Early onset of diffuse melanosis cutis under pembrolizumab therapy illustrates the limitations of anti-PD-1 checkpoint inhibitors

Abstract

Anti-PD-1 targeted immunotherapies have revolutionized the treatment of advanced melanoma and other tumor entities, and long disease-free intervals have been reported in responding patients. However, a considerable number of patients still progress rapidly after the start of anti-PD-1 antibodies. Here, we document two patients, 78 and 85-year old, who suffered from advanced BRAF-V600 wild-type melanoma and received pembrolizumab 2 mg/kg every 3 weeks as the first systemic treatment. After only one, respectively, two infusions of pembrolizumab, both patients developed melanuria and diffuse melanosis cutis (DMC) on sun-exposed areas of their skin. Both also had liver metastases, which have been reported to be associated with DMC before. Pembrolizumab was stopped because of rapid tumor progression and both patients died within 2 months after manifestation of DMC. We conclude that DMC is a condition that may be a negative predictor of response to anti-PD-1 treatment. With respect to the very short survival, which is even shorter than that reported after conventional therapies, it needs to be evaluated whether immunotherapy may be a (relative) contraindication in DMC patients when another treatment option, that is targeted therapy, is available.

Pembrolizumab induced hyperpigmentation in a patient with lung adenocarcinoma: a case report

“…The other one reported that an 85-year-old male melanoma patient therapy with pembrolizumab (2 mg/kg every 3 weeks) and shortly after the first infusion of pembrolizumab, dark gray hyperpigmentation of his face and upper trunk appeared and melanuria developed. [11] Shruti et al also reported that a white man with chronic lymphocytic leukemia in his early 40s developed diffuse hyperpigmentation on the back of pembrolizumab. [12] In summary, the incidence of skin hyperpigmentation caused by pembrolizumab is not high, it is more common on the face, and may occur in the treatment of gastric cancer, melanoma, and chronic lymphocytic leukemia.…”

“…[4] Conversely, Alexander Thiema et all reported that hyperpigmentation is a condition that may be a negative predictor of response to pembrolizumab treatment for melanoma patients. [11,12] Thus, we speculate that cutaneous adverse events of hyperpigmentation, might be a negative predictor of response to pembrolizumab in metastatic lung adenocarcinoma patients.…”

Diffuse Hyperpigmentation in a Patient With an Axillary Mass

“…The role immunotherapy played in the manifestation of DMC in this case is unclear. One case series of patients who developed DMC after immunotherapy initiation concluded that DMC may be a negative predictor of response to anti–PD-1 (programmed cell death 1) treatment . In particular, it remains unclear whether immunotherapy promotes DMC development or just cannot control DMC that would inevitably develop.…”

Cutaneous Events Associated with Immunotherapy of Melanoma: A Review

“…The early onset of disseminate melanosis cutis on photoexposed areas during treatment with pembrolizumab has also been reported in two patients with rapid metastatic melanoma disease progression and failure, suggesting that this condition could be a predictor of negative response to anti-PD-1 therapy [ 44 ].…”