Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations.

Abstract

BACKGROUND:

Inherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in CDKN2A mutation carriers with metastatic melanoma were evaluated.

METHODS:

CDKN2A mutation carriers that have developed metastatic melanoma and undergone immunotherapy treatments were identified among carriers enrolled in follow-up studies for familial melanoma. The carriers' responses were compared with responses reported in phase III clinical trials for CTLA-4 and PD-1 inhibitors. From publicly available data sets, melanomas with somatic CDKN2A mutation were analysed for association with tumour mutational load.

RESULTS:

Eleven of 19 carriers (58%) responded to the therapy, a significantly higher frequency than observed in clinical trials (p=0.03, binomial test against an expected rate of 37%). Further, 6 of the 19 carriers (32%) had complete response, a significantly higher frequency than observed in clinical trials (p=0.01, binomial test against an expected rate of 7%). In 118 melanomas with somatic CDKN2A mutations, significantly higher total numbers of mutations were observed compared with 761 melanomas without CDKN2A mutation (Wilcoxon test, p<0.001).

CONCLUSION:

Patients with CDKN2A mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses.

• Authors: Hildur Helgadottir, Paola Ghiorzo, Remco van Doorn, Susana Puig, Max Levin, Richard Kefford, Martin Lauss, Paola Queirolo, Lorenza Pastorino, Ellen Kapiteijn, Miriam Potrony, Cristina Carrera, Håkan Olsson, Veronica Höiom, Göran Jönsson
• Journal: Journal of medical genetics (J Med Genet) Vol. 57 Issue 5 Pg. 316-321 (05 2020) ISSN: 1468-6244 [Electronic] England
• PMID: 30291219 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• CDKN2A protein, human
• CTLA-4 Antigen
• CTLA4 protein, human
• Cyclin-Dependent Kinase Inhibitor p16
• Immune Checkpoint Inhibitors
• Ipilimumab
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor

Topics

• Adult
• Aged
• CTLA-4 Antigen (antagonists & inhibitors, genetics)
• Clinical Trials as Topic
• Cyclin-Dependent Kinase Inhibitor p16 (genetics)
• Female
• Germ-Line Mutation (genetics)
• Humans
• Immune Checkpoint Inhibitors (administration & dosage, adverse effects)
• Immunotherapy (adverse effects)
• Ipilimumab (administration & dosage, adverse effects)
• Male
• Melanoma (drug therapy, genetics, pathology)
• Middle Aged
• Neoplasm Metastasis
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, genetics)