Genomic Features of Exceptional Response in Vemurafenib ± Cobimetinib-treated Patients with BRAFV600-mutated Metastatic Melanoma

Yibing Yan, Matthew J Wongchenko, Caroline Robert, James Larkin, Paolo A Ascierto, Brigitte Dréno, Michele Maio, Claus Garbe, Paul B Chapman, Jeffrey A Sosman, Zhen Shi, Hartmut Koeppen, Jessie J Hsu, Ilsung Chang, Ivor Caro, Isabelle Rooney, Grant A McArthur, Antoni Ribas

Research output: Contribution to journalArticle

Abstract

Purpose: Previous investigations identified transcriptional signatures associated with innate resistance to anti-programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for BRAFV600-mutated metastatic melanoma.Patients and Methods: This exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with cobimetinib combined with vemurafenib or vemurafenib alone. Associations of gene expression with progression-free survival or overall survival were assessed by Cox proportional hazards modeling.Results: Whole-exome sequencing showed that MITF and TP53 alterations were more frequent in tumors from patients with rapid progression, while NF1 alterations were more frequent in tumors from patients with complete response. However, the low frequency of alterations in any one gene precluded their characterization as drivers of response/resistance. Analysis of RNA profiles showed that expression of immune response-related genes was enriched in tumors from patients with complete response, while expression of keratinization-related genes was enriched in tumors from patients who experienced rapid progression.Conclusions: These findings suggest that enriched immune infiltration might be a shared feature favoring response to both targeted and immune therapies, while features of innate resistance to targeted and immune therapies were distinct.

Original languageEnglish
JournalClinical Cancer Research
DOIs
Publication statusPublished - 2019

Fingerprint

Melanoma
Exome
Neoplasms
Programmed Cell Death 1 Receptor
Genes
RNA Sequence Analysis
Therapeutics
Mitogen-Activated Protein Kinase Kinases
Disease-Free Survival
Disease Progression
GDC-0973
PLX4032
RNA
Gene Expression
Survival

Cite this

Genomic Features of Exceptional Response in Vemurafenib ± Cobimetinib-treated Patients with BRAFV600-mutated Metastatic Melanoma. / Yan, Yibing; Wongchenko, Matthew J; Robert, Caroline; Larkin, James; Ascierto, Paolo A; Dréno, Brigitte; Maio, Michele; Garbe, Claus; Chapman, Paul B; Sosman, Jeffrey A; Shi, Zhen; Koeppen, Hartmut; Hsu, Jessie J; Chang, Ilsung; Caro, Ivor; Rooney, Isabelle; McArthur, Grant A; Ribas, Antoni.

In: Clinical Cancer Research, 2019.

Research output: Contribution to journalArticle

Yan, Y, Wongchenko, MJ, Robert, C, Larkin, J, Ascierto, PA, Dréno, B, Maio, M, Garbe, C, Chapman, PB, Sosman, JA, Shi, Z, Koeppen, H, Hsu, JJ, Chang, I, Caro, I, Rooney, I, McArthur, GA & Ribas, A 2019, 'Genomic Features of Exceptional Response in Vemurafenib ± Cobimetinib-treated Patients with BRAFV600-mutated Metastatic Melanoma', Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-18-0720
Yan, Yibing ; Wongchenko, Matthew J ; Robert, Caroline ; Larkin, James ; Ascierto, Paolo A ; Dréno, Brigitte ; Maio, Michele ; Garbe, Claus ; Chapman, Paul B ; Sosman, Jeffrey A ; Shi, Zhen ; Koeppen, Hartmut ; Hsu, Jessie J ; Chang, Ilsung ; Caro, Ivor ; Rooney, Isabelle ; McArthur, Grant A ; Ribas, Antoni. / Genomic Features of Exceptional Response in Vemurafenib ± Cobimetinib-treated Patients with BRAFV600-mutated Metastatic Melanoma. In: Clinical Cancer Research. 2019.
@article{eee54e12604a41dc9cf9671b199d976d,
title = "Genomic Features of Exceptional Response in Vemurafenib ± Cobimetinib-treated Patients with BRAFV600-mutated Metastatic Melanoma",
abstract = "Purpose: Previous investigations identified transcriptional signatures associated with innate resistance to anti-programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for BRAFV600-mutated metastatic melanoma.Patients and Methods: This exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with cobimetinib combined with vemurafenib or vemurafenib alone. Associations of gene expression with progression-free survival or overall survival were assessed by Cox proportional hazards modeling.Results: Whole-exome sequencing showed that MITF and TP53 alterations were more frequent in tumors from patients with rapid progression, while NF1 alterations were more frequent in tumors from patients with complete response. However, the low frequency of alterations in any one gene precluded their characterization as drivers of response/resistance. Analysis of RNA profiles showed that expression of immune response-related genes was enriched in tumors from patients with complete response, while expression of keratinization-related genes was enriched in tumors from patients who experienced rapid progression.Conclusions: These findings suggest that enriched immune infiltration might be a shared feature favoring response to both targeted and immune therapies, while features of innate resistance to targeted and immune therapies were distinct.",
author = "Yibing Yan and Wongchenko, {Matthew J} and Caroline Robert and James Larkin and Ascierto, {Paolo A} and Brigitte Dr{\'e}no and Michele Maio and Claus Garbe and Chapman, {Paul B} and Sosman, {Jeffrey A} and Zhen Shi and Hartmut Koeppen and Hsu, {Jessie J} and Ilsung Chang and Ivor Caro and Isabelle Rooney and McArthur, {Grant A} and Antoni Ribas",
note = "{\circledC}2019 American Association for Cancer Research.",
year = "2019",
doi = "10.1158/1078-0432.CCR-18-0720",
language = "English",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",

}

TY - JOUR

T1 - Genomic Features of Exceptional Response in Vemurafenib ± Cobimetinib-treated Patients with BRAFV600-mutated Metastatic Melanoma

AU - Yan, Yibing

AU - Wongchenko, Matthew J

AU - Robert, Caroline

AU - Larkin, James

AU - Ascierto, Paolo A

AU - Dréno, Brigitte

AU - Maio, Michele

AU - Garbe, Claus

AU - Chapman, Paul B

AU - Sosman, Jeffrey A

AU - Shi, Zhen

AU - Koeppen, Hartmut

AU - Hsu, Jessie J

AU - Chang, Ilsung

AU - Caro, Ivor

AU - Rooney, Isabelle

AU - McArthur, Grant A

AU - Ribas, Antoni

N1 - ©2019 American Association for Cancer Research.

PY - 2019

Y1 - 2019

N2 - Purpose: Previous investigations identified transcriptional signatures associated with innate resistance to anti-programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for BRAFV600-mutated metastatic melanoma.Patients and Methods: This exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with cobimetinib combined with vemurafenib or vemurafenib alone. Associations of gene expression with progression-free survival or overall survival were assessed by Cox proportional hazards modeling.Results: Whole-exome sequencing showed that MITF and TP53 alterations were more frequent in tumors from patients with rapid progression, while NF1 alterations were more frequent in tumors from patients with complete response. However, the low frequency of alterations in any one gene precluded their characterization as drivers of response/resistance. Analysis of RNA profiles showed that expression of immune response-related genes was enriched in tumors from patients with complete response, while expression of keratinization-related genes was enriched in tumors from patients who experienced rapid progression.Conclusions: These findings suggest that enriched immune infiltration might be a shared feature favoring response to both targeted and immune therapies, while features of innate resistance to targeted and immune therapies were distinct.

AB - Purpose: Previous investigations identified transcriptional signatures associated with innate resistance to anti-programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for BRAFV600-mutated metastatic melanoma.Patients and Methods: This exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with cobimetinib combined with vemurafenib or vemurafenib alone. Associations of gene expression with progression-free survival or overall survival were assessed by Cox proportional hazards modeling.Results: Whole-exome sequencing showed that MITF and TP53 alterations were more frequent in tumors from patients with rapid progression, while NF1 alterations were more frequent in tumors from patients with complete response. However, the low frequency of alterations in any one gene precluded their characterization as drivers of response/resistance. Analysis of RNA profiles showed that expression of immune response-related genes was enriched in tumors from patients with complete response, while expression of keratinization-related genes was enriched in tumors from patients who experienced rapid progression.Conclusions: These findings suggest that enriched immune infiltration might be a shared feature favoring response to both targeted and immune therapies, while features of innate resistance to targeted and immune therapies were distinct.

U2 - 10.1158/1078-0432.CCR-18-0720

DO - 10.1158/1078-0432.CCR-18-0720

M3 - Article

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

ER -