BIG BANG study (EPOC1703): multicentre, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy with binimetinib, encorafenib and cetuximab in patients with BRAF non-V600E mutated metastatic colorectal cancer

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

While the BRAF V600E mutation occurs in 5%–15% of metastatic colorectal cancer (mCRC), BRAF non-V600E mutations were recently reported to range from 1.6% to 5.1%. We have previously reported that BRAF non-V600E mutations could have a negative impact on efficacy outcomes as well as BRAF V600E mutation for antiepidermal growth factor receptor (EGFR) antibody treatment for pretreated patients with mCRC. Recently, simultaneous inhibitions of mitogen-activated protein kinase kinase (MEK), BRAF and EGFR exhibited relevant antitumour activities in patients with BRAF V600E mutant and also in BRAF non-V600E mutant but only in the preclinical model.

Trial design

The BIG BANG (study is a multicentre, phase II study to assess the efficacy, safety and proof of concept of the combinations of binimetinib+encorafenib+cetuximab in patients with BRAF non-V600E mutated mCRC, identified by either tumour tissue (tumour tissue group) or blood samples (liquid biopsy group). Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1, mCRC with BRAF non-V600E mutant and RAS wild type, refractory or intolerant to at least one fluoropyrimidine-based regimen and no prior history of regorafenib, and no prior history of anti-EGFR antibody treatment (primary analysis cohort and liquid biopsy cohort) or refractory to prior anti-EGFR antibody treatment in patients with class 3 BRAF mutations (anti-EGFR antibody refractory class three cohort). Enrolled patients receive binimetinib (45 mg, two times per day), encorafenib (300 mg, once a day) and cetuximab (initially 400 mg/m ² and subsequently 250 mg/m ², once per week). The primary endpoint is the confirmed objective response rate in the primary analysis cohort.

Trial registration numbers

UMIN000031857 and 000031860.

Related collections

Most cited references 16

Record: found
Abstract: found
Article: not found

Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer

Rona Yaeger, Walid K. Chatila, Marla D Lipsyc … (2018)

Metastatic colorectal cancers (mCRCs) are clinically heterogeneous, but the genomic basis of this variability remains poorly understood. We performed prospective targeted sequencing of 1134 CRCs. We identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1 , increasing oncogenic WNT pathway alterations to 96% of CRCs. Right-sided primary site in microsatellite stable mCRC was associated with shorter survival, older age at diagnosis, increased mutations, and enrichment of oncogenic alterations in KRAS , BRAF , PIK3CA , AKT1 , RNF43 , and SMAD4 compared to left-sided primaries. Left-sided tumors frequently had no identifiable genetic alteration in mitogenic signaling, but exhibited higher mitogenic ligand expression. Our results suggest different pathways to tumorigenesis in right- and left-sided microsatellite stable CRC that may underlie clinical differences.

0 comments Cited 353 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer.

Ryan B. Corcoran, Thierry André, Chloe E Atreya … (2018)

Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.Significance: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 428-43. ©2018 AACR.See related commentary by Janku, p. 389See related article by Hazar-Rethinam et al., p. 417This article is highlighted in the In This Issue feature, p. 371.

0 comments Cited 229 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS

Zhan Yao, Rona Yaeger, Vanessa S Rodrik-Outmezguine … (2017)

Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants—those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS–GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

0 comments Cited 224 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): ESMO Open

Journal ID (iso-abbrev): ESMO Open

Journal ID (hwp): esmoopen

Journal ID (publisher-id): esmoopen

Title: ESMO Open

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2059-7029

Publication date Collection: 2020

Publication date (Electronic): 10 February 2020

Volume: 5

Issue: 1

Electronic Location Identifier: e000624

Affiliations

[1 ] departmentDepartment of Gastrointestinal Oncology , National Cancer Center Hospital East , Kashiwa, Chiba, Japan

[2 ] departmentDepartment of Clinical Oncology , Aichi Cancer Center Hospital , Nagoya, Japan

[3 ] departmentDepartment of Cancer Chemotherapy , Hokkaido University Hospital , Sapporo, Hokkaido, Japan

[4 ] departmentDepartment of Gastroenterological Medicine , Cancer Institute Hospital of Japanese Foundation for Cancer Research , Tokyo, Japan

[5 ] departmentDepartment of Clinical Oncology , St. Marianna University School of Medicine , Kawasaki, Japan

[6 ] departmentFrontier Science for Cancer and Chemotherapy , Osaka University , Suita, Osaka, Japan

[7 ] departmentDepartment of Gastrointestinal Medical Oncology , National Hospital Organization Shikoku Cancer Center , Matsuyama, Japan

[8 ] departmentDepartment of Gastrointestinal and Medical Oncology , National Kyushu Cancer Center , Fukuoka, Japan

[9 ] departmentClinical Research Support Office , National Cancer Center Hospital East , Kashiwa, Chiba, Japan

[10 ] departmentPathology Division, Research Center for Innovative Oncology , National Cancer Center Hospital East , Kashiwa, Chiba, Japan

[11 ] departmentDepartment of Gastrointestinal Oncology , National Cancer Center Hospital East , Chiba, Japan

[12 ] departmentDivision of Oncological Pathology , Aichi Cancer Center Research Institute , Nagoya, Aichi, Japan

Author notes

[Correspondence to ] Dr Hideaki Bando; hbando@ 123456aichi-cc.jp

Author information

Daisuke Kotani http://orcid.org/0000-0002-4196-555X

Hideaki Bando http://orcid.org/0000-0001-5041-2765

Takayuki Yoshino http://orcid.org/0000-0002-0489-4756

Article

Publisher ID: esmoopen-2019-000624

DOI: 10.1136/esmoopen-2019-000624

PMC ID: 7046405

PubMed ID: 33551068

SO-VID: da13e767-e2a6-4a8b-9185-6fcfb81ed3b9

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, any changes made are indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 24 October 2019

Date revision received : 11 November 2019

Date accepted : 12 November 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100009619, Japan Agency for Medical Research and Development;

Custom metadata

special-feature unlocked

Keywords: braf non-v600e,metastatic colorectal cancer,binimetinib,encorafenib,cetuximab

Data availability:

Keywords: braf non-v600e, metastatic colorectal cancer, binimetinib, encorafenib, cetuximab

BIG BANG study (EPOC1703): multicentre, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy with binimetinib, encorafenib and cetuximab in patients with BRAF non-V600E mutated metastatic colorectal cancer

Read this article at

Abstract

Background

Trial design

Trial registration numbers

Related collections

Efficacy of Communicating Science

Most cited references 16

Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer

Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer.

Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS

Author and article information

Journal

Affiliations

Author notes

Author information

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 664

Cited by 9

Most referenced authors 629