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Long-Term Response to Intermittent Binimetinib in Patients with NRAS-Mutant Melanoma.

ABSTRACT: Melanoma can be classified based on the detection of relevant oncogenic driver mutations. These mutations partially determine a patient's treatment options. MEK inhibitors have demonstrated little efficacy in patients with NRAS-mutated melanoma owing to primary and secondary resistance. We report two patients with NRAS-mutant metastatic melanoma with long-term response to intermittent MEK-inhibitor binimetinib therapy. Intermittent dosing schedules could play a key role in preventing resistance to targeted therapy. This article highlights the efficacy of an intermittent dosing schedule, toxicities associated with binimetinib, and possible mechanisms preventing resistance in targeted therapy. Intermittent MEK-inhibitor therapy may be considered in patients with NRAS-mutated melanoma that have failed all standard therapies. KEY POINTS: Melanomas harbor NRAS mutations in 10%-30% of the cases. These mutations promote hyperactivation of the MAPK pathway, leading to proliferation and prolonged survival of tumor cells. Currently, drugs directly targeting NRAS are not available. Downstream inhibition of the MAPK pathway can be considered as a therapeutic option after immunotherapeutic failure. Intermittent administration of kinase inhibitors might be the way to partially overcome the development of drug resistance by (a) inducing a fitness deficit for drug-resistant cells on treatment break, (b) increasing the immunogenicity, and (c) inducing apoptosis and cell cycle arrest. It also enhances expression of numerous immunomodulating molecules, and reduction of immunosuppressive factors, which suggests better access of the immune system to the tumor.

SUBMITTER: Matter AV

PROVIDER: S-EPMC7648363 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Long-Term Response to Intermittent Binimetinib in Patients with NRAS-Mutant Melanoma.

Matter Alexandra Valeska AV Micaletto Sara S Urner-Bloch Ursula U Dummer Reinhard R Goldinger Simone M SM

The oncologist 20200921 11

Melanoma can be classified based on the detection of relevant oncogenic driver mutations. These mutations partially determine a patient's treatment options. MEK inhibitors have demonstrated little efficacy in patients with NRAS-mutated melanoma owing to primary and secondary resistance. We report two patients with NRAS-mutant metastatic melanoma with long-term response to intermittent MEK-inhibitor binimetinib therapy. Intermittent dosing schedules could play a key role in preventing resistance ...[more]

PMID: 32886824

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Project description:Simple Summary Targeted radionuclide therapy (TRT) aims to selectively deliver radioactive molecules to tumor cells. For this purpose, we deliver iodine-131 ([131I]) to melanoma cells by using our laboratory-developed melanin specific radiotracer, the ICF01012. Approximately 50% and 20%–30% of human melanomas have activating mutation in BRAF or NRAS genes, respectively. These mutations lead to a constitutive activation of the MAPK/ERK pathway, which is known to be involved in tumor cells’ radioresistance. In this work, we showed using 3D in vitro tumor models, an additive efficiency of combining [131I]ICF01012-TRT and MAPK/ERK inhibitors in BRAF- and NRAS-mutant melanoma cells. In mice bearing NRASQ61K-mutated melanoma, TRT induced an impressive decrease in tumor growth, as well as a highly extended survival. Additionally, we showed that TRT reduces the metastatic capacity of melanoma, especially through lymph-node dissemination. These results are therefore of great interest, especially for patients with NRAS-mutant metastatic melanoma who currently lack specific efficient therapies. Abstract Purpose: To assess the efficiency of targeted radionuclide therapy (TRT), alone or in combination with MEK inhibitors (MEKi), in melanomas harboring constitutive MAPK/ERK activation responsible for tumor radioresistance. Methods: For TRT, we used a melanin radiotracer ([131I]ICF01012) currently in phase 1 clinical trial (NCT03784625). TRT alone or combined with MEKi was evaluated in three-dimensional melanoma spheroid models of human BRAFV600E SK-MEL-3, murine NRASQ61K 1007, and WT B16F10 melanomas. TRT in vivo biodistribution, dosimetry, efficiency, and molecular mechanisms were studied using the C57BL/6J-NRASQ61K 1007 syngeneic model. Results: TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant spheroids. NRASQ61K spheroids were highly radiosensitive towards [131I]ICF01012-TRT. In mice bearing NRASQ61K 1007 melanoma, [131I]ICF01012 induced a significant extended survival (92 vs. 44 days, p < 0.0001), associated with a 93-Gy tumor deposit, and reduced lymph-node metastases. Comparative transcriptomic analyses confirmed a decrease in mitosis, proliferation, and metastasis signatures in TRT-treated vs. control tumors and suggest that TRT acts through an increase in oxidation and inflammation and P53 activation. Conclusion: Our data suggest that [131I]ICF01012-TRT and MEKi combination could be of benefit for advanced pigmented BRAF-mutant melanoma care and that [131I]ICF01012 alone could constitute a new potential NRAS-mutant melanoma treatment.

Dataset Information

Long-Term Response to Intermittent Binimetinib in Patients with NRAS-Mutant Melanoma.

Publications

Long-Term Response to Intermittent Binimetinib in Patients with NRAS-Mutant Melanoma.

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