Histological examination confirms clinical clearance of actinic keratoses following treatment with ingenol mebutate 0·05% gel

Summary Background To date, studies with ingenol mebutate gel have used clinical clearance, not histological clearance, as a primary efficacy endpoint. Objectives This phase I, multicentre, single‐arm, open‐label study sought to confirm histologically the clinical clearance of actinic keratoses (AKs) to support a treatment effect deep in the epidermis. Methods Patients (n = 108) aged ≥ 18 years with histologically confirmed AK within a 25‐cm2 contiguous treatment area on the trunk and extremities received ingenol mebutate 0·05% gel for two consecutive days and were followed up on day 3 and week 8. One AK was randomly preselected at day 1 for clinical and histological evaluation at week 8 and for reflectance confocal microscopy (RCM) in a subset of patients. The primary endpoint was clinical and histological clearance of AKs at week 8. Results The observed agreement rate between clinical and histological assessments of clearance of a single AK was 81·9% and the positive predictive value of a clinical assessment of clearance was 87%. Agreement between the two pathologists was 88%. The common composite 8‐week complete clearance rate was 41% (95% confidence interval 32–50). Observed agreement rates between RCM and pathologist I and II assessments of clearance were 72·9% and 81·4%, respectively. Overall, 30 patients (27·8%) experienced 38 adverse events (AEs). Application‐site pain (four patients, 3·7%) was the most common treatment‐related AE inside the treatment area. Conclusions Ingenol mebutate achieves histopathological clearance of AKs that correlates with observed clinical clearance. Clinical clearance is a good predictor for histological clearance. What's already known about this topic? Ingenol mebutate treats the deeper layers of the epidermis and the observed clinical clearance is not just a superficial effect. What does this study add? This study confirms that clinical clearance correlates with histopathological clearance. Agreement between reflectance confocal microscopy and histopathological diagnosis of clear skin was high, indicating that diagnosis of clearance using reflectance confocal microscopy may preclude the need for histopathological assessment and invasive biopsies. Linked Comment: Rivers. Br J Dermatol 2017; 176:8–9. Plain language summary available online