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Genomic Features of Exceptional Response in Vemurafenib

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Genomic Features of Exceptional Response in Vemurafenib Published OnlineFirst March 1, 2019; DOI: 10.1158/1078-0432.CCR-18-0720 Clinical Trials: Immunotherapy Clinical Cancer Research Genomic Features of Exceptional Response in Vemurafenib Æ Cobimetinib–treated Patients with BRAFV600-mutated Metastatic Melanoma Yibing Yan1, Matthew J.Wongchenko1, Caroline Robert2, James Larkin3, Paolo A. Ascierto4, Brigitte Dreno 5, Michele Maio6, Claus Garbe7, Paul B. Chapman8, Jeffrey A. Sosman9, Zhen Shi1, Hartmut Koeppen1, Jessie J. Hsu1, Ilsung Chang1, Ivor Caro1, Isabelle Rooney1, Grant A. McArthur10, and Antoni Ribas11 Abstract Purpose: Previous investigations identified transcriptional Results: Whole-exome sequencing showed that MITF and signatures associated with innate resistance to anti– TP53 alterations were more frequent in tumors from patients programmed cell death protein 1 therapy in melanoma. This with rapid progression, while NF1 alterations were more analysis aimed to increase understanding of the role of base- frequent in tumors from patients with complete response. line genetic features in the variability of response to BRAF However, the low frequency of alterations in any one gene and MEK inhibitor therapy for BRAFV600-mutated metastatic precluded their characterization as drivers of response/ melanoma. resistance. Analysis of RNA profiles showed that expression Patients and Methods: This exploratory analysis compared of immune response–related genes was enriched in tumors genomic features, using whole-exome and RNA sequencing, of from patients with complete response, while expression of baseline tumors from patients who had complete response keratinization-related genes was enriched in tumors from versus rapid progression (disease progression at first postbase- patients who experienced rapid progression. line assessment) on treatment with cobimetinib combined Conclusions: These findings suggest that enriched immune with vemurafenib or vemurafenib alone. Associations of gene infiltration might be a shared feature favoring response to both expression with progression-free survival or overall survival targeted and immune therapies, while features of innate were assessed by Cox proportional hazards modeling. resistance to targeted and immune therapies were distinct. Introduction with response to either targeted therapies or immunotherapies to allow consideration of treatment that will optimize benefits The introduction of small-molecule inhibitors of BRAF and for the individual patient. An investigation of genomic features MEK and mAbs targeting programmed cell death protein 1 in responders compared with nonresponders identified (PD-1) and CTL–associated antigen 4 have remarkably improv- transcriptional signatures associated with innate resistance to ed treatment outcomes for patients with metastatic melano- anti–PD-1 therapy (16, 17), although no common feature was ma (1–15). With the emergence of distinct classes of therapies, identified to predict the response. While previous investigation there is a need to better understand baseline features associated of the mechanisms of acquired resistance to inhibitors of the MAPK pathway identified MAPK reactivation by various genetic 1Genentech, Inc., South San Francisco, California. 2Institut Gustave Roussy, and epigenetic alterations developed during treatment (18, 19), Villejuif, France. 3The Royal Marsden NHS Foundation Trust, The Royal Marsden baseline features predicting response to MAPK-targeted thera- Hospital, London, United Kingdom. 4Istituto Nazionale Tumori Fondazione pies have not been examined. 5 6 Pascale, Napoli, Italy. Nantes University, CHU Nantes, France. Center for Combined MEK and BRAF inhibition with cobimetinib Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, and vemurafenib has been shown to improve response rates, Italy. 7Universitatsklinikum€ Tubingen,€ Tubingen,€ Germany. 8Memorial Sloan Kettering Cancer Center, New York, New York. 9Robert H. Lurie Comprehensive progression-free survival (PFS; refs. 4, 5), and overall survival (OS; Cancer Center of Northwestern University, Chicago, Illinois. 10Peter MacCallum ref. 6) compared with BRAF inhibitor monotherapy. Responses Cancer Centre, Melbourne, Australia and University of Melbourne, Parkville, to BRAF and MEK inhibitors vary between patients; while some Australia. 11Jonsson Comprehensive Cancer Center at the University of Califor- patients achieve complete response (CR), a proportion of patients nia, Los Angeles, David Geffen UCLA School of Medicine, Los Angeles, California. demonstrate rapid disease progression suggestive of some degree Note: Supplementary data for this article are available at Clinical Cancer of innate resistance. A better understanding of the mechanisms Research Online (http://clincancerres.aacrjournals.org/). underlying the variability of patient responses to these BRAF and Corresponding Author: Antoni Ribas, Jonsson Comprehensive Cancer Center at MEK inhibitors is required to target therapy more effectively. the University of California, Los Angeles, 10833 LeConte Avenue, Los Angeles, The objective of this retrospective, exploratory analysis was to CA 90095. Phone: 310-206-3928; Fax: 310-825-2493; E-mail: compare genomic features of pretreatment tumors from complete [email protected] responders with those from rapid progressors on treatment with doi: 10.1158/1078-0432.CCR-18-0720 cobimetinib combined with vemurafenib or vemurafenib alone V600 Ó2019 American Association for Cancer Research. in patients with BRAF -mutated metastatic melanoma. www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst March 1, 2019; DOI: 10.1158/1078-0432.CCR-18-0720 Yan et al. assessment] according to Response Evaluation Criteria in Solid Translational Relevance Tumors, version 1.1, on treatment with cobimetinib combined Our exploratory analysis of baseline BRAFV600-mutated mel- with vemurafenib or vemurafenib alone. anoma samples from the BRAF inhibitor in melanoma (BRIM) Each of the trials was conducted in accordance with the studies aimed to identify genetic characteristics of patients with a Declaration of Helsinki and the principles of Good Clinical complete response or no response to combined BRAF and MEK and Laboratory Practice and with the approval of appropriate inhibition with vemurafenib and cobimetinib. No individual ethics committees. All participants in each study provided written mutation was identified as a population-wide driver of excep- informed consent. tional response, but certain gene expression signatures were found to distinguish the 2 extremes of response. Melanomas Whole-exome sequencing from patients with complete response possessed higher preex- Baseline formalin-fixed, paraffin-embedded (FFPE) tumor isting tumor immunity features, while those from patients with samples from patients with complete response and patients with rapid progression had a keratin signature similar to one previ- rapid progression were analyzed by whole-exome sequencing fi ously associated with poor prognosis. These ndings suggest that (WES). Patient samples where BRAF mutations were not detected fi enriched immune in ltration of melanomas may be a shared were excluded from the analysis. feature of favorable response to both targeted and immune DNA exomes were captured using the Agilent SureSelect 51 Mb therapies, while features of innate resistance to immune and Kit (SQ756; Agilent Technologies, Inc.) and sequenced to a target fi targeted therapies were distinct. We anticipate these ndings depth of 100 Â. Reads were aligned to human reference genome could assist in optimization of treatment selection for patients GRCh38 using genomic short-read nucleotide alignment pro- BRAFV600 with -mutated metastatic melanoma. gram (20). Variants were called using LoFreq (21). For variant filtering, sequencing data pooled from normal tissue samples from 106 patients in the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies and data from the Exome Aggregation Consortium (ExAC) Patients and Methods database (22) were used as reference data in the variant calling algorithm. Copy-number alterations were identified using Analysis population CODEX (23). Variants and copy-number alterations were anno- BRAFV600 Data from patients with -mutated metastatic mel- tated using the Ensembl Variant Effect Predictor tool (24). anoma treated with cobimetinib combined with vemurafenib or vemurafenib in the BRIM-2, BRIM-3, BRIM-7, and coBRIM RNA sequencing studies were included in the analysis. Detailed methods A subset of baseline tumor samples from patients with CR have previously been reported for each study. BRIM-2 and patients with PD were evaluated by RNA sequencing (ClinicalTrials.gov ID, NCT00949702) was a multicenter, (RNA-Seq) to identify transcriptional signatures. mRNA librar- single-arm phase II study in which patients were treated with ies were prepared using TruSeq RNA Access (Illumina). Paired- vemurafenib 960 mg twice daily (1). BRIM-3 (ClinicalTrials. end 2 Â 100 base reads were generated on a HiSeq system gov ID, NCT01006980) was a multicenter, randomized, open- (Illumina). Reads were aligned to human reference genome label phase III study in which patients were randomly assigned GRCh38 using a genomic short-read nucleotide alignment to receive vemurafenib 960 mg twice daily or dacarbazine program, and reads that overlapped gene exonic regions were 1,000 mg/m2 every 3 weeks (2, 3). BRIM-7 (ClinicalTrials.gov counted (20). Differentially expressed
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