Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with <i>BRAF</i>V600E Mutation

Hong, David S.; Morris, Van K.; Osta, Badi El; Sorokin, Alexey V.; Janků, Filip; Fu, Siqing; Overman, Michael J.; Piha-Paul, Sarina A.; Subbiah, Vivek; Kee, Bryan K.; Tsimberidou, Apostolia M.; Fogelman, David R.; Bellido, Jorge; Shureiqi, Imad; Huang, Helen J.; Atkins, Johnique T.; Tarcic, Gabi; Sommer, Nicolas; Lanman, Richard B.; Meric‐Bernstam, Funda; Kopetz, Scott

doi:10.1158/2159-8290.cd-16-0050

Cited by 199 publications

(173 citation statements)

References 31 publications

(34 reference statements)

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“…These results suggest that mutation clonality, as it exists in tumor tissue, can be estimated from properly normalized relative cfDNA VAFs, as has been previously hypothesized (28). High accuracy in VAF estimation is likely key to the success of this approach, and notably, VAFs measured by the cfDNA NGS assay used in this study show good agreement with digital droplet PCR (29,30). This approach points to the possibility of analyzing the clonal structures of tumors from cfDNA sequencing data, unencumbered by the complications of tumor heterogeneity and tumor impurity introduced by single-region tissue sampling.…”

Section: Discussionsupporting

confidence: 77%

The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

Zill

Banks

Fairclough

et al. 2018

Clinical Cancer Research

296

249

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Running title: Somatic genomic landscape of circulating tumor DNA Keywords: circulating tumor DNA, tumor heterogeneity, resistance, genomic landscape, cfDNA clonality Financial support: The study was funded by and conducted at Guardant Health, Inc. No additional grant support or administrative support was provided for the study. *Corresponding author:Stephen R. Fairclough Translational relevanceThis study describes genomic alterations from the largest cell-free circulating tumor DNA cohort to date, as derived from regular clinical practice. The high prevalence of resistance alterations found in advanced, treated cancer patients necessitated accurate methods for determining mutation clonality and driver/resistance status from plasma. We provide such methods, thereby extending the utility of cell-free DNA sequencing analysis. Our finding of an association between estimated circulating tumor DNA (ctDNA) levels and tumor mutational burden ascertained from plasma suggests that ctDNA level is likely an important variable to consider for immunotherapy applications of ctDNA analysis. Although cell-free DNA can provide a summary of tumor heterogeneity across multiple metastatic sites in a patient, our findings of high variability in ctDNA levels across patients, and its impact on variant detection, highlight the need for an improved understanding of factors influencing ctDNA levels and safe methods for maximizing them at the time of ctDNA testing. AbstractPurpose: Cell-free DNA (cfDNA) sequencing provides a non-invasive method for obtaining actionable genomic information to guide personalized cancer treatment, but the presence of multiple alterations in circulation related to treatment and tumor heterogeneity complicate the interpretation of the observed variants.Experimental Design: We describe the somatic mutation landscape of 70 cancer genes from cfDNA deep-sequencing analysis of 21,807 patients with treated, late-stage cancers across >50 cancer types. To facilitate interpretation of the genomic complexity of circulating tumor DNA in advanced, treated cancer patients, we developed methods to identify cfDNA copy-number driver alterations and cfDNA clonality.Results: Patterns and prevalence of cfDNA alterations in major driver genes for non-small cell lung, breast, and colorectal cancer largely recapitulated those from tumor tissue sequencing compendia (TCGA and COSMIC;, with the principle differences in alteration prevalence being due to patient treatment. This highly sensitive cfDNA sequencing assay revealed numerous subclonal tumor-derived alterations, expected as a result of clonal evolution, but leading to an apparent departure from mutual exclusivity in treatment-naïve tumors. Upon applying novel cfDNA clonality and copy-number driver identification methods, robust mutual exclusivity was observed among predicted truncal driver cfDNA alterations (FDR=5x10 -7 for EGFR and ERBB2), in effect distinguishing tumor-initiating alterations from secondary alterations. Treatment-associated resistance, including both novel ...

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Section: Discussionsupporting

confidence: 77%

The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

Zill

Banks

Fairclough

et al. 2018

Clinical Cancer Research

296

249

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“…However, the prognostic information might guide other clinical decisions. To improve outcomes for these patients, recent studies have evaluated feasibility of treatment with anti-EGFR antibodies and other targeted agents (38,39).…”

Section: Discussionmentioning

confidence: 99%

Analysis of KRAS/NRAS Mutations in a Phase III Study of Panitumumab with FOLFIRI Compared with FOLFIRI Alone as Second-line Treatment for Metastatic Colorectal Cancer

Peeters

Oliner

Price

et al. 2015

Clinical Cancer Research

163

140

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Purpose: We evaluated the influence of RAS mutation status on the treatment effect of panitumumab in a prospective-retrospective analysis of a randomized, multicenter phase III study of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) versus FOLFIRI alone as second-line therapy in patients with metastatic colorectal cancer (mCRC; ClinicalTrials.gov, NCT0039183).Experimental Design: Outcomes were from the study's primary analysis. RAS mutations beyond KRAS exon 2 (KRAS exons 3, 4; NRAS exons 2, 3, 4; BRAF exon 15) were detected by bidirectional Sanger sequencing in wild-type KRAS exon 2 tumor specimens. Progression-free survival (PFS) and overall survival (OS) were coprimary endpoints.Results: The RAS ascertainment rate was 85%; 18% of wild-type KRAS exon 2 tumors harbored other RAS mutations. For PFS and OS, the hazard ratio (HR) for panitumumab plus FOLFIRI versus Patients with RAS mutations were unlikely to benefit from panitumumab. Among RAS wild-type patients, the objective response rate was 41% in the panitumumab-FOLFIRI group versus 10% in the FOLFIRI group.Conclusions: Patients with RAS mutations were unlikely to benefit from panitumumab-FOLFIRI and the benefit-risk of panitumumab-FOLFIRI was improved in the wild-type RAS population compared with the wild-type KRAS exon 2 population. These findings support RAS testing for patients with mCRC.

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“…This phase I study of the BRAF inhibitor LGX818 in combination with cetuximab, with or without the PIK3CA inhibitor BYL719, in advanced BRAF-mutated and KRAS wild-type colorectal cancer patients reported no complete responses but 7 ($30%) partial responses from the dual combination of LGX818 with cetuximab and 6 ($30%) partial responses from the triple combination of LGX818, cetuximab, and BYL719 (81). Finally, preliminary results from a phase Ib trial of vemurafenib in combination with irinotecan and cetuximab in BRAFmutated advanced cancers and colorectal cancer patients reported that 6 of 17 evaluable BRAF V600E-mutated colorectal cancer patients achieved a partial response Hong and colleagues (82).…”

Section: Role Of Egfrmentioning

confidence: 99%

Genomically Driven Tumors and Actionability across Histologies:BRAF-Mutant Cancers as a Paradigm

Turski¹,

Vidwans²,

Janků

et al. 2016

Molecular Cancer Therapeutics

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The diagnosis, classification, and management of cancer are traditionally dictated by the site of tumor origin, for example, breast or lung, and by specific histologic subtypes of site-oforigin cancers (e.g., non-small cell versus small cell lung cancer). However, with the advent of sequencing technologies allowing for rapid, low cost, and accurate sequencing of clinical samples, new observations suggest an expanded or different approach to the diagnosis and treatment of cancer-one driven by the unique molecular features of the tumor. We discuss a genomically driven strategy for cancer treatment using BRAF as an example. Several key points are highlighted: (i) molecular aberrations can be shared across cancers; (ii) approximately 15% of all cancers harbor BRAF mutations; and (iii) BRAF inhibitors, while approved only for melanoma, have reported activity across numerous cancers and related disease types bearing BRAF aberrations. However, BRAF-mutated colorectal cancer has shown poor response rate to BRAF inhibitor monotherapy, striking a cautionary note. Yet, even in this case, emerging data suggest BRAF-mutated colorectal cancers can respond well to BRAF inhibitors, albeit when administered in combination with other agents that impact resistance pathways. Taken together, these data suggest that molecular aberrations may be the basis for a new nosology for cancer. Mol Cancer Ther; 15(4); 533-47. Ó2016 AACR.

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Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation

Cited by 199 publications

References 31 publications

The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

Analysis of KRAS/NRAS Mutations in a Phase III Study of Panitumumab with FOLFIRI Compared with FOLFIRI Alone as Second-line Treatment for Metastatic Colorectal Cancer

Genomically Driven Tumors and Actionability across Histologies:BRAF-Mutant Cancers as a Paradigm

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