4.2.1. Efficacy
In both the non-head and head studies, the proportion of patients achieving complete clearance of all AK lesions at day 57 was statistically significantly greater in the ingenol mebutate gel groups compared with the vehicle gel groups; Absolute risk differences ranged from 23.1% to 42.0% across the included trials. Efficacy results from the individual trials are similar to that of a published pooled analysis of the non-head and head studies.10 The proportion of patients achieving partial clearance (reduction of 75% or more in the number of lesions) at day 57 was naturally higher than those achieving complete clearance, but between-treatment differences were also higher than those observed for complete clearance; absolute-risk differences ranged from 37.5% to 59.5%. However, partial clearance of AK lesions was considered to be of lesser clinical importance by the clinical expert consulted for this review, as residual lesions in the treatment area would require retreatment. Similarly, the FDA medical review for ingenol mebutate stated that it wasn’t clear that partial clearance is clinically meaningful, as a 75% or greater reduction in the number of AK lesions could leave the largest AK lesion in the treatment area unaffected, which could then progress to SCC.15
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▬ This may be associated with the increased severity of LSRs observed during or shortly following treatment with ingenol mebutate (Section 4.2.2 Harms).
While the reviewed trials provide support for the efficacy of ingenol mebutate versus no treatment (vehicle), in terms of clearance of lesions, the available evidence has a number of limitations, including the lack of an active comparator, the short duration of the trials, and uncertain applicability to the manufacturer’s requested listing criteria. No RCTs comparing ingenol mebutate with other topical treatments for AK were identified. Ingenol mebutate has a shorter course of treatment compared with 5-FU and imiquimod, which may potentially impact treatment adherence and outcome. A cross-sectional online/telephone survey of 300 adults with AK living in the UK found that rates of non-adherence and non-persistence increased with increasing lengths of treatment regimens.20 However, given the lack of active-comparator trials, the comparative efficacy of ingenol mebutate is unknown. A recent Cochrane review21 of interventions for AK concluded that field-directed treatments (including ingenol mebutate, imiquimod, and 5-FU) have similar efficacy. However, the between-trial heterogeneity makes direct comparisons challenging.
Trials included in the present review were of short duration (57 days) and do not provide evidence of long-term efficacy or whether ingenol mebutate reduces the risk of progression to SCC. Two observational, 12-month follow-up studies reported that approximately 50% of patients who achieved complete clearance in studies PEP005-028, PEP005-016, and PEP005-025 experienced at least one new or recurrent AK lesion within the treatment area (APPENDIX 6: LONG-TERM EFFICACY AND HARMS FROM EXTENSION STUDIES). The clinical expert consulted for this review noted that this is consistent with what is observed in clinical practice with other topical treatments for AK.
The manufacturer is requesting that ingenol mebutate be listed for patients who have failed or are intolerant to 5-FU, however the included trials are not specific to this subpopulation of patients. Approximately 20% of patients in the reviewed trials had received prior AK treatment with 5-FU. The manufacturer provided pooled post-hoc subgroup analyses comparing the incidence of complete clearance between treatment-naive and previously treated patients. However, the subgroup analyses suffer from a number of limitations, including not being pre-planned or having used stratified randomization, and uncertain statistical power and a lack of adjustment for multiple comparisons. In addition, as previous treatment with 5-FU was not necessarily in the target treatment area that was subsequently treated with ingenol mebutate, it is difficult to glean useful information from this analysis. Finally, the clinical expert consulted for this review indicated that, while failure to achieve lesion clearance in clinical practice would prompt retreatment, it would not necessarily prompt a change in treatment.
The reviewed trials enrolled patients with four to eight AK lesions within a 25 cm2 contiguous area. However, the clinical expert consulted for this review indicated that this would not be typically seen in clinical practice, where AK patients may have scattered lesions not necessarily within a contiguous area. The Health Canada-approved product monograph indicates that ingenol mebutate gel should be applied to a treatment field area of 25 cm2, and that clinical data on treatment of more than one area are not available.
Although ingenol mebutate gel is indicated for the treatment of AK, the clinical expert consulted on this review indicated that the potential for off-label use is high due to misdiagnosis of lesions that are similar in appearance to AK. These lesions include irritated seborrheic keratosis, psoriasis, lichen planus, traumatic lesions, and eczema. Clinical trials are currently being conducted investigating the effect of ingenol mebutate on other indications such as SCC, BCC, and seborrheic keratosis. The clinical expert also noted that the definition for non-hyperkeratotic, non-hypertrophic AK, the Health Canada-approved indication for ingenol mebutate, may be difficult to interpret and will likely vary between clinicians.
4.2.2. Harms
The overall safety results in the non-head and head studies revealed an increase in the incidence of adverse events with the application of ingenol mebutate gel compared with vehicle gel. The most common treatment-related adverse events were administration site conditions, including pain, pruritus, and irritation. In the studies looking at the face and scalp, there was an increased incidence of ocular adverse events in the ingenol mebutate group compared with the vehicle group, possibly due to the proximity of the target treatment area to the eye in the face and scalp studies. The incidence of serious adverse events and withdrawals due to adverse events was low and balanced between treatment groups. There were no deaths reported in all included studies. In all included studies, there was minimal change in hypopigmentation, hyperpigmentation, and scarring after treatment with ingenol mebutate or vehicle gel.
Composite LSR scores (erythema, flaking or scaling, crusting, swelling, vesiculation or pustulation, erosion or ulceration) at the application site were reported at each study visit. Composite LSR scores, post-baseline, were notably higher in the ingenol mebutate groups compared with vehicle gel in both non-head and head studies. LSR scores peaked at day three or day eight for the non-head studies, and at day four for the head studies, with scores declining to near-baseline values by day 29. The maximum mean composite LSR score in the head studies was higher than that of the non-head studies. The clinical expert consulted for this review stated that this is due to the skin on the face and scalp being more delicate and more susceptible to swelling.
The types of local skin reactions experienced with ingenol mebutate are comparable to those reported for other topical therapies for AK such as 5-FU and imiquimod.22–24 Patient input indicated that these adverse skin reactions made it difficult to complete the full course of treatment with 5-FU and imiquimod due to increasing discomfort.
