Small-Molecule Targeted Therapies
David E. Thurston, Ilona Pysz in 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
Sherry X. Yang, Janet E. Dancey in 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].
Hyperkeratotic Reactions
Gabriella Fabbrocini, Mario E. Lacouture, Antonella Tosti in Dermatologic Reactions to Cancer Therapies, 2019
These BRAF inhibitor–induced hyperkeratotic lesions are thought to be the result of a paradoxical activation of the RAS-RAF-MEK-ERK (mitogen-activated protein kinase, MAPK) pathway in wild-type BRAF cells, leading to increased keratinocyte proliferation. Interestingly, the incidence of squamoproliferative toxic effects is significantly abrogated by the combination with a MEK inhibitor (either vemurafenib and cobimetinib, dabrafenib and trametinib, or encorafenib and binimetinib) (19,21–25,50,51). Concurrent inhibition with a MEK inhibitor of the MAPK pathway downstream may prevent this paradoxical activation, and consequently may reduce the development of secondary keratotic lesions.
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
These results prompted a phase III trial (COLUMBUS), in which patients with BRAFV600E/K-mutated, locally advanced, unresectable or metastatic cutaneous or unknown primary melanoma who were previously untreated or had progressed on or after first-line immunotherapy were randomized to receive one of three regimens: oral encorafenib 450 mg daily plus binimetinib 45 mg twice daily; oral encorafenib alone at a dose of 300 mg daily; oral vemurafenib alone at a dose of 960 mg twice daily [46,81]. The primary study endpoint of PFS was assessed at a median follow-up of 32.1 months. Median PFS was longest in the encorafenib plus binimetinib group (14.9 months) compared to encorafenib (9.6 months) and vemurafenib (7.3 months) alone. PFS was significantly longer for encorafenib plus binimetinib versus vemurafenib (HR = 0.51, 95% CI 0.39–0.67). In the first direct comparison of two BRAF inhibitors, PFS was also longer for encorafenib alone versus vemurafenib alone (HR = 0.68, 95% CI 0.52–0.88). Complete or partial response was seen in 64% of patients in the encorafenib plus binimetinib group, 52% with encorafenib alone and 41% with vemurafenib alone (Table 1) [46].
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 systemic exposure of binimetinib is approximately dose proportional. After twice-daily (BID) dosing, the accumulation of binimetinib is 1.5-fold and the CV% of the AUC is < 40% at steady state. Following oral administration, ≥ 50% of the binimetinib dose is absorbed, and the Cmax is reached in a median time of 1.6 hours. The recommended therapeutic dose for binimetinib is 45 mg BID. Binimetinib is primarily metabolized through glucuronidation by the uridine diphosphate glucuronosyl trasferase (UGT1A1) (61% of drug); secondary metabolism mechanisms include N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. Unchanged binimetinib represents ~60% of drug exposure in plasma, with the active metabolite M3 (produced by CYP1A2 and CYP2C19) representing 8.6% of exposure. Binimetinib has a mean t½ of 3.5 h: excretion is 62% in feaces (32% unchanged drug) and 31% in urine (6.5% unchanged). There is no clinically meaningful impact of age, sex, bodyweight, mild hepatic or severe renal impairment, on the pharmacokinetics of binimetinib. Binimetinib AUC appears to be increased twofold in subjects with moderate or severe hepatic impairment, compared with subjects with normal liver function. Thus, binimetinib is not recommended in patients with moderate or severe hepatic impairment. No clinically meaningful drug interactions involving binimetinib have been observed, including no significant impact of encorafenib co-administration. Caution is recommended for concomitant use of binimetinib with UGT1A1 inducers and inhibitors, in absence of dedicated drug-drug interaction studies.
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.
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