posted on 2023-03-31, 22:42authored byAlexander N. Shoushtari, Walid K. Chatila, Arshi Arora, Francisco Sanchez-Vega, Havish S. Kantheti, Jorge A. Rojas Zamalloa, Penina Krieger, Margaret K. Callahan, Allison Betof Warner, Michael A. Postow, Parisa Momtaz, Suresh Nair, Charlotte E. Ariyan, Christopher A. Barker, Mary Susan Brady, Daniel G. Coit, Neal Rosen, Paul B. Chapman, Klaus J. Busam, David B. Solit, Katherine S. Panageas, Jedd D. Wolchok, Nikolaus Schultz
(A) Oncoprint showing similar rates of driver alterations between cutaneous melanomas and melanomas of unknown primary. This suggests the vast majority of melanomas of unknown primary arose from regressed cutaneous sites. (B) Sequenced melanomas arising in females (N=244) have a lower median TMB than those arising in males (N=475; 15.7 vs 17.6 mut/Mb, p= 0.024). (C) The median fraction of alterations associated with an ultraviolet signature varies by MAPK Driver (p=9.6e-9). (D) The median fraction of alterations associated with an ultraviolet signature varies by primary site (p=3.9e-10).
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ARTICLE ABSTRACT
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 (N = 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; P < 0.0001). Driver group remained significant, independent of tumor mutational burden and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab (N = 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.