Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer

Abstract

Purpose: To evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600-mutant metastatic colorectal cancer (mCRC).

Patients and methods: A total of 43 patients with BRAF V600-mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples.

Results: Of 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft-bearing mice and the biopsied lesions from each corresponding patient.

Conclusion: The combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600-mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted.

Trial registration: ClinicalTrials.gov NCT01072175.

Fig 1.

(A) Waterfall plot of maximum percent reduction in target lesion size by RECIST. Horizontal lines at + 20% and − 30% denote boundaries of stable disease. (B) Computed tomography images and photographs from patient achieving complete response. (C) Time receiving study treatment plot.

Fig 2.

Pharmacodynamic biomarkers from nine evaluable paired pre- and during-treatment (day 15, 2 to 4 hours after dabrafenib [D] plus trametinib [T] dosing) tumor biopsies. (A) Representative images of phosphorylated ERK (P-ERK) immunohistochemistry staining in pre- (left) and during-treatment (right) biopsies. (B) H scores for P-ERK and (C) percent change in P-ERK H score in patients with BRAF V600–mutant colorectal cancer (CRC) treated with dabrafenib (150 mg twice daily) and trametinib (2 mg daily) as compared with patients with BRAF-mutant melanoma treated with dabrafenib only (70 to 200 mg twice daily; P < .001 by paired t test). (D) Phosphorylated AKT H scores before and during treatment. (E) Change in abundance of specific proteins or phosphoproteins in during-treatment biopsies relative to paired pretreatment biopsies was analyzed by reverse-phase protein array. Targets showing greatest average increase (yellow) or decrease (blue) after treatment are shown. Specific targets of interest are labeled, with mitogen-activated protein kinase pathway targets shown in green and mammalian target of rapamycin pathway targets shown in purple. PDGFRβ, platelet-derived growth factor receptor–β.

Fig 3.

487-gene mutational analysis of archival tumor specimens available from 15 patients. RECIST value is maximum percent reduction in measurement of target lesions from baseline. Whole-exome sequencing was performed on tumor from patient achieving complete response. PDGFRβ, platelet-derived growth factor receptor–β; PFS, progression-free survival; PI3K, phosphatidylinositol 3-kinase.

Fig 4.

Patient-derived xenograft (PDX) –bearing mice (seven to 10 per group) treated with vehicle or dabrafenib (D) plus trametinib (T) daily for 21 days. (A) Plotted is change in PDX tumor volume after treatment, relative to initial tumor volume (all P < .001 by unpaired t test). (B) Computed tomography images showing lesion in patient who was biopsied to generate PDX pretreatment and at maximal response (weeks 32, 8, 3, and 8, respectively). First patient had spinal intramuscular mass biopsied, which regressed by 23% after 8 weeks of treatment and was not measurable by week 16 (overall best response in patient, confirmed partial response). Second patient had liver lesion biopsied, which regressed by 41% after 8 weeks of treatment (overall best response in patient, stable disease). Third patient had superficial paraumbilical nodule biopsied. This patient was not evaluable (ended study treatment because of toxicity), but imaging at week 3 showed early response in biopsied lesion. Fourth patient had posterior vaginal mass resected pretreatment, with anterior rectal recurrence by first restaging (overall best response in patient, progressive disease). If positron emission tomography was performed, maximum standardized uptake value (SUV) is noted for biopsied lesion.

Fig A1.

Kaplan-Meier curves for progression-free survival (PFS) by (A) PTEN expression (loss or present) and (B) microsatellite stability (MSS) or instability (MSI). HR, hazard ratio.