Novel BRAF-Inhibitor Cream Ameliorates Rash From EGFR Inhibitors

An investigational novel cream containing a BRAF inhibitor appears to ameliorate the acneiform rash associated with epidermal growth factor receptor (EGFR) inhibitors such as cetuximab (Erbitux) and panitumumab (Vectibix).

The results come from a first-in-human, phase 1 clinical trial conducted in 10 patients with metastatic colorectal cancer who were receiving treatment with either cetuximab or panitumumab and who developed a grade 1 or grade 2 rash while on treatment.

All were treated with the novel topical cream, dubbed LUTO14 (under development by Lutris Pharmaceutical).

For 6 of the 10 patients, the acneiform rash improved, say the investigators, led by Mario Lacouture, MD, Memorial Sloan Kettering Cancer Center, New York City.

The study was published online April 28, 2021 in Cancer Discovery.

“Based on preclinical modeling and early clinical trial testing, we conclude that improving a topmost adverse event of EGFR inhibitor therapy with topical LUT014 could allow [maintenance of] quality of life and dose intensity, thereby maximizing the antitumor effects [from EGFR inhibitor therapy] while locally inhibiting dose-limiting skin toxicities,” the investigators conclude.

The cream was well tolerated, and no dose-limiting toxicity or maximum tolerated dose was observed, although the cream did appear to be more effective at lower doses.

Rash is a common side effect of EGFR inhibitors. Previous studies have reported that 75% to 90% of patients experience “some form of papulopustular, acneiform rash, which frequently leads to…suboptimal anti-cancer treatment due to treatment interruptions, dose reductions or permanent discontinuation of EGFR inhibitor therapy,” they note.

Paradoxical Mechanism of Action

How the novel cream containing a BRAF inhibitor helps ameliorate EGFR inhibitor–induced skin toxicity is complicated, but at a cellular level, the mechanism seems somewhat paradoxical, the team comments. Skin toxicity experienced in the setting of EGFR inhibitor therapy is induced by inhibition of the mitogen-activated protein kinase (MAPK) pathway. Downstream inhibition of the MAPK pathway in turn results in, among other effects, inflammatory changes in epithelial cells that mediate the acneiform rash on the skin.

In contrast, “BRAF inhibitors given systemically have an opposite effect on epithelial cells, resulting in paradoxical activation of the MAPK pathway,” the authors explain. They hypothesized that topical administration of BRAF inhibitors similarly activates the MAPK pathway in epithelial cells, although it was important to develop a specific BRAF inhibitor that would optimally induce paradoxical MAPK activation. That they managed to do so was shown when they evaluated LUT014 in cell culture systems.

The next phase of the study is designed to include approximately 120 patients recruited from centers in the United States and Israel. Interim results are expected by the end of 2021.

The study was funded by Lutris-Pharma, the company developing LUT014.

Cancer Discov. Published online April 28, 2021. Abstract

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