Short communication
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Acneiform eruption in a patient with metastatic melanoma after ceasing combination dabrafenib/trametinib therapy Pablo Uribea,e, Rachael M. Anfortha,c, Richard F. Keffordb,c,d and Pablo Fernandez-Peñasa,c BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) increase survival in BRAF mutant metastatic melanoma patients; however, they induce a well-known spectrum of cutaneous side effects during treatment. Whereas the BRAFi dabrafenib induces cutaneous squamous cell carcinomas and verrucal keratosis, the MEKi trametinib frequently induces acneiform eruptions that are reversible after drug discontinuation. Furthermore, when dabrafenib and trametinib are used in combination, there are fewer cutaneous toxicities. We report a patient with BRAFV600E mutant metastatic melanoma treated with the BRAFi/MEKi combination therapy who developed an acneiform eruption after treatment discontinuation rather than during active therapy. Moreover, the eruption resolved when the combination treatment was reintroduced and recurred after increasing the dose of trametinib. The eruption may be explained by the longer half-life of trametinib (4.5 days) compared with dabrafenib (5.2 h). This is the first case
Introduction The concurrent usage of a dabrafenib (BRAFi) and trametinib (MEKi) has shown higher tumour response and progression-free survival than dabrafenib alone [1–4]. These agents have a well-known spectrum of cutaneous toxicities. Whereas BRAFi induce cutaneous squamous cell carcinomas (cuSCCs) and verrucal keratosis [5], MEKi frequently produce an acneiform eruption [6]. The BRAFi/MEKi combination treatment has shown fewer cutaneous side effects, with a notable reduction in the development of cuSCC and acneiform reactions. Here, we report a patient with BRAFV600E metastatic melanoma treated with the dabrafenib/trametinib combination therapy who developed an acneiform eruption after every treatment discontinuation rather than during active therapy.
Case report In February 2011, a 37-year-old woman was diagnosed with multiple pulmonary melanoma metastases and a large mediastinal mass. The primary melanoma had been excised in 2008 from the left sole of her foot, and left inguinal lymph node metastases had been treated with an ilioinguinal femoral lymph node dissection and radiotherapy in 2010. The lymph node metastasis was positive for the BRAFV600E mutation and in June 2011 she was enroled in the phase I/II trial combining the BRAFi dabrafenib (formerly GSK2118436, 150 mg twice daily) 0960-8931 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
reported with this particular side effect induced after stopping the treatment and could become more frequent as the BRAFi/MEKi combination of drugs is more frequently prescribed. Melanoma Res 24:501–503 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Melanoma Research 2014, 24:501–503 Keywords: acne, acneiform eruptions, dabrafenib, metastatic melanoma, trametinib Departments of aDermatology, bMedical Oncology, Westmead Hospital, cSydney Medical School, The University of Sydney, dMelanoma Institute Australia, Sydney, New South Wales, Australia and eDepartment of Dermatology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile Correspondence to Rachael Anforth, MD, Department of Dermatology, Westmead Hospital, Darcy Road, Westmead, Sydney, NSW 2145, Australia Tel: + 61 2 9845 7149; fax: + 61 2 9845 9673; e-mail: [email protected] Received 9 January 2014 Accepted 8 May 2014
with the MEKi trametinib (formerly GSK1120212, 2 mg once daily) (NCT01072175). After 2 months of treatment, the patient developed pyrexia and rigors. Dabrafenib and trametinib were ceased for 10 days, with resolution of the pyrexia. Prednisone (10 mg/day) was commenced, with the reintroduction of the medications at day 10. Five days after stopping dabrafenib/trametinib, she developed a slightly itchy pustular eruption. The patient was evaluated in the dermatology department 8 days after the rash appeared and 3 days after the dabrafenib/trametinib combination was reintroduced. On examination, multiple small pustules on the trunk, forehead and chin were observed (Fig. 1). With the probable diagnoses of a grade 1 druginduced acneiform eruption versus acute folliculitis, she was treated empirically with cephalexin for 7 days and chlorhexidine-based body washes, with complete response. The patient continued to have periodic episodes of pyrexia despite ongoing therapy with oral prednisone. Dabrafenib/trametinib were once again ceased and reintroduced with a lower dose of trametinib (1 mg/day). Eight days after ceasing the medications, the patient experienced a milder acneiform eruption, which improved after reintroduction of the combined medications, and without any specific treatment. A third transitory flare occurred when trametinib was increased from DOI: 10.1097/CMR.0000000000000096
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
502 Melanoma Research
2014, Vol 24 No 5
Fig. 1
Clinical photographs of the acneiform eruption. (a, b) Rash distribution on seborrhoeic areas of the back, face and chest (not shown). (c, d) Multiple small follicular pustules on the back and forehead.
1 to 2 mg/day. A fourth and final flare occurred when the combination therapy was ceased to allow for a course of radiotherapy to a mediastinal mass. During this time, an acneiform eruption was noted and completely improved after medications were reintroduced. Despite the initial partial response to dabrafenib/trametinib therapy, the patient died in August 2013 as a result of disease progression.
Discussion In this new and promising era, a number of medications have become available that have high antimelanoma activity. Although they target specific mutated proteins, they induce side effects within normal cells, the mechanisms of which remain to be elucidated in many
cases. The BRAFi dabrafenib has been shown to induce the development of keratotic hyperproliferative lesions including verrucal keratosis, cuSCCs and plantar keratoderma. Patients on dabrafenib also develop Grover’s disease, panniculitis, hair changes and epidermal cysts. Acneiform eruptions can be found in up to 7% of patients [7]. Conversely, the MEKi trametinib frequently induces acneiform eruptions (75%) [6], diarrhoea, peripheral oedema, fatigue, nausea, xerosis cutis, paronychia, and acral fissures [8]. The acneiform rash usually appears on the face and trunk, it is usually more inflammatory (with papules, pustules and crusting) than cystic, and is completely reversible after discontinuation of the drug. Interestingly, this acneiform eruption is very similar to those induced by epidermal growth factor receptor
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Acneiform eruption after dabrafenib/trametinib Uribe et al. 503
inhibitors [9]. The combination of dabrafenib and trametinib reduces the frequency of cutaneous side effects, including acneiform eruptions, which are decreased to 16% [3,5], but it increases the possibility of pyrexia to around 70% [3].
by resuming the treatment, and it could become more frequent when this combination of drugs is prescribed more frequently.
In the patient described here, every discontinuation of the combination treatment led to the development of an acneiform eruption. It is well known that systemic corticosteroids can induce acneiform eruptions, usually starting after 2 weeks of treatment. However, in our patient, the eruption was not related to corticosteroid use as it appeared before starting systemic corticosteroids and improved while still on prednisone therapy. Moreover, the eruption always completely improved with reintroduction of the combination treatment and recurred after increasing trametinib. The eruption may be explained by the longer half-life of trametinib (4.5 days) compared with dabrafenib (5.2 h) [2,6]. Therefore, 1 day after ceasing the combination therapy, the patient was only effectively exposed to trametinib, which frequently induces acneiform eruptions.
Acknowledgements
The precise mechanisms of the MEKi-induced acneiform eruption and the resolution of the condition with the introduction of a BRAFi are unknown. The profile of cutaneous side effects induced by trametinib is similar to those induced by epidermal growth factor receptor inhibitors, and are probably related to the abrupt inhibition of the MAPK ERK pathway in keratinocytes. This induces an acute keratinocyte stress response that leads to apoptosis, alteration in epidermal homoeostasis and inflammation [9,10]. In BRAFWT cells, the combination of BRAFi and MEKi therapy could preclude a total MAPK ERK blockage or activate other pathways that prevent an acute keratinocyte stress response and subsequent acneiform eruptions. This is the first case reported with this particular side effect induced by stopping the treatment and improved
Conflicts of interest
Dr Kefford reported institutional reimbursement for GSK Advisory Boards. For the remaining authors there are no conflicts of interest.
References 1
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364:2507–2516. 2 Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012; 379:1893–1901. 3 Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012; 367:1694–1703. 4 Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, openlabel, phase 3 randomised controlled trial. Lancet 2012; 380:358–365. 5 Anforth R, Fernandez-Penas P, Long GV. Cutaneous toxicities of RAF inhibitors. Lancet Oncol 2013; 14:e11–e18. 6 Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13:773–781. 7 Anforth RM, Blumetti TC, Kefford RF, Sharma R, Scolyer RA, Kossard S, et al. Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma. Br J Dermatol 2012; 167:1153–1160. 8 Zimmer L, Vaubel J, Livingstone E, Schadendorf D. Side effects of systemic oncological therapies in dermatology. J Dtsch Dermatol Ges 2012; 10:475–486. 9 Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 2006; 6:803–812. 10 Schad K, Baumann Conzett K, Zipser MC, Enderlin V, Kamarashev J, French LE, Dummer R. Mitogen-activated protein/extracellular signalregulated kinase kinase inhibition results in biphasic alteration of epidermal homeostasis with keratinocytic apoptosis and pigmentation disorders. Clin Cancer Res 2010; 16:1058–1064.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
501
Acneiform eruption in a patient with metastatic melanoma after ceasing combination dabrafenib/trametinib therapy Pablo Uribea,e, Rachael M. Anfortha,c, Richard F. Keffordb,c,d and Pablo Fernandez-Peñasa,c BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) increase survival in BRAF mutant metastatic melanoma patients; however, they induce a well-known spectrum of cutaneous side effects during treatment. Whereas the BRAFi dabrafenib induces cutaneous squamous cell carcinomas and verrucal keratosis, the MEKi trametinib frequently induces acneiform eruptions that are reversible after drug discontinuation. Furthermore, when dabrafenib and trametinib are used in combination, there are fewer cutaneous toxicities. We report a patient with BRAFV600E mutant metastatic melanoma treated with the BRAFi/MEKi combination therapy who developed an acneiform eruption after treatment discontinuation rather than during active therapy. Moreover, the eruption resolved when the combination treatment was reintroduced and recurred after increasing the dose of trametinib. The eruption may be explained by the longer half-life of trametinib (4.5 days) compared with dabrafenib (5.2 h). This is the first case
Introduction The concurrent usage of a dabrafenib (BRAFi) and trametinib (MEKi) has shown higher tumour response and progression-free survival than dabrafenib alone [1–4]. These agents have a well-known spectrum of cutaneous toxicities. Whereas BRAFi induce cutaneous squamous cell carcinomas (cuSCCs) and verrucal keratosis [5], MEKi frequently produce an acneiform eruption [6]. The BRAFi/MEKi combination treatment has shown fewer cutaneous side effects, with a notable reduction in the development of cuSCC and acneiform reactions. Here, we report a patient with BRAFV600E metastatic melanoma treated with the dabrafenib/trametinib combination therapy who developed an acneiform eruption after every treatment discontinuation rather than during active therapy.
Case report In February 2011, a 37-year-old woman was diagnosed with multiple pulmonary melanoma metastases and a large mediastinal mass. The primary melanoma had been excised in 2008 from the left sole of her foot, and left inguinal lymph node metastases had been treated with an ilioinguinal femoral lymph node dissection and radiotherapy in 2010. The lymph node metastasis was positive for the BRAFV600E mutation and in June 2011 she was enroled in the phase I/II trial combining the BRAFi dabrafenib (formerly GSK2118436, 150 mg twice daily) 0960-8931 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
reported with this particular side effect induced after stopping the treatment and could become more frequent as the BRAFi/MEKi combination of drugs is more frequently prescribed. Melanoma Res 24:501–503 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Melanoma Research 2014, 24:501–503 Keywords: acne, acneiform eruptions, dabrafenib, metastatic melanoma, trametinib Departments of aDermatology, bMedical Oncology, Westmead Hospital, cSydney Medical School, The University of Sydney, dMelanoma Institute Australia, Sydney, New South Wales, Australia and eDepartment of Dermatology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile Correspondence to Rachael Anforth, MD, Department of Dermatology, Westmead Hospital, Darcy Road, Westmead, Sydney, NSW 2145, Australia Tel: + 61 2 9845 7149; fax: + 61 2 9845 9673; e-mail: [email protected] Received 9 January 2014 Accepted 8 May 2014
with the MEKi trametinib (formerly GSK1120212, 2 mg once daily) (NCT01072175). After 2 months of treatment, the patient developed pyrexia and rigors. Dabrafenib and trametinib were ceased for 10 days, with resolution of the pyrexia. Prednisone (10 mg/day) was commenced, with the reintroduction of the medications at day 10. Five days after stopping dabrafenib/trametinib, she developed a slightly itchy pustular eruption. The patient was evaluated in the dermatology department 8 days after the rash appeared and 3 days after the dabrafenib/trametinib combination was reintroduced. On examination, multiple small pustules on the trunk, forehead and chin were observed (Fig. 1). With the probable diagnoses of a grade 1 druginduced acneiform eruption versus acute folliculitis, she was treated empirically with cephalexin for 7 days and chlorhexidine-based body washes, with complete response. The patient continued to have periodic episodes of pyrexia despite ongoing therapy with oral prednisone. Dabrafenib/trametinib were once again ceased and reintroduced with a lower dose of trametinib (1 mg/day). Eight days after ceasing the medications, the patient experienced a milder acneiform eruption, which improved after reintroduction of the combined medications, and without any specific treatment. A third transitory flare occurred when trametinib was increased from DOI: 10.1097/CMR.0000000000000096
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
502 Melanoma Research
2014, Vol 24 No 5
Fig. 1
Clinical photographs of the acneiform eruption. (a, b) Rash distribution on seborrhoeic areas of the back, face and chest (not shown). (c, d) Multiple small follicular pustules on the back and forehead.
1 to 2 mg/day. A fourth and final flare occurred when the combination therapy was ceased to allow for a course of radiotherapy to a mediastinal mass. During this time, an acneiform eruption was noted and completely improved after medications were reintroduced. Despite the initial partial response to dabrafenib/trametinib therapy, the patient died in August 2013 as a result of disease progression.
Discussion In this new and promising era, a number of medications have become available that have high antimelanoma activity. Although they target specific mutated proteins, they induce side effects within normal cells, the mechanisms of which remain to be elucidated in many
cases. The BRAFi dabrafenib has been shown to induce the development of keratotic hyperproliferative lesions including verrucal keratosis, cuSCCs and plantar keratoderma. Patients on dabrafenib also develop Grover’s disease, panniculitis, hair changes and epidermal cysts. Acneiform eruptions can be found in up to 7% of patients [7]. Conversely, the MEKi trametinib frequently induces acneiform eruptions (75%) [6], diarrhoea, peripheral oedema, fatigue, nausea, xerosis cutis, paronychia, and acral fissures [8]. The acneiform rash usually appears on the face and trunk, it is usually more inflammatory (with papules, pustules and crusting) than cystic, and is completely reversible after discontinuation of the drug. Interestingly, this acneiform eruption is very similar to those induced by epidermal growth factor receptor
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Acneiform eruption after dabrafenib/trametinib Uribe et al. 503
inhibitors [9]. The combination of dabrafenib and trametinib reduces the frequency of cutaneous side effects, including acneiform eruptions, which are decreased to 16% [3,5], but it increases the possibility of pyrexia to around 70% [3].
by resuming the treatment, and it could become more frequent when this combination of drugs is prescribed more frequently.
In the patient described here, every discontinuation of the combination treatment led to the development of an acneiform eruption. It is well known that systemic corticosteroids can induce acneiform eruptions, usually starting after 2 weeks of treatment. However, in our patient, the eruption was not related to corticosteroid use as it appeared before starting systemic corticosteroids and improved while still on prednisone therapy. Moreover, the eruption always completely improved with reintroduction of the combination treatment and recurred after increasing trametinib. The eruption may be explained by the longer half-life of trametinib (4.5 days) compared with dabrafenib (5.2 h) [2,6]. Therefore, 1 day after ceasing the combination therapy, the patient was only effectively exposed to trametinib, which frequently induces acneiform eruptions.
Acknowledgements
The precise mechanisms of the MEKi-induced acneiform eruption and the resolution of the condition with the introduction of a BRAFi are unknown. The profile of cutaneous side effects induced by trametinib is similar to those induced by epidermal growth factor receptor inhibitors, and are probably related to the abrupt inhibition of the MAPK ERK pathway in keratinocytes. This induces an acute keratinocyte stress response that leads to apoptosis, alteration in epidermal homoeostasis and inflammation [9,10]. In BRAFWT cells, the combination of BRAFi and MEKi therapy could preclude a total MAPK ERK blockage or activate other pathways that prevent an acute keratinocyte stress response and subsequent acneiform eruptions. This is the first case reported with this particular side effect induced by stopping the treatment and improved
Conflicts of interest
Dr Kefford reported institutional reimbursement for GSK Advisory Boards. For the remaining authors there are no conflicts of interest.
References 1
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364:2507–2516. 2 Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012; 379:1893–1901. 3 Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012; 367:1694–1703. 4 Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, openlabel, phase 3 randomised controlled trial. Lancet 2012; 380:358–365. 5 Anforth R, Fernandez-Penas P, Long GV. Cutaneous toxicities of RAF inhibitors. Lancet Oncol 2013; 14:e11–e18. 6 Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13:773–781. 7 Anforth RM, Blumetti TC, Kefford RF, Sharma R, Scolyer RA, Kossard S, et al. Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma. Br J Dermatol 2012; 167:1153–1160. 8 Zimmer L, Vaubel J, Livingstone E, Schadendorf D. Side effects of systemic oncological therapies in dermatology. J Dtsch Dermatol Ges 2012; 10:475–486. 9 Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 2006; 6:803–812. 10 Schad K, Baumann Conzett K, Zipser MC, Enderlin V, Kamarashev J, French LE, Dummer R. Mitogen-activated protein/extracellular signalregulated kinase kinase inhibition results in biphasic alteration of epidermal homeostasis with keratinocytic apoptosis and pigmentation disorders. Clin Cancer Res 2010; 16:1058–1064.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
