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Expert Opinion on Investigational Drugs Volume 25, 2016 - Issue 1
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Reviews

An overview of tyrosine kinase inhibitors for the treatment of epithelial ovarian cancer

Zhijie WangDepartment of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX77030, USA;Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Beijing Institute for Cancer Research, Beijing, China
&
Siqing FuDepartment of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX77030, USACorrespondence[email protected]
, MD, PhD
Pages 15-30 | Published online: 26 Nov 2015

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  • Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.
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  • Friedlander M, Hancock KC, Rischin D, et al. A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol. 2010;119:32–37.

•• A Phase II study confirmed that a small-molecule TKI against VEGF receptors had promising antitumor activity as a single agent.

  • Pignata S, Lorusso D, Scambia G, et al. Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): a randomised, open-label, Phase 2 trial. Lancet Oncol. 2015;16:561–568.

•• An important Phase II study demonstrated survival benefits by the use of pazopanib in combination with paclitaxel.

•• A Phase III study showed survival benefit with maintenance pazopanib.

  • Secord AA, Nixon AB, Hurwitz HI. The search for biomarkers to direct antiangiogenic treatment in epithelial ovarian cancer. Gynecol Oncol. 2014;135:349–358.
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  • Matei D, Sill MW, Lankes HA, et al. Activity of sorafenib in recurrent ovarian cancer and primary peritoneal carcinomatosis: a gynecologic oncology group trial. J Clin Oncol. 2011;29:69–75.

• The first study showed that a small-molecule TKI had limited antitumor activity.

  • Ramasubbaiah R, Perkins SM, Schilder J, et al. Sorafenib in combination with weekly topotecan in recurrent ovarian cancer, a Phase I/II study of the Hoosier Oncology Group. Gynecol Oncol. 2011;123:499–504.
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  • Matulonis UA, Berlin S, Ivy P, et al. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol. 2009;27:5601–5606.

•• The first Phase II study showed that a small-molecule TKI against VEGF receptors had promising antitumor activity as a single agent.

  • Ledermann JA, Perren TJ, Raja FA, et al. Randomised double-blind Phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: results of the ICON6 trial. Eur J Cancer. 2013;49(Suppl 3):LBA10.
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  • Azad NS, Posadas EM, Kwitkowski VE, et al. Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol. 2008;26:3709–3714.

• The first study demonstrated synergistic antitumor activity through the complementary inhibition of a single signaling pathway.

  • Lee JM, Annunziata CM, Hays JL, et al. A Phase II study of intermittent sorafenib with bevacizumab (B) in B-naive and prior B-exposed epithelial ovarian cancer (EOC) patients. J Clin Oncol. 2014;32(5s suppl):abstr 5553.
  • Baumann KH, du Bois A, Meier W, et al. A Phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy. Ann Oncol. 2012;23:2265–2271.
  • Campos SM, Penson RT, Matulonis U, et al. A Phase II trial of sunitinib malate in recurrent and refractory ovarian, fallopian tube and peritoneal carcinoma. Gynecol Oncol. 2013;128:215–220.
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  • Hong D, Kurzrock R, Wheler JJ, et al. Phase I dose-escalation study of the multikinase inhibitor lenvatinib in patients with advanced solid tumors and in an expanded cohort of patients with melanoma. Clin Cancer Res. 2015;21:4801–4810.
  • Sonpavde G, Hutson TE. Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep. 2007;9:115–119.
  • Fu S, Hou MM, Naing A, et al. Phase I study of pazopanib and vorinostat: a therapeutic approach for inhibiting mutant p53-mediated angiogenesis and facilitating mutant p53 degradation. Ann Oncol. 2015;26:1012–1018.
  • Raja FA, Griffin CL, Qian W, et al. Initial toxicity assessment of ICON6: a randomised trial of cediranib plus chemotherapy in platinum-sensitive relapsed ovarian cancer. Br J Cancer. 2011;105:884–889.
  • Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008;68:4774–4782.
  • du Bois A, Kristensen G, Ray-Coquard I. AGO-OVAR 12: a randomized placebo-controlled GCIG/ENGOT-intergroup Phase III trial of standard frontline chemotherapy +/− nintedanib for advanced ovarian cancer. Int J Gynecol Cancer. 2013;23(Suppl 1):LBA1.
  • Roy S, Narang BK, Rastogi SK, et al. A novel multiple tyrosine-kinase targeted agent to explore the future perspectives of anti-angiogenic therapy for the treatment of multiple solid tumors: cabozantinib. Anticancer Agents Med Chem. 2015;15:37–47.
  • Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298–2308.
  • Buckanovich RJ, Berger R, Sella A, et al. Activity of cabozantinib (XL184) in advanced ovarian cancer patients (pts): results from a Phase II randomized discontinuation trial (RDT). J Clin Oncol. 2011;29(suppl):abstr 5008.
  • Ciardiello F, Caputo R, Damiano V, et al. Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Clin Cancer Res. 2003;9:1546–1556.
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  • Annunziata CM, Walker AJ, Minasian L, et al. Vandetanib, designed to inhibit VEGFR2 and EGFR signaling, had no clinical activity as monotherapy for recurrent ovarian cancer and no detectable modulation of VEGFR2. Clin Cancer Res. 2010;16:664–672.
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• An important article to delineate molecular aberrations of ovarian cancer.

  • Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123–134.

•• This trial showed antitumor activity of olaparib in cancer associated with the BRCA1/2 mutation, leading to the first approval in the PARP inhibitor class.

  • Ang JE, Gourley C, Powell CB, et al. Efficacy of chemotherapy in BRCA1/2 mutation carrier ovarian cancer in the setting of PARP inhibitor resistance: a multi-institutional study. Clin Cancer Res. 2013;19:5485–5493.
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  • Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33:244–250.

• This study confirmed the antitumor activity of olaprib across different tumor types associated with germline BRCA1/2 mutations.

  • Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376:245–251.
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  • Liu JF, Barry WT, Birrer M, et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised Phase 2 study. Lancet Oncol. 2014;15:1207–1214.

•• This trial revealed synergistic antitumor effect and survival benefit between VEGF and PARP inhibition in recurrent platinum-sensitive ovarian cancer.

  • Kristeleit RS, Burris HA, LoRusso P, et al. Phase 1/2 study of oral rucaparib: final Phase 1 results. J Clin Oncol. 2014;32(5s suppl):abstr 2573.
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  • Kummar S, Ji J, Morgan R, et al. A Phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. Clin Cancer Res. 2012;18:1726–1734.
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• This trial showed the importance of MEK1/2 inhibition in low-grade serous ovarian cancer.

  • Aarts M, Sharpe R, Garcia-Murillas I, et al. Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1. Cancer Discov. 2012;2:524–539.
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•• This trial provided preliminary evidence on the role of a Wee1 kinase inhibitor across different tumor types associated with germline BRCA1/2 mutations.

  • Leijen S, Van Geel R, Sonke GS, et al. Phase II study with Wee1 inhibitor AZD1775 plus carboplatin in patients with p53 mutated ovarian cancer refractory or resistant (<3 months) to standard first line therapy. J Clin Oncol. 2015;33(suppl):abstr 2507.
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  • Lheureux S, Weberpals JI, Hendrickson AEW, et al. A randomized, placebo-controlled Phase II trial comparing gemcitabine monotherapy to gemcitabine in combination with AZD 1775 (MK 1775) in women with recurrent, platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancers: Trial of Princess Margaret, Mayo, Chicago, and California consortia. J Clin Oncol. 2015;33(suppl):abstr TPS5613.
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