To the Editor: Enfortumab vedotin (EV) is an antibody-drug conjugate that binds to nectin-4 and releases a microtubule disrupting agent in refractory urothelial carcinoma.1 Treatment-related cutaneous adverse events (CAEs) occur in 54% of patients and may result in severe reactions such as toxic epidermal necrolysis.2 Rashes may occur because of nectin-4 expression in epidermal keratinocytes and adnexal structures.3 We sought to identify risk factors associated with the development of CAEs. We also evaluated treatment responses, grade of CAEs despite prolonged EV exposure, and cancer outcomes.
The electronic medical record of the Mayo Clinic Health System was used to identify patients aged ≥18 years and treated with EV for urothelial carcinoma between 2010 and 2021. A cycle of EV was defined as 3 infusions on days 1, 8, and 15 of a 28-day cycle. The grade of reaction was defined by the Common Terminology Criteria for Adverse Events v5.0.4 Tumor response was defined by the Response Evaluation Criteria in Solid Tumors.5 Patient demographics, treatment characteristics, and previous treatments were described. Exploratory analysis of clinically relevant associations for CAE development in a time-to-event framework was performed using univariate Cox proportional hazard models.
Overall, 58 adult patients treated with EV were identified. Fifteen (25.86%) developed a CAE to EV including a maculopapular rash (46.7%), macular rash (20.0%), bullous dermatoses (6.7%), generalized pruritus (6.7%), symmetric drug-related intertriginous and flexural exanthema (6.7%), and an unspecified rash (13.3%). All patients had a grade 1 to 2 reaction. Patient demographics and previous treatments are summarized in Table I. The mean time of onset from first infusion to CAE was 19.9 days (range, 7-63 days). Median number of treatment cycles before CAEs was 1 (range, 1-3). Out of 15 patients, 9 (60%) did not require a change in the EV dose regimen because of the CAE. Four (26%) patients required a reduction in dose or frequency and 2 (13.3%) patients discontinued therapy. If dose reduction was required, the dose was reduced by 10% to 15% in 40% of the patients, 25% in 40% patients, and 44% in 20% of patients. If therapy was continued despite the development of a CAE, the rash persisted with additional cycles in 46.7% and resolved in 40% of the patients. The grade of reaction remained unchanged despite continued therapy in 50% of patients, whereas 50% had a reduction in the grade.
Table I.
Demographics, treatment characteristics, and previous treatments by group
| Group |
|||
|---|---|---|---|
| Control (n = 43) | Rash (n = 15) | Total (N = 58) | |
| Demographics | |||
| Age, Mean (SD) | 70.9 (9.7) | 72.0 (8.8) | 71.2 (9.4) |
| Male Sex, n (%) | 33 (76.7) | 11 (73.3) | 44 (75.9) |
| White Race, n (%) | 38 (88.4) | 15 (100.0) | 53 (91.4) |
| Not Hispanic or Latino Ethnicity, n (%) | 42 (97.7) | 15 (100.0) | 57 (98.3) |
| Treatment | |||
| Enfortumab vedotin Dose (mg), Mean (SD) | 91.5 (22.6) | 82.0 (19.9) | 89.0 (22.2) |
| Duration, Mean (SD) | 14.0 (14.0) | 19.3 (11.8) | 15.4 (13.5) |
| Tx Cycles, Mean (SD) | 3.1 (2.7) | 4.5 (2.7) | 3.5 (2.7) |
| Previous Treatments | |||
| Atezolizumab, n (%) | 7 (16.3) | 3 (20.0) | 10 (17.2) |
| Avelumab, n (%) | 5 (11.6) | 0 (0.0) | 5 (8.6) |
| BCG, n (%) | 5 (11.6) | 5 (33.3) | 10 (17.2) |
| Carboplatin, n (%) | 13 (30.2) | 5 (33.3) | 18 (31.0) |
| Cisplatin, n (%) | 23 (53.5) | 13 (86.7) | 36 (62.1) |
| Doxorubicin, n (%) | 2 (4.7) | 2 (13.3) | 4 (6.9) |
| Etoposide, n (%) | 1 (2.3) | 0 (0.0) | 1 (1.7) |
| Gemcitabine, n (%) | 29 (67.4) | 13 (86.7) | 42 (72.4) |
| Ifosfamide, n (%) | 1 (2.3) | 0 (0.0) | 1 (1.7) |
| MVAC, n (%) | 3 (7.0) | 2 (13.3) | 5 (8.6) |
| Nab Paclitaxel, n (%) | 1 (2.3) | 0 (0.0) | 1 (1.7) |
| Nivolumab, n (%) | 2 (4.7) | 0 (0.0) | 2 (3.4) |
| Paclitaxel, n (%) | 6 (14.0) | 3 (20.0) | 9 (15.5) |
| Pembrolizumab, n (%) | 22 (51.2) | 9 (60.0) | 31 (53.4) |
| Radiation, n (%) | 9 (20.9) | 9 (60.0) | 18 (31.0) |
| Vinblastine, n (%) | 3 (7.0) | 2 (13.3) | 5 (8.6) |
| Zoledronic acid, n (%) | 8 (18.6) | 3 (20.0) | 11 (19.0) |
BCG, Bacillus Calmette-Guerin; MVAC, Methotrexate, vinblastine, doxorubicin, and cisplatin.
Most CAEs were treated with topical or systemic corticosteroids. The starting dose for oral prednisone ranged from 5 to 40 mg daily. Mean overall treatment duration was 14 weeks (range, 1-41 weeks). Treatment response for CAEs was 80%, with 60% of the patients achieving complete response. Detailed treatment regimens are summarized in Table II. Associations for developing CAEs included previous exposure to cisplatin (Hazard Ratio [95% CI], 4.61 [1.04, 20.48]; P =.044) or radiation therapy (Hazard Ratio [95% CI], 4.76 [1.69, 13.48]; P =.003). CAEs were not predictive of tumor response.
Table II.
Treatment regimen for cutaneous adverse events
| Total (N = 15) | |
|---|---|
| Treatment, n (%) | |
| Betamethasone cream | 2 (13.3) |
| Triamcinolone cream | 3 (20) |
| Hydrocortisone 2.5% cream | 6 (40) |
| Prednisone 5 mg | 1 (6.7) |
| Prednisone 10 mg | 1 (6.7) |
| Prednisone 20-40 mg | 1 (6.7) |
| Oral antihistamines | 7 (46) |
| Clindamycin lotion | 1 (6.7) |
| Treatment Duration (wk) | |
| N (Missing) | 13 (2) |
| Mean (SD) | 14.1 (13.8) |
| Range | 1.0, 41.0 |
| Treatment Response, n (%) | |
| Complete | 9 (60.0) |
| N/A | 2 (13.3) |
| Partial | 3 (20.0) |
| Stable | 1 (6.7) |
In summary, grade 1 to 2 reactions to EV often occur after initial infusion, may not warrant dose adjustments, and are responsive to topical and oral steroids. The grade of reaction remains unchanged or reduces despite additional therapy. CAEs were not predictive of tumor response. Studies are needed to further characterize grade ≥3 reactions.
Conflict of interest
Dr Ho has received honoraria from Exelixis, Genentech, EMD-Serono, Pfizer, Macrogenics, Cardinal Health, Ipsen, and Aveo; research funding from Novartis; Dr Mangold has the following disclosures: Consulting: Kyowa (past), Eli Lilly (past), Momenta (past), UCB (past), Regeneron (past), Genentech (past), PHELEC (current), Soligenix (current), Incyte (Current), Argenx (Current), Clarivate (Current); Research Grants/Investigator: Kyowa (current), Miragen (current), Regeneron (current), Corbus (current), Sun Pharma (current), Incyte (current), Pfizer (current), Lilly (past), Elorac (past), Novartis (current), Jansen (past), Soligenix (current), Abbvie (current), Palvella(current), Akari (current), Argenx (Current).
Footnotes
Funding sources: Supported by the Department of Dermatology, Mayo Clinic Arizona.
IRB approval: Reviewed and approved by Mayo Clinic Arizona (20-012166).
References
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