Efficacy of intermittent combined RAF and MEK inhibition in a patient with concurrent BRAF and NRAS mutant malignancies
Menée sur un patient atteint d'un mélanome présentant la mutation V600K du gène BRAF et ayant développé une leucémie avec mutation du gène NRAS à la suite d'un traitement par vémurafenib, cette étude met en évidence l'efficacité d'une administration intermittente de cobimetinib, un inhibiteur de MEK, en complément du vémurafenib
Vemurafenib, a RAF inhibitor, extends survival in patients with BRAFV600-mutant melanoma but activates ERK signaling in RAS-mutant cells. In a patient with a BRAFV600K-mutant melanoma responding to vemurafenib, we observed accelerated progression of a previously unrecognized NRAS-mutant leukemia. We hypothesized that combining vemurafenib with a MEK inhibitor would inhibit ERK activation in the melanoma and prevent ERK activation by vemurafenib in the leukemia and thus suppress both malignancies. We demonstrate that intermittent administration of vemurafenib led to a near-complete remission of the melanoma and the addition of the MEK inhibitor cobimetinib (GDC-0973) caused suppression of vemurafenib-induced leukemic proliferation and ERK activation. Anti-melanoma and anti-leukemia response have been maintained for nearly 20 months as documented by serial measurements of tumor-derived DNA in plasma in addition to conventional radiographic and clinical assessments of response. These data support testing of intermittent ERK pathway inhibition in the therapy of both RAS-mutant leukemia and BRAF-mutant melanoma.