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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Published in:Clinical cancer research Vol. 27; no. 8; p. 2226
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 15.04.2021
Subjects:
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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Summary: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.
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ISSN:1557-3265
1557-3265
DOI:10.1158/1078-0432.CCR-20-4189