Small-Molecule Targeted Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Based on the growing understanding of B-RAF signaling, it was hypothesized that a combination of vemurafenib and an inhibitor of one of the downstream signalling kinases, MEK or ERK, could improve clinical activity as it should reduce any “breakthrough” signalling from the B-RAFV600E kinase. A clinical study of vemurafenib in combination with cobimetinib (CotellicTM), a MEK inhibitor developed by Exelixis Inc and Genentech (Roche), demonstrated an improvement in both Progression-Free Survival (PFS) and Overall Survival (OS) compared with patients treated with vemurafenib alone. This was a key result which led to the 2015 FDA approval of a combination of vemurafenib and cobimetinib for the treatment of unresectable or metastatic melanoma with a B-RAF V600E or V600K mutation, representing a new standard of treatment for patients with this disease. Cobimetinib itself is not indicated for the treatment of patients with wild-type B-RAF melanoma where no clinical benefit is provided. Vemurafenib was also evaluated as a treatment for non-small-cell lung cancer (NSCLC) patients carrying the B-RAFV600 mutation with some evidence of clinical activity.
Emerging serine-threonine kinase inhibitors for treating ovarian cancer
Published in Expert Opinion on Emerging Drugs, 2019
Asaf Maoz, Marcia A. Ciccone, Shinya Matsuzaki, Robert L. Coleman, Koji Matsuo
Cobimetinib is a MEK1/2 inhibitor that is approved, in combination with a BRAF inhibitor, for the treatment of certain BRAF mutated melanomas. MEK1/2 are components of the RAS-RAF-MEK-ERK/JNK pathway, which has many functions, including proliferation, survival, and differentiation of cells [58]. It has been extensively studied in melanoma but data in ovarian cancer is limited. Preclinical data suggest that a combination with other agents is necessary to achieve an anti-tumor activity in ovarian cancer [67]. Cobimetinib is being studied in combination with immunotherapy, anti-angiogenesis agents, and PARP inhibitors for ovarian cancer [89]. These trials are not expected to end until 2022/2023 and it may be difficult to discern the benefit of cobimetinib from the benefit of other agents in these combination regimens. Cobimetinib may be more active in RAS-RAF-MEK-ERK/JNK dysregulated ovarian cancers although its combination with immunotherapy has suggested activity regardless of KRAS/BRAF status [90]. Cobimetinib has a known and acceptable toxicity profile including dermatologic, gastrointestinal and retinal effects. Potential cardiac toxicity has been a concern but is rare [91,92].
Experimental drugs for fallopian cancer: promising agents in the clinical trials and key stumbling blocks for researchers
Published in Expert Opinion on Investigational Drugs, 2022
Raffaella Cioffi, Federica Galli, Emanuela Rabaiotti, Massimo Candiani, Francesca Pella, Giorgio Candotti, Luca Bocciolone, Patrizia De Marzi, Giorgia Mangili, Alice Bergamini
Atezolizumab is a monoclonal antibody against PDL-1. In the first-line setting, atezolizumab was tested in a phase III trial that did not show superiority to the placebo when given in combination with paclitaxel, carboplatin, and bevacizumab in naïve patients with advanced disease [61]. Ongoing combinations being tested include the association with doxorubicin, cobimetinib, and guadecitabine (SGI-110) plus a CDX-1401 vaccine (NCT03206047) [62]. BEACON trial is currently recruiting patients with recurrent platinum-resistant EOC to test the safety and effectiveness of the combination between cobimetinib, bevacizumab, and atezolizumab. Cobimetinib blocks Mitogen-activated protein kinase (MEK), which is involved in the proliferation of cancer cells (NCT03363867) [63].
Atezolizumab, cobimetinib, and vemurafenib as first-line treatment for unresectable metastatic BRAF V600 mutated melanoma
Published in Expert Review of Anticancer Therapy, 2022
Andreas M Schmitt, Lucy Dumas, James Larkin
Cobimetinib is a reversible oral small-molecule inhibitor of the mitogen-activated protein kinase (MAPK) pathway via inhibition of the MEK1/2 signaling node, thereby reducing cell proliferation [52]. Its molecular weight is 531 g/mol, and its molecular formula is C21-H21-F3-I-N3-O2 [52]. The maximal recommended dose is 60 mg with dosing levels of 20 mg intervals, taken on day 1–21 of each 28-day cycle as established in a phase I trial [53]. The Tmax is 2.4 hours, the mean elimination half-life is 43.6 hours (range 23.1–69.6 hours) [54]. Cobimetinib was granted an FDA license in combination with vemurafenib in 2015 following the publication of a phase 3 study of the combination in previously untreated, advanced BRAF mutated melanoma.
Related Knowledge Centers
- Atezolizumab
- Dabrafenib
- Fever
- Melanoma
- Orphan Drug
- Chemotherapy
- Vemurafenib
- Mitogen-Activated Protein Kinase
- Progression-Free Survival
- Pi3K/Akt/Mtor Pathway