Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas

Cutaneous and unknown primary melanomas frequently harbor alterations that activate the MAPK pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown. Patients with melanoma were prospectively offered tumor sequencing of 341-468 genes....

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Vydáno v:	Clinical cancer research Ročník 27; číslo 8; s. 2226
Hlavní autoři:	Shoushtari, Alexander N, Chatila, Walid K, Arora, Arshi, Sanchez-Vega, Francisco, Kantheti, Havish S, Rojas Zamalloa, Jorge A, Krieger, Penina, Callahan, Margaret K, Betof Warner, Allison, Postow, Michael A, Momtaz, Parisa, Nair, Suresh, Ariyan, Charlotte E, Barker, Christopher A, Brady, Mary Susan, Coit, Daniel G, Rosen, Neal, Chapman, Paul B, Busam, Klaus J, Solit, David B, Panageas, Katherine S, Wolchok, Jedd D, Schultz, Nikolaus
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 15.04.2021
Témata:	Adolescent Adult Aged Aged, 80 and over Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Child Drug Resistance, Neoplasm - genetics Female Gain of Function Mutation Humans Immune Checkpoint Inhibitors - pharmacology Immune Checkpoint Inhibitors - therapeutic use Ipilimumab - pharmacology Ipilimumab - therapeutic use Kaplan-Meier Estimate Male MAP Kinase Signaling System - genetics Melanoma - drug therapy Melanoma - genetics Melanoma - mortality Melanoma - secondary Middle Aged Mitogen-Activated Protein Kinases - genetics Neoplasms, Unknown Primary - drug therapy Neoplasms, Unknown Primary - genetics Neoplasms, Unknown Primary - immunology Neoplasms, Unknown Primary - mortality Nivolumab - pharmacology Nivolumab - therapeutic use Prognosis Programmed Cell Death 1 Receptor - antagonists & inhibitors Prospective Studies Retrospective Studies Skin Neoplasms - drug therapy Skin Neoplasms - genetics Skin Neoplasms - immunology Skin Neoplasms - mortality Time Factors Treatment Outcome Young Adult
ISSN:	1557-3265, 1557-3265
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Shrnutí:	Cutaneous and unknown primary melanomas frequently harbor alterations that activate the MAPK pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown. Patients with melanoma were prospectively offered tumor sequencing of 341-468 genes. Oncogenic alterations in 28 RTK-RAS-MAPK pathway genes were used to construct MAPK driver groups. Time to treatment failure (TTF) was determined for patients who received first-line programmed cell death protein 1 (PD-1) monotherapy, nivolumab plus ipilimumab, or subsequent genomically matched targeted therapies. A Cox proportional hazards model was constructed for TTF using driver group and clinical variables. A total of 670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had ≥1 driver. Nine driver groups varied by clinical presentation and mutational burden. TTF of PD-1 monotherapy ( = 181) varied by driver, with worse outcomes for NRAS Q61 and BRAF V600 versus NF1 or other alterations (median 4.2, 7.5, 22, and not reached; < 0.0001). Driver group remained significant, independent of tumor mutational burden and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab ( = 141). Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 27 were treated with genomically matched therapy, and eight (30%) derived clinical benefit lasting ≥6 months. Targeted capture multigene sequencing can detect oncogenic RTK-RAS-MAPK pathway alterations in almost all cutaneous and unknown primary melanomas. TTF of PD-1 monotherapy varies by mechanism of ERK activation. Oncogenic kinase fusions can be successfully targeted in immune checkpoint inhibitor-refractory melanoma.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1557-3265 1557-3265
DOI:	10.1158/1078-0432.CCR-20-4189