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Case Report/Case Series |

MEK Inhibitor–Induced Dusky Erythema Characteristic Drug Hypersensitivity Manifestation in 3 Patients FREE

Urvi Patel, MD1; Lynn Cornelius, MD1; Milan J. Anadkat, MD1
[+] Author Affiliations
1Division of Dermatology, Washington University School of Medicine, St Louis, Missouri
JAMA Dermatol. 2015;151(1):78-81. doi:10.1001/jamadermatol.2014.3207.
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Published online

ABSTRACT

Importance  MEK inhibitors are being evaluated in clinical trials for treatment of different malignant neoplasms; trametinib dimethyl sulfoxide was approved by the US Food and Drug Administration for melanoma in 2013. We present 3 cases of patients receiving MEK inhibitors who developed an atypical eruption.

Observations  Three patients who were receiving different MEK inhibitors (selumetinib, cobimetinib, and trametinib) developed an eruption, all associated with unique duskiness. Drug hypersensitivity was confirmed by histopathologic testing in 2 of the 3 cases. The skin eruption responded well to corticosteroids and did not recur when treatment with the MEK inhibitor was restarted in 2 of the patients.

Conclusions and Relevance  The typical skin reaction associated with MEK inhibitors is a papulopustular eruption. To our knowledge, the dusky erythema that occurred in the 3 patients described here has not previously been reported for this drug class.

Figures in this Article

INTRODUCTION

As an emerging class of targeted therapies, MEK inhibitors have been studied for treatment of multiple malignant neoplasms. In 2013, trametinib dimethyl sulfoxide became the first MEK inhibitor to be approved by the US Food and Drug Administration that showed1 survival benefit over traditional chemotherapy with either dacarbazine or paclitaxel for the treatment of advanced metastatic melanoma with a BRAF V600E or V600K mutation. Thirteen other MEK inhibitors, including selumetinib and cobimetinib, are currently in clinical trials for treatment of melanoma and other solid-organ malignant neoplasms, including pancreatic, hepatocellular, colorectal, and non–small cell lung cancer.2

Our understanding of dermatologic toxic effects associated with MEK inhibitors is evolving. The most common of the toxic effects is an acneiform eruption of similar phenotype but decreased severity compared with that seen with epidermal growth factor receptor inhibitors. We describe 3 patients who received MEK inhibitors and developed a novel phenotype of dermatologic toxic reaction.

Each patient provided written informed consent to participate in an ongoing institutional review board–approved study at Washington University School of Medicine to evaluate cutaneous chemotherapy-induced reactions (CCT-REACT).

REPORT OF CASES

Case 1

A man in his 60s with stage 4 pancreatic cancer was receiving the MEK inhibitor selumetinib, 100 mg/d, and the Akt inhibitor MK2206, 135 mg/wk, as part of a clinical trial. Twelve days after the start of therapy, he presented with a generalized eruption and mild pruritus. He had diffuse targetoid patches with central duskiness (Figure 1). The eruption was grade 2 according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (Table).3 Study medications were withheld because of the eruption. The eruption had started to fade with topical corticosteroid treatment before the drugs were discontinued; however, the therapy was not restarted owing to an elevated alkaline phosphatase level and fatigue. The eruption had resolved by the time of the patient’s follow-up visit 4 weeks after discontinuation of the study drugs.

Place holder to copy figure label and caption
Figure 1.
Skin Eruption in Patient 1 During Selumetinib Therapy

Targetoid patches with central duskiness.

Graphic Jump Location
Table Graphic Jump LocationTable.  Maculopapular Rash Grading According to CTCAE, Version 4.0a
Case 2

A woman in her 40s was receiving vemurafenib, 960 mg, twice daily on days 1 to 28 and study drug GDC-0973 (cobimetinib), 60 mg/d, on days 1 to 21 for metastatic melanoma that was BRAF V600E mutated. She developed a diffuse eruption on day 28 of treatment. Findings from the physical examination revealed coalescing urticarial patches with surrounding duskiness that was grade 2 according to the CTCAE, version 4.0 (Figure 2A). Histopathologic examination showed a superficial perivascular lymphocytic infiltrate with rare eosinophils (Figure 2B and C). Both medications were stopped for 7 days by the oncologist owing to the eruption, and a slow tapering regimen of oral prednisone, starting at 60 mg/d, was instituted. Cobimetinib therapy was reinstituted at 40 mg/d, and the patient continued to receive oral prednisone, 10 mg/d, throughout treatment because of arthralgias associated with vemurafenib. There was no recurrence of the eruption 1 year after cobimetinib therapy was restarted.

Place holder to copy figure label and caption
Figure 2.
Skin Eruption in Patient 2 During Cobimetinib Therapy

A, Urticarial plaques with diffuse central duskiness. B, Histopathologic findings with superficial perivascular infiltrate (hematoxylin-eosin, original magnification ×10). C, Mixed infiltrate composed of lymphocytes, mast cells, neutrophils, and rare eosinophils (hematoxylin-eosin, original magnification ×40).

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Case 3

A woman in her 50s with metastatic melanoma that was BRAF V600E mutated was receiving dabrafenib mesylate, 150 mg twice a day, and trametinib dimethyl sulfoxide, 2 mg/d. She developed a worsening, mildly pruritic eruption 7 weeks into treatment. On examination, she had grade 3 (according to the CTCAE, version 4.0) urticarial patches and plaques with surrounding diffuse duskiness (Figure 3A). Biopsy results were consistent with urticarial dermatitis, with superficial and deep perivascular and interstitial infiltrate with lymphocytes, mast cells, neutrophils, and rare eosinophils (Figure 3C and D). Trametinib treatment was withheld because of the eruption, and a 1-month-long tapering regimen of oral prednisone at 60 mg/d was started. One week after the onset of the eruption, trametinib therapy was restarted and the eruption had not returned by the time of the 1-month follow-up visit (Figure 3B).

Place holder to copy figure label and caption
Figure 3.
Skin Eruption in Patient 3 During Trametinib Therapy

A, Generalized urticarial plaques with surrounding duskiness. B, The eruption resolved after temporary cessation of the MEK inhibitor treatment and initiation of oral corticosteroid treatment. C, Histopathologic analysis showed superficial perivascular infiltrate (hematoxylin-eosin, original magnification ×5). D, Inflammatory infiltrate composed of lymphocytes and eosinophils (yellow arrowhead and inset) (hematoxylin-eosin, original magnification ×20 and ×63).

Graphic Jump Location

DISCUSSION

Targeted therapies have become a part of treatment for many malignant neoplasms, including metastatic melanoma. The mitogen-activated protein kinase (MAPK) pathway, also known as the RAS/RAF/MEK/ERK pathway, has become a new target for cancer therapy owing to its downstream position in the signaling cascade.4 The MAPK pathway influences multiple cellular functions, including cell survival, proliferation, differentiation, and apoptosis.5 Mutations in the MAPK pathway can be driver mutations in cancer development and play a role in the development of drug resistance. Such mutations have been noted5 in several cancers, including melanomas. Multiple agents that inhibit MEK and other kinases in this pathway are currently in clinical trials as adjuvant treatment for several malignant neoplasms, including pancreatic cancer and metastatic melanoma.6

A cutaneous eruption is one of the most commonly reported adverse effects for the MEK inhibitor class of targeted therapies.6,7 The incidence of skin eruption ranged from 57% to 93% in phase 1, 2, and 3 clinical studies610 and was typically of grade 1 or 2 severity. The incidence of grade 3 or greater skin toxic effects secondary to MEK inhibitors was reported to be less than 10%.8 Skin eruption has been recognized as a dose-limiting toxic effect of MEK inhibitors, but in most cases it did not require drug cessation.9,10 Commonly reported dermatologic adverse effects of MEK inhibitors are similar to those of epidermal growth factor receptor inhibitors, although with a lower level of severity. The most common dermatologic adverse effect reported with MEK inhibitors is a papulopustular eruption, with an incidence of 40% to 93%.11 Other adverse effects have included paronychia and fissuring, hair changes, xerosis, mucositis, and pruritus. Other types of eruptions include a maculopapular eruption and erythema. We report unusual drug hypersensitivity, with lesions ranging from urticarial to targetoid but all with a distinctive central duskiness. Although this eruption is reminiscent of erythema multiforme, the lack of interface changes and dyskeratosis on histopathologic examination clearly distinguishes between the 2 diagnoses.

Recognition of this unique clinical phenotype is significant for helping the physician determine the culprit drug because many patients with cancer may be receiving multiple medications. Other than pruritus, the eruption was asymptomatic in our series of patients. No mucosal involvement or other systemic symptoms were noted. In distinction to the use of BRAF inhibitors (in particular, vemurafenib) as a solo agent, an increased incidence of squamous cell carcinomas has not been noted with MEK inhibitors used alone or in combination with other agents. As shown in our patients, successful treatment of this MEK inhibitor–associated cutaneous eruption can include a drug holiday and oral corticosteroid therapy, with reinstitution of the drug at a lower dose without recurrence.

CONCLUSIONS

The MEK inhibitors are a newer class of targeted therapies, and one of these, trametinib, was recently approved by the US Food and Drug Administration for treatment of metastatic melanoma. Cutaneous toxic effects have been reported as one of the most common adverse drug events. We present a drug hypersensitivity eruption to MEK inhibitors that is distinctive because of the characteristic duskiness. It responds well to temporary drug cessation and oral prednisone therapy.

ARTICLE INFORMATION

Accepted for Publication: August 22, 2014.

Corresponding Author: Milan J. Anadkat, MD, Division of Dermatology, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8123, St Louis, MO 63110 (manadkat@dom.wustl.edu).

Published Online: November 26, 2014. doi:10.1001/jamadermatol.2014.3207.

Author Contributions: Drs Patel and Anadkat had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Cornelius and Anadkat contributed equally to the study.

Study concept and design: Anadkat.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Patel, Anadkat.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Anadkat.

Administrative, technical, or material support: All authors.

Study supervision: Cornelius, Anadkat.

Conflict of Interest Disclosures: Dr Cornelius has received a research grant from Genentech and is a clinical subinvestigtor for GlaxoSmithKline. Dr Anadkat has received honoraria as a speaker and/or consultant from AstraZeneca, Bristol-Myers Squibb, Eisai, ImClone, and Therakos. No other disclosures were reported.

REFERENCES

Flaherty  KT, Robert  C, Hersey  P,  et al; METRIC Study Group.  Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107-114.
PubMed   |  Link to Article
Akinleye  A, Furqan  M, Mukhi  N, Ravella  P, Liu  D.  MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013;6:27.
PubMed   |  Link to Article
Cancer Therapy Evaluation Program. Common terminology criteria for adverse events, version 4.0, DCTD, National Cancer Institute, National Institutes of Health, Dept of Health and Human Services; revised June 2010.http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed June 3, 2014.
Frémin  C, Meloche  S.  From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J Hematol Oncol. 2010;3:8.
PubMed   |  Link to Article
Dhillon  AS, Hagan  S, Rath  O, Kolch  W.  MAP kinase signalling pathways in cancer. Oncogene. 2007;26(22):3279-3290.
PubMed   |  Link to Article
Balagula  Y, Barth Huston  K, Busam  KJ, Lacouture  ME, Chapman  PB, Myskowski  PL.  Dermatologic side effects associated with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886). Invest New Drugs. 2011;29(5):1114-1121.
PubMed   |  Link to Article
Curry  JL, Torres-Cabala  CA, Kim  KB,  et al.  Dermatologic toxicities to targeted cancer therapy: shared clinical and histologic adverse skin reactions. Int J Dermatol. 2014;53(3):376-384.
PubMed   |  Link to Article
Kim  KB, Kefford  R, Pavlick  AC,  et al.  Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013;31(4):482-489.
PubMed   |  Link to Article
Adjei  AA, Cohen  RB, Franklin  W,  et al.  Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008;26(13):2139-2146.
PubMed   |  Link to Article
Infante  JR, Fecher  LA, Falchook  GS,  et al.  Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(8):773-781.
PubMed   |  Link to Article
Jänne  PA, Shaw  AT, Pereira  JR,  et al.  Selumetinib plus docetaxel for KRAS-mutant advanced non–small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013;14(1):38-47.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Skin Eruption in Patient 1 During Selumetinib Therapy

Targetoid patches with central duskiness.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Skin Eruption in Patient 2 During Cobimetinib Therapy

A, Urticarial plaques with diffuse central duskiness. B, Histopathologic findings with superficial perivascular infiltrate (hematoxylin-eosin, original magnification ×10). C, Mixed infiltrate composed of lymphocytes, mast cells, neutrophils, and rare eosinophils (hematoxylin-eosin, original magnification ×40).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Skin Eruption in Patient 3 During Trametinib Therapy

A, Generalized urticarial plaques with surrounding duskiness. B, The eruption resolved after temporary cessation of the MEK inhibitor treatment and initiation of oral corticosteroid treatment. C, Histopathologic analysis showed superficial perivascular infiltrate (hematoxylin-eosin, original magnification ×5). D, Inflammatory infiltrate composed of lymphocytes and eosinophils (yellow arrowhead and inset) (hematoxylin-eosin, original magnification ×20 and ×63).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  Maculopapular Rash Grading According to CTCAE, Version 4.0a

References

Flaherty  KT, Robert  C, Hersey  P,  et al; METRIC Study Group.  Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107-114.
PubMed   |  Link to Article
Akinleye  A, Furqan  M, Mukhi  N, Ravella  P, Liu  D.  MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013;6:27.
PubMed   |  Link to Article
Cancer Therapy Evaluation Program. Common terminology criteria for adverse events, version 4.0, DCTD, National Cancer Institute, National Institutes of Health, Dept of Health and Human Services; revised June 2010.http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed June 3, 2014.
Frémin  C, Meloche  S.  From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J Hematol Oncol. 2010;3:8.
PubMed   |  Link to Article
Dhillon  AS, Hagan  S, Rath  O, Kolch  W.  MAP kinase signalling pathways in cancer. Oncogene. 2007;26(22):3279-3290.
PubMed   |  Link to Article
Balagula  Y, Barth Huston  K, Busam  KJ, Lacouture  ME, Chapman  PB, Myskowski  PL.  Dermatologic side effects associated with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886). Invest New Drugs. 2011;29(5):1114-1121.
PubMed   |  Link to Article
Curry  JL, Torres-Cabala  CA, Kim  KB,  et al.  Dermatologic toxicities to targeted cancer therapy: shared clinical and histologic adverse skin reactions. Int J Dermatol. 2014;53(3):376-384.
PubMed   |  Link to Article
Kim  KB, Kefford  R, Pavlick  AC,  et al.  Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013;31(4):482-489.
PubMed   |  Link to Article
Adjei  AA, Cohen  RB, Franklin  W,  et al.  Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008;26(13):2139-2146.
PubMed   |  Link to Article
Infante  JR, Fecher  LA, Falchook  GS,  et al.  Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(8):773-781.
PubMed   |  Link to Article
Jänne  PA, Shaw  AT, Pereira  JR,  et al.  Selumetinib plus docetaxel for KRAS-mutant advanced non–small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013;14(1):38-47.
PubMed   |  Link to Article

Correspondence

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