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Oncologist. 2019 Aug 8. pii: theoncologist.2019-0297. doi: 10.1634/theoncologist.2019-0297. [Epub ahead of print]

Phase Ib Study of Combination Therapy with MEK Inhibitor Binimetinib and Phosphatidylinositol 3-Kinase Inhibitor Buparlisib in Patients with Advanced Solid Tumors with RAS/RAF Alterations.

Author information

1
Department of Hematology/Oncology, Massachusetts General Hospital Cancer Center; Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York New York, USA gounderm@mskcc.org.
3
Medical Oncology Department, Vall D'Hebron Institute of Oncology, VHIO, Barcelona, Spain.
4
Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
5
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
6
Department of Medical Oncology, GHS Cancer Institute, Greenville, South Carolina, USA.
7
Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
8
Department of Medical Oncology, West German Cancer Center, University Duisburg-Essen, and German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany.
9
Department of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
10
Department of Medical Oncology, Yale Cancer Center, New Haven, Connecticut, USA.
11
Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
12
Novartis Pharma AG, Basel, Switzerland.
13
Department of Medical Oncology, National Cancer Centre Singapore, Singapore.

Abstract

BACKGROUND:

This multicenter, open-label, phase Ib study investigated the safety and efficacy of binimetinib (MEK inhibitor) in combination with buparlisib (phosphatidylinositol 3-kinase [PI3K] inhibitor) in patients with advanced solid tumors with RAS/RAF alterations.

MATERIALS AND METHODS:

Eighty-nine patients were enrolled in the study. Eligible patients had advanced solid tumors with disease progression after standard therapy and/or for which no standard therapy existed. Evaluable disease was mandatory, per RECIST version 1.1 and Eastern Cooperative Oncology Group performance status 0-2. Binimetinib and buparlisib combinations were explored in patients with KRAS-, NRAS-, or BRAF-mutant advanced solid tumors until the maximum tolerated dose and recommended phase II dose (RP2D) were defined. The expansion phase comprised patients with epidermal growth factor receptor (EGFR)-mutant, advanced non-small cell lung cancer, after progression on an EGFR inhibitor; advanced RAS- or BRAF-mutant ovarian cancer; or advanced non-small cell lung cancer with KRAS mutation.

RESULTS:

At data cutoff, 32/89 patients discontinued treatment because of adverse events. RP2D for continuous dosing was buparlisib 80 mg once daily/binimetinib 45 mg twice daily. The toxicity profile of the combination resulted in a lower dose intensity than anticipated. Six (12.0%) patients with RAS/BRAF-mutant ovarian cancer achieved a partial response. Pharmacokinetics of binimetinib were not altered by buparlisib. Pharmacodynamic analyses revealed downregulation of pERK and pS6 in tumor biopsies.

CONCLUSION:

Although dual inhibition of MEK and the PI3K pathways showed promising activity in RAS/BRAF ovarian cancer, continuous dosing resulted in intolerable toxicities beyond the dose-limiting toxicity monitoring period. Alternative schedules such as pulsatile dosing may be advantageous when combining therapies.

IMPLICATIONS FOR PRACTICE:

Because dysregulation of the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K) pathways are both frequently involved in resistance to current targeted therapies, dual inhibition of both pathways may be required to overcome resistance mechanisms to single-agent tyrosine kinase inhibitors or to treat cancers with driver mutations that cannot be directly targeted. A study investigating the safety and efficacy of combination binimetinib (MEK inhibitor) and buparlisib (PI3K inhibitor) in patients harboring alterations in the RAS/RAF pathway was conducted. The results may inform the design of future combination therapy trials in patients with tumors harboring mutations in the PI3K and MAPK pathways.

KEYWORDS:

Binimetinib; Buparlisib; Ovarian cancer; Phase Ib; RAS/RAF

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