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      Vinorelbine in BRAF V600E mutated metastatic colorectal cancer: a prospective multicentre phase II clinical study

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          Abstract

          Background

          BRAF V600E mutation defines a specific colorectal cancer (CRC) subgroup with poor prognosis. Promising preclinical data showed synthetically lethal activity of mitotic spindle poisons on BRAF-mutated and BRAF-like CRC models. We designed a phase II trial to test the activity of vinorelbine in patients with BRAF V600E mutated metastatic CRC (mCRC).

          Patients and methods

          Patients progressed to or not deemed eligible for standard treatments received oral (60 mg/sqm) or intravenous (25 mg/sqm) vinorelbine, on days 1 and 8 every 21 days. Primary endpoint was objective response rate (ORR).

          Results

          Twenty patients were enrolled; 75% of them were highly pretreated. No responses were observed (0%); only one patient had a confirmed disease stabilisation (5%). Median progression-free survival was 1 month (95% CI 0.8 to 1.8), median overall survival was 2.1 months (95% CI 1.6 to 3.7). No serious adverse events were observed.

          Conclusions

          Despite encouraging preclinical data, our study did not show signs of clinical activity for vinorelbine in this patients’ population. Further investigations on molecular heterogeneity and dynamic evolution of BRAF V600E mutated mCRC are needed.

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          Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations.

          Leanne G. Ahronian, Erin Sennott, Eliezer M Van Allen … (2015)
          BRAF mutations occur in approximately 10% of colorectal cancers. Although RAF inhibitor monotherapy is highly effective in BRAF-mutant melanoma, response rates in BRAF-mutant colorectal cancer are poor. Recent clinical trials of combined RAF/EGFR or RAF/MEK inhibition have produced improved efficacy, but patients ultimately develop resistance. To identify molecular alterations driving clinical acquired resistance, we performed whole-exome sequencing on paired pretreatment and postprogression tumor biopsies from patients with BRAF-mutant colorectal cancer treated with RAF inhibitor combinations. We identified alterations in MAPK pathway genes in resistant tumors not present in matched pretreatment tumors, including KRAS amplification, BRAF amplification, and a MEK1 mutation. These alterations conferred resistance to RAF/EGFR or RAF/MEK combinations through sustained MAPK pathway activity, but an ERK inhibitor could suppress MAPK activity and overcome resistance. Identification of MAPK pathway reactivating alterations upon clinical acquired resistance underscores the MAPK pathway as a critical target in BRAF-mutant colorectal cancer and suggests therapeutic options to overcome resistance.
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            Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients.

            Rona Yaeger, Andrea Cercek, Eileen M O'Reilly … (2015)
            BRAF-mutant metastatic colorectal cancer (mCRC) forms an aggressive subset of colorectal cancer with minimal response to selective RAF inhibitors. Preclinical data show that reactivation of EGFR signaling occurs in colorectal tumor cells treated with RAF inhibitors and that the addition of an EGFR inhibitor enhances antitumor activity. These data suggest that combined therapy with RAF and EGFR inhibitors could be an effective strategy for treating BRAF V600E mCRC.
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              Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation.

              David S. Hong, Van Morris, Badi El Osta … (2016)
              In vitro, EGFR inhibition, combined with the BRAF inhibitor vemurafenib, causes synergistic cytotoxicity for BRAF(V600E) metastatic colorectal cancer, further augmented by irinotecan. The safety and efficacy of vemurafenib, irinotecan, and cetuximab in BRAF-mutated malignancies are not defined. In this 3+3 phase I study, patients with BRAF(V600E)-advanced solid cancers received cetuximab and irinotecan with escalating doses of vemurafenib. Nineteen patients (18 with metastatic colorectal cancer and 1 with appendiceal cancer) were enrolled. Three patients experienced dose-limiting toxicities. The MTD of vemurafenib was 960 mg twice daily. Six of 17 evaluable patients (35%) achieved a radiographic response by Response Evaluation Criteria in Solid Tumors 1.1 criteria, consistent with in vivo models demonstrating tumor regressions with the triplet regimen. Median progression-free survival was 7.7 months. BRAF(V600E) circulating cell-free DNA (cfDNA) trends correlated with radiographic changes, and acquired mutations from cfDNA in genes reactivating MAPK signaling were observed at progression.
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                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: 2017
                Publication date (Electronic): 10 August 2017
                Volume: 2
                Issue: 3
                Electronic Location Identifier: e000241
                Affiliations
                [1 ]departmentUnit of Medical Oncology 2 , Azienda Ospedaliero-Universitaria Pisana , Pisa, Italy
                [2 ]departmentDepartment of Translational Research and New Technologies in Medicine and Surgery , University of Pisa , Pisa, Italy
                [3 ]departmentDepartment of Medical Oncology , Fondazione IRCCS Istituto Nazionale dei Tumori , Milan, Italy
                [4 ]departmentDepartment of Oncology , ASST Ospedale di Cremona , Cremona, Italy
                [5 ]departmentUnit of Medical Oncology 1, Department of Clinical and Experimental Oncology , Istituto Oncologico Veneto IRCCS , Padua, Italy
                [6 ]departmentDepartment of Medical Oncology Fondazione Policlinico , Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore , Rome, Italy
                [7 ]departmentDepartment of Oncology and Hemato-Oncology , University of Milan , Milan, Italy
                Author notes
                [Correspondence to ] Chiara Cremolini; chiaracremolini@ 123456gmail.com

                CC and FP contributed equally.

                Article
                Publisher ID: esmoopen-2017-000241
                DOI: 10.1136/esmoopen-2017-000241
                PMC ID: 5703381
                SO-VID: 17ac496e-1d59-47b3-8871-097c653e13f8
                Copyright © © European Society for Medical Oncology (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
                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 and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                Date received : 29 June 2017
                Date revision received : 14 July 2017
                Date accepted : 17 July 2017
                Categories
                Subject: Original Research
                Subject: 1506
                Custom metadata
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                Keywords: vinorelbine,brafv600e,metastatic colorectal cancer
                Data availability:
                Keywords: vinorelbine, brafv600e, metastatic colorectal cancer

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