Abstract
Background
BRAF mutations are a validated target for cancer therapy. A second-generation BRAF inhibitor with an improved preclinical safety profile (RG7256) was evaluated in a first-in-man study in order to determine the safety, efficacy, pharmacokinetics and pharmacodynamics in patients with BRAF V600-mutated advanced solid tumors.
Patients and Methods
Patients received RG7256 orally over 8 dose levels from 200 mg once a day (QD) to 2400 mg twice a day (BID) (50-, 100- and 150-mg tablets) using a classic 3 + 3 dose escalation design.
Results
In total, 45 patients were enrolled; most (87 %) had advanced melanoma (94 % BRAF V600E). RG7256 was rapidly absorbed, with limited accumulation and dose-proportional increase in exposure up to 1950 mg BID. The maximal tolerated dose (MTD) was not reached. The most common drug-related adverse events (AEs) were dyspepsia (20 %), dry skin (18 %), rash (18 %), fatigue (16 %) and nausea (13 %), mainly grade 1. Three patients (7 %) developed cutaneous squamous cell carcinoma. Photosensitivity, arthralgia and increased liver enzyme levels were each observed in only one patient each. Of 44 evaluable patients, 14 (32 %) had a partial response (melanoma and thyroid cancer). At high dose levels (>1200 mg BID), 10 of 16 (63 %) patients had a partial response. A decrease in maximum standardized uptake value (SUVmax) on FDG-PET of ≥25 % was observed in 19 of 37 patients. On-treatment reductions in pERK were documented in eight of ten paired tumor samples.
Conclusions
RG7256 has a favorable safety profile compared to other BRAF inhibitors while maintaining clinical activity, and MTD was not reached. The excessive pill burden needed to provide the desired exposure, and thus concerns about patient compliance, limited further development of this agent.
Study Identifier: ClinicalTrials.gov (NCT01143753)
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Acknowledgments
We thank the patients and their families who participated in this study, Mei Liu for bioanalysis of PK samples, and Sarah MacKenzie for medical writing assistance. RG7256/PLX3603 was developed in collaboration with Plexxikon.
Conflict of Interest
This study was funded by Hoffmann-La Roche, which provided institutional research support to UL, JD, MPB and JT. RD and JC have no conflicts of interest to declare. SE, FS, WZ, FB, BL, and KS, and VM are employees of Hoffmann-La Roche. SE, WZ, FB, BL, and KS hold stock of Hoffman-La Roche as an employment benefit.
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Supplementary Fig. 1
A Representative images showing changes in proliferation (Ki-67) and MAPK pathway activity (pERK) with RG7256 treatment. Tumor sample sections from a 37-year-old woman with acral lentiginous malignant melanoma who started treatment at 1950 mg BID, had a partial response (non-confirmed) at cycle 3, and progressed at cycle 5. Strong inhibition of proliferation (Ki-67) and MAPK signaling (pERK) is seen at cycle 1 day 8 (C1D8) relative to baseline, with a return to baseline levels at cycle 5 correlating with disease progression. 1 B Correlation between changes in Ki-67 or pERK concentrations at cycle 1 day 8 compared to baseline, according to the AUC at day 15 (steady state) and RECIST response. Tumor sections were stained with anti-phosphorylated ERK (anti-pERK) or anti-Ki-67 antibodies, and percentage change in H-score was calculated. Eight of the ten patients with available paired samples showed a reduction in pERK and Ki-67. (PPTX 724 kb)
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Dienstmann, R., Lassen, U., Cebon, J. et al. First-in-Man Dose-Escalation Study of the Selective BRAF Inhibitor RG7256 in Patients with BRAF V600-Mutated Advanced Solid Tumors. Targ Oncol 11, 149–156 (2016). https://doi.org/10.1007/s11523-015-0381-x
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DOI: https://doi.org/10.1007/s11523-015-0381-x