Safety and Efficacy of Prophylactic Topical Steroid Administration for Enfortumab Vedotin–related Cutaneous Toxicity

Abstract

Enfortumab vedotin (EV) is used to treat unresectable/metastatic urothelial carcinoma but often causes cutaneous toxicity (EVRCT) because of Nectin4 expression in the skin, which reduces patients’ quality of life and can lead to dose adjustments or discontinuation. We explored whether applying topical steroids prophylactically to intertriginous areas could prevent EVRCT. Five patients received clobetasol propionate on one side and Vaseline on the other. Three patients developed grade ≥2 EVRCT at Vaseline-treated sites, but no EVRCT at clobetasol-treated sites. The results suggest that prophylactic topical steroid application can reduce the incidence of EVRCT, which prompted early study termination and progression to the next trial phase.

Patient summary

A drug called enfortumab vedotin (EV) used to treat advanced cancer of the urinary tract can cause severe skin reactions. We compared application of a steroid cream or Vaseline to the skin in five patients who were starting EV therapy. Three patients had an EV reaction on Vaseline-treated skin patches but not on steroid-treated skin patches. Because of these positive results, we are testing steroid cream at the start of EV treatment in a larger study.

Enfortumab vedotin (EV) is commonly used in the treatment of unresectable or metastatic urothelial carcinoma, either as monotherapy or in combination with pembrolizumab. However, EV frequently causes EV-related cutaneous toxicity (EVRCT), which is associated with Nectin4 expression in the skin [1], [2]. This toxicity can significantly impair patients’ quality of life and often necessitates a dose reduction, withdrawal, or discontinuation of EV treatment. Although the exact mechanisms underlying EVRCT are not fully understood, corticosteroids, either topical or oral, are commonly administered at the onset of symptoms. Notably, EVRCT is more prevalent in intertriginous areas such as the groin and axilla [3], and there is no established intervention to prevent this condition. The aim of our study was to investigate whether prophylactic application of topical steroids to the inguinal and axillary intertriginous areas at initiation of EV therapy could prevent EVRCT.

This physician-led clinical study (jRCTs051230118; https://jrct.niph.go.jp/en-latest-detail/jRCTs051230118) received approval from the ethics committee of Kyoto University (study ID: Y0166). Written informed consent was obtained from all participants. Five subjects (three males and two females) with a median age of 74 yr (range 65–80 yr) were enrolled in the study. All subjects commenced EV therapy at a dosage of 1.25 mg/kg as third-line treatment following failure of chemotherapy and immune checkpoint inhibitors. Participants applied 0.05% clobetasol propionate ointment to the right groin and axilla, and petrolatum ointment to the left groin and axilla at a dose of 1 fingertip unit (FTU) per site twice daily, morning and evening, for 4 wk from the start of EV therapy. The intervention was ceased if grade ≥2 EVRCT (Common Terminology Criteria for Adverse Events v5.0) was observed at the study drug application sites.

Three of the five subjects developed grade ≥2 EVRCT, all at petrolatum-treated sites, while no EVRCT events occurred at clobetasol propionate–treated sites (Table 1). The remaining two subjects did not develop EVRCT bilaterally. One patient (KUEV03) experienced a grade 2 rash limiting instrumental activities of daily living (ADL) on the petrolatum-treated side on day 14 of EV therapy, necessitating study termination and commencement of treatment with clobetasol propionate ointment on the affected side (Fig. 1A). The patient’s condition progressed to grade 3 by day 22, with oral steroids required (Fig. 1B). Consequently, EV was withdrawn and later resumed at a reduced dose once the EVRCT had improved. Throughout this period, the clobetasol propionate–treated side remained unaffected by EVRCT. The other two patients (KUEV04 and KUEV05) developed grade 2 maculopapular rashes limiting instrumental ADL on the petrolatum-treated side on days 15 and 6, respectively, of EV therapy. Following study termination and initiation of treatment with clobetasol propionate ointment, the rashes resolved within 1 wk. In all five subjects, no EVRCT was observed at the site of prophylactic topical steroid application within a median follow-up period of 4.9 mo, including after topical steroid application was terminated as part of the study. No adverse events attributable to clobetasol propionate ointment were reported.

Table 1.

Summary of the clinical course for the five cases

Parameter	KUEV01	KUEV02	KUEV03	KUEV04	KUEV05
Age	80 yr	72 yr	65 yr	74 yr	76 yr
Sex	Female	Female	Male	Male	Male
EVRCT at topical application sites
Petrolatum	None	None	Grade 3	Grade 2	Grade 2
Clobetasol propionate	None	None	None	None	None
Time from EV initiation to EVRCT onset	NA	NA	14 d	15 d	6 d
Adverse events due to clobetasol propionate	None	None	None	None	None

EV = enfortumab vedotin; EVRCT = EV-related cutaneous toxicity; NA = not applicable.

Fig. 1.

Photographs of bilateral application sites in case KUEV03 (A) at the time of EVRCT onset and (B) highest EVRCT grade.

These findings suggest that prophylactic topical steroid application can greatly reduce the incidence of EVRCT. Limitations include the small number of cases in this study, although the study design, which includes comparisons within the same subject, increases the reliability of the results. Considering these promising results, the efficacy and safety evaluation committee recommended early discontinuation of the study, which will now proceed to the next phase; a multicenter, placebo-controlled, randomized, double-blind, parallel-group study of the efficacy of prophylactic topical steroids in EVRCT.



Author contributions: Takashi Kobayashi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.



Study concept and design: Kita, Nomura.

Acquisition of data: Kita, Nomura, Nakajima, Yonekura, Murakami, Sumiyoshi, Masui, Goto, Saito.

Analysis and interpretation of data: Kita.

Drafting of the manuscript: Kita.

Critical revision of the manuscript for important intellectual content: Nomura, Nakajima, Kabashima, Kobayashi.

Statistical analysis: None.

Obtaining funding: Kita.

Administrative, technical, or material support: None.

Supervision: Kobayashi.

Other: None.



Financial disclosures: Takashi Kobayashi certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Yuki Kita and Takashi Kobayashi reports advisory board fees, speaking honoraria, and research grants from Astellas. The remaining authors have nothing to disclose.



Funding/Support and role of the sponsor: This study was funded by Astellas Pharma Inc.. The sponsor played no direct role in the study.



Acknowledgments: This study was conducted in collaboration with the Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital. We thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Associate Editor: M. Carmen Mir