The Future of Antiangiogenic Therapies in Ovarian Cancer: A Series of Community and Academic Grand Rounds

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Review a downloadable slide deck by Deborah K. Armstrong, MD, covering the most clinically relevant new data reported from The Future of Antiangiogenic Therapies in Ovarian Cancer: A Series of Community and Academic Grand Rounds.

Target Audience
This activity has been designed to meet the unique learning needs of oncologists, surgeons, gynecologists, and other healthcare professionals involved in the treatment of patients with ovarian cancer.

Format: Microsoft PowerPoint (.ppt) | File size: 9.7 MB | Date posted: 8/06/2012

Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of August 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.


Usage Rights
This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.

Activity Overview
Although progress continues to be made in the treatment of ovarian cancer, making clinical decisions remains a challenge due to the many treatment options available in several different settings. Selective inhibitors of the VEGF/PDGF/FGF pathways have shown activity in patients with ovarian cancer in phase II and III clinical trials either as monotherapy or in combination with other chemotherapy. Community and academic oncologists who treat patients with ovarian cancer need to stay abreast of the latest research that can affect treatment decisions and patient outcomes.

As controversy still exists regarding how and when to incorporate the use of antiangiogenic agents into the treatment paradigm for ovarian cancer patients, this case-based activity developed by expert faculty will provide clinicians with the practical application of new data into community and academic practice settings.

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  • I think discussing what one might do differently for an optimal patient with no residual disease (who were not eligible for GOG 218) and an optimal patient with visible residual (who would have been) is a good discussion point
  • Piccart, MJ, Bertelsen K, Stuart G, et al. Long-term follow-up confirms a survival advantage of the paclitaxel–cisplatin regimen over the cyclophosphamide–cisplatin combination in advanced ovarian cancer. International Journal of Gynecological Cancer. 2003;13(s2):144–148. Reference for notes from Dr. Thigpen: http://www.medscape.com/viewarticle/429839_16 GOG 111 and OV 10: GOG protocol 111 randomized patients with large volume advanced disease to either cyclophosphamide plus cisplatin, or paclitaxel plus cisplatin. This study showed superiority for the paclitaxel and cisplatin regimen compared with cyclophosphamide and cisplatin in regards to 5 parameters: (1) response rate, (2) clinical complete response rate, (3) percentage of patients grossly disease-free at second-look laparotomy, (4) progression-free survival, and (5) overall survival. A confirmatory study from a European-Canadian consortium called OV 10 also randomized patients to either cyclophosphamide and cisplatin, or paclitaxel and cisplatin. The population here was stage II B through IV disease and included both small volume and large volume patients. The paclitaxel and platinum combination was superior to the cyclophosphamide and platinum combination in regard to response rate, clinical complete response rate, progression-free survival, and overall survival. The numbers closely reproduced those numbers that were seen with GOG protocol 111. GOG 158 and AGO: Two large trials were done, a German trial and a GOG trial here in the United States. The German trial was presented in 1998 at the American Society of Clinical Oncology meetings and randomized 798 patients with advanced ovarian cancer to either paclitaxel and cisplatin, or paclitaxel and carboplatin. The results showed equivalency between the 2 regimens with regard to response rate, clinical complete response rate, progression-free survival, and overall survival. The large number of patients in this study, 798, made it possible to conclude that the regimens were equivalent. Confirmation of that came from GOG protocol 158, a study that focused on patients with stage III optimal or minimal residual disease. Patients were again randomized to either paclitaxel and cisplatin, or paclitaxel and carboplatin. The results showed equivalency between the 2 regimens with regard to pathologic complete response rate and progression-free survival. As a result of these 2 large trials, it was concluded that cisplatin and carboplatin were equivalent in combination with paclitaxel, and that it would be feasible to treat these patients with paclitaxel plus carboplatin, an easier regimen to give. Drugs: carboplatin (Paraplatin®) cisplatin (Platinol®-AQ) cyclophosphamide (Cytoxan®, Neosar®) paclitaxel (Onxol®, Taxol®)
  • Avastin is a recombinant humanized monoclonal antibody of the IgG 1 isotype. 1 Avastin has been shown to bind all isoforms of VEGF (VEGF-A). 2 At least 4 different VEGF isoforms, with different molecular weights (206, 189, 165, and 121 kD) and heparin-binding properties, are created by alternative splicing of the VEGF-A gene. 3 The estimated half-life of Avastin is about 20 days (with a range of 11 to 50 days). 1 1. Avastin™ (Avastin) PI. February 2004. 2. Presta et al. Cancer Res . 1997;57:4593. 3. Ferrara et al. Nat Med. 2003;9:669. KEY MESSAGE Avastin is a recombinant humanized monoclonal antibody that specifically binds to the VEGF ligand.
  • 2008
  • The Japanese GOG dose dense weekly paclitaxel regimen with every 3 week carboplatin was used in Arm I of GOG 252 and a modification of the GOG 172 IV/IP regimen was used in Arm III of GOG 252 indicating that bevacizumab can be given with these regimens without a safety concern being raised. However results from this trial are not yet available.
  • CG Data show that the most important growth factor is VEGF , but recent data suggest that FGF plays a critical role as well
  • Answer 1: Correct: this is considered standard in this situation Answer 2: Incorrect: while commonly used, there is no data that more prolonged paclitaxel and carboplatin improves clinical outcome in patients who have attained a response. Answer 3: Correct: this is an option. In GOG 178 PFS was significantly improved for 12 months of paclitaxel compared to 3 but OS was not improved Answer 4: Incorrect because neither of the upfront randomized trials in ovarian cancer, GOG 218 and ICON 7 used bevacizumab just as maintenance. This is being evaluated with other VEGF targeted agents but has not yet been shown to improve outcome Answer 5: see answer 4
  • Xyotax: (paclitaxel poliglumex - PPX
  • Another interesting drug is sorafenib is a tyrosine kinase inhibitor targeting raf and other receptor kinases (VEGF-R, PDGF-R, Flt3, c-KIT). Sorafenib may have anti-angiogenic activity through inhibition of VEGF-R. This phase II study in patients with recurrent EOC the PFS at least 6 months rate was 20%. Two patients had partial responses; 20 had stable disease. A Phase IIb RCT placebo controlled Maintenance study of p atients with stage III/IV ovarian epithelial cancer or PPC who have achieved clinical CR after standard platinum/taxane therapy and cytoreductive surgery is closed. The primary endpoint is PFS. Hopefully we will hear these results soon.
  • Answer 1: this is a reasonable choice but expected response rate is 6-16% in a less heavily pretreated population (i.e. in first relapse platinum refractory patients) Answer 2: this is also a reasonable choice but expected response rate is 21% (In GOG protocol 126-N weekly paclitaxel had a response rate of 21%) in a less heavily pretreated population (i.e. in first relapse platinum resistant patients) Answer 3: Based on recently reported data from the AURELIA trial, this is likely the treatment with the best response rate. Chemotherapy plus bevacizumab had RECIST RR of 27%, CA-125 RR of 32%. Answer 4: Bevacizumab is a reasonable choice. In GOG protocol 170D bevacizumab showed a response rate of 21% in this population. Answer 5: platinum-based therapy is not indicated in this patient with platinum-refractory disease. Answer 6: platinum-based therapy with bevacizumab is not indicated in this patient with platinum-refractory disease. Naumann RW , Coleman RL . Management strategies for recurrent platinum-resistant ovarian cancer. Drugs. 2011 Jul 30;71(11):1397-412.
  • Drug: pegylated liposomal doxorubicin (Doxil®) References: Muggia FM, Hainsworth JD, Jeffers S, et al. Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol. 1997;15(3):987-893. Gordon AN, Granai CO, Rose PG, et al. Phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer. J Clin Oncol. 2000;18(17):3093-3100. Gordon AN, Fleagle JT, Guthrie D, et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol . 2001;19(14):3312-3322. Ferrandina G, Ludovisi M, Lorusso D, et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol. 2008;26(6):890-896.
  • The GOG queue for platinum resistant ovarian cancer, 126, has identified 5 agents that meet the threshold of ORR >10% and 4 meeting a clinical threshold of ORR >20%. Three of these 4 agents are taxanes, the 4th is pemetrexed, which is not FDA approved for ovarian cancer. In a randomized trial NXTR-102, a topoisomerase I polymer conjugate that provides continuous concentration of active drug with reduced peak concentrations was shown to have activity in this population.
  • Three bevacizumab trials have been performed in recurrent ovarian cancer, one with metronomic, daily low dose cyclophosphamide. Together they demonstrate ORR of 16-21%. GI perforations were seen in two of the three trials and led to early discontinuation of one (Cannistra et.al.)
  • The overall incidence of bowel perforation in bevacizumab trials in recurrent ovarian cancer is about 5%. While the clear etiology of this toxicity is not clear, many feel that prior pSBO or ongoing bowel dysfunction increases risk. Most today would consider this patient at increased risk of bowel perforation given the bowel wall involvement with disease. Reference: Han E, Monk BJ. What is the risk of bowel perforation associated with bevacizumab therapy in ovarian cancer? Gynecol Oncol. 2007;105(1):3-6.
  • PR= Progesterone receptor; uPAR = urokinase plasminogen activator receptor. The GOG has studied a number of biologic agents in recurrent ovarian cancer. Thile bevacizumab, sorafenib and temsirolimus have met the 6 month PFS criteria of 15-35%, only bevacizumab has met the trial threshold for ORR of 10-25%
  • In addition to bevacizumab, other VEGF targeted drugs have been tested as single agent therapy. Of these, cedirinib, cabozantinib and pazopanib have met an arbitrary criteria of ORR >15%
  • While aflibercept (VEGF-Trap) does not have single agent activity in ovarian cancer, it has been shown to be beneficial in management of ascites with an increase in the time to repeat paracentesis from 23 to 55 days compared to placebo. Fatal GI perforations were seen in 3 of 30 (10%) of patients treated with aflibercept.
  • AMG-386 blocks interactions between Ang1 and Ang2 and their receptor Tie2. AMG-386 peptide-Fc fusion protein (peptibody).
  • Key Points: This is a randomized, double-blind, placebo controlled trial to determine if addition of AMG 386 to paclitaxel therapy is superior to paclitaxel therapy alone in women with recurrent, partially platinum sensitive or resistant epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer The dose of AMG 386 being used in this trial is higher than that used in the Phase II trial References: http://www.clinicaltrials.gov. Accessed April 19, 2011.
  • The patient would have been eligible for the recently reported AURELIA trial which allowed up to two prior anticancer regimens. Patients received either standard chemotherapy consisting of weekly paclitaxel, topotecan (either weekly or using the daily x 5 regimen), or PLD at the choosing of their oncologist, with or without bevacizumab.
  • This study showed a statistically significant improvement in PFS from a median of 3.4 months for chemotherapy alone to 6.7 months for chemotherapy plus bevacizumab.
  • ORR was more than doubled whether looking at response based on RECIST and/or CA-125
  • No new signals of toxicity were seen in the bevacizumab plus chemotherapy arm.
  • Carbo/gem from AGO trial (identical dose and schedule), allowed up to 10 cycles in responding pts. Bev continued until progression in contrast to GOG-0218 and ICON7. All pts had measurable disease as defined by RECIST (older criteria). Stratification by cytoreductive surgery was probably not necessary as all pts had measurable disease – driven by thoughts that treatment paradigm was changing in US
  • Job #24919 Aghajanian OCEANS PM
  • This patient was treated on GOG protocol 170D with single agent bevacizumab. as can be seen on the comparison CT images after 4 cycles, she had complete resolution of pelvic ascites and marked improvement in upper abdominal ascites. The gastric wall thickening has decreased consistent with improved carcinomatosis and the gastric distensibility is improved . She remained on bevacizmab for 21 months.
  • The Future of Antiangiogenic Therapies in Ovarian Cancer: A Series of Community and Academic Grand Rounds

    1. 1. DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is current as of August 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice,diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
    2. 2. DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline forpatient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. DISCLOSURE OF UNLABELED USEThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Albert Einstein College ofMedicine and IMER do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Albert Einstein College of Medicine and IMER. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
    3. 3. Disclosure of Conflicts of Interest Deborah K. Armstrong, MDReported a financial interest/relationship or affiliation in theform of: Consultant, Eisai Inc.; Contracted Research, Eisai,Inc., MedImmune, LLC, Roche Pharmaceuticals, Inc.
    4. 4. Learning Objectives Upon completion of this activity, participants should be better able to: Assess data on recent clinical trials incorporating antiangiogenic agents into the treatment of patients with ovarian cancer Implement effective toxicity prophylaxis and side-effect management for patients receiving antiangiogenic therapies Assess optimal dose and schedule when incorporating antiangiogenic agents into the treatment of patients with ovarian cancer Implement the use of antiangiogenic agents into the treatment paradigm in newly diagnosed, maintenance, or relapse settings
    5. 5. Activity Agenda Activity Overview (5 mins) Incorporating Antiangiogenic Therapies Into the Treatment Armamentarium (50 mins) – Case Study 1: Managing a newly diagnosed ovarian cancer patient – Case Study 2: Managing a patient in the maintenance setting – Case Study 3: Managing a patient with recurrent disease (platinum-resistant and platinum-sensitive) Questions & Answers (5 mins)
    6. 6. Case Study 1:Managing A Newly Diagnosed Ovarian Cancer Patient
    7. 7. Case Study 1: Front-Line Therapy A 52-yr-old small business owner presents with ascites and an adnexal pelvic mass on exam and CT scan – Omental cake and ascites seen on CT; CA-125 = 580  Exploratory laparotomy with radical tumor debulking including TAH/BSO, omentectomy, appendectomy, lymphadenectomy  Optimally cytoreduced stage IIIC papillary serous ovarian cancer  PS = 0; No significant comorbiditiesCT = computed tomography; CA-125 = cancer antigen-125;TAH = total abdominal hysterectomy; BSO = bilateral salpingo-oophorectomy;PS = performance status.
    8. 8. Question 1What treatment would you recommend forthis patient?1) IV carboplatin and IV paclitaxel2) IV platinum and taxane plus bevacizumab3) IV paclitaxel, IP cisplatin, and IP paclitaxel4) IP cisplatin, IV paclitaxel, and IP paclitaxel with bevacizumab
    9. 9. Ovarian Cancer: Chemotherapy  Standard front-line chemotherapy today is paclitaxel 175 mg/m2 plus carboplatin AUC 6– 7, q21days for 6 cycles  Result of several studies over last decade – GOG 111 and OV10 – paclitaxel/cisplatin vs. cyclophosphamide/cisplatin – GOG 158 and AGO OVAR-3 – carboplatin instead of cisplatinAUC = area under the curve; GOG = Gynecologic Oncology Group;AGO = Arbeitsgemeinschaft Gynaekologische Onkologie.NCCN, 2012; McGuire et al, 1996; Piccart et al, 2000; Ozols et al, 2003;du Bois et al, 2003.
    10. 10. GOG 172 Survival PFS OS 1.0 1.0 0.9 Rx Group PF Failed Total IV 50 160 210 0.9 0.8 IP 63 142 205 0.8 Proportion PFS (%) 0.7 IV: 18 mos 0.7 0.6 IP: 24 mos 0.6 HR: 0.80, p = .05 0.5 0.5 IV: 50 mos 0.4 IP: 66 mos 0.4 HR: 0.75, p = .03 0.3 0.3 0.2 0.2 Rx Group Alive Dead Total 0.1 IV 93 117 210 0.1 IP 117 88 205 0.0 0.0 0 12 24 36 48 60 0 12 24 36 48 60 Time (mos on study) Time (mos on study)PFS = progression-free survival; OS = overall survival.Armstrong et al, 2006.
    11. 11. JGOG: Dose-Dense Wkly Paclitaxel PFS OSJGOG = Japanese Gynecologic Oncology Group.Katsumata et al, 2009.
    12. 12. The VEGF/VEGF-Receptor Axis VEGF-A VEGF-C VEGF-D VEGF-A VEGF-E VEGF-B PlGF NRP-1 VEGF-C NRP-2 VEGF-D NRP-1 NRP-2 VEGFR-2 VEGFR-1 VEGFR-3 Angiogenesis Vasculogenesis LymphangiogenesisVEGF = vascular endothelial growth factor.Courtesy of Dr. Bradley Monk.
    13. 13. VEGF Ligand Agents in the Clinic Bevacizumab Aflibercept Presta et al, 1997 Hu et al, 2005
    14. 14. GOG 218: Schema Arm C AUC 6 P 175 mg/m 2 I Front-Line (CP) EOC, PP, or FT Placebo • Stage III optimal (macroscopic) C AUC 6 1:1:1 • Stage III suboptimal P 175 mg/m 2 II • Stage IV (CP + Bev) Bev 15 mg/kg Placebo N = 1,800 (planned) C AUC 6 Stratification variables – GOG PS P 175 mg/m 2 III – Stage/debulking status (CP + Bev) (Bev) Bev 15 mg/kg Cytotoxic Maintenance 15 mos (6 cycles) (16 cycles)C = carboplatin; P = paclitaxel; EOC = epithelial ovarian cancer;PP = primary peritoneal; FT = fallopian tube.Burger et al, 2011.
    15. 15. GOG 218: Investigator-Assessed PFS Arm I Arm II Arm III CP CP + Bev CP + Bev  Bev (n = 625) (n = 625) (n = 623) 1.0 423 418 360 Patients with event (n; %) (67.7) (66.9) (57.8) 0.9 Median PFS (mos) 10.3 11.2 14.1 Stratified analysis HR 0.908 0.717 Proportion PFS (%) (95% CI) (0.759–1.040) (0.625–0.824) 0.8 One-sided p value (log rank) .080a < .0001a 0.7 0.6 CP (Arm I) 0.5 + Bev (Arm II) + Bev  Bev maintenance (Arm III) 0.4 0 12 24 36 Time (Mos Since Randomization) 0.3a p = .0116Burger et al, 2010.
    16. 16. GOG 218: OS Analysis At Time of Final PFS Analysis (January 2010) 1.0 0.9 0.8 Arm I Arm II Arm III Proportion Alive (%) 0.7 CP CP + Bev CP + Bev  Bev (n = 625) (n = 625) (n = 623) 0.6 Patients with 156 150 138 0.5 events (n; %) (25.0) (24.0) (22.2) Median (mos) 39.3 38.7 39.7 0.4 HRa 1.036 0.915 0.3 (95% CI) (0.827–1.297) (0.727–1.152) 0.2 One-sided .361 .252 p value 0.1 0 12 24 36 48 0 Time (Mos Since Randomization) No. at risk 625/625/623 442/432/437 173/162/171 46/39/40Stratified analysis.aBurger et al, 2010.
    17. 17. ICON7: Study Design Primary end point: a C AUC 6 PFS 2 Front-Line P 175 mg/m A EOC, PP, or m Ar Secondary end points: FT • Stage I/IIA (grade 3) OS, RR, QOL, safety, • Stage IIB/C • Stage III cost-effectiveness, • Stage IV a Ar C AUC 6 m translational N = 1,520 (planned) B 2 P 175 mg/m No IRC present  Stratification variables Bev 7.5 mg/kg – Stage/surgery – Time since surgery 12 mos – GCIG groupVaMight vary based on GCIG group.GCIG = Gynecologic Cancer Intergroup; IRC = independent review committee;RR = response rate; QOL = quality of life.Perren et al, 2011.
    18. 18. ICON7 PFS: Updated 17.4 19.8 Control ResearchKristensen et al, 2011.
    19. 19. PFS: “High Risk” Subgroup (Ad Hoc Analysis) Control Research High Risk: Stage IIIC Suboptimal/Stage IV (n = 234) (n = 231) Proportion Alive Without Progression (%) 1.00 Events, n (%) 173 (74) 158 (68) Median (mos) 10.5 15.9 0.75 Log-rank test p < .001 HR (95% CI) 0.68 (0.55–0.85) Restricted mean 13.3 16.5 0.50 0.25 Control Research 10.5 15.9 0 Time 0 3 6 9 12 15 18 21 24 27 30 (mos) No. At Risk Control 234 205 98 36 14 2 Research 231 213 159 56 10 1Kristensen et al, 2011.
    20. 20. ICON7 OS by Risk GroupsKristensen et al, 2011.
    21. 21. GOG 252: Stage II/III Disease: Small Volume Residual  EOC  Optimal stage III Carboplatin AUC = 6 (IV)  No prior therapy I Paclitaxel 80 mg/m2 (Days 1, 8, 15, 3 hrs) Bevacizumab (C2+ C22) x 21 days Carboplatin AUC = 6 (IP) II Paclitaxel 80 mg/m2 (Days 1, 8, 15, 3 hrs) Bevacizumab (C2+ C22) x 21 days Cisplatin 75 mg/m2 (IP Day 2) Paclitaxel 135 mg/m2 (Day 1, 3 hrs) III Paclitaxel 60 mg/m2 (Day 8, IP) Bevacizumab (C2+ C22) x 21 days Open: 27 Jul 2009 Phase III Closed: November 2011 Accrual: 1,100 end point PFS primaryUS NIH, 2009a.
    22. 22. Nintedanib (BIBF 1120) – First Triple Angiokinase Inhibitor: Mode of Action By Targeting 3 Major Angiogenesis Signalling Pathways, Nintedanib Prevents Further Tumor Growth and Related Tumor Escape Mechanisms Ligands Stimulation Cell Type/Receptors VEGFs Endothelial Cells VEGFRs, FGFRs BIBF 1120 Pericytes FGFs PDGFRs Smooth Muscle Cells PDGFs FGFRs, PDGFRsFGF = fibroblast growth factor; PDGF = platelet-derived growth factor.Hilberg et al, 2008.
    23. 23. AGO-OVAR12: Nintedanib Consolidation Multicenter, Randomized, Double-Blind, Phase III Trial to Investigate the Efficacy and Safety of Nintedanib in Combination With Standard Treatment of Carboplatin and Paclitaxel Compared to Placebo Plus Carboplatin and Paclitaxel in Patients With Advanced Ovarian Cancer C C C C C C T T T T T T = Nintedanib 2 x 200 mg po qd 2 S U Nintedanib / Placebo R R C = Carboplatin AUC 5–6 Day 1 - No intake on days of chemotherapy - Dose: 200 mg po bid (combi + mono) G T = Paclitaxel 175 mg/m2 (3 hrs) Day 1 - Dose adaptation in case of undue toxicity E q21days / 6 courses - Max. duration of 120 wks in non-progressing patients R 1 Y C C C C C C T T T T T T = Placebo N = 1,300 ≤ 120 wksUS NIH, 2009b.
    24. 24. Nintedanib: Phase II PFS and OS Randomized Phase II Placebo-Controlled Trial of Maintenance Therapy Using the Oral Triple Angiokinase Inhibitor BIBF 1120 After Chemotherapy for Relapsed Ovarian Cancer PFS OS (A)OSLedermann et al, 2011.
    25. 25. TRINOVA-3 (GOG 3001): TC ± AMG 386 as First-Line Therapy of Stage III–IV Ovarian Cancer Concurrent Treatment Maintenance Phase ARM A: AMG 386 AMG 386 Monotherapy Paclitaxel Until Progression END OF Carboplatin (TC) or 18 mos TREATMENT Progressive disease or unacceptable toxicity or ARM B: AMG 386 Placebo withdrawal of Placebo Monotherapy consent or death Paclitaxel Until Progression Carboplatin or 18 mos Neoadjuvant Chemo + Interval Debulking Paclitaxel 175 mg/m2 IV q3wks Allowed in Both Arms Carboplatin AUC 5 or 6 IV q3wks After 3 Courses for Maximum of 6 cycles N = 2,000 + AMG 386 15 mg/kg IV qwk or AMG 386 Placebo IV qwkUS NIH, 2011.
    26. 26. Key Takeaways Bevacizumab with and following chemotherapy improves PFS Patients with large volume disease may benefit most Bevacizumab can be given with IP therapy but impact on outcome is unknown Bevacizumab can be given with dose-dense paclitaxel regimen based on completion of GOG 252 (and 262) without stopping for safety concerns
    27. 27. Case Study 2:Managing A Patient In The Maintenance Setting
    28. 28. Case Study 2  A 62-yr-old woman comes to you to ask your opinion about maintenance therapy after treatment for ovarian cancer. She had stage IV disease based on thoracic nodal involvement and was treated with 6 cycles of paclitaxel and carboplatin with excellent tolerance. At completion of chemotherapy CA-125 had normalized, CT shows persistent enlarged thoracic nodes up to 1.5 cm but PET shows no uptake in these nodes.  She wants to know if you recommend any further treatment for her at this time.PET = positron emission tomography.
    29. 29. Clinical Decision Question What do you recommend for her at this time? 1) No further therapy 2) Three more cycles of paclitaxel and carboplatin 3) Paclitaxel alone q4wks x 12 4) Bevacizumab 5) Another VEGF targeted agent
    30. 30. Consolidation Therapy: GOG 178 R Paclitaxel (3 hrs) 175 mg/m2 q28days x 3 A EOC, FT, PP N Stage III/IV Prior chemo 5–6 cycles D Register 3–8 wks O CCR Neuropathy ≤ grade II M I Paclitaxel (3 hrs) Z 175 mg/m2 q28days x 12 N = 450 anticipated E Accrual closed 9/6/01 N = 277; 222 with FU End points 54 progression events • PFS • OSFU = follow-up.Markman et al, 2003.
    31. 31. GOG 178: Consolidation Unadjusted Log Rank p (1-sided) = .0035 Adjusted Log Rank p (1-sided) = .0023Markman et al, 2003.
    32. 32. GCIG Intergroup Protocol: GINECO Paclitaxel (3 hrs) R 175 mg/m2 q21days x 6 A Carboplatin French/German Study AUC = 5.0 q21days x 6 N Group D EOC (Stage IIB–IV) O All Strata M I Paclitaxel (3 hrs) 175 mg/m2 q21days x 6 N = 1,308 Z Carboplatin E AUC = 5.0 q21days x 6 Topotecan 1.25 mg/m2 q21days x 4Pfisterer et al, 1999.
    33. 33. Maintenance Therapy: GOG 212 R Observation A EOC, FT, PP N Stage III/IV D Prior chemo 5–8 cycles Paclitaxel (3 hrs) Register 3–8 wks O 135 mg/m2 q28days x 12 CCR M Neuropathy ≤ grade II I Z PG-Ptx (paclitaxel poliglumex) E 135 mg/m2 q28days x 12 End points N = 1,400 anticipated • PFS Phase III; Superiority Design • OSUS NIH, 2005.
    34. 34. AGO-OVAR16: Pazopanib Consolidation  EOC, FT, or PP  Primary platinum-based therapy (IV, IP, neoadjuvant permitted)  CR, PR, or SD after initial therapy  Primary end point: PFS  Secondary end point: OS (with interim analysis) I Pazopanib 800 mg po qd (2 yrs) Primary Rx: Platinum and Taxane II Placebo po qd (2 yrs)  Estimated Enrollment: 900  Study Start: May 2009  Estimated Completion: March 2013CR = complete response; PR = partial response; SD = stable disease.US NIH, 2009c.
    35. 35. Sorafenib: Study 12007 (Phase IIb Maintenance)  Patients stratified according to the degree of residual disease following initial diagnosis and surgical debulkment  Primary objective: PFS  Secondary objectives: Abnormal CA-125, OS  1:1 randomization Sorafenib Patients with FIGO stage 400 mg po bid, III/IV ovarian epithelial continuous dosing cancer or PPC who have achieved clinical CR after R standard platinum/taxane therapy and cytoreductive surgery Placebo 400 mg po bid,  Estimated Enrollment: 247 continuous dosing  Study Start: November 2008  Primary Completion: July 2011  Estimated Study Completion July 2012**This trial is ongoing, but not recruiting participants - status updated April 2012US NIH, 2008.
    36. 36. Key Takeaways Given the high rate of disease recurrence in ovarian cancer, there is impetus to consider consolidation or maintenance therapy Continuingpaclitaxel for 1 year after initial chemotherapy past 6 cycles improves PFS Bevacizumab with and following chemotherapy improves PFS and OS in some situations There is no data on using only bevacizumab for maintenance therapy, after chemotherapy
    37. 37. Case Study 3: Managing A Patient In TheResistant/Refractory Setting (Platinum- Resistant and Platinum-Sensitive)
    38. 38. Case Study 3  A 60-yr-old woman with a PMH of HTN presents with extensive pelvic and peritoneal implants, ascites, and large volume disease at the root of the mesentery. A diagnosis of ovarian cancer was made by paracentesis showing papillary serous carcinoma. She was deemed unresectable by a gynecologic oncologist.  Received neoadjuvant paclitaxel and carboplatin x 3 without response  She then received topotecan x 3 without response  She now has persistent ascites requiring paracentesis q5–8days for palliation  CA-125 = 6,916  PS = 1PMH = past medical history; HTN = hypertension.
    39. 39. Paclitaxel, Carboplatin, and TopotecanRefractory, Platinum-Resistant Ovarian Cancer CA-125 = 6,516, exam shows marked ascites The patient requires frequent paracenteses wkly PS = 1
    40. 40. Clinical Decision Question Based on data presented at ASCO 2012 what treatment would you recommend for this patient? 1) Pegylated liposomal doxorubicin (PLD, doxil, lipodox) 2) Wkly paclitaxel 3) 1 or 2 with bevacizumab 4) Bevacizumab 5) Gemcitabine, carboplatin 6) Gemcitabine, carboplatin, bevacizumab
    41. 41. Recurrent Ovarian Carcinoma: Pegylated Liposomal Doxorubicin Platinum-Refractory Platinum-Sensitive Author/Year Dose (< 6 mos) Response (> 6 mos) Response Muggia et al, 1997* 50 mg/m2 9/35 26% -- -- q3wks Gordon et al, 2000 40–50 mg/m2 15/82 18% -- -- q4wks Gordon et al, 2001 50 mg/m2 16/130 12% 31/109 28% q4wks Ferrandina et al, 40 mg/m2 11/70 16% -- -- 2008* q4wks*Enrolled patients with platinum-refractory and platinum-sensitive disease.
    42. 42. Platinum-Resistant Ovarian Cancer Cytotoxic Therapy STUDY* AGENT N RR (%) 126-J Docetaxel 58 22 126-N Wkly Paclitaxel 48 21 126-M Ixabepilone 50 14 126-Q Pemetrexed 48 21 126-R nab-Paclitaxel 47 23 *1 prior line. Thresholds: 10%, 25% Randomized 145 mg/m2 q14days 33 21 Phase II, 145 mg/m2 q21days 31 23 NKTR-102* *Median of 3 prior lines.Vergote et al, 2010.
    43. 43. Bevacizumab Trials: Relapsed EOC GOG 170-D* NCI 5789** Genentech Study*** (N = 62) (N = 70) (N = 44) BV 10 mg/kg q2wks Single-agent Study Single-agent BV + low-dose oral BV 15 mg/kg Treatment 15 mg/kg q3wks cyclophos. q3wks Prior 1 – 21/62 (34%) Median = 2 2 – 23/44 (52%) Regimens 2 – 41/62 (62%) Range 1–3 3 – 21/44 (48%) Platinum- 42% 40% 100% Resistant Efficacy ORR 21% 24% 16% 6-mos PFS 39% 56% 27% GIP or Fistula 0 4 (6%) 5 (11%)*Burger et al, 2007.**Garcia et al, 2008.***Cannistra et al, 2007.
    44. 44. GI Perforations With Bevacizumab in Ovarian Cancer Study Gl Perforations Burger (GOG 170D) 0/62 (0) Garcia (ASCO, 2005) 2/29 (6.9) Cannistra (ASCO, 2006) 5/44 (11.4) Wright (ASCO, 2006) 4/62 (6.5) Friberg (ASCO, 2006) 2/13 (15.4) Monk (Gyn Oncol, 2006) 1/32 (3.1) Wright (Cancer, 2006) 2/23 (8.7) Bidus (Gyn Oncol, 2006) 0/3 (0) Penson (ASCO, 2006) 0/30 Total 16/298 (5.4%)  Note: A recent history of bowel obstruction symptoms may be associated with GI perforationGI = gastrointestinal.Han et al, 2007.
    45. 45. Ovarian Cancer: GOG Trials of Targeted Therapy Study* Agent Target N RR (%) PFS at 6 Mos (%) 170-C Gefitinib EGFR 27 3.7 14.8 170-D Bevacizumab VEGFA 62 21 40.3 170-E Imatinib bcr-abl/c-kit/PDGFR 56 1.8 16.1 170-F Sorafenib VEGFR/PDGRR/Raf 59 3.4 23.7 170-G Lapatinib EGRR/HER2neu 26 0 7.7 170-H Vorinostat HDAC 27 3.7 7.4 170-I Temsirolimus¥ mTor 54 9.3 24.1 170-J Enzastaurin PKC-beta 27 7.4 11.1 170-K Mifepristone PR 22 4.5 13.6 170-M Dasatinib Scr/bcr-abl/c-kit 34 0 20.6 170-N A6 uPAR 31 0 6.5 170-P AMG-102 HGF (c-met) Suspended after first stage 170-Q EGEN-001 IL-12 First stage accrual in progress  Thresholds: RR – 10%, 25%; PFS – 15%, 35%*1–2 priors; ¥1–3 priors.
    46. 46. Ovarian Cancer: VEGF Targeted Therapy Reference Agent Target N RR (%)Tew et al, 2007 Aflibercept 2 mg/kg 3.8 (VEGF-TRAP) VEGF 215 4 mg/kg 7.3Biagi et al, 2011 Sunitinib VEGF/PDGF 30 3.3(NCIC-CTEP)Matulonis Cediranib VEGF/c-kit 46 17et al, 2009(DFCI-CTEP)Buckanovich Cabozantinib VEGFR2/c-met 70 24et al, 2011Friedlander Pazopanib VEGFR/PDGFR/ 36 18et al, 2010 c-kit
    47. 47. Aflibercept for Ascites in Advanced Ovarian Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase II Study Time to Repeat ParacentesisKaplan-Meier curve Waterfall plot Median 55 vs. 23 days Fatal GI Perforation: Aflibercept 3/30 Placebo 1/25Gotlieb et al, 2011.
    48. 48. Randomized Phase II Trial of Wkly Paclitaxel +/- AMG 386 in Recurrent Ovarian Cancer Wkly Paclitaxel EOC, FT, R AMG 386 10 mg/kg IV wkly or PP A N = 161 (n = 53) Wkly Paclitaxel N 1–3 Prior D AMG 386 3 mg/kg IV wkly Lines O (n = 53) AMG 386 Wkly Paclitaxel PD MI 10 mg/kg IV Placebo Paclitaxel 80 mg/m2 IV wkly, 3 wks on/1 wk off Z wkly (n = 55) E 10 mg/kg 3 mg/kg Placebo *Median PFS (mos) 7.2 5.7 4.6 *HR (Arm A+B vs. placebo) = 0.76 (80% CI, 0.59, 0.98), p = .17 Trend Test, p = .037 ORR (CR + PR; %) 37 19 27PD = progressive disease.Karlan et al, 2012.
    49. 49. TRINOVA-1: Randomized Phase III on AMG 386 in Combination With Paclitaxel in Advanced Recurrent Ovarian Cancer Screening FU Treatment Phase Enrollment Phase AMG 386 15 mg/kg* IV qwk + † Paclitaxel 80 mg/m2 IV qwk (3 on/1 off) Placebo* IV qwk + UF YT EF AS Paclitaxel 80 mg/m2 IV qwk UF MRET GN OL N O T AZ MODNAR (3 on/1 off) T NE M AE RT F O DNE - N = 900 I I T* Blinded.† Radiographic PD, unacceptable toxicity, withdrawal of consent, or death.US NIH, 2010.
    50. 50. AURELIA Trial Design Platinum-Resistant OCa Chemotherapy Treat to Optional BEV • ≤ 2 prior anticancer PD/toxicity c monotherapyc regimens • No history of bowel R obstruction/abdominal Investigator’s fistula, or clinical/ 1:1 BEV 15 mg/kg q3wkb b Treat to choice radiological evidence of + chemotherapy PD/toxicity (without BEV) rectosigmoid involvement Stratification Factors Chemotherapy Options • Chemotherapy selected (investigator’s choice) • Prior antiangiogenic therapy • Paclitaxel 80 mg/m2 Days 1, 8, 15, & 22 q4wks • Treatment-free interval • Topotecan 4 mg/m2 Days 1, 8, & 15 q4wks (< 3 vs. 3–6 months from previous (or 1.25 mg/m2, Days 1–5 q3wks) platinum to subsequent PD) • PLD 40 mg/m2 Day 1 q4wksa EOC, FT, or PP.b Or 10 mg/kg q2wks.c 15 mg/kg q3wks, permitted on clear evidence of progression.Pujade-Lauraine et al, 2012.
    51. 51. Progression-Free Survival CT BEV + CT (n = 182) (n = 179) 1.0 Events, n (%) 166 (91%) 135 (75%) Estimated Probability (%) Median PFS (mos) 3.4 6.7 0.8 (95% CI) (2.2‒3.7) (5.7‒7.9) HR (unadjusted) 0.48 (95% CI) (0.38‒0.60) 0.6 Log-Rank p Value < .001 (2-sided, unadjusted) 0.4 0.2 3.4 6.7 0 0 6 12 18 24 30 Time (mos) No. at risk: CT 182 93 37 20 8 1 1 0 0 BEV + CT 179 140 88 49 18 4 1 1 0Median duration FU: 13.9 mos (CT arm) vs. 13.0 mos (BEV + CT arm)Pujade-Lauraine et al, 2012.
    52. 52. Summary of Best ORR 50 45 CT BEV + CT 40 35 30.9 31.8 Patients (%) 30 p < .001a 27.3 p < .001a 25 p = .001a 20 15 12.6 11.8 11.6 10 5 0 Responders (RECIST and/ RECIST responders CA-125 responders or CA-125) (n=350) (n=287) (n=297)2-sided chi-square test with Schouten correction.aPujade-Lauraine et al, 2012.
    53. 53. Adverse Events of Special Interest Grade ≥ 3 Adverse Events of Special CT BEV + CT Interest, n (%) (n = 181) (n = 179) HTN 2 (1.1) 13 (7.3) Grade ≥ 2 12 (6.6) 36 (20.1) Proteinuria 0 3 (1.7) Grade ≥ 2 1 (0.6) 19 (10.6) GI perforation 0 3 (1.7) Grade ≥ 2 0 4 (2.2) Fistula/Abscess 0 2 (1.1) Grade ≥ 2 0 4 (2.2) Bleeding 2 (1.1) 2 (1.1) Thromboembolic Event 8 (4.4) 9 (5.0) Arterial 0 4 (2.2) Venous 8 (4.4) 5 (2.8) Wound-Healing Complication 0 0 RPLS 0 1 (0.6) CHF 1 (0.6) 1 (0.6) Cardiac Disorders (excluding CHF) 0 0RPLS = reversible posterior leukoencephalopathy syndrome;CHF = congestive heart failure.Pujade-Lauraine et al, 2012.
    54. 54. OCEANS: Study Schema CG + PL C AUC 4 Platinum-Sensitive Recurrent OCa G 1,000 mg/m2, Day 1 & 8 • Measurable disease • ECOG 0/1 PL q3wks until progression • No prior chemo for recurrent ovarian cancer • No prior BEV N = 484 C AUC 4 G 1,000 mg/m2, Day 1 & 8 CG + BEV BEV 15 mg/kg q3wks until progression Stratification Variables • Platinum-free interval CG for 6 (up to 10) cycles (6–12 vs. > 12 mos) • Cytoreductive surgery for recurrent disease (yes vs. no)ECOG = Eastern Cooperative Oncology Group.a EOC, FT, or PP.
    55. 55. OCEANS: PFS, ORR, and DOR 30 GC + BEV (n = 242) (n = 242) GC + PL 24 GC + PL GC + BV (n = 242) (n = 242) PFS by INV Time (mos) 18 Median PFS (mos) 8.4 12.4 INV-Assessed Stratified Analysis, HR 0.484 (0.388–0.605) (95% CI) 12 Log-Rank p Value < .0001 PFS by IRC 8.6 12.3 Median PFS (mos) 6 Stratified analysis, HR 0.451 (0.351–0.580) (95% CI) Log-Rank p Value < .0001 0 1.0 0.6 0.0 0.8 0.4 0.2Data cutoff date: September 17, 2010 ORR and DOR by INV Proportion PFS (%) ORR (%) 57 79 Median DOR (mos) 7.4 10.4 HR (95% CI) 0.53 (0.41–0.70)DOR = duration of response; INV = investigator-assessed;IRC = independent review committee; ORR = objective response rate.Aghajanian et al, 2012.
    56. 56. OCEANS: OS Analyses 1.0 First Interim Analysisa Second Interim Analysisb 1.0 Proportion Surviving (%) Proportion Surviving (%) 0.8 0.8 0.6 0.6 0.4 0.4 0.2 GC + PL GC + BEV 0.2 (n = 242) (n = 242) 0.0 0.0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 48 54 Time (mos) Time (mos) GC + PL GC + BV GC + PL GC + BV (n = 242) (n = 242) (n = 242) (n = 242) No. Events (%) 78 (32.2) 63 (26.0) No. Events (%) 112 (46.3) 123 (50.8) Median OS (mos) 29.9 35.5 Median OS (mos) 35.2 33.3 HR (95% CI) 0.751 (0.537–1.052) HR (95% CI) 1.027 (0.792–1.331) Log-Rank p Value .0944 Log-Rank p Value .8422a Data cutoff date: September 17, 2010. Median FU 24 mos in both arms, with 141deaths (29% of patients).b Data cutoff date: August 29, 2011. Median FU 33.7 mos in PL arm and 35.4 mos inBV arm, with 235 deaths (49% of patients)..Aghajanian et al, 2012.
    57. 57. OCEANS: Objective Response Difference: 21.1% % p < .0001 100 78.5 DOR CG + PL CG + BV 80 (n = 139) (n = 190) 60 57.4 PR = 61 Median (mos) 7.4 10.4 PR = 48 HR (95% CI) 0.534 40 (0.408–0.698) 20 p < .0001a CR = 9 CR = 17 0 CG + PL CG + BV (n = 242) (n = 242)Compared for descriptive purposes only.aAghajanian et al, 2012.
    58. 58. Single-Agent Bevacizumab inRefractory Ovarian Cancer: GOG 170D Pre-Treatment Post-4 cycles
    59. 59. Key Takeaways There are multiple cytotoxic agents with modest activity in platinum-refractory and platinum-resistant ovarian cancer Antiangiogenic agents have significant single-agent activity in recurrent ovarian cancer Bevacizumab added to chemotherapy improves response and PFS in recurrent ovarian cancer (platinum- resistant and platinum-sensitive) A recent history of bowel obstruction symptoms may be associated with an increased risk of perforation in patients treated with bevacizumab

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