Abstract

Background Recessive dystrophic epidermolysis bullosa (RDEB) is an epithelial fragility disease primarily affecting the skin and is caused by variants in the COL7A1 gene. Individuals with RDEB are predisposed to develop highly aggressive cutaneous squamous cell carcinomas (SCCs) which are 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 antitumour activity and safety of the polo-like kinase-1 (PLK1) inhibitor, rigosertib, two investigator-initiated open-label, single-arm phase II studies were opened in Europe and the USA and enrolled five patients with RDEB diagnosed with locally advanced and/or metastatic SCCs whose disease had not previously responded successfully to standard care.Methods Using a common protocol, patients were offered either oral or intravenous (IV) administration of rigosertib with consultation from the treating physician. Patients were monitored with clinical photography, biopsy, positron emission tomography/computed tomography scans and quality of life (QoL) questionnaires over the 12-month duration of the trial. The pharmacokinetics of drug absorption was monitored in four patients.Results Antitumour efficacy with acceptable toxicity was seen in patients on IV or oral therapy and two patients had a complete response within 6 months of treatment. Their QoL was not negatively impacted by treatment and drug absorption exceeded that seen in previous patient populations presumably due to the relatively high dosing in a cohort of underweight patients.Conclusions These data identify rigosertib as a promising drug therapy for patients with RDEB-SCC where there is a substantial unmet need, absence of approved therapies and where tumours arise on a background of a unique fibrotic and inflammatory environment characterized by germline mutations in COL7A1 that promote the development of homogenous primary tumours with aberrant PLK1 activity. An author video to accompany this article is available online.Conclusions These data identify rigosertib as a promising drug therapy for patients with RDEB-SCC where there is a substantial unmet need, absence of approved therapies and where tumours arise on a background of a unique fibrotic and inflammatory environment characterized by germline mutations in COL7A1 that promote the development of homogenous primary tumours with aberrant PLK1 activity. An author video to accompany this article is available online.Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited disease characterized by fragile skin. It is caused by a fault in the COL7A1 gene, which codes for the type VII collagen protein. The type VII collagen protein doesn't function properly in people with RDEB. This causes blisters and skin wounds to develop after minor trauma in people with RDEB. People with RDEB can also develop skin cancers called squamous cell carcinomas (SCCs). These SCCs are the most common cause of premature death in these patients. Effective prevention or treatment options are lacking for people with RDEB-SCC.In this article, we report on two single-arm phase II studies carried out in Europe and the USA. We investigated the action and safety of the drug rigosertib in a 12-month trial. We studied patients with RDEB and late-stage SCC who had not responded to prior treatment. Patients chose oral or intravenous (injection) rigosertib, in consultation with their doctor. We monitored our patients over the 12 months. We used clinical photography, biopsy, PET-CT scans and quality of life questionnaires. We also monitored drug absorption and duration of exposure in our patients' blood. Drug absorption exceeded that seen in previous patient populations. Patients' quality of life was not worsened by the treatment. We noted a reduction in our patients' tumours with acceptable toxicity. Two patients were tumour-free within 6 months of treatment. Adverse events were recorded, including noninfective cystitis, haematuria or urinary urgency/frequency. The drug doses were reduced in some patients.Our findings suggest that rigosertib could be a promising drug for treating patients with RDEB-SCC.Patients with recessive dystrophic epidermolysis bullosa (RDEB)-associated squamous cell carcinoma (SCC) receiving the experimental therapeutic rigosertib either via intravenous (IV) infusion or orally showed antitumour efficacy with acceptable toxicity and two patients had a complete response (CR) within 6 months of treatment.