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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, 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].
Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunction
Published in Platelets, 2019
Amanda J. Unsworth, Alexander P. Bye, Neline Kriek, Tanya Sage, Ashley A. Osborne, Dillon Donaghy, Jonathan M. Gibbins
Following oral administration, cobimetinib is reported to reach a plasma concentration of approximately 18 nM [30] while trametinib reaches approximately 9.7 nM [31]. Following treatment with similar concentrations of cobimetinib or trametinib in vitro, whilst ablation of CRP or TRAP-6 evoked phosphorylation of ERK1/2 T185/Y187 was observed, no alteration in platelet aggregation, integrin activation, alpha granule secretion or adhesion and spreading on collagen, fibrinogen or vWF was detected. Although the concentration-effect relationship observed in vitro may not directly translate into the effects observed in vivo. The window between the effects on platelet function and MEK inhibition was sufficiently large (approximately 1,000-fold) that acute drug induced platelet dysfunction during treatment with cobimetinib or trametinib can effectively be ruled out.
PD-L1 inhibitors in the pipeline: Promise and progress
Published in OncoImmunology, 2018
Vito Vanella, Lucia Festino, Martina Strudel, Ester Simeone, Antonio M. Grimaldi, Paolo A. Ascierto
In an earlier cohort of this phase Ib study, atezolizumab was combined with vemurafenib alone (i.e., without cobimetinib) in patients with BRAF-mutant metastatic melanoma.32 Among the 17 patients treated with the combination, ORR was 76% with 3 complete responses. Median duration of response was 20.9 months and median PFS was 10.9 months. In another earlier study, atezolizumab was also evaluated in combination with cobimetinib (i.e., without vemurafenib).33 Patients received various dose regimens, with cobimetinib escalated from 20 to 60 mg daily for the first 21 d of a 28-day cycle and atezolizumab given as 800 mg every 2 weeks. Excluding 2 patients with ocular melanoma, ORR was 45% and DCR was 75% in the remaining 20 patients. Median PFS was 12 months. After a median follow-up of 18.9 months, the median OS had not yet been reached. Ten patients were BRAF-mutant and 10 were BRAF wild-type and response rates were similar irrespective of BRAF mutation status. However, median PFS was 15.7 months in the wild-type BRAF group, compared with 11.9 months in BRAF-mutated patients. Based on these findings, a phase III study will investigate the combination of atezolizumab plus cobimetinib compared with atezolizumab alone in patients with untreated BRAF wild-type unresectable melanoma.