Phase Ib/II Study of the Efficacy and Safety of Binimetinib (MEK162) Plus Panitumumab for Mutant or Wild-Type RAS Metastatic Colorectal Cancer

Author:

Van Cutsem Eric1ORCID,Yaeger Rona2ORCID,Delord Jean-Pierre3,Tabernero Josep4ORCID,Siu Lillian L5ORCID,Ducreux Michel6,Siena Salvatore78,Elez Elena9ORCID,Kasper Stefan10,Zander Thomas1112,Steeghs Neeltje13,Murphy Danielle14,Edwards Michelle15,Wainberg Zev A16

Affiliation:

1. Digestive Oncology, University Hospitals Gasthuisberg , Leuven and KU Leuven, Leuven , Belgium

2. Department of Medicine, Memorial Sloan Kettering Cancer Center , New York, NY , USA

3. Medical Oncology Department, Institut Claudius Regaud, IUCT-Oncopole , Toulouse , France

4. Medical Oncology Department, Vall d’Hebron Campus Hospital and Institute of Oncology (VHIO), IOB-Quiron, UVic-UICC , Barcelona , Spain

5. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network , Toronto, ON , Canada

6. Department of Medical Oncology , Gustave Roussy, Cancer Campus, Université Paris-Saclay, Villejuif , France

7. Department of Oncology and Hemato-Oncology, Università degli Studi di Milano , Milan , Italy

8. Department of Oncology , Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan , Italy

9. Medical Oncology Department, Vall d’Hebron Campus Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona (UAB) , Barcelona , Spain

10. West German Cancer Center, Department of Medical Oncology, University Hospital Essen , Essen , Germany

11. Department of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne, University of Cologne , Duesseldorf , Germany

12. Department of Internal Medicine I, Gastrointestinal Cancer Group Cologne (GCGC), University Clinic Cologne , Cologne , Germany

13. Department of Medical Oncology and Clinical Pharmacology, Netherlands Cancer Institute , Amsterdam , The Netherlands

14. Translational Oncology , Pfizer, La Jolla, CA , USA

15. North American Medical Affairs , Pfizer, New York, NY , USA

16. Division of Hematology/Oncology, David Geffen School of Medicine at UCLA , Los Angeles, CA , USA

Abstract

Abstract Introduction Activating RAS gene mutations occur in approximately 55% of patients with metastatic colorectal cancer (mCRC) and are associated with poorer clinical outcomes due to epidermal growth factor receptor (EGFR) blockade resistance. Combined EGFR and mitogen-activated protein kinase (MEK) inhibition may extend response to EGFR inhibition and overcome acquired resistance. This phase Ib/II dose escalation trial evaluated the safety and activity of dual inhibition with binimetinib (MEK1/2 inhibitor) and panitumumab (EGFR inhibitor [EGFRi]) in patients with RAS mutant or BRAF wild type (WT)/RAS WT mCRC. Methods Phase Ib dose escalation started with binimetinib 45 mg twice daily plus panitumumab 6 mg/kg administered every 2 weeks. In the phase II study, patients with measurable mCRC were enrolled into 4 groups based on previous anti-EGFR monoclonal antibody therapy and RAS mutational status. Results No patients in the phase Ib portion (n = 10) had a response; 70% of patients had stable disease. In the phase II portion (n = 43), overall response rate (ORR, confirmed) was 2.3% with one partial response in the RAS WT group, DCR was 30.2%, and median progression-free survival was 1.8 months (95%CI, 1.6-3.3). All patients experienced ≥1 adverse event, with the most common being diarrhea (71.7%), vomiting (52.8%), nausea (50.9%), fatigue (49.1%), dermatitis acneiform (43.4%), and rash (41.5%). Most patients required treatment interruption or dose reduction due to difficulties tolerating treatment. Conclusions The combination of binimetinib and panitumumab had substantial toxicity and limited clinical activity for patients with mutant or WT RAS mCRC, independent of EGFRi treatment history (Trial registration: NCT01927341).

Funder

Array Biopharma in collaboration with Novartis

National Institutes of Health Cancer Center

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

Reference28 articles.

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