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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Encorafenib (BraftoviTM) (Figure 6.45) is a small-molecule B-RAF inhibitor developed initially by Novartis and then by Array BioPharma. It works as an ATP-competitive RAF kinase inhibitor, decreasing ERK phosphorylation and down-regulating cyclin D1, thus arresting the cell cycle in G1 phase and inducing senescence without apoptosis. Therefore, it is only effective in melanoma cells that carry a B-RAF mutation (~50% of all melanomas). Encorafenib gained approval from the FDA in 2018 as a combination treatment with the MEK inhibitor binimetinib (MektoviTM) (see Section 6.2.1.6.9.2) for the treatment of patients with unresectable or metastatic B-RAFV600E or B-RAFV600K mutation–positive melanoma. Structure of encorafenib (BraftoviTM).
The Challenges with Multi-Arm Targeted Therapy Trials
Published in Zoran Antonijevic, Robert A. Beckman, Platform Trial Designs in Drug Development, 2018
Ryan J. Sullivan, Keith T. Flaherty
Both the NCI-MATCH and TAPUR studies involve therapy selection for molecular subtypes, and are offering front line targeted therapy for a specific molecular abnormality (in this case “targeted therapy” includes immune checkpoint inhibitor therapy for selected molecular subsets in the TAPUR study). Interestingly, there are multi-arm studies investigating combination therapy for patients who have developed resistance on prior therapy. The first example was the LOGIC-2 study (NCT02159066) that enrolled patients with BRAF mutant melanoma either prior to or after failure of BRAF-targeted therapy, treated these patients with the combination of encorafenib and binimetinib (enco/bini), and at time of treatment resistance, offered therapy with enco/bini plus a third agent selected based on molecular analysis of the time of BRAF-inhibitor resistance biopsy. While this study theoretically was sound in conception, the major challenge was that none of the selected triplet therapies had been completed testing in Phase I clinical trials prior to this study, and so the recommended Phase II dose of the regimen was not known. Ultimately, this is a challenge that may not be able to be overcome. While the trial has closed to enrollment and data is not yet available, the study will have difficulty meeting its ambitious goal of defining second targeted therapy for BRAF mutant melanoma based on analysis of resistance biopsies. This is due to the fact that it likely is not feasible to give full dose triplet regimens, as was recently described in a Phase I/II study of one of the triplets (encorafenib, binimetinib, and ribociclib) (44). Still, as the knowledge of resistance mechanisms improves for targeted and immunotherapy, it is expected that many similar studies will be launched and that the next generation of trials will incorporate various molecular biomarkers of responsiveness and non-responsiveness to define treatment options in the frontline setting as well.
Overview of Therapeutic Biomarkers in Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Sherry X. Yang, Janet E. Dancey Treatment
Mutations in the components of the mitogen-activated protein kinase (MAPK) pathway occur in many cancers. BRAF encodes a serine-threonine kinase causing downstream activation of MAPK signaling and BRAF mutations have been described in melanoma (50–60%), colorectal (10%), thyroid (30–50%), and NSCLC (3%), as well as hairy cell leukemia (100%). The kinase inhibitor vemurafenib, selectively targets the activating BRAFV600 mutation, was first approved for patients with metastatic melanoma with BRAFV600 mutation in 2011 (Chapter 17) [44–47]. The mutation is detected by an approved companion diagnostic—the COBAS® 4800 BRAF V600E mutation test. In 2013, the FDA granted approval of another BRAF inhibitor dabrafenib for metastatic or inoperable melanoma with the BRAF V600E mutation, and a MEK inhibitor trametinib for patients whose tumors harbor the BRAF V600E or V600K mutation as single-agent or in combination and the THxID BRAF kit as a companion diagnostic device. The confirmation of BRAF V600 mutation status prior to administration of dabrafenib or vemurafenib is critical because the drug may paradoxically promote BRAF-wildtype melanoma growth. In June 2017, dabrafenib and trametinib administered in combination was approved for patients with metastatic NSCLC with BRAFV600 mutation (Table 1.2). It marks the onset of clinical use of this class of agents beyond melanoma. The FDA also permitted the Oncomine Dx Target Test, a next-generation sequencing (NGS) test, to detect multiple gene mutations for lung cancer in a single test from a single tissue specimen. The assay detects the presence of BRAF, ROS1, and EGFR gene mutations in tumor tissue, which can be used to select NSCLC patients with the BRAFV600 mutation for the dabrafenib/trametinib combination treatment. Notably, this approval is the first NGS oncology panel test for multiple companion biomarker indications. In 2018, dabrafenib in combination with trametinib was approved for adjuvant treatment of melanoma patients with BRAF V600E or V600K mutations after complete resection. Recently, combination therapy with dabrafenib and trametinib was approved for the treatment of patients with unresectable or metastatic BRAF V600E-positive anaplastic thyroid cancer. The regulatory agency approved another BRAF inhibitor encorafenib and the MEK inhibitor binimetinib for the treatment of BRAF-mutant unresectable or metastatic melanoma in 2018, based on the survival advantage over vemurafenib alone.
Encorafenib in combination with binimetinib for unresectable or metastatic melanoma with BRAF mutations
Published in Expert Review of Clinical Pharmacology, 2019
Claudia Trojaniello, Lucia Festino, Vito Vanella, Paolo A. Ascierto
Encorafenib in combination with binimetinib was also evaluated in a phase Ib/II clinical trial in cutaneous melanoma patients naïve to BRAF inhibitor therapy. This trial enrolled 55 patients into three treatment arms involving binimetinib 45 mg twice daily combined with encorafenib once daily at a dose of either 400 mg, 450 mg or 600 mg. Among all patients, the most frequent adverse events were nausea, diarrhoea, fatigue, arthralgia, vomiting, pyrexia, and increased aspartate aminotransferase (AST). Grade 3/4 adverse events occurred in 64% of patients treated with the highest encorafenib dose (600 mg), including increased alanine aminotransferase (ALT) (18%), lipase (15%), AST (13%), and creatine phosphokinase (13%). Among patients receiving the lower encorafenib 400/450 mg doses, grade 3/4 adverse events occurred in 67% of patients; increased lipase (22%) was the only event occurring in more than one patient. Photosensitivity and pyrexia of grade 3/4 were rare. The response rate was 78% in patients treated with encorafenib 400/450 mg and 72% in patients treated with encorafenib 600 mg. Median progression-free survival (PFS) (95% CI) in all patients was 11.3 months (range 7.4–14.6) [37].
The discovery and development of binimetinib for the treatment of melanoma
Published in Expert Opinion on Drug Discovery, 2020
A multicenter, open-label, Phase 1B/2 study (NCT01543698) was initiated to investigate dual inhibition of BRAF and MEK through combination treatment with the BRAF inhibitor, encorafenib (LGX818 or BRAFTOVI) and the MEK inhibitor, binimetinib [27–29]. The primary objective of the Phase 1B study was to determine the recommended Phase 2 dose for the combination. A range of 50 to 600 mg encorafenib daily and 45 mg of binimetinib twice daily were studied in patients with BRAF-mutant tumors. No serious adverse events were observed in Phase 1B and three doses of encorafenib would be explored in phase 2: 400, 450 (current single dose recommendation), or 600 mg encorafenib QD in combination with 45 mg BID of binimetinib. Between these three arms, a total of 48 subjects was treated out of 55 enrolled: 9 in the 400 or 450 mg encorafenib dose cohort and 39 subjects in the 600 mg encorafenib dose cohort. Adverse event rates observed in the 600 mg encorafenib group included nausea (54% of patients), diarrhea (44%), fatigue (33%), arthralgia (33%), and vomiting, pyrexia, and AST elevation (31% each). The 400/450 mg encorafenib cohort adverse event rates were 44% for nausea, 44% for fatigue, and 33% each for elevated AST, vomiting, and diarrhea. Grade 3 and 4 adverse events occurred in 64% of 600 mg encorafenib cohort subjects and in 67% of 400/450 mg encorafenib cohort, however, the only adverse event occurring in more than one patient was increased lipase for the lower (400/450 mg encorafenib) dose group. Due to the safety and tolerability of the 450 mg encorafenib plus 45 mg BID binimetinib group, this dose was chosen for the phase 3 COLUMBUS trial.