The new BRAF inhibitory cream enhances the eruption of EGFR inhibitors

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A new research cream containing a BRAF inhibitor appears to improve the acneiform rash associated with epidermal growth factor receptor (EGFR) inhibitors, such as cetuximab (Erbitux) i panitumumab (Vectibix).

The results come from a first phase 1 clinical trial in humans performed in 10 patients with metastasis colon cancer who were receiving treatment with cetuximab or panitumumab and who developed a grade 1 or grade 2 rash while on treatment.

All were treated with the new topical cream, called LUTO14 (developed by Lutris Pharmaceutical).

For 6 of 10 patients, the acne rash improved, according to the researchers, led by Mario Lacouture, MD, Memorial Sloan Kettering Cancer Center, New York.

The study was published online April 28, 2021 a Discovery of cancer.

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

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

The rash is a common side effect of EGFR inhibitors. Previous studies have reported that between 75% and 90% of patients experience “some form of papulopustular acne eruption, which often leads to … suboptimal anti-cancer treatment due to treatment interruptions, reduction of dose or permanent discontinuation of treatment with EGFR inhibitors “. signal.

Paradoxical mechanism of action

How the new cream containing a BRAF inhibitor helps improve skin toxicity induced by EGFR inhibitors is complicated, but at the cellular level the mechanism seems a bit paradoxical, the team says. Skin toxicity experienced in the environment of EGFR inhibitor therapy is induced by inhibition of the mitogen-activated protein kinase (MAPK) pathway. Inhibition downstream of the MAPK pathway in turn causes, among other effects, inflammatory changes in epithelial cells that mediate acneiform rash on the skin.

In contrast, “systemically administered BRAF inhibitors have an adverse 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 optimally induced paradoxical MAPK activation. That they were able to do so was demonstrated 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. Provisional results are expected by the end of 2021.

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

Discov cancer. Published online April 28, 2021. Summary

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