Clinical investigation of receptor and non-receptor tyrosine kinase inhibitors for the treatment of epithelial ovarian cancer.
BACKGROUND
Epithelial ovarian cancer (EOC) is the second most common gynecologic malignancy and the leading cause of death from gynecologic cancer in the USA. EOC is an exquisitely chemo-sensitive disease with response rates of over 75% in the upfront setting. Despite this, due to high rates of recurrence and development of chemo-resistance, the overall survival of EOC remains about 25%. Thus, there is a great need for new therapeutic approaches to render more durable responses. Based on preclinical and early phase clinical studies, key targeted pathways include targets that drive angiogenesis and chemo-resistance. Receptor tyrosine kinases and non-receptor tyrosine kinases play important roles in these processes and several small molecule tyrosine kinase inhibitors (TKIs) are in clinical development.


METHODS
This review summarizes clinical rationale, mechanisms of action and clinical data for the TKIs under evaluation in the Phase III setting for EOC.


CONCLUSIONS
Despite reasonable preclinical activity, small molecule TKIs are unlikely to improve patient survival as single agent therapies in an unselected EOC population. Incorporation of tissue evaluation during ongoing clinical trials is required to identify molecularly defined groups that respond to single agents and direct rational combination strategies based on mechanisms of resistance to improve outcomes in EOC.
Beth Israel Deaconess Medical Center, Division of Hematology-Oncology , Boston, MA 02215 , USA.
Samuel J
SJ
Klempner
Andrea P
AP
Myers
Gordon B
GB
Mills
Shannon N
SN
Westin
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000627:therapeutic use; D000077216:Carcinoma, Ovarian Epithelial; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D007191:Indazoles; D007211:Indoles / Q000627:therapeutic use; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use
D000970:Antineoplastic Agents; D052117:Benzodioxoles; D007191:Indazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D013449:Sulfonamides; C516667:pazopanib; C515233:saracatinib; D000069347:Erlotinib Hydrochloride; C530716:nintedanib; C500926:cediranib