Upstream MAPK pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients.

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9071 Background: The presence of activating BRAF mutations in about 60% of all metastatic melanomas (mM) has led to the development of inhibitors (i) targeting the RAF and MEK kinases. MEK is the downstream effector of BRAF. However, the blockage of the MAPK pathway is limited due to the development of resistance mechanisms. MEK resistance can confer cross-resistance to BRAF inhibition, whereas BRAF resistance is independent from the MAPK pathway. Hence, it seems reasonable to start a MAPK pathway inhibition by a BRAFi. An upstream inhibition beginning the treatment reversed with a MEKi followed by a BRAFi has not yet been clinically explored. Methods: Patients at the Dermatology Department of the University Hospital of Zurich with mM harboring a BRAF mutation formed the study cohort. Patients were divided into a group who was treated initially with a BRAFi (vemurafenib or LGX818) followed by a MEKi (AZD6244, trametinib, or MEK 162), and a group who first received a MEKi and was later treated with a BRAFi. Duration of disease control (DDC) was measured in time from the initiation of the treatment to discontinuation due to disease progression or toxicity. Results: A total of 16 patients (7 females, 9 males, age 30-73 years) with BRAF mutated mM were evaluated. The median DDC (mDDC) was similar in both groups. When patients were treated first with a BRAFi (n=7), the mDDC for BRAFi was 7.6 and for MEKi 1.7 months, respectively. In contrast, when the treatment sequence was inversed (n=9), the mDDC for MEKi was 3.9 and for BRAFi 4.7 months. We observed some benefit (partial response, stable disease) using chemotherapy after BRAFi/MEKi progression. Conclusions: This analysis indicates that the sequential MEK-RAF inhibition of the MAPK pathway is acceptable in BRAF mutant mM patients. The sum of the DDC of both groups (9.3 and 8.6 months) is comparable to the promising BRAFi/MEKi combination therapy (median PFS 9.4 months). Besides the sequenced administration analyzed here, an intermittent administration should be further studied.