Kurzfassung

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is an epithelial fragility disease primarily affecting the skin and caused by variants in the COL7A1 gene. Individuals with RDEB are predisposed to develop highly aggressive cutaneous squamous cell carcinomas (SCC) which represent the most common cause of premature death. There is a lack of effective prevention or treatment options for patients with RDEB-SCC.

OBJECTIVES: To evaluate the anti-tumor activity and safety of the polo-like kinase-1 (PLK1) inhibitor, rigosertib, two investigator initiated open-label, single arm phase 2 studies were opened in Europe and the United States and enrolled five RDEB patients diagnosed with locally advanced and/or metastatic SCCs that had failed prior standard of care.

METHODS: Using a common protocol, patients were offered either oral or intravenous administration of rigosertib with consultation from the treating physician. Patients were monitored with clinical photography, biopsy, PET-CT scans and quality of life questionnaires over the 12 months duration of the trial. Pharmacokinetics of drug absorption was monitored in 4 patients.

RESULTS: Patients on intravenous or oral therapy showed anti-tumor efficacy with acceptable toxicity and two patients had a complete response within six months of treatment. Quality of life was not negatively impacted by treatment and drug absorption exceeded previous patient populations presumably due to the relatively high dosing in an underweight patient cohort.

CONCLUSIONS: These data identify rigosertib as a promising drug therapy for RDEB-SCC where there is a substantial unmet need, absence of approved therapies and where tumors arise on the background of a unique fibrotic and inflammatory environment characterized by germline mutations in COL7A1 that promote development of homogenous primary tumors with aberrant PLK1 activity.