Ovarian cancer is the uncontrolled growth of abnormal cells in one or both ovaries. Almost 314,000 women worldwide are diagnosed with ovarian cancer, and more than 200,000 die from the disease each year. Ovarian cancer is the most fatal gynecological malignancy worldwide due to ineffective screening, unclear early symptoms, inadequate descriptions of biomarkers, and a lack of efficient treatment regimens. Due to the late development of symptoms, ovarian cancer is frequently detected at an advanced stage, making curative treatment difficult [1,2].
For individuals dealing with this difficult diagnosis, the development of targeted therapies has recently offered some hope. One such breakthrough is the development and application of cobimetinib in the treatment of ovarian cancer. In this blog, we shed light on the profound impact of cobimetinib on ovarian cancer care.
Understanding cobimetinib
Cobimetinib has emerged as a promising addition to the arsenal of targeted therapies for ovarian cancer. It belongs to a class of drugs called MEK1/2 (Mitogen-activated protein kinase) inhibitors, which inhibit a certain protein pathway essential for the development of cancer cells. Its potential in the treatment of ovarian cancer was first discovered in preclinical research and early-stage clinical trials, despite being first approved for the treatment of melanoma [2,3].
Cobimetinib is approved, in combination with a BRAF inhibitor, for the treatment of specific BRAF-mutated tumors. MEK1/2 are elements of the RAS-RAF-MEK-ERK/JNK pathway, which has several functions, including:
cell proliferation,
survival, and
differentiation.
While melanoma has been the subject of substantial research, little is known about ovarian cancer. According to preclinical studies, drug combinations are important to produce anti-tumor efficacy in ovarian cancer. For ovarian cancer, cobimetinib is now being tested in combination with immunotherapy, antiangiogenetic drugs, and PARP inhibitors [2,3].
Cobimetinib journey: From research to reality
A clinical trial testing cobimetinib combined with bevacizumab (a vascular endothelial growth factor, VEGF inhibitor) and programmed Cell Death Protein 1 (PD-L1) inhibition provides more evidence for VEGF inhibition as a therapy for high-grade serous ovarian carcinoma. The adaptive immune resistance frequently presented by tumor cells in response to anti-tumor activity is regulated by the PD-L1 pathway. It has been demonstrated that MEK inhibition with cobimetinib in combination with a monoclonal antibody blocking PD-L1 (atezolizumab) may have potential synergistic efficacy in the treatment of metastatic colon cancer [2].
In a phase II clinical trial for the treatment of recurrent platinum-resistant high-grade serous ovarian carcinoma (ClinicalTrials.gov Identifier: NCT03363867), the triple combination of atezolizumab (PD-L1 inhibitor), bevacizumab, and cobimetinib (MEK inhibitor) is being investigated. Cobimetinib, bevacizumab, and atezolizumab have been used alone or in combination in the treatment of many other cancers [2].
Additional combination therapy for the treatment of ovarian cancer may be investigated, as cobimetinib is FDA-approved for use in combination with the BRAF inhibitor vemurafenib for the treatment of metastatic melanomas with the BRAF (V600E/K) mutation. This approval marked a significant milestone for targeted therapies. Subsequently, the impact of cobimetinib on ovarian cancer care became more marked when, it received FDA approval in combination with another drug, bevacizumab, for the treatment of advanced ovarian cancer [2,3].
Impact of cobimetinib on ovarian cancer care
The approval of cobimetinib for ovarian cancer brought new hope to patients with this fatal condition. In addition to increasing progression-free survival and enhancing overall quality of life, the combination therapy was also well-tolerated and efficient. Although its use in combination with immunotherapy has demonstrated action independent of KRAS/BRAF status, cobimetinib may be more effective in ovarian tumors with RAS-RAF-MEK-ERK/JNK dysregulation. Cobimetinib has a known and acceptable toxicity profile including effects on the skin, gastrointestinal system, and retina. Although rare, potential cardiac toxicity has been a concern [2,3].
Looking to the future
Cobimetinib's journey from research to reality represents amazing progress and this targeted therapy has revolutionized ovarian cancer care, giving progression-free survival to patients. The use of cobimetinib in the treatment of ovarian cancer represents a promising shift towards more targeted and effective therapies. As researchers explore the potential of cobimetinib in various contexts and combinations, its role in the treatment of ovarian cancer continues to evolve.
References
1. Skorda, A. et al. 'Kinase Inhibitors in the Treatment of Ovarian Cancer: Current State and Future Promises'. Cancers. (2022) 14(24), 6257. DOI: 10.3390/cancers14246257.
2. Colic, E. et al. 'Aberrant MAPK Signaling Offers Therapeutic Potential for Treatment of Ovarian Carcinoma'. Onco Targets Ther. (2022) 15, 1331–1346. DOI: 10.2147/OTT.S361512.
3. Maoz, A. et al. 'Emerging serine-threonine kinase inhibitors for treating ovarian cancer'. Expert Opin Emerg Drugs. (2019) 24(4), 239–253. DOI: 10.1080/14728214.2019.1696773.
