DAY101 is an oral and highly selective investigational pan-RAF inhibitor. The RAS-RAF-MEK-ERK pathway is an essential signaling pathway which regulates key cell functions such as growth and survival. This pathway is one of the most commonly mutated oncogenic pathways in cancer. Genomic alterations in BRAF can lead to constitutive pathway activation, thus driving tumor growth.
DAY101 is currently in clinical development for the treatment of patients with cancer that harbor genetic alterations in RAF. This unique type II RAF-inhibitor has comparably high brain distribution and exposure in comparison to other MAPK pathway inhibitors, thus providing new hope that it may benefit patients with primary brain tumors or brain metastases of solid tumors.
Genomic alterations in BRAF occur in approximately 7-8% of human cancer. The BRAF-V600E point mutation is
the most frequently occurring mutation which drives hyperactivation of the signaling pathway. BRAF mutations occur frequently in patients with a wide range of diseases, including melanoma, papillary thyroid cancer, colorectal cancer, lung cancer, hairy cell leukemia, and craniopharyngioma. BRAF mutations also occur frequently in a number of pediatric cancers, including low and high-grade glioma and Langerhans cell histiocytosis.
Beyond mutations, BRAF wild-type fusions have also been reported in human cancer. These occur when a portion of the BRAF gene becomes fused to a portion of another gene, resulting in constitutive pathway activation and driving oncogenic cell growth. BRAF fusions have been identified in a large percentage of pediatric patients with low-grade gliomas, as well as in a variety of adult cancers, including melanoma, lung cancer, and subtypes of pancreas cancer.
Currently approved medications that target alterations in BRAF are only active in tumors harboring BRAF-V600 mutations, exhibit limited activity in brain tumors, and cannot be used in patients harboring BRAF wild-type fusions. New treatments are needed for patients with tumors dependent on BRAF V600 mutations and BRAF wild-type fusions as well as in patients with brain tumors.
To date, more than 200 patients have been treated with DAY101 as a single agent or in combination with other anti-cancer treatments. Results of a Phase 1 study demonstrated that DAY101 was capable of causing tumor shrinkage in patients with melanoma bearing an activating mutation in BRAF. The most commonly reported treatment-emergent adverse events (any grade) in this population were fatigue, anemia (low red blood cell count), constipation, and rash.
DAY101 is currently being studied in a pediatric Phase 1 clinical trial that is evaluating its safety and clinical activity as a monotherapy in children with recurrent or progressive low-grade astrocytoma associated with BRAF alterations, including BRAF point mutations and the KIAA1549:BRAF wild-type fusion. Information about the open Phase 1 study (PNOC014) can be found here. Day One will be announcing new studies with DAY101 soon.