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Published on: December 7, 2014
ERK1/2 Inhibitor Ulixertinib in Pan-cancer Patients with BRAF Fusions or Non-V600E/K Mutations: Results from the
Vivek Subbiah1, Fengmin Zhao2, Ragini R Kudchadkar3
1Stanford University Palo Alto, CA United States.
Purpose:
Mutations in BRAF at codons other than V600 (non-V600) and BRAF fusions confer dependence on RAF-MEK-ERK pathway. Subprotocol Z1L (EAY131-Z1L) investigated the clinical activity of ulixertinib (ERK1/2 inhibitor) in patients with tumors harboring these alterations.
Patients And Methods:
In this single-arm study, patients with BRAF non-V600 mutation or BRAF fusion were given ulixertinib orally, at a dose of 600 mg twice daily, continuously for each 28-day cycle until progression or intolerability. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS).
Results:
Among 34 eligible patients, median age was 66.5; 50% were female, 88% were white, 9% black, 3% Asian. ECOG PS 1 in 74% of patients. Median number of prior therapies was 4. Tumor types included multiple gastrointestinal malignancies (n = 16), lung cancer, melanoma (n = 3 each), among others. No patients achieved CR or PR, resulting in ORR = 0%. Stable disease was the best response in 7/26 centrally confirmed cases. Median PFS was 1.7 months (90% CI: 1.1, 2.2), 6-month PFS rate was 5% (90% CI: 0.6%, 17.7%), and median OS was 3.5 months (90% CI: 1.9, 5.4). Twenty patients (57%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity as their worst toxicity; there were no grade 5 toxicities.
Conclusion:
Ulixertinib had no demonstrable evidence of clinical activity in this small, heavily pretreated population of patients with tumors harboring BRAF fusions, or with non-V600E, non-V600K BRAF mutations.
Insights
Ulixertinib showed no clinical activity in patients with BRAF non-V600 mutations or fusions. This study found no objective responses, with limited progression-free and overall survival in heavily pretreated individuals.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- BRAF mutations, excluding V600, and BRAF fusions create dependency on the RAF-MEK-ERK pathway.
- Ulixertinib targets ERK1/2, a key component of this signaling cascade.
Purpose of the Study:
- To evaluate the clinical activity of ulixertinib in patients with tumors harboring BRAF non-V600 mutations or BRAF fusions.
- To assess objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Main Methods:
- A single-arm study (Subprotocol Z1L) administered ulixertinib 600 mg orally twice daily.
- Patients with BRAF non-V600 mutations or BRAF fusions were enrolled.
- Treatment continued until disease progression or intolerance.
Main Results:
- No objective responses were observed (ORR = 0%) in 34 eligible patients.
- Median progression-free survival was 1.7 months, and median overall survival was 3.5 months.
- High rates of grade 3 (57%) and grade 4 (3%) toxicities were reported.
Conclusions:
- Ulixertinib demonstrated no significant clinical activity in this patient population.
- The drug was ineffective in treating tumors with BRAF fusions or non-V600E/K mutations.
- Further investigation may be warranted for specific BRAF alterations, but this study showed limited benefit.
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