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First-in-Man Dose-Escalation Study of the Selective BRAF Inhibitor RG7256 in Patients with BRAF V600-Mutated Advanced
Rodrigo Dienstmann1,2, Ulrik Lassen3, Jonathan Cebon4
1Vall d'Hebron University Hospital, Medical Oncology, Barcelona, Spain. rdienstmann@vhio.net.
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).
Insights
RG7256, a novel BRAF inhibitor, showed promising safety and clinical activity in patients with BRAF V600-mutated cancers. However, high pill burden limited its further development.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- BRAF mutations are a key target in cancer therapy.
- RG7256 is a second-generation BRAF inhibitor with a preclinical safety advantage.
- A first-in-human study assessed RG7256 in advanced solid tumors with BRAF V600 mutations.
Purpose of the Study:
- To evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of RG7256.
- To determine the maximum tolerated dose (MTD) of RG7256.
- To assess RG7256 in patients with BRAF V600-mutated advanced solid tumors.
Main Methods:
- A Phase I, 3+3 dose escalation study.
- Patients received RG7256 orally across 8 dose levels (200 mg QD to 2400 mg BID).
- Safety, efficacy, PK/PD, and MTD were assessed.
Main Results:
- 45 patients enrolled, mostly with advanced melanoma (87%).
- RG7256 showed rapid absorption, dose-proportional exposure up to 1950 mg BID; MTD not reached.
- Partial responses observed in 32% of evaluable patients, with higher response rates at higher doses (63%).
Conclusions:
- RG7256 demonstrated a favorable safety profile and clinical activity compared to other BRAF inhibitors.
- The MTD was not reached, but excessive pill burden and patient compliance concerns halted development.
- RG7256 showed on-treatment reductions in pERK, indicating target engagement.
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