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Updated: Aug 3, 2025
A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
Dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors
Meghan J Mooradian1,2, James M Cleary2,3, Anita Giobbie-Hurder4
1Division of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.
Background:
Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines.
Methods:
Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones.
Results:
Twenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3 + 3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N = 12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150 mg twice daily, oral trametinib 2 mg once daily, and intravenous AT13387 260 mg/m2 on days 1, 8, and 15. The best response was a partial response in two patients and stable disease in eight patients, with an overall response rate of 9.5% (90% exact confidence interval [CI], 2%-27%), a disease control rate of 47.6% (90% CI, 29%-67%), and a median overall survival of 5.1 months (90% CI, 3.4-7.6 months). There were no consistent proteomic changes associated with response or resistance, although responders did have reductions in BRAF expression, and epidermal growth factor receptor downregulation using HSP90 inhibition was observed in one patient who had colorectal cancer.
Conclusions:
HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.
Insights
Combining heat shock protein 90 (HSP90) inhibition with BRAF/MEK inhibitors showed safety and modest disease control in BRAF V600E-mutant solid tumors. Further research is needed to identify optimal patient populations and resistance mechanisms for this combination therapy.
Area of Science:
- Oncology
- Molecular Biology
- Clinical Trials
Background:
- BRAF and MEK inhibitor therapy is a standard treatment for BRAF V600E-mutated tumors but is limited by resistance.
- Preclinical studies suggest that heat shock protein 90 (HSP90) inhibition can enhance BRAF inhibitor efficacy in both sensitive and resistant cell lines.
Purpose of the Study:
- To assess the safety and efficacy of combining an HSP90 inhibitor (AT13387) with dabrafenib and trametinib in patients with BRAF V600E/K-mutant solid tumors.
- To evaluate correlative analyses of HSP90 client proteins and chaperones in response to combination therapy.
Main Methods:
- A Phase 1, 3+3 dose-escalation study (NCT02097225) enrolled 22 patients with metastatic BRAF V600E-mutant solid tumors.
- Patients received oral dabrafenib, oral trametinib, and intravenous AT13387. Dose-limiting toxicities were recorded to determine the maximum tolerated dose.
- Correlative analyses assessed proteomic changes related to HSP90 inhibition.
Main Results:
- Twenty-one patients were evaluable for efficacy. The most common tumor type was colorectal cancer (n=12).
- The maximum tolerated dose was established. The overall response rate was 9.5%, and the disease control rate was 47.6%. Median overall survival was 5.1 months.
- Responders showed reduced BRAF expression; one patient with colorectal cancer exhibited epidermal growth factor receptor downregulation with HSP90 inhibition.
Conclusions:
- Combination HSP90 inhibition with BRAF/MEK inhibitors is safe and demonstrates modest disease control in heavily pretreated patients.
- Further translational research is warranted to identify specific tumor types and resistance mechanisms that may benefit most from this therapeutic approach.
