Dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors.

Autor: Mooradian MJ; Division of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Cleary JM; Harvard Medical School, Boston, Massachusetts, USA.; Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Giobbie-Hurder A; Division of Biostatistics, Departments of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Darville LNF; Department of Proteomics and Metabolomics Core, Moffitt Cancer Center, Tampa, Florida, USA., Parikh A; Division of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Buchbinder EI; Harvard Medical School, Boston, Massachusetts, USA.; Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Cohen JV; Division of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Lawrence DP; Division of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Shapiro GI; Harvard Medical School, Boston, Massachusetts, USA.; Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Keer H; Astex Pharmaceuticals Inc., Pleasanton, California, USA., Chen HX; Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA., Ivy SP; Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA., Smalley KSM; Department of Tumor Biology, Moffitt Cancer Center, Tampa, Florida, USA., Koomen JM; Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida, USA., Sullivan RJ; Division of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA.
Jazyk: angličtina
Zdroj: Cancer [Cancer] 2023 Jun 15; Vol. 129 (12), pp. 1904-1918. Date of Electronic Publication: 2023 Apr 11.
DOI: 10.1002/cncr.34730
Abstrakt: 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/m 2 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.
(© 2023 American Cancer Society.)
Databáze: MEDLINE
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