Clubfoot is a birth defect where one or both feet are rotated inward and downward. Congenital clubfoot, is the most common congenital malformation of the foot with an incidence of 1 per 1000 births. In approximately 50% of cases, clubfoot affects both feet, but it can present unilaterally causing one leg or foot to be shorter than the other. Most of the time, it is not associated with other problems. Without appropriate treatment, the foot deformity will persist and lead to pain and impaired ability to walk, which can have a dramatic impact on the quality of life.The exact cause is usually not identified. Both genetic and environmental factors are believed to be involved. There are two main types of congenital clubfoot: idiopathic (80% of cases) and secondary clubfoot (20% of cases). The idiopathic congenital clubfoot is a multifactorial condition that includes environmental, vascular, positional, and genetic factors. There appears to be hereditary component for this birth defect given that the risk of developing congenital clubfoot is 25% when a first-degree relative is affected. In addition, if one identical twin is affected, there is a 33% chance the other one will be as well. The underlying mechanism involves disruption of the muscles or connective tissue of the lower leg, leading to joint contracture. Other abnormalities are associated 20% of the time, with the most common being distal arthrogryposis and myelomeningocele.
The trial measured how many subjects experienced complete or partial shrinkage (by a certain amount) of their tumors during treatment (overall response rate). For subjects harboring a PDGFRA exon 18 mutation, the overall response rate was 84%, with 7% having a complete response and 77% having a partial response. For the subgroup of subjects with PDGFRA D842V mutations, the overall response rate was 89%, with 8% having a complete response and 82% having a partial response. While the median duration of response was not reached, 61% of the responding subjects with exon 18 mutations had a response lasting six months or longer (31% of subjects with an ongoing response were followed for less than six months).The FDA approved avapritinib based on evidence from one clinical trial (NCT02508532) of 204 subjects with GIST. The trial was conducted at 17 sites in the United States, Europe and Asia.Avapritinib showed a median PFS of 4.2 months compared to 5.6 months for regorafenib. The difference in median PFS between the avapritinib and regorafenib groups was not statistically significant. The overall response rate was 17 percent for the avapritinib group and 7 percent for the regorafenib group. The VOYAGER trial evaluated the efficacy and safety of avapritinib (N=240) versus regorafenib (N=236) in patients with third- or fourth-line GIST.Avapritinib was approved for medical use in the European Union in September 2020.Ayvakit was granted approval for advanced systemic mastocytosis by the FDA on June 16th 2021. References
Further reading
Wu CP, Lusvarghi S, Wang JC,  et al. (July 2019).