Ingenol mebutate to treat lentigo maligna of the head (face and scalp): A prospective, multicenter, single-arm phase 2 trial indicates no benefit
Authors: Henri Montaudié, Florence Le Duff, Catherine Butori, Véronique Hofman, Eric Fontas, Coralie Roger-Cruzel, Philippe Bahadoran, Jean-Luc Perrot, Eve Desmedt, Délphine Legoupil, Thierry Passeron, Jean-Philippe Lacour
Journal: Journal of the American Academy of Dermatology (2019)

To the Editor: Lentigo maligna (LM) is the most common subtype of melanoma in situ, arising predominantly on chronically sun-damaged skin of elderly persons. The standard treatment is surgery.1DeWane M.E. Kelsey A. Oliviero M. Rabinovitz H. Grant-Kels J.M. Melanoma on chronically sun damaged skin: lentigo maligna and desmoplastic melanoma.J Am Acad Dermatol. 2019; 81: 823-833Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Nevertheless, resectability, age, and patient preference can preclude surgical resection. Alternative treatments (ie, imiquimod and radiation) are not always effective and well tolerated.1DeWane M.E. Kelsey A. Oliviero M. Rabinovitz H. Grant-Kels J.M. Melanoma on chronically sun damaged skin: lentigo maligna and desmoplastic melanoma.J Am Acad Dermatol. 2019; 81: 823-833Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Thus, there is a need for an effective and safe topical treatment. Ingenol mebutate (IM) is indicated to treat actinic keratoses. IM has been shown to induce apoptosis of melanoma cells in vitro.2Gillespie S.K. Zhang X.D. Hersey P. Ingenol 3-angelate induces dual modes of cell death and differentially regulates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in melanoma cells.Mol Cancer Ther. 2004; 3: 1651-1658PubMed Google Scholar But clinical data are lacking; only 1 case reports efficacy in vivo.3Mansuy M. Nikkels-Tassoudji N. Arrese J.E. Rorive A. Nikkels A.F. Recurrent in situ melanoma successfully treated with ingenol mebutate.Dermatol Ther (Heidelb). 2014; 4: 131-135Crossref PubMed Scopus (13) Google Scholar We hypothesized that IM might have clinical and histologic efficacy against LM of the head, and thus, we conducted a prospective, multicenter, single-arm phase 2 trial (NCT02723721), planned according to Simon optimal 2-stage design4Simon R. Optimal two-stage designs for phase II clinical trials.Control Clin Trials. 1989; 10: 1-10Abstract Full Text PDF PubMed Scopus (2872) Google Scholar for a total sample size of 23 patients. Patients were excluded if their LM had a surface area >25 cm2 or were previously treated with imiquimod. The primary endpoint was complete response (CR) defined as a complete clearing of the LM at 2 months, confirmed by a centralized histologic analysis by 2 independent pathologists. Discordant cases were reviewed by using multihead microscope. The intensity of short-term local adverse events was evaluated by the local skin reaction (LSR) score. In addition, the adverse events were graded by using the Common Terminology Criteria for Adverse Events version 4. The concentration of 150 μg/g was chosen,3Mansuy M. Nikkels-Tassoudji N. Arrese J.E. Rorive A. Nikkels A.F. Recurrent in situ melanoma successfully treated with ingenol mebutate.Dermatol Ther (Heidelb). 2014; 4: 131-135Crossref PubMed Scopus (13) Google Scholar and IM was applied daily for 3 consecutive days (1 cycle). For patients with no CR or only a partial remission at 2 months, a second cycle was done. Twelve patients with a median age of 73 (range 62-96) years were recruited. The mean size ± standard deviation of LM was 2.52 ± 1.2 cm (range 1-5 cm), and the mean area ± standard deviation to treat was 9.6 ± 6.9 cm2 (range 4-25 cm2). The characteristics and outcome of patients are detailed in Table I. The results of this trial are negative; only 2 patients had a CR (patient nos. 5 and 6; Table I), 1 of whom (no. 5) relapsed at 8 months. No correlation was observed between IM-induced inflammation and clinical and histologic clearance (6/10 nonresponders had a strong IM-induced reaction; Fig 1). In addition, the safety profile also appears to be a limitation, with a majority (66%) of local adverse events being grade 3-4. All patients experienced an LSR score of ≥3 at least once, and the mean LSR score was 12 (range 3-22; Table I). Because of the lack of effect and study design,4Simon R. Optimal two-stage designs for phase II clinical trials.Control Clin Trials. 1989; 10: 1-10Abstract Full Text PDF PubMed Scopus (2872) Google Scholar this study ceased at the end of step 1.Table IPatients' characteristics and use of ingenol mebutate gelPatient no.Age, y/sex/phototypeLocation of LMNo. biopsies to confirm diagnosisLM size, cm/surface area treated, cm2No. cyclesLSR score, day 1/2/3/8/and mon 1/2∗To ensure uniform reporting, LSRs were assessed quantitatively by using a grading scale and photographic guide images, a method similar to that used in published studies of ingenol mebutate. The 6 following responses were assessed on a scale that ranged 0-4 (with higher numbers indicating more severe reactions): swelling, vesiculation or pustulation, erosion or ulceration, flaking or scaling, crusting, and erythema. The composite LSR score was defined as the sum of the 6 individual scores (maximum composite score = 24). Patients were assessed on days 1, 2, 3, and 8 and at months 1 and 2. If a second cycle of ingenol mebutate was given, the LSR score was evaluated on days 86, 87, and 88 and at months 3 and 5.No. biopsies to confirm response type at 1st/2nd cycleLSR score, day 86/87/88/and mon 3/5∗To ensure uniform reporting, LSRs were assessed quantitatively by using a grading scale and photographic guide images, a method similar to that used in published studies of ingenol mebutate. The 6 following responses were assessed on a scale that ranged 0-4 (with higher numbers indicating more severe reactions): swelling, vesiculation or pustulation, erosion or ulceration, flaking or scaling, crusting, and erythema. The composite LSR score was defined as the sum of the 6 individual scores (maximum composite score = 24). Patients were assessed on days 1, 2, 3, and 8 and at months 1 and 2. If a second cycle of ingenol mebutate was given, the LSR score was evaluated on days 86, 87, and 88 and at months 3 and 5.Follow-up responseOutcome of patients196/F/IIICheek13/1620/8/19/7/3/01/NAData missingNA, NR after 1 cycleLost to follow-up after 2nd cycle281/F/IICheek15/2520/5/7/3/2/12/20/3/9/6/1/0NA, NR after 2 cyclesSurgery confirming persistence of LM with microinvasive component373/M/IICheek32/1226/9/10/3/0/01/20/9/15/1/0NA, NR after 2 cyclesSurgery confirming persistence of LM with microinvasive component468/F/IIICheek13/1320/11/13/7/2/01/20/14/17/5/1NA, NR after 2 cyclesSurgery confirming persistence of LM after failure of radiotherapy (42 Gy, 6 times)562/M/IIEar lobe11/421/12/6/3/2/01/10/13/12/22/6/0PR after 1 cycle, CR after 2 cycles then clinical and histologic relapse at 8 monSurgery revealed LM relapse670/M/IIEar lobe11.8/5.5115/20/18/12/0/01/NANACR at mon 18 after 1 cycleCR at mon 18773/F/IICheek13/4.524/5/7/6/1/01/14/4/6/5/1/0NA, NR after 2 cyclesImiquimod, clinical clearance881/F/IICheek14.5/16.6212/13/15/3/2/21/18/14/12/11/4/1NA, NR after 2 cyclesSurgery confirming persistence of LM973/M/IICheek11,4/423/3/3/10/1/01/11/2/3/1/0/0NA, NR after 2 cyclesSurgery confirming persistence of LM1085/F/IIINose12/3.825/4/6/4/0/01/12/5/4/8/0/0NA, NR after 2 cyclesRefused any further treatment1162/F/IIICheek12/628/9/9/9/1/01/19/10/12/10/1/0NA, NR after 2 cyclesSurgery confirming persistence of LM1277/M/IIINose11.5/515/13/14/6/0/01/NANANA, NR after 1 cycleLost to follow-up after 1st cycleCR, Complete response; F, female; LM, lentigo maligna; LSR, local skin response; M, male; NA, not applicable; NR, no response; PR, partial response.∗ To ensure uniform reporting, LSRs were assessed quantitatively by using a grading scale and photographic guide images, a method similar to that used in published studies of ingenol mebutate. The 6 following responses were assessed on a scale that ranged 0-4 (with higher numbers indicating more severe reactions): swelling, vesiculation or pustulation, erosion or ulceration, flaking or scaling, crusting, and erythema. The composite LSR score was defined as the sum of the 6 individual scores (maximum composite score = 24). Patients were assessed on days 1, 2, 3, and 8 and at months 1 and 2. If a second cycle of ingenol mebutate was given, the LSR score was evaluated on days 86, 87, and 88 and at months 3 and 5. Open table in a new tab CR, Complete response; F, female; LM, lentigo maligna; LSR, local skin response; M, male; NA, not applicable; NR, no response; PR, partial response. Our study should be interpreted with caution because of its limitations, such as the lack of a comparative arm and the heterogeneity of LM. Nevertheless, its design4Simon R. Optimal two-stage designs for phase II clinical trials.Control Clin Trials. 1989; 10: 1-10Abstract Full Text PDF PubMed Scopus (2872) Google Scholar enables us to conclude that IM at 150 μg/g daily for 3 days (even after 2 cycles) is not a good option for treating LM of the head. Its use with a more intense regimen would be limited by a poor safety profile. We thank the patients whose faces are pictured in this article for granting permission to publish this information. We are indebted to Meri Tulic for assistance with English editing of this manuscript. We are grateful also to Laurence Laroche, MD, PhD (Department of Dermatology, Avicenne Hospital, Assistance Publique des Hôpitaux de Paris, University Paris 13, 93000 Bobigny, France), Philippe Saiag, MD, PhD (Department of Dermatology, University of Versailles-Saint Quentin en Yvelines, Assistance Publique des Hôpitaux de Paris, Boulogne, France), Alain Dupuy, MD, PhD (Department of Dermatology, Rennes University Hospital, Rennes, France), and Brigitte Dreno, MD, PhD (Department of Dermatology, Nantes University Hospital, Nantes, France, INSERM U892, 9 quai Montcousu 44093, Nantes, France), for their contribution to this study.