Cutaneous Oncology: Recent Drug Approvals Part 1

Keith Flaherty, MD & George Martin, MD

The hot topics of discussion at Maui Derm 2012 were January’s FDA approval of two innovative products in the cutaneous oncology arena: (Picato®), ingenol mebutate 0.015% gel and 0.05% gel for the treatment of actinic keratoses (AKs) and Erivedge®  (vismodegib) for the treatment of advanced basal cell carcinoma.  At Maui Derm, Dr Martin discussed the data on Picato® and Dr. Keith Flaherty, an oncologist from MGH, discussed ErivedgeTM.

Ingenol Mebutate (Picato®): 0.015% and 0.05% gel

Ingenol Mebutate is derived from the sap of the plant Euphorbia peplus, a commonly found plant whose sap has been used in traditional medicine for the treatment of a wide variety of skin lesions ranging from warts to skin cancer. The active pharmacologic ingredient, ingenol mebutate (ingenol‐3‐angelate), has been formulated as a field therapy for the treatment of AKs.

Mechanism of Action

Extensive work has been done to determine the mechanism of action of ingenol mebutate.  In high concentrations it induces tumor cell necrosis. It also up-regulates keratinocyte and endothelial cell cytokine and chemokine production presumably via the protein kinase C (PKC) pathway.  In response to ingenol mebutate, IL-8 a neutrophil chemo-attractant is produced in significant quantities by rapidly proliferating keratinocytes and endothelial cells following exposure to ingenol mebutate.  Also upregulated in response to ingenol mebutate is the expression of adhesion molecules ICAM-1 and E-selectin by endothelial cells, which in turn promotes neutrophil migration into the treatment area. In mouse models ingenol mebutate was show to reduce mutated p53 patches of skin in UV irradiated mice compared to placebo.

Two Strengths/Two Dosing Regimens

Ingenol mebutate was approved for the treatment of AKs using two different concentrations employing different dosing regimens. Ingenol mebutate 0.015% gel applied daily for 3 consecutive days was approved for treatment of AKs of the face and scalp. Ingenol mebutate 0.05% gel applied daily for 2 consecutive days was approved for treatment of AKs on the trunk and extremities.

In two multicenter, randomized, parallel-group, double-blind, vehicle controlled pivotal phase III trials the efficacy and safety of ingenol mebutate 0.015% gel applied daily for 3 consecutive days to the face and scalp was evaluated as a field therapy (4-8 AKs in a 25 cm2 area).  Of the treated patients completing both studies, 37% and 47% of drug treated patients achieved 100% clearance compared to 2% and 5% for vehicle controls.  Partial clearance (≥ 75% lesions cleared) was achieved in 60% and 68% of drug treated patients compared to 7% and 8% for vehicle controls.  Median percent lesion reduction for drug treated side were (83.3%) and (86.6%) compared to (0%) and (0%) for vehicle controls.  These clearance rates are comparable or better than currently FDA approved AK field therapies used on the face and scalp. Hypopigmentation and hyperpigmentation were ≤ 1%.  No scarring was reported.  There was no systemic absorption of ingenol mebutate above the limit of quantification in blood samples of subjects evaluated.

The efficacy and safety of ingenol mebutate 0.05% gel applied daily for 2 consecutive days (4 – 8 AKs in a 25 cm2 area) to trunk and extremity lesions (arm, back of hand, chest, back, shoulder and leg) was evaluated in two multicenter, randomized, parallel-group, double-blind, vehicle controlled pivotal phase III trials. Of the treated patients completing both studies, 28% and 42% of drug treated patients achieved 100% clearance compared to 5% and 5% for vehicle controls.  Partial clearance ( ≥ 75% lesions cleared) was achieved in 44% and 55% of drug treated patients compared to 7% and 7% for vehicle controls.  Median lesion percent reduction for drug treated side were (69%) and (75%) compared to (0%) and (0%) for vehicle controls. Hypopigmentation and hyperpigmentation were ≤1 %. There was no systemic absorption of ingenol mebutate above the limit of quantification in the blood samples of subjects evaluated.

A 12-month follow-up study was performed evaluating patients who completely cleared their lesions during the phase III studies. No recurrent lesions were observed in 46.1% of patients treated on the face or scalp and in 44% of patients treated for trunk and extremity lesions.  The overall reduction in AKs from baseline to 12 months was 87.2% for face and scalp lesions and 86.8% for trunk and extremity lesions

Clinical Pearls

The take home points on both 0.015% and 0.05% gel is that they have comparable or better efficacy in clearing AKs in comparison to currently FDA approved field therapies, produce sustained clearance in 12 month follow-up studies, cause limited downtime (peak inflammation on day 4 for the face/scalp with resolution of scabbing by day 8; peak inflammation on the trunk and extremities by day 4 – 8 with resolution by day 15), achieve excellent patient compliance with the 3 and 2 day application regimens and induce minimal side-effects post therapy in terms of hypopigmentation, hyperpigmentation and scarring.