|Year : 2019 | Volume
| Issue : 3 | Page : 154-156
A case with psoriasis-like lesions induced by olmutinib (HM61713) while treating epidermal growth factor receptor T790M mutant advanced lung adenocarcinoma
Chu-Ju Hung1, Po-Ju Lai2, Jen-Jung Cheng3, Shiow-Jiuan Wey3, Yu-Ping Hsiao4, Ming-Fang Wu5
1 Department of Dermatology, Chung Shan Medical University Hospital; School of Medicine, Chung Shan Medical University, Taichung, Taiwan
2 Department of Dermatology, Chung Shan Medical University Hospital; Institute of Biochemistry, Microbiology, and Immunology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
3 Department of Dermatology, Chung Shan Medical University Hospital, Taichung, Taiwan
4 Department of Dermatology, Chung Shan Medical University Hospital; Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
5 Institute of Medicine, School of Medicine, Chung Shan Medical University; Department of Internal Medicine, Division of Chest Medicine and Medical Oncology, Chung Shan Medical University Hospital, Taichung, Taiwan
|Date of Submission||13-Dec-2017|
|Date of Acceptance||24-Dec-2018|
|Date of Web Publication||26-Sep-2019|
Dr. Ming-Fang Wu
Department of Internal Medicine, Division of Chest Medicine and Medical Oncology, Chung Shan Medical University Hospital, Taichung
Source of Support: None, Conflict of Interest: None
Olmutinib (HM61713) is a third-generation tyrosine kinase inhibitor active against mutant EGFR, including T790M in nonsmall cell lung cancer. The most common side effect of olmutinib to date includes diarrhea, rash, nausea, and pruritus. To the best of our knowledge, it is the first case of psoriasis-like lesions that occurred after treatment with olmutinib. Although the pathogenesis for skin manifestations is presently unknown, we present this case to increase awareness of this unique cutaneous side effect.
Keywords: Adverse drug reaction, epidermal growth factor receptor-tyrosine kinase inhibitor, lung adenocarcinoma, olmutinib, psoriasis, T790M mutation
|How to cite this article:|
Hung CJ, Lai PJ, Cheng JJ, Wey SJ, Hsiao YP, Wu MF. A case with psoriasis-like lesions induced by olmutinib (HM61713) while treating epidermal growth factor receptor T790M mutant advanced lung adenocarcinoma. Dermatol Sin 2019;37:154-6
|How to cite this URL:|
Hung CJ, Lai PJ, Cheng JJ, Wey SJ, Hsiao YP, Wu MF. A case with psoriasis-like lesions induced by olmutinib (HM61713) while treating epidermal growth factor receptor T790M mutant advanced lung adenocarcinoma. Dermatol Sin [serial online] 2019 [cited 2019 Dec 8];37:154-6. Available from: http://www.dermsinica.org/text.asp?2019/37/3/154/267888
| Introduction|| |
Olmutinib (HM61713), a third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) is now ongoing a phase II trial (ClinicalTirals.gov identifier: NCT02485652) in patients with T790M-positive nonsmall cell lung cancer (NSCLC) after treatment with the first- or second-generation EGFR-TKI. While the efficacy of the treatment is the aim, the safety is also important. Herein, we present a case of psoriasis-like lesions after taking olmutinib.
| Case Report|| |
A 64-year-old male presented with a 2-week history of erythematous papules and plaques on the extremities. On physical examination, widespread erythematous to purpuric papules and plaques were seen on the elbow, sacrum, knee, shin, sparing the mucosa [Figure 1]a and b]. The patient had a six-year history of advanced lung adenocarcinoma with bone, liver metastasis. He also had hypertension, type 2 diabetes mellitus with regular follow-up and medical control. Previous chemotherapeutic agents included vinorelbine (Navelbine), gefitinib (Iressa) for 2 years, pemetrexed (Alimta), and docetaxel (Taxotere). Due to disease progression and having EGFR T790M mutation, he began to take olmutinib 800 mg daily. Two weeks later, he developed the skin eruption. The erythematous plaques caused mild pruritus. Burning, painful sensation or other systemic symptoms such as fever or arthralgia were not reported. No other medication is identified for the cause of skin eruption except olmutinib (other medications such as symptoms relieved agents, blood sugar control agents were used for >1 year). A skin biopsy of the papule on the right thigh [Figure 1]a revealed regular psoriasiform hyperplasia, marked parakeratosis and hypogranulosis, the tortuous dilated vessel in the papillary dermis [Figure 2]. Extravasations of erythrocytes in the upper dermis without destruction of the blood vessel, eosinophil, and lymphocyte perivascular infiltration were also seen. Results of laboratory examination, including white blood cell counts, eosinophil counts, platelet counts, prothrombin time, and partial thromboplastin time were normal. The liver and renal function tests were within the normal limit. Periodic acid–Schiff stain was negative for fungal organisms. Direct immunofluorescence (DIF) examination showed no evidence of immunocomplex in the superficial blood vessel. The patient stopped olmutinib and started to apply betamethasone valerate with gentamycin cream (trade name: Betaderm cream) and urea-containing cream (trade name: Urea A. D. E cream) twice daily. He presented in followed-up 2 weeks later, with markedly improved of the papulosquamous eruption [Figure 1]c, without the new onset of skin lesions. He started to treat with olmutinib 600 mg daily this time. Similar skin lesions (Grade 1) gradually reappeared in 1 week. A second skin biopsy was suggested but was refused by the patient. Lymphocyte transformation tests (LTTs) for olmutinib and gefitinib were both positive, while sorafenib showed weakly positive. Given these findings, the re-challenged test together with the LTTs was consistent with a reactive hypersensitivity process, including drug eruption. Finally, he decided to withdraw from the study because of intolerance of the side effect.
|Figure 1: (a) Well-demarcated erythematous papules and plaques on right knee (Circle: biopsy area), (b) Reddish plaques on the elbows with silver-white scales, (c) The rashes diminished after stopped taking olmutinib and applied on topical agents on the sacrum|
Click here to view
|Figure 2:(a) Regular psoriasiform hyperplasia of the epidermis. Parakeratosis and hypogranulosis, tortuous dilated vessel in the papillary dermis indicated a psoriasiform eruption (H and E, ×100), (b) Superficial perivascular infiltration of lymphocytes, and eosinophils (arrowhead) with red blood cell extravasation (arrow) (H and E, ×400)|
Click here to view
| Discussion|| |
The activating mutations of epidermal growth factor receptor (EGFR) in advanced lung adenocarcinoma occur more frequently in East Asian patients (30%–40%) than in Caucasian patients (10%–15%)., While those patients treated with the first- or second-generation EGFR-TKIs such as Gefitinib, Erlotinib, or Giotrif, the progression-free survival is between 10 and 12 months.,
The most common mechanism of acquired resistance to these EGFR-targeted agents is the EGFR T790M acquired mutation., Olmutinib (HM61713) is a third-generation TKI designed for selective inhibition of T790M mutant EGFR while sparing the wild-type EGFR.,
In an early phase II study of patients with T790M-positive NSCLC, 76 patients had received olmutinib at the recommended dose of 800 mg once daily. The overall response rate was 62%, and the disease control rate was 91%. The most common drug-related adverse events were (all/Grade 3) diarrhea (55%/0%), rash (38%/5%), nausea (37%/0%), and pruritus (36%/1%). Skin manifestations of olmutinib included (all/Grade 3) rashes (38%/5%), pruritus (36%/1%), dry skin (29%/1%), hand-foot syndrome (29%/3%), and skin exfoliation (21%/0%). Comparing to the common drug-related skin eruptions termed the PRIDE (Papulopustules and/or paronychia, Regulatory abnormalities of hair growth, itching, and dryness due to EGFR inhibitors) syndrome of the first- and second-generation EGFR-TKI, olmutinib seems to have less effects on the hair and nail.
The clinical appearance of erythematous papules may give the differential diagnosis to psoriasis, lichenoid drug eruption, leukocytoclastic vasculitis, and to a lesser extend, Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). There was no mucosal involvement or painful skin detachments, nor did the histopathology revealed epidermal necrosis, which SJS/TEN could be ruled out. No lichenoid infiltration of the inflammatory cell, no destruction or fibrinoid change of the blood vessels, negative DIF findings indicated less likely of lichenoid drug eruption or leukocytoclastic vasculitis. Histopathology features with psoriasiform acanthosis, confluent parakeratosis, tortuous blood vessels, and perivascular infiltration of lymphocyte and eosinophils without neutrophils aggregate in the stratum corneum and epidermis preferable the diagnosis of psoriasiform eruption rather than psoriasis.
Furthermore, presentation of erythematous plaques on the extensor site of extremities, sacrum area together pointed to the diagnosis of a psoriasis-like lesions.
EGFR is expressed in the epidermal and pilosebaceous units. Thus, it plays an important role in the development and function of normal skin. Inhibition of EGFR may induce an imbalance in downstream molecular pathway directing to keratinocyte proliferation. EGFR has the effect in restraining interleukin-1, interleukin-8, and tumor necrosis factor-alpha, which is clearly consistent with the high incidence of skin reactions to EGFR inhibitors.
Except for the epidermis, EGFR also expressed in some endothelial cells. Consequently, the disruption in the normal EGFR pathway may give rise to abnormal vascular formation and impairment of blood vessel walls. These then lead to red blood cell extravasation and purpuric eruption seen in our patient.,
In addition, hyperstimulation of EGFR is thought to be an underlying mechanism in the development of psoriasis. Some case reports about patients treated with EGFR-TKI for advanced adenocarcinoma and concomitant psoriasis showed a beneficial effect in the resolution of psoriasis., On the contrary, exacerbation and induction of psoriasis after treatment with an EGFR-TKI in a patient with advanced adenocarcinoma were also reported., Dual effect of EGFR in psoriasis merits further investigation.
To the best of our knowledge, we herein reported an unusual case of psoriasis-like lesions induced by olmutinib in the literature. The true mechanism of this cutaneous side effect remains to be found. Topical steroids may relieve the symptoms but cannot prevent discontinuation of the drug.
The Chung Shan Medical University Hospital institution review board approves this study and the Institutional Review Board Project NO. CS2-15065 was obtained on June.25, 2019.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 2010;10:760-74.
Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al.
Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26.
Paz-Ares L, Soulières D, Moecks J, Bara I, Mok T, Klughammer B, et al.
Pooled analysis of clinical outcome for EGFR TKI-treated patients with EGFR mutation-positive NSCLC. J Cell Mol Med 2014;18:1519-39.
Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al.
Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327-34.
Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169-81.
Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al.
Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 2013;19:2240-7.
Park K, Lee JS, Han JY, Lee KH, Kim JH, Cho EK, et al
. Efficacy and safety of BI 1482694 (HM61713), an EGFR mutant-specific inhibitor, in T790M-positive NSCLC at the recommended phase II dose. DOI: https://doi.org/10.1016/S1556-0864(16)30243-X
Russo A, Franchina T, Ricciardi GRR, Smiroldo V, Picciotto M, Zanghì M, et al.
Third generation EGFR TKIs in EGFR-mutated NSCLC: Where are we now and where are we going. Crit Rev Oncol Hematol 2017;117:38-47.
Kim ES. Olmutinib:First global approval. Drugs 2016;76:1153-7.
Macdonald JB, Macdonald B, Golitz LE, LoRusso P, Sekulic A. Cutaneous adverse effects of targeted therapies: Part I: Inhibitors of the cellular membrane. J Am Acad Dermatol 2015;72:203-18.
Cho YT, Chen KL, Sheen YS, Yang CW, Liau JY, Cheng YP, et al.
Purpuric drug eruptions caused by epidermal growth factor receptor inhibitors for non-small cell lung cancer: A clinicopathologic study of 32 cases. JAMA Dermatol 2017;153:906-10.
Schreier B, Gekle M, Grossmann C. Role of epidermal growth factor receptor in vascular structure and function. Curr Opin Nephrol Hypertens 2014;23:113-21.
Okamoto K, Maeda H, Shiga T, Shiga M, Dabanaka K, Hanazaki K, et al.
Cetuximab and panitumumab in a patient with colon cancer and concomitant chronic skin disease: A potential beneficial effect on psoriasis vulgaris. World J Gastroenterol 2015;21:3746-9.
Overbeck TR, Griesinger F. Two cases of psoriasis responding to erlotinib: Time to revisiting inhibition of epidermal growth factor receptor in psoriasis therapy? Dermatology 2012;225:179-82.
Selam M. Psoriasis aggravation due to lapatinib. BMJ Case Rep 2013;2013. pii: bcr2012007592.
Marinello E, Pastorelli D, Alaibac M. A case of psoriasis pustolosa palmaris induced by cetuximab. BMJ Case Rep 2016;2016. pii: bcr2016214582.
[Figure 1], [Figure 2]