encorafenib and Carcinoma--Squamous-Cell

This year again, several breaking news were published in our field of oncodermatology, especially in the domain of immunotherapy. Many works have reported results on predictive biomarker identification. Concerning melanoma treatment, we were disappointed by the negative results of the phase III trial evaluating the IDO1 inhibitor epacadostat + pembrolizumab versus pembrolizumab. However, many promising preliminary results involving the combinations of anti-PD1 and innate immunity activators have been published. We also have a new anti-BRAF + anti-MEK combination: encorafenib + binimetinib with a good benefit/risk ratio and a particularly favorable safety profile as compared with existing similar combinations. Major steps forward were obtained for locally advanced Merkel cell carcinoma and squamous cell carcinoma with anti-PDL-1 avelumab and anti-PD1 cemiplimab respectively.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Benzimidazoles; Biomarkers, Tumor; Carbamates; Carcinoma, Merkel Cell; Carcinoma, Squamous Cell; Clinical Trials as Topic; Dermatology; Humans; Melanoma; Skin Neoplasms; Sulfonamides; Survival Analysis

BRAF inhibitor (BRAFi) therapy is associated with the induction of neoplasia, most commonly cutaneous squamous cell carcinoma (cuSCC). This toxicity is explained in part by "paradoxical ERK activation," or the hyperactivation of ERK signaling by BRAFi in BRAF wild-type cells. However, the rate of cuSCC induction varies widely among BRAFi. To explore this mechanistically, we profiled paradoxical ERK activation by vemurafenib, dabrafenib, encorafenib (LGX818), and PLX8394, demonstrating that vemurafenib induces ERK activation the greatest, while dabrafenib and encorafenib have higher "paradox indices", defined as the pERK activation EC80 divided by the IC80 against A375, corresponding to wider therapeutic windows for achieving tumor inhibition without paradoxical ERK activation. Our results identify differences in the paradox indices of these compounds as a potential mechanism for the differences in cuSCC induction rates and highlight the utility of using ERK activity as a biomarker for maximizing the clinical utility of BRAFi.

Topics: Apoptosis; Carbamates; Carcinoma, Squamous Cell; Cell Line; Cell Line, Tumor; Enzyme Activation; Heterocyclic Compounds, 2-Ring; Humans; Imidazoles; Indoles; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib