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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
After promising preclinical studies and early clinical trials, it reached Phase III in 2015 for ovarian cancer, and B-RAF- and N-RASQ61-mutant melanomas. In the mutant-N-RAS melanoma trial, patients receiving binimetinib had a median Progression-Free Survival (PFS) of 2.8 months versus 1.5 months for those on standard dacarbazine treatment, and on this basis an NDA was submitted in mid-2016. However, the Phase III trial in low-grade ovarian cancer was less successful with no efficacy demonstrated. In 2017, the FDA informed Array BioPharma that the Phase III trial data were insufficient for approval as a single agent, which led to withdrawal of the NDA, although in 2018 the FDA did approve a combination of binimetinib and the B-RAF inhibitor encorafenib (BraftoviTM) based on evidence from a clinical trial (NCT01909453) of 383 patients with unresectable or metastatic B-RAFV600E or B-RAFV600K mutation–positive melanoma. This combination of agents is also recommended for the same purpose by NICE in the UK.
Biomarkers for the Management of Malignancies with BRAF Mutation
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
MEK inhibitors have also been extensively investigated in BRAF-mutant-driven tumors [21]. In melanoma, phase 1 and 2 trials of the MEK inhibitor trametinib reported improvement in both PFS and OS [23, 24]. MEK inhibitors did not show the paradoxical MAPK pathway activation response observed with single agent vemurafenib or dabrafenib. However, the efficacy of MEK inhibitors as single agents is relatively modest compared to the combination of BRAF and MEK inhibitors in BRAF-mutant cancers [23–25, 26]. Therefore, BRAF and MEK inhibitor combinatorial treatments, in the form of trametinib/dabrafenib, cobimetinib/vemurafenib, and encorafenib/binimetinib were approved by the US Food and Drug Administration (FDA) for patients with advanced BRAF V600E/K melanoma [23, 26, 27]. In addition, dabrafenib and trametinib in combination are approved for adjuvant treatment of melanoma with BRAF V600E or V600K mutations, and involvement of lymph node(s) following complete resection [28].
Malignant Melanoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Given that MEK inhibitors block the MAP kinase pathway, it was thought that they may be effective in NRAS mutation-positive melanoma. The NEMO trial randomized 402 patients with unresectable stage III or stage IV NRAS mutant melanoma to the MEK inhibitor binimetinib or standard therapy with dacarbazine.30 Median progression-free survival was longer with binimetinib (2.8 months) than with dacarbazine (1.5 months) but still somewhat disappointing. Binimetinib is not currently approved in this setting.
Safety and efficacy evaluation of encorafenib plus binimetinib for the treatment of advanced BRAF-mutant melanoma patients
Published in Expert Opinion on Drug Safety, 2020
The recommended dosage of encorafenib is 450 mg (six 75 mg capsules) orally QD, in combination with binimetinib 45 mg (three 15 mg tablets) orally BID (approximately 12 hours apart), until disease progression or unacceptable toxicity. Both drugs may be taken with or without food. Dose reductions and modifications for specific adverse reactions during encorafenib and binimetinib therapies, as well as indications for treatment discontinuation are provided in both drugs’ prescribing information [13,14]. Importantly, if encorafenib is discontinued, binimetinib should be permanently discontinued. While, if binimetinib is withheld, encorafenib dose should be temporarily reduced to 300 mg QD, and subsequently discontinued in case of permanent binimetinib’s discontinuation [13,14].
Update on BRAF and MEK inhibition for treatment of melanoma in metastatic, unresectable, and adjuvant settings
Published in Expert Opinion on Drug Safety, 2019
Kristy Kummerow Broman, Lesly A Dossett, James Sun, Zeynep Eroglu, Jonathan S Zager
At the lowest tested dose in the Phase Ib/II study (encorafenib 450 mg daily plus binimetinib 45 mg twice daily), 67% of patients experienced grade 3 or 4 AE. The most common AE were nausea, diarrhea, fatigue, arthralgia, vomiting, pyrexia, and elevated aminotransferase levels. Photosensitivity, rash and grade 3 or 4 pyrexia werepyrexia rare [82]. The phase II study included 89 patients and similarly established lower incidences of pyrexia (13.5%), photosensitivity (0%), and rash (7%) with encorafenib-binimetinib than with other BRAF-MEK inhibitor combinations [83]. The most common AE of encorafenib plus binimetinib therapy identified in the phase II study were nausea, diarrhea, fatigue, serous retinopathy and elevation in creatine phosphokinase. Grade 3 or 4 toxicities were observed in 15.7% of patients [83].
Refractory and relapsed hairy-cell leukemia (HCL): casting light on promising experimental drugs in clinical trials
Published in Expert Opinion on Investigational Drugs, 2023
Most patients with classical HCL have a BRAF gene mutation. For patients without this mutation, drugs that target MEK, including binimetinib, trametinib or cobimetinib, can be a treatment option [84]. Recently, a phase 2 study evaluated the safety and activity of binimetinib in patients with RR HCL and a wild BRAF gene, and patients with HCLv (ClinicalTrials.gov Identifier: NCT04322383). Binimetinib is administered orally 45 mg BID, continuously for 28-day cycles and no resting period between cycles. Primary outcome includes best overall CR or PR following therapy and secondary outcomes include CR rate, OS, time to next treatment, safety, PFS and time from start of binimetinib treatment to the following line.