Jae Kwan Lee. Division of Gynecologic Oncology Department of Obstetrics and Gynecology Korea University College of Medicine

Transcription

1 Jae Kwan Lee Division of Gynecologic Oncology Department of Obstetrics and Gynecology Korea University College of Medicine

2 Targeted Therapy: Categories Anti-angiogesis therapy (1) VEGF-axis dependent Monoclonal antibodies against VEGF (Bevacizumab) Multi-targeted tyrosine kinase inhibitor (Pazopanib, Sunitinib, Brivanib Cediranib) (2) Non-VEGF mediated mechanisms PDGFR antibodies (Imatinib) FGR antibodies (AZD4547) Anti-vascular therapy: vascular disrupting agents (CA4P, DMXAA) Anti-angiopoietin therapy (Nesvacumab, Trebananib) Other pathway targeting Anti-EGF therapy EGFR antibodies (Cetuximab, Matuzumab/EMD 72000) Tyrosine kinase inhibitor of EGFR (Lapatinib, Erlotinib, Gefitinib) Others: PARP inhibitor, mtor Inhibitors, HDAC inhibitor, Notch inhibitor, IGF (Figitumumab), Hydalazine, etc.

3 Agenda Targeted therapy in Ovarian cancer - Anti-angiogenic therapy( VEGF Ab,TKI) - PARP inhibitors - Other target(egf, Ras/Raf/MEK/ERK, potential target) Targeted therapy in Cervical cancer - Anti-angiogenic therapy(vegf Ab, TKI) - Anti EGFR - Other target(hdac, mtor, WEE, Folic acid, PARP, potential target) Targeted therapy in Endometrial cancer - PI3K/AKT/PTEN/mTOR pathway - Other target(egfrs, VEGF, potential target) Summary

4 Ov ca Targeted therapy in Ovarian cancer Banerjee S and Kaye SB. Clin Cancer Res 2013;19:

5 Ov ca

6 Ov ca Ovarian Cancer: GOG Trials of Targeted Therapy

7 Ov ca Anti-angio

8 Ov ca Anti-angio GOG 218: Schema Burger et al, 2010.

9 a p =.0116 Burger et al, Ov ca Anti-angio GOG 218: Investigator-Assessed PFS

10 Ov ca Anti-angio ICON7: Study Design

11 Ov ca Anti-angio ICON7 PFS: Updated Kristensen et al, 2011.

12 Ov ca Anti-angio OCEANS: Study Schema

13 Ov ca Anti-angio OCEANS: PFS, ORR, and DOR DOR = duration of response; INV = investigator-assessed; IRC = independent review committee; ORR = objective response rate. Aghajanian et al, 2012.

14 Ov ca Anti-angio OCEANS: OS Analyses Aghajanian et al, 2012.

15 Ov ca Anti-angio AURELIA Trial Design

16 Ov ca Anti-angio Progression-Free Survival Pujade-Lauraine et al, 2012.

17 Ov ca Anti-angio Adverse Events of Special Interest RPLS = reversible posterior leukoencephalopathy syndrome; CHF = congestive heart failure. Pujade-Lauraine et al, 2012.

18 Ov ca Anti-angio GOG 252: Stage II/III Disease: Small Volume Residual N = 1,560 pts PFS 26.8 months 28.7 months 27.8 months grade 3 neutropenia - 2/3 IP cisplatin probably shouldn t be combined with bevacizumab because it causes severe hypertension

19 Ov ca Anti-angio AMG 386: Targeting Angiopoietin/Tie pathway AMG386

20 Ov ca Anti-angio TRINOVA-3 (GOG 3001): TC ± AMG 386 as First-Line Therapy of Stage III IV Ovarian Cancer

21 Ov ca Anti-angio TRINOVA-1:Randomized Phase III on AMG 386 in Combination With Paclitaxel in Advanced Recurrent Ova Ca Recurrent EOC 3 prior anticancer regi mens Evaluable or measurabl e disease GOG Performance Statu s of 0 or 1 PFI < 12 months R 1:1 Weekly Paclitaxel + Placebo Weekly Paclitaxel + Trebananib Treat to PD/toxicity Treat to PD/toxicity Lancet Oncol, 2014 Jul;15(8),

22 Ov ca Anti-angio TRINOVA- 1 : Progression-free Survival Event-free Probability Pac + Placebo (n = 458) Pac + Trebananib (n = 461) Events, n (%) 361 (79) 310 (67) Median PFS, months HR = 0.66 (95% CI, ) P (stratified log rank) < Patients at risk: Study Month Lancet Oncol, 2014 Jul;15(8),

23 Ov ca Anti-angio TRINOVA- 1 : Overall Survival (Interim Analysis) Event-free Probability Pac + Placebo (n = 458) Pac + Trebananib (n = 461) Events, n (%) 163 (36) 150 (33) Median OS, months HR = 0.86 (95% CI, ) P (stratified log rank) = Patients at risk: Study Month Lancet Oncol, 2014 Jul;15(8),

24 Ov ca Anti-angio VEGF Targeted, Ab and TKI

25 Ov ca Anti-angio ICON 6: Cediranib with Platinum-based Chemotherapy in platinum-sensitive relapsed ovarian cancer Cediranib: TKI of VEGFR1,2,3 Relapse > 6 months after c ompletion of first line plati num-based chemotherapy N=456 pts Randomise 2 : 3 : 3 6 Cycles platinum-based Chemotherapy Carboplatin/paclitaxel Carboplatin/Gemcitabine Single agent platinum Arm A (Chemo only) Chemotherapy + placebo Arm B (Concurrent) Chemotherapy + cediranib Arm C (Maintenance) Chemotherapy + cediranib Maintenance phase Continue placebo Switch to placebo Maintenance cediranib Treatment continued to 18 months or until pr ogression (>18 for patients continuing to ben efit Ledermann et al Lancet 2016

26 Ov ca Anti-angio ICON 6: Survival analysis Immature Chemo. Maint. OS Median, months Log-rank test p=0.042 HR (95% CI) 0.77 ( ) Test for non-proportionality p=0.001 Restricted means, months Chemo. Maint. PFS Median, months Log-rank test P < HR (95% CI) 0.57 ( ) Test for non-proportionality p=0.001 Restricted means, months Ledermann et al Lancet 2016

27 Ov ca Anti-angio Pazopanib oral, multikinase inhibitor of VEGFR-1, -2, -3, PDGFR-α and -β, and c-kit.

28 Ov ca Anti-angio AGO-OVAR16 A Phase III Study to Evaluate the Efficacy and Safety of Pazopanib Monotherapy Versus Placebo in Women Who Have not Progressed after First Line Chemotherapy for Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer First-line Chemotherapy (allow ip, neoadj) Screening Baseline If not PD R A N D O M I Z E Treatment Period Pazopanib (12 months) Placebo (12 months) Post-Treatment Period Observation (to PD) Follow-up Period Survival Follow-up (post-pd)

29 Ov ca Anti-angio Pazopanib:AGO-OVAR16 Floquet A, et al. Gynecol Oncol. 2015

30 Ov ca Anti-angio Nintedanib (BIBF 1120) First Triple Angiokinase Inhibitor: Mode of Action

31 Ov ca Anti-angio Nintedanib: Phase II PFS and OS Ledermann et al, 2011.

32 Ov ca Anti-angio AGO-OVAR12: Phase III Trial Nintedanib Consolidation Du Bois A,2013

33 Ov ca Anti-angio AGO-OVAR12: Phase III Trial Nintedanib Consolidation marginally-longer median PFS (17.3 vs.16.6 ms) HR=0.84; 95% CI= ; p=0.0239). du Bois A et al. J Clin Oncol.2013;31(18suppl):LBA5503.

34 Ov ca Anti-angio Angiogenesis as a Target in Ovarian Cancer: Anti-VEGF-VEGFR Pathway Anti-vascular endothelial growth factor (VEGF) therapy PFS GOG 218* Front-line: Bevacizumab HR = 0.72; 95% CI, ICON 7* Front-line: Bevacizumab HR = 0.81; 95% CI, AGO-OVAR12 Front-line: Nintedanib HR = 0.84; 95% CI, 0.72, AGO-OVAR16 Maintenance: Pazopanib HR = 0.77; 95% CI, AURELIA** Platinum-resistant, recurrent / 1 or 2 prior regimens: Bevacizumab HR = 0.48; 95% CI, OCEANS* Platinum-sensitive, recurrent / 1 prior regimen: Bevacizumab HR = 0.48; 95% CI, ICON6 Platinum-sensitive, recurrent / 1 prior regimen: Cediranib HR = 0.57; 95% CI, Burger RA et al. N Engl J Med. 2011;365: Perren TJ et al. N Engl J Med. 2011;365: du Bois A et al. J Clin Oncol. 2013;31(18suppl):LBA du Bois A et al. LBA ESGO 2013 Liverpool, UK 5. Pujade-Lauraine E et al. J Clin Oncol. 2012;30(18suppl):LBA Aghajanian C et al. J Clin Oncol. 2012;30: Ledermann JA et al. Eur J Cancer. 2013;49(suppl):LBA *EMA Approved *FDA Approved

35 Ov ca PARP inhibitor PARP inhibitors Poly ADP ribose polymerase (PARP) catalyzes the poly ADP-ribosylation of proteins involved in DNA repair. J Gynecol Oncol. 2014;25:249-59

36 Ov ca PARP inhibitor Phase 2 Randomized Placebo-controlled Study of Olaparib in Pts with Platinum-Sensitive relapsed Serous OC n = 265 Ledermann et al, 2012.

37 Ov ca PARP inhibitor Progression free survival Ledermann et al, 2012.

38 Ov ca PARP inhibitor Subgroup analysis of PFS Ledermann et al, 2012.

39 Ov ca Other Target Other Targets in Ovarian cancer Banerjee S and Kaye SB. Clin Cancer Res 2013;19:

40 Ov ca Other Target Ras/Raf/MEK/ERK pathway Activation of the mitogen-activated protein kinase(mapk) signaling pathway may be very important as BRAF and KRAS mutations were initially reported in up to 68% of cases Phase II trial of the MEK1/2 inhibitor selumetinib (AZD6244) ORR 15.4%, median PFS 11 mos. Phase II trials of other MEK inhibitors,trametinib(gsk ) planned EGF family clinical trial results with single agent EGFR inhibitors (erlotinib, gefitinib) are disappointing HER2-targeted therapy (trastuzumab,pertuzumab) has proven to be of no benefit

41 Ov ca Other Target Another potential target Wee-1 kinase; regulates the G2 M checkpoint phase I clinical trials of MK-1775 selective aurora kinase A; Randomized trials in combination with paclitaxel - MLN8237) folate receptor, farletuzumab (MORab-003, Morphotek Inc.) EZH2 key role in the maintenance of a drug-resistant stem cell like subpopulation of tumor key mutations identified in genes ARID1A (clear cell and endometrioid subtype), TP53 ( high-grade serous subtype) are not directly "druggable."

42 Ov ca Key Takeaways - Targeted tx in Ov ca Angiogenesis inhibitors are the most promising therapy for ovarian cancer patients. Bevacizumab can be included as maintenance therapy in standard chemotherapeutic regimens for advanced disease, though tyrosine kinases inhibitors need to be elucidated. multi-targeted inhibitors( Pazopanib,Trebananib, Cediranib, Nintedananib) has been shown to a have promising efficacy and be an agent of interest. PARP and mtor inhibitors are also attractive targeted agents for ovarian cancer therapy.

43 Ov ca Key Takeaways - Targeted tx in Ov ca More phase III studies are needed to further evaluate the efficacy and toxicity of these new agents. Importantly, the identification of certain predictive biomarkers may optimize treatment s efficacy distinguishing the target group that would derive the most benefit through this patient-tailored approach.

44 Cx Ca Targeted therapy in cervical cancer Archives of Medical Research, Volume 45, Issue 7, 2014,

45 Cx Ca Anti-angio Ab Bevacizumab Studies in Cervical Cancer Recurrent ca GOG 227C: Phase 2 trial, persistent or recurrent ca RTOG 0417 : Phase 2 trial, stage IB-IIIB Phase 2 trial, persistent or recurrent ca Ther Adv Med Oncol. 2014;6:280-92

46 Cx Ca Anti-angio Ab Recent Promising Outcome! GOG 240 Paclitaxel + cisplatin/topotecan with or without bevacizumab for stage IVB, recurrent, or persistent cervical cancer (phase 3) Study period: April 2009-Jan 2012 n= 452

47 Cx Ca Anti-angio Ab GOG 240 (1) Bevacizumab vs. No Bevacizumab Response rate (48% vs. 36%) Significant improvement in OS and PFS in the bevacizumab arms relative to non-bevacizumab controls NEJM. 2014;370:734-43

48 Cx Ca Anti-angio Ab GOG 240 (2) Subgroup analysis of overall survival Benefits of bevacizumab persisted in recurrent disease in a previously irradiated field, which was hypothesized to be relatively hypoxic. NEJM. 2014;370:734-43

49 Cx Ca Anti-angio Ab GOG 240 (3) Adverse Events

50 Cx Ca Anti-angio Ab GOG 240 Significance of GOG 240 Results The first time, a targeted anti-angiogenic agent has shown an improvement in OS in gynecologic cancer Within 1 month of public presentation of the data, the cisplatin paclitaxel bevacizumab triplet from GOG 240 was listed as Category 2B in NCCN Guidelines for cervical cancer. NCCN 2015 v.2

51 Cx Ca Anti-angio Ab Evolution of 3 bevacizumab-containing triplets cisplatin vs. cisplatin+topotecan (favor!) Paclitaxel+cisplatin vs. Paclitaxel+carboplatin (non inferioty!) cisplatin vs. cisplatin+paclitaxel (favor!) Clin Adv Hematol Oncol. 2014;12:737-48

52 Cx Ca Anti-angio - TKI Multiple Targets Involved in Angiogenesis J Gastrointest Oncol. 2013;4:253-63

53 Cx Ca Anti-angio - TKI Multi-targeted VEGFR Tyrosine Kinase Inhibitors (TKIs) Receptor tyrosine kinase ckit plays a role in cervical carcinogenesis. PDGF and FGF have been identified as targets in the angiogenic cascade. PDGF binding to the PDGF receptor β : Essential for pericyte recruitment and blood vessel maturation FGF family of ligands : Activates angiogenesis via interaction with FGF receptors 1 and 2 Signaling via these alternate pathways (PDGF, FGF) may mediate resistance to VEGF inhibition, supporting a multi-targeted approach

54 Cx Ca Anti-angio - TKI Molecules from Recent Studies (1) Pazopanib Selective, oral multi targeted inhibitor that targets VEGFR, PDGFR, c-kit FDA approval for metastatic renal cell carcinoma, metastatic soft tissue sarcomas in October 2009 (2) Sunitinib Analogous, oral multi-tki that inhibit VEGFR-1/2/3, PDGF α/β FDA approval for metastatic renal cell carcinoma, gastrointestinal stromal tumors in Jan 2006 * Lapatinib Oral, small-molecule, dual TKI of EGFR, Her2/neu (not VEGFR) FDA approval for Her2/neu-overexpressing metastatic breast cancer in combination with capecitabine in March 2007

55 Cx Ca Anti-angio - TKI Non-bevacizumab Anti-angiogenic Trials in Cx ca 1) 2) 3) Eskander et al. Ther Adv Med Oncol. 2014;6:280-92

56 Cx Ca Anti-angio - TKI Pazopanib (Phase 2 trial, Monk et al. in 2010) To date, the largest study exploring non-bevacizumab anti-angiogenic agents in the treatment of cervical cancer (NCT ) Combination arm: early terminated, because the futility boundary was crossed. Pazopanib improved PFS (HR = 0.66; 90% CI: ; p = 0.013) and OS (HR = 0.67; 90% CI: ; p = 0.045) The only grade 3 AE >10%: diarrhea (11% pazopanib, 13% lapatinib) Grade 4 AEs: 12% (pazopanib) and 9% (lapatinib) Demonstrated the benefit of pazopanib based on the prolonged PFS and favorable toxicity profile in in advanced and recurrent cervical cancer J Clin Oncol.2010;28:

57 Cx Ca Anti-angio - TKI Sunitinib (Phase 2 trial, Mackay et al. in 2010) There were no documented objective responses on therapy, but, morbidity was significant (fistula rate of 26%). Median time to progression was reported as 3.5 months. Sunitinib has insufficient activity as a single agent in cervical cancer. Promising Ongoing Trial! Sunitinib (NCT ) Sunitinib with hydroxychloroquine in patients with advanced solid tumors who have not responded to chemotherapy (NCI, phase 1) Study period: Jan 2010-July 2013 (The results will be forthcoming) n=21 Gynecol Oncol. 2010;116:

58 Cx Ca Anti-angio - TKI CIRCCa Phase 2 trial: Cediranib , advanced Cx ca(n=69) - toxic effects (mainly diarrhea, hypertension, and febrile neutropenia) - demonstrated the efficacy of cediranib in advanced cervical cancer, which deserves a phase 3 study. Symonds RP, Lancet Oncol. 2015

59 Cx Ca Anti-angio - TKI Brivanib Brivanib in treating patients with persistent or recurrent cervical cancer (GOG0227G, NCT , phase 2) Brivanib: Oral, dual inhibitor of VEGFR-2 & FGR1 Study period: April 2011-Feb 2013 (closed, report yet to be published) n=51

60 Cx Ca Anti-angio - VDA Another Promising Avenue! Anti-vascular Therapy Vascular disrupting agents (VDAs) 5,6-dimethylxanthenone-4-acetic acid (DMXAA, ASA404, vadimezan) The most extensively studied VDA in cervical cancer Mechanisms of action Induction of cytokines (TNF-alpha, serotonin, NO), anti-vascular and anti-angiogenic effects For refractory tumors (NCT , phase 1 trial in 2003) DMXAA (22 mg/kg IV over 20 min) resulted in a partial response in 1 patient with metastatic cervical squamous carcinoma Clin Cancer Res. 2006;12(6):

61 Cx Ca Anti-EGFR Targeting Other Pathways: anti-egfr EGFR: a membrane tyrosine kinase (EGFR 1/ 2(Her-2/neu)/ 3/ 4) Ligand binding: lead to cell proliferation, motility, resistance to apoptosis In cervix (1) Epithelial cells secrete EGF-like growth factors that activate EGFR. (2) HPV E6 causes activation of EGFR. Cetuximab Gefitinib

62 Cx Ca Anti-EGFR Ab Cetuximab: Murine monoclonal anti-egfr antibody Phase 2 clinical trials 2011 GOG277E 2011 GOG26DD 2009 GINECO trial Cetuximab alone appears to be well tolerated, it had limited activity. J Gynecol Oncol. 2014;25:249-59

63 Cx Ca Anti-EGFR Ab Promising Ongoing Trial! Combination therapy MITO Cervix 2 trial in advanced and/or recurrent cervical cancer (NCT , phase 2) Study period: Oct 2009-Oct 2015 n=108

64 Cx Ca Anti-EGFR TKI Small-molecular TKI of EGFR Gefitinib: HER1/EGFR TKI Erlotinib: EGFR-1 and HER1 TKI Phase 2 clinical trials GOG 227D TKI alone had limited activity. J Gynecol Oncol. 2014;25:249-59

65 Cx Ca Anti-EGFR TKI Recent Promising Trial! Erlotinib Phase 2 clinical trials in patients with locally advanced cervical cancer (IIB-IIIb) Erlotinib before and in combination with cisplatin CCRT Promising activity! 94.4%: complete response, 5.6%: partial response DFS: 1Y (94.4%), 2Y (80.6%), 3Y (73.6%) OS: 1Y (97.2%), 2Y (91.7%), 3Y (79.9%) Well tolerated Treatment with erlotinib appears to be safe and exerts significant activity against locally advanced cervical cancer. Cancer. 2014;120:

66 Cx Ca Other target Other targets Beyond angiogenesis blockade: targeted therapy for advanced cervical cancer RN Eskander and KS Tewari JGO

67 Cx Ca Other target Anti-folate agents Pemetrexed (anti-folate, disrupts folate-dependent metabolic processes) Clinical trials Authors Drugs Phase Subjects n Response Ramez N et al. (2014) provided Pemetrexed 1 Chemotherapy naïve cervical cancer patients NA 21% response rate Miller DS et al. (2008) GOG 127T Pemetrexed 2 Persistent or recurrent cervical carcinoma 29 15% response rate (partial response) Grade 3/4 AE: anmia (41%), leukopenia (30%), neutropenia (26%), infection (26%) GOG77G,G NCT (Not published yet) Cisplatin +Pemetrexed 3 Recurrent, metastatic cervical cancer 55 31% response rate (1 of complete, 16 partial) Most common grade 2 AE: neutropenia (35%), leukopenia (28%), metabolic (28%) J Gynecol Oncol. 2014;25:249-59

68 Cx Ca Other target Clinical Trials: HDAC(Histone Deacetylase) Inhibitors Authors Drugs Phase Subjects n Response Chavez- Blanco A al. (2005) valproate 1 Stage 2B to 4B cervical carcinoma 12 Tumor deacetylase activity decreased in 80%. Candelaria M et al. (2010) weekly cisplatin based CCRT + valproate and hydralazine 2 Stage 3B squamous and adenosquamo us cervical cancer % response rate Coronel J et al. (2011) (1) Arm VH: cisplatin +topotecan +valproate + hydralazine (2) Arm placebo 3 Stage IVB, recurrent, or persistent cervical cancer VH: 17 Placebo: 19 Partial responses: 24% (4/17) in HV arm vs. 5.2% (1/19) in placebo PFS: 10 months in HV arm vs. 6 months in placebo (p=0.0384) Hydralazine: DNA methyltransferase inhibitor Chavez-Blanco A et al. Mol Cancer. 2005;4:22 Coronel J et al. Med Oncol. 2011;28 Suppl 1:S540-6 Candelaria M et al. Eur J Gynaecol Oncol. 2010;31:386-91

69 Cx Ca Other target Clinical Trials: mtor inhibitors Authors Drugs Phase Subjects n Response Janku F et al. (2012) Temsirolimus 1 Advanced squamous cell cervical ca 14 2/5 (40%) partial response Temkin SM et al. (2010) Temsirolimus and Topotecan 1 Advanced/recurre nt squamous cell carcinoma of the cervix 2 1 (50%) stable disease Dose-limiting toxicity: myelosuppression Tinker AV et al. (2013) : NCIC-CTG-IND199 Temsirolimus 2 Advanced cervical carcinoma 38 1/33 (3%) partial response No grade 4 to 5 adverse events Janku F et al. J Clin Oncol. 2012;30: Temkin SM et al. Gynecol Oncol. 2010;117:473 6 Tinker AV et al. Gynecol Oncol. 2013;180:269 74

70 Cx Ca Other target Clinical Trials: mtor inhibitors with Pending Result Trial No. Drugs Phase n Subjects Start date End date NCT Everolimus (RAD001) 1 14 Locally advanced cervical cancer Dec 2011 April 2014 (complete) NCT Temsirolimus 2 32 Cervical cancer that is recurrent, locally advanced, metastatic, or cannot be removed by surgery Dec 2009 Nov 2012 (complete)

71 Cx Ca Other target WEE1 inhibition WEE1 functions as a mitotic inhibitor, regulating the G2-M transition. Abrogation of the G2-M arrest Releases cells with unrepaired DNA damage into premature mitosis, resulting in mitotic catastrophe and apoptotic cell death Combination treatment with DNA damaging cytotixic agents and WEE1 inhibition, is hypothesized to prime these cells for apoptosis. Phase 1/2 clinical Trials (NCT ) MK1775 (potent and selective ATP-competitive inhibitor of WEE1) In combination with topotecan + cisplatin for advanced, metastatic, and recurrent cervical cancer

72 Cx Ca Other target Promising Trial! Notch Inhibitor VEGF & Notch pathways are tightly linked: VEGFR3 is modulated by Notch. Notch inhibitor in patients with advanced solid tumors (NCT , phase 1) Study period: Aug 2010-Aug 2012 (Status: closed to accrual with results pending) n=35 But, no current active clinical trials in cervical cancer

73 Cx Ca Other target Heat Shock Protein 90 Hsp90 plays a central role in supporting all of the six hallmark traits of cancer. Geldanamycin (HSP90 inhibitor) : No current active clinical trials in cx ca. J Gynecol Oncol. 2014;25:249-59

74 Cx Ca Other target PARP inhibitors The activity of PARP inhibitors is not limited to BRCA mutation carriers, suggesting that even PARP inhibitors may be considered for study in patients with advanced cervical carcinoma. Promising ongoing trials Trial No. Drugs Phase n Subjects Start date End date NCT Carboplatin and Olaparib 1 77 Refractory or recurrent breast, ovarian, uterine, or cervical cancer Oct 2010 Nov 2014 NCT Paclitaxel, Cisplatin, and Veliparib 1/2 66 Advanced, persistent, or recurrent cervical cancer April 2011 March 2020

75 Cx Ca Key Takeaways - Targeted tx in Cx ca Bevacizumab appears to be more effective and tolerable than subsequent antiangiogenic agents that have been evaluated. Studies evaluating EGFR TKIs have not shown them to be beneficial. Possibly related to the degree of tumor EGFR expression, amplification, lack of mutation of the receptor The role of small-molecular weight TKIs targeting VEGFR and other angiogenic pathways, when given in combination with chemotherapy will be of great interest. Pazopanib,Cediranib (multi-targeted inhibitor) has been shown to a have promising efficacy and be an agent of interest.

76 Em Ca Targetable pathways in endometrial cancer Dedes, K. J. et al. (2010) Emerging therapeutic targets in endometrial cancer Nat. Rev. Clin. Oncol.

77 Em Ca Genetic alterations in endometrial cancer But, most clinical trials have not stratified patients according to type.

78 Em Ca Completed phase II trials for recurrent or metastatic endometrial cancer Dedes, K. J. et al. (2010) Emerging therapeutic targets in endometrial cancer Nat. Rev. Clin. Oncol

79 Em Ca mtor inhibitor mtor inhibitors: PI3K/AKT/PTEN/mTOR pathway Temsirlimus - phase II study recurrent or metastatic endometrial cancer Ctx-naive group(33); 14%(PR) Ctx treated group(27); 4%(PR) response was found to be independent of PTEN status Ridaforolimus - phase II study 28%(RR) Everolimus- phase II study 21%(RR) Oza AM, et al. J Clin Oncol Colombo N, J Clin Oncol Slomovitz BM, Cancer 2010.

80 Em Ca mtor inhibitor Ongoing Clinical trial mtor inhibitor

81 Em Ca Anti-angio Ab,TKI Angiogenesis inhibitor 56 66% of EM ca express high levels of VEGF Some Phase II study bevacizumab monotherapy had some activity Dedes, K. J. et al. (2010) Emerging therapeutic targets in endometrial cancer Nat. Rev. Clin. Oncol

82 Em Ca Anti-angio Ab,TKI Ongoing Clinical trial angiogenesis inhibitor bevacizumab monotherapy had some activity

83 EM Ca Anti EGF Anti EGFR therapy Phase II study of oral erlotinib 12.5%(PR) Phase II study of Gefitinib 3.8%(RR) newer compounds that inhibit both EGFR and HER2

84 EM Ca Anti EGF Ongoing Clinical trial - Anti EGFR therapy

85 Em Ca Other target Another potential target Fibroblast growth factor receptor (FGFR) family EphA2 EpCAM Hypoxia inducible factor 1 α PARP inhibitors phase II trial BSI-201 in combination with standard chemotherapy

86 Em Ca Key Takeaways - Targeted tx in Em ca Endometrial cancer is a heterogeneous disease with distinct molecular characteristics The most frequent aberration is the activation of the PI3K/PTEN/AKT/mTOR pathway Targeted therapies are yet to be introduced in clinical practice EGFR, mtor, HER2 and VEGFR inhibitors have been tested in phase II trials as single agents with modest results The development of more potent inhibitors of the PI3K/PTEN/AKT/mTOR pathway and the identification of new druggable targets has led to the initiation of several biology-driven clinical trials

87 Summary Targeted therapy in Gynecologic cancer Gynecologic cancer has a distinct biology and may no longer be treated as a single disease. A better understanding of the tumor molecular biology and identification of predictive biomarkers are essential steps in selecting the best treatment strategies to improve survival in patients. Further investigation into the molecular biology and genetics of gynecologic cancer is warranted. More phase III studies are needed to further evaluate the efficacy and toxicity of these new agents.

88 Thank you for your attention!