Work

Olmutinib-induced palmoplantar keratoderma

Year: 2017

Type: article

Abstract: Dear Editor, Olmutinib is a third‐generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) for the treatment of non‐smallcell lung cancer (NSCLC), especially for those harbouring T790M mutations, the most common reason for other EGFR‐TKI resistance.1 We describe three patients who, after taking olmutinib developed acquired palmoplantar keratoderma (PPK), an adverse event that has not been reported in previous generations of EGFR‐TKIs. The study was approved by the Research Ethics Committee of the National Taiwan University Hospital (201309042RINB). Patient 1 is a 74‐year‐old woman with NSCLC, with EGFR L858R mutations. The disease progressed despite an 11‐month course of gefitinib from August 2014 to July 2015 and chemotherapy with pemetrexed and carboplatin in the following 4 months. She was confirmed to harbour EGFR T790M mutations and therefore commenced olmutinib 800 mg daily in January 2016. One month later, asymptomatic diffuse thickening of the soles developed with discrete hyperkeratotic patches and plaques on the shins (Fig. 1a). The lesions persisted during the period of treatment with olmutinib and resolved spontaneously 1 month after discontinuation of olmutinib (Fig. 1b). A skin biopsy from the right sole showed acanthosis, hyperkeratosis, focal parakeratosis and papillary dermal elongation with minimal dermal inflammation, which were compatible with the pathological features of acquired PPK (Fig. 1c). An immunohistochemistry study showed Ki‐67‐positive cells confined to the basal and suprabasal layers of the epidermis (Fig. 1d). Patient 1. (a) About 1 month after the initiation of olmutinib therapy, brownish asymptomatic dispersed hyperkeratotic patches and plaques developed on the bilateral soles of the feet and shins. (b) The lesions resolved spontaneously at 1 month after discontinuation of olmutinib. (c) The pathology study showed acanthosis, hyperkeratosis and papillary dermal elongation with minimal dermal inflammation (haematoxylin and eosin; original magnification × 100). (d) The immunohistochemistry study showed Ki‐67‐positive cells confined to the basal and suprabasal layers (Ki‐67 stain; original magnification × 100). Patient 2. (e) Asymptomatic, focal hyperkeratotic plaques mainly on the pressure points of the soles and (f) tips of the toes and fingers, but sparing the nails. Patient 2 is a 54‐year‐old woman with NSCLC and EGFR exon 19 deletion mutations. The patient had received a 14‐month course of therapy with erlotinib in 2013, and had received an 11‐month course of afatinib in 2015. Due to disease progression and confirmation of EGFR T790M mutations, afatinib was discontinued in April 2016 and olmutinib 800 mg daily was introduced in May 2016. One month later, asymptomatic and focal hyperkeratotic plaques developed on the pressure points of the soles (Fig. 1e), as well as on the tips of her toes and fingers (Fig. 1f). A skin biopsy from the right sole showed findings suggestive of acquired PPK with positive Ki‐67 staining. Patient 3 is a 59‐year‐old man with NSCLC. He had experienced disease progression despite 3 months of chemotherapy with pemetrexed and carboplatin in 2014, as well as 8 months of erlotinib in 2015. Treatment with olmutinib 800 mg daily was started in January 2016 due to confirmed EGFR T790M mutations. About 1 month after commencing olmutinib, the patient developed asymptomatic palmoplantar hyperkeratotic patches and plaques, which spontaneously resolved 1 month after olmutinib was stopped. PPK comprises a heterogeneous group of disorders that can be acquired or hereditary. None of our patients had a family history of PPK, nor did they have medical issues or contact with medications known to be related to acquired PPK.2 All of them developed PPK about 1 month after commencing olmutinib, and patients 1 and 3 experienced normalization of PPK after discontinuing olmutinib. The wash‐out period for prior EGFR‐TKIs was 6 months in patient 1 and 1 month in the other two patients. In our previous 5‐year retrospective study reviewing 146 patients who received gefitinib, erlotinib or afatinib, none of those patients developed PPK.3 Therefore it appears that acquired PPK is a specific adverse effect associated with olmutinib. Although the authors are not aware of any cases of PPK reported in clinical trials investigating olmutinib or postapproval safety surveillance, our experience that PPK developed in three out of a total of five patients treated with olmutinib in our hospital during this period would suggest this could be a relatively common adverse effect. Patients 1 and 3 had diffuse PPK, whereas in patient 2 the PPK was focally distributed at the pressure points. None of them had nail changes. All three patients experienced asymptomatic thickening of the skin, which was different from painful PPK due to multikinase inhibitors.4 The pathogenesis of olmutinib‐induced PPK remains unclear. However, activation of EGFR signalling appears to play a role in several different hereditary PPKs: (i) in Buschke‐Fischer‐Brauer‐type punctate PPK, loss‐of‐function mutations in AAGAB result in elevated EGFR protein expression and tyrosine phosphorylation;5 (ii) in tylosis with familial oesophageal cancer syndrome, dominant RHBDF2 (iRHOM2) mutations increase the activity of ADAM17 in keratinocytes, which further activate EGFR signalling pathways;6 and (iii) in Olmsted syndrome with focal PPK, a gain‐of‐function mutation in TRPV3 was found to be associated with EGFR pathway activation7 and, interestingly, erlotinib has been successfully used to treat a patient with Olmsted syndrome.8 In contrast to the first‐ and second‐generation EGFR‐TKIs, olmutinib induces irreversible inhibition of EGFR with the T790M mutation while sparing wild‐type EGFR. Paradoxical activation of downstream signalling in the Ras/Raf/MEK/ERK pathway is a possible mechanism and warrants further investigation. Funding sources: This work was supported by the National Taiwan University Hospital (NTUH 103‐S2366 and 106‐S3535). M.E.L. is funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748. Conflicts of interest: M.E.L. is a consultant for Boehringer Ingelheim International GmbH. C.Y.C. received honoraria from Boehringer Ingelheim International GmbH for being a consultant and speaker, and from Novartis for being a consultant. The other authors declare no conflicts of interest.

Source: British Journal of Dermatology

DOI: 10.1111/bjd.15935