

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

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

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Conflict of interest statement

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