Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas
- 28 January 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 27 (8), 2226-2235
- https://doi.org/10.1158/1078-0432.ccr-20-4189
Abstract
Purpose: Cutaneous and unknown primary melanomas frequently harbor alterations that activate the Mitogen Activated Protein Kinase (MAPK) pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown.Methods:Patients with melanoma were prospectivelyofferedtumor sequencingof 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 determinedfor patients who received frontline PD-1 monotherapy,nivolumab plus ipilimumab,or subsequentgenomically matched targeted therapies.A Cox proportional hazards model was constructed for TTF using driver group and clinical variables.Results:670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had {greater than or equal to}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 TMB 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 8 (30%) derived clinical benefit lasting {greater than or equal to}6 months. Conclusion: Targeted capture multigene sequencingcan detect oncogenicRTK-RAS-MAPK pathway alterations in almost allcutaneous and unknown primary melanomas. Time to treatment failure of PD-1 monotherapy varies by mechanism of ERK activation.Oncogenic kinase fusionscan be successfully targetedin immune checkpointinhibitor-refractory melanoma.Keywords
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Funding Information
- NCI (P30CA008748)
- NIH (T32 GM132083)
- NIH (R01CA229624)
This publication has 28 references indexed in Scilit:
- Pembrolizumab versus Ipilimumab in Advanced MelanomaThe New England Journal of Medicine, 2015
- Association BetweenNRASandBRAFMutational Status and Melanoma-Specific Survival Among Patients With Higher-Risk Primary MelanomaJAMA Oncology, 2015
- Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancerScience, 2015
- Nivolumab in Previously Untreated Melanoma withoutBRAFMutationThe New England Journal of Medicine, 2015
- Genetic Basis for Clinical Response to CTLA-4 Blockade in MelanomaThe New England Journal of Medicine, 2014
- Loss of NF1 in Cutaneous Melanoma Is Associated with RAS Activation and MEK DependenceCancer Research, 2014
- Relief of Profound Feedback Inhibition of Mitogenic Signaling by RAF Inhibitors Attenuates Their Activity in BRAFV600E MelanomasCancer Cell, 2012
- A Landscape of Driver Mutations in MelanomaCell, 2012
- The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics DataCancer Discovery, 2012
- KIT as a Therapeutic Target in Metastatic MelanomaJAMA, 2011