Severe skin toxicity with organ damage under the combination of targeted therapy following immunotherapy in metastatic melanoma

Abstract

Targeted therapy combination (TTC: antiRAF+antiMEK) is known to improve metastatic melanoma survival. Few severe skin toxicities (grade ≥3) are described with first-line TTC (17% for vemurafenib+cobimetinib and none for dabrafenib+trametinib) in a phase III trial. Among our 42 patients treated by TTC between January 2014 and March 2017, 4.8% (2/42) of those treated in the first line presented severe skin rash versus 19% (8/42) of patients treated in the second line after previous immunotherapy. In particular, we observed one case of Stevens-Johnson syndrome and four cases of severe drug reaction with eosinophilia and systemic symptoms syndrome under TTC in patients who had received immunotherapy previously. Thus, previous immunotherapy appears to play an important role in the skin rash onset and severity induced by TTC.

Cutaneous adverse reactions in B-RAF positive metastatic melanoma following sequential treatment with B-RAF/MEK inhibitors and immune checkpoint blockade or vice versa. A single-institutional case-series

“…Most of these reported cases used single agent vemurafenib without concurrent MEK inhibition following ICB. This is in contrast to our series and a series by another group [8] where the B-RAF/MEK combination was used, albeit with similar findings. For now, mechanisms dictating augmented toxicity with vemurafenib containing combinations following ICB remain unclear, which has prompted us to modify our clinical practice by incorporating dabrafenib instead of vemurafenib for B-RAF inhibition when choosing TT combinations after disease progression on ICB.…”

“…In this case series, we discuss cutaneous toxicity patterns in patients with B-RAF positive metastatic melanoma treated with sequential strategies involving ICB and TT in response to disease progression. Although very recently similar findings have been described by others in patients receiving TT after ICB [8], we provide a broader description of the unique histopathological characteristics and also attempt to address questions relating to management strategies as well as the feasibility of re-challenging patients with these agents in certain circumstances.…”

“…Our patients lacked the severe transaminitis, eosinophilia, and extended latency periods commonly seen in DRESS syndrome, but did have features that would support a diagnosis of “possible” or “probable” cases by RegiSCAR criteria [16], including fevers, facial swelling, and duration of the rash. Interestingly, this atypical pattern of DRESS syndrome, lack of eosinophilia and shorter latency periods for grade-4 rash, has been described in other series of patients receiving TT following ICB [8]. Nevertheless, a high index of suspicion for SJS or toxic epidermal necrolysis (TEN) should be maintained in all patients presenting with rapid-onset, diffuse rashes after changes in drug therapy.…”

Vemurafenib and cobimetinib‐induced toxic epidermal necrolysis in a patient with metastatic melanoma

“…Some serious cutaneous adverse events as a result of a monotherapy have also been reported, such as, vemurafenib-induced toxic epidermal necrolysis (TEN) (Bellón, Lerma, González-Valle, González Herrada, & de Abajo, 2016;Jeudy et al, 2015;Tahseen, & Patel, 2018) and vemurafenib-induced Stevens-Johnson syndrome (SJS) (Minor, Rodvien, & Kashani-Sabet, 2012). Recent findings confirmed cases of focal necrotizing myopathy with "dropped-head syndrome" (Gauci et al, 2017) To our knowledge, there is only one, recently published case of SJS under combined target therapy (vemurafenib plus cobimetinib) in a patient who had previously received immunotherapy (Lamiaux et al, 2018). Also, DRESS syndrome induced by vemurafenib as part of firstline metastatic treatment of BRAF mutant melanoma with vemurafenib and cobimetinib has been noted (Ros & Muñoz-Couselo, 2018).…”

Cytokine release syndrome as an important differential diagnosis of severe skin toxicity with organ damage during switch from immunotherapy to targeted therapy in metastatic melanoma

“…Lamiaux and colleagues [1] found that 19% of the patients treated with BRAF/MEK inhibitors (BRAFi/ MEKi) after previous immunotherapy (IT) may present a severe skin rash (grade ≥ 3), even complicated by systemic involvement and organ damage. Among the 10 cases of severe skin toxicity, eight patients had received previous IT, whereas the median time of onset was 12 days after the treatment initiation of BRAFi/MEKi.…”