48IN - Targeted therapy of ovarian cancer: Beyond angiogenesis

Date 28 September 2014
Event ESMO 2014
Session Targeted therapy in gynaecological cancer
Topics Anti-Cancer Agents & Biologic Therapy
Ovarian Cancer
Presenter Nicoletta Colombo
Citation Annals of Oncology (2014) 25 (suppl_4): iv18-iv19. 10.1093/annonc/mdu300
Authors N. Colombo
  • Gynecologic Oncology, European Institute of Oncology, 20141 - Milan/IT

Abstract

Body

Abstract:

Targeted therapy of ovarian cancer: Beyond angiogenesis Ovarian cancer is still the most lethal gynecological malignancy and strategies incorporating molecular targeted therapies are urgently needed. Besides angiogenesis, homologous recombination deficiency can be present in at least 50% of high-grade serous tumors. After the demonstrated efficacy of the PARP inhibitor olaparib in prolonging PFS of patients with platinum-sensitive recurrent ovarian cancer, phase III trials are now ongoing in both first line and second line maintenance setting in patients with BRCA mutations. Recently, the combination of olaparib with cediranid (an oral tyrosine kinase inhibitor of VEGFR-1,-2,-3) has shown a promising activity in recurrent platinum sensitive ovarian cancer patients. Activation of PI3K pathway is seen in up to 30% of clear cell and endometrioid ovarian carcinoma and represents a possible target for these neoplasms. BRAF and KRAS mutations were initially reported in up to 68% of cases with low grade serous tumors. A phase II study of the MEK1/2 inhibitor selumetinib in 52 patients with recurrent low grade serous tumor indicated a response rate of 15,4% and a disease stabilization in 65% of patients. Phase II studies of other MEK inhibitors are now ongoing. High grade serous ovarian cancer are characterized by aberration in the P53 tumor suppressor gene which is a cell cycle G1 checkpoint regulator. Inhibition of Wee-1, a tyrosine kinase that regulates the G2 cell cycle checkpoint, sensitizes p53-deficient tumor to chemotherapy by reducing tumor cell capacity to repair DNA damage. A randomized phase II study is evaluating paclitaxel and carboplatin with or without the Wee-1 inhibitor MK-1775 in women with p53 mutation-positive platinum sensitive recurrent ovarian cancer. The selective inhibitor of Aurora Kinase A (a tyrosine kinase that regulates the G2 cell cycle checkpoint), MLN8237 (alisertib), is currently under evaluation in a randomized phase II in combination with paclitaxel. Finally, Nivolumab, an anti-PD-1 antibody, achieved 17% response rate and 44% disease-control rate in 20 patients with heavily pretreated platinum resistant ovarian cancer, including 2 complete remissions. These encouraging results open the way for further exploration of immunotherapy in ovarian cancer.

Disclosure:

N. Colombo: Astra Zeneca, advisory board.