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Ovarian Cancer: Standards of Care and New Opportunities

Ovarian Cancer: Standards of Care and New Opportunities. Robert L. Coleman, M.D. Professor & Vice Chair, Clinical Research Department of Gynecologic Oncology M.D. Anderson Cancer Center. Ovarian Cancer: Liner Notes. Globally 7 th most incident and lethal cancer

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Ovarian Cancer: Standards of Care and New Opportunities

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  1. Ovarian Cancer: Standards of Care and New Opportunities Robert L. Coleman, M.D. Professor & Vice Chair, Clinical Research Department of Gynecologic Oncology M.D. Anderson Cancer Center

  2. Ovarian Cancer: Liner Notes Globally 7th most incident and lethal cancer New cases: 225,000 annually Deaths: 140,000 annually Burden of disease is greater in developed countries The incidence increases with age Almost 75% of cases present with advanced stage III / IV disease Risk of relapse of advanced stage disease is as high as 70% CA Cancer, 2013

  3. Ovarian Cancer: Natural History Progression Death Diagnosis Evaluation ? SLL Secondary Surgery Chemo #2 Chemotherapy #1 Chemo #3+ Symptoms Maintenance Supportive Care Staging Progression-Free Survival (12-28 mos) Post Progression Survival (12-38 mos) Duration

  4. Surgical Management of Primary Ovarian Cancer • Theoretical: • Reduced the volume of hypoxic, poorly perfused cells • Host immunocompetence is improved with lower tumor burden • Recruitment of residual cells into G1 potentiating the effects of cytotoxic therapy • Removal of chemoresistant clones • Practical: • “Biology vs Brawn”

  5. The Impact of Residual Tumor: WhatIs Optimal Debulking? % Progression-free Survival HR (95%CI) 1-10 mm vs. 0 mm: 2.52 (2.26;2.81)>10 mm vs. 1-10 mm: 1.36 (1.24;1.50) log-rank: p < 0.0001 0 mm 1-10 mm > 10 mm Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) N = 3126 pts % Overall Survival HR (95%CI) 1-10 mm vs. 0 mm: 2.70 (2.37; 3.07)>10 mm vs. 1-10 mm: 1.34 (1.21; 1.49) log-rank: p < 0.0001 0 mm 1-10 mm > 10 mm DuBois, Cancer (2009)115:1234

  6. Primary Approach: What’s Best? PDS: 12 mos NACT: 12 mos HR: 0.99 (0.87-1.13) PFS PDS: 29 months IDS: 30 months HR: 0.98 (0.85, 1.14) OS N Engl J Med (2010) 363:943

  7. 1/20/11 Neoadjuvant Chemotherapy in Ovarian Cancer 9/21/10

  8. Primary Approach: What’s Best? PDS: 12 mos NACT: 12 mos HR: 0.99 (0.87-1.13) PFS PDS: 29 months IDS: 30 months HR: 0.98 (0.85, 1.14) OS N Engl J Med (2010) 363:943

  9. OV.21 CHORUSChemotherapy Or Upfront Surgery Neoadjuvant Chemotherapy X 3-4 courses Randomized IV-Arm IP-Arm Pac/Carbo + Pac/Carbo (IP) + • Pac (d8) Pac (IP, d8) ICON-8 Pre-randomization Strata for NACTor PDS Randomized Standard Pac/Carbo Exp A DD-Pac/Carbo Exp B DD - Pac/DD-Carbo RCOG

  10. Principle Approach: Iº Therapy Chemotherapy - - - Paclitaxel/Cisplatin Cytoxan/Cisplatin OS PFS McGuire New Engl J Med (1996) 334:1 Ozols, J ClinOncol (2003) 21:3194 Armstrong New Engl J Med (2006) 354:34

  11. International Phase III Experience No Significant Effect More ≠ Better Different ≠ Better

  12. Establishing a Front-Line Adjuvant Standard Moving The Bar: Primary Therapy • Dose-dense therapy • IP Chemotherapy • Biologics: Anti-angiogenesis, PARPi, angiopoeitin inhibitors

  13. Dose Dense: Weekly Therapy Ovarian Epithelial, PP, FT FIGO Stage II-IV Stratification; Residual disease: <1cm, > 1cm FIGO Stage： II vs. III vs. IV Histology： clear cell/mucinous vs serous/others R Paclitaxel 180mg/m2 Carboplatin AUC 6.0 q 21 days (6-9 cycles) Dose density: 60 mg/m2/wk Paclitaxel 80mg/m2, days 1, 8, 15 Carboplatin AUC 6.0, day 1 q 21 days (6-9 cycles) Dose density: 80 mg/m2/wk (+33%) Katsumata, Lancet 2009

  14. JGOG 3016: Long-Term Follow-Up Katsumata N, ASCO Abstract 5003, 2012

  15. iPocc JGOG Trial: Schema Epithelial Ovarian Cancer Stages II-IV Including Bulky Tumor RANDOMIZATION Paclitaxel 80 mg/m2 IV Day 1,8,15 Carboplatin AUC 6 IP Q21, 6-8 Cycles Paclitaxel 80 mg/m2 IV Day 1,8,15 Carboplatin AUC 6 IV Q21, 6-8 Cycles Dose dense−TCiv Dose dense−TCip Primary Endpoint: PFS Secondary Endpoint: OS, Toxicity, QOL Accrual Goal: 746 pts / 511 events

  16. GOG-0218 study schema Establishing a Front-Line Adjuvant Standard Arm Carboplatin AUC 6 I Paclitaxel 175 mg/m2 • Previously untreated epithelial ovarian, primary peritoneal, or fallopian tube cancer • Stage III optimal (macroscopic) • Stage III • suboptimal • Stage IV • n=1873 (CP + PLA → PLA) Placebo Carboplatin AUC 6 1:1:1 II RANDOM I Z E Paclitaxel 175 mg/m2 (CP + BEV → PLA) Bevacizumab 15 mg/kg Placebo Carboplatin AUC 6 III • Stratification variables: • GOG performance status • Stage/debulking status Paclitaxel 175 mg/m2 (CP + BEV  BEV) Bevacizumab 15 mg/kg Cytotoxic (6 cycles) Maintenance (16 cycles) 15 months Burger et al. N Engl J Med 2011;365:2473-83

  17. Establishing a Front-Line Adjuvant Standard Schema Carboplatin AUC 5/6 • Stratification variables: • Stage & extent of debulking: I–III debulked ≤1cm vs stage I–III debulked >1 cm vs stage IV and inoperable stage III • Timing of intended treatment start≤4 vs >4 weeks after surgery • GCIG group Paclitaxel 175 mg/m2 1:1 R Carboplatin AUC 5/6 n=1528* Paclitaxel 175 mg/m2 Bevacizumab 7.5 mg/kg q3w 18 cycles *Dec 2006 to Feb 2009 Academic-led, industry-supported trial to investigate use of bevacizumab and to support licensing Perrin, N Engl J Med 2011;365:2484-96

  18. Anti-VEGF Targeting: Frontline PFS GOG 218 ICON7 HR: 0.87 17.4vs 19.8 mos Median D: 2.4 mos HR: 0.73 10.4 vs 13.9 mos Median D: 3.5 mos Burger, NEJM (2011) 365:2473 Perren, NEJM (2011) 365:2484

  19. Anti-VEGF Targeting: Frontline OverallSurvival GOG 218 ICON7 Burger, NEJM (2011) 365:2473 Perren, NEJM (2011) 365:2484

  20. 1.0 30 0.9 25 1.0 0.8 0.9 20 0.8 0.7 0.7 15 0.6 0.6 10 0.5 0.5 20 0.4 5 0.4 18 0.3 16 0.3 0 14 0.2 0 6 12 18 24 30 36 12 0.1 0.2 10 -5 0 8 0 6 12 18 24 30 36 0.1 6 -10 4 0.0 2 0 6 12 18 24 30 36 -15 0 0 6 12 18 24 30 36 GOG-0218 and ICON7: Restricted Means Estimate – Benefit During Exposure Only? 13.3 vs 16.5 3 months’ difference 14 vs 17 3 months’ difference Research Arm Research Arm GOG-0218 ICON7 (III suboptimal and IV subgroup) Research Arm Research Arm Time (months) Time (months)

  21. GOG Ovarian Strategy: 262 Bevacizumab q 3 wk (If chosen) Maintenance to Progression IV Paclitaxel 80 mg/m2 weekly IV Carboplatin AUC 6 q 3 wk IV Bevacizumab 15 mg/kg (optional) 262 Suboptimal (> 1 cm Residual) Neoadjuvant allowed CT Perfusion Scan IV Paclitaxel 175 mg/m2 IV Carboplatin AUC 6 IV Bevacizumab 15 mg/kg (optional) N: 702/625 (OPEN only for ACRIN Component Primary endpoint: PFS

  22. Phase III GOG 252 Schema Cycles 1-6* Cycles 7-22* IV Paclitaxel 80 mg/m2days 1, 8, 15 IV Carboplatin AUC 6 day 1 Bevacizumab 15 mg/kg q3w Bevacizumab 15 mg/kg q3w† IV Paclitaxel 80 mg/m2 days 1, 8, 15 IP Carboplatin AUC 6 day 1 Bevacizumab 15 mg/kg q3w RANDOMIZATION N = 1250 Bevacizumab 15 mg/kg q3w† IV Paclitaxel 135 mg/m2 day 1 IP Cisplatin 75 mg/m2 day 2 IP Paclitaxel 60 mg/m2 day 8 Bevacizumab 15 mg/kg q3w Bevacizumab 15 mg/kg q3w† N: 1554 (CLOSED) Primary endpoint: PFS *Each cycle is 3 weeks; †Begin cycle 2. Walker JL. Am Soc Clin Oncol Ed Book. 2009:308-312.

  23. Other Pursuits in Front-Line Therapy • VEGF TKI’s • Nintedanib (BIBF1120) • PARPi • Veliparib (OVM1102) • Angiopoeitin inhibitors • TRINOVA-3: Trebananib (AMG-386)

  24. Bottom Line… • Determine good candidates for surgery • Potential for better selection tools, e.g. Laparoscopy • Optimal radical resection • Goal: R0 • Adjuvant therapy • IP and dose dense are my favorite options • Good place for clinical trial

  25. Maintenance: The Stakes are High! Progression Death Diagnosis Evaluation ? SLL Secondary Surgery Chemo #2 Symptoms Chemotherapy #1 Chemo #3+ Maintenance Supportive Care Staging • What we know… • Rate of response is high (CR + PR) >75% • Second assessment operations find disease > 40% of CR’s • Clinical CR’s have >50% recurrence risk at 2 years • Pathological CR’s have >40% risk at 2 years • Option applies to CR’s and documented PR’s

  26. Maintenance Therapy Scorecard

  27. Maintenance Trials: Ongoing GOG-212 • Bevacizumab (GOG 252, 262) • Pazopanib (OVAR-16) • Nintedanib (BIBF 1120) • Trebananib (TRINOVA-3) • CVAC: Muc-1 Dendritic Cell vaccine • PARPi, • pvKLH + OPT-821 [GOG-255] (II° maintenance) • FAKi (GSK2256098) – GOG concept approved 8/11 EOC, PP, FT cancer Paclitaxel Carboplatin Paclitaxel X 12 mos CTI-2103 X 12 mos No Treatment N = 1100 patients Survival primary endpoints QOL endpoints

  28. Bottom Line… • Experimental but evidence of PFS impact has been demonstrated • I always have the conversation (longest of any counseling session) but it is only infrequently taken by the patient

  29. Recurrent Therapy: Ovarian Cancer Progression Death Diagnosis Evaluation ? SLL Secondary Surgery Chemo #2 Symptoms Chemotherapy #1 Chemo #3+ Maintenance Supportive Care Staging • What we know (Recurrence): • Nearly all patients will succumb to progression • Options are plentiful • Nothing a “homerun”

  30. Treatment Free Interval: Traditional Model Time from last platinum exposure (TFI) Treatment Completion 6 mos Platinum Resistant/Refractory Platinum Sensitive Platinum Retreatment Non-Platinum Treatment

  31. Treatment-Free Interval and Survival 1000900800700600500400300200100 100908070605040302010 Days Percentage Lauraine, Proc ASCO #829, 2002

  32. Summary of Phase III Single Agent Trials:Resistant Ovarian Cancer

  33. Summary of Phase III Combination Trials: PR

  34. AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC) R A N D O M I Z E • Recurrent EOC • platinum resistant • ≤ 2 prior therapies • no clinical or radiologic evidence of bowel involvement Non-Platinum Chemotherapy Treat to progression Non-Platinum Chemotherapy + Bevacizumab 15 mg/kg Treat to progression N= 361 Stratified chemotherapy PFI (< 3 vs 3-6 mo) prior anti-angiogenesis • Chemotherapy Options • Paclitaxel 80 mg/m2 d 1,8,15, 22 q28 • Topotecan4 mg/m2 d 1, 8 ,15 q28or • Topotecan 1.25 mg/m2 d 1-5 q21 • PLD 40 mg/m2 d 1 q28 Pujade-LauraineE, et al. J ClinOncol. 2012; Suppl. Abstract LBA5002.

  35. AURELIA: Patient Characteristics Pujade-LauraineE, et al. J ClinOncol. 2012; Suppl. Abstract LBA5002.

  36. AURELIA Progression-Free Survival C T BEV + C T 1.0 (n = 182) (n = 179) Events, n (%) 166 (91%) 135 (75%) 0.8 Median PFS, months 3.4 6.7 (95% CI) (2.2-3.7) (5.7-7.9) HR (unadjusted) 0.48 0.6 (95% CI) (0.38-0.60) Estimated Probability < 0.001 Log-rnak -value P (2-sided, unadjusted) 0.4 0.2 3.4 6.7 0.0 0 6 12 18 24 30 T ime (months) Number at risk 182 93 37 20 8 1 1 0 0 C T 179 140 88 49 18 4 1 BEV + CT 1 Pujade-LauraineE, et al. J ClinOncol. 2012; Suppl. Abstract LBA5002.

  37. Subgroup analysis of PFS 0.2 0.3 0.5 1 2 3 4 5 aUnadjusted.bMissing n=8

  38. aTwo-sided chi-square test with Schouten correction Summary of best overall response rates p<0.001a p<0.001a p=0.001a Patients (%)

  39. AURELIA: Conclusions • No alarming safety signals • PLD – HFS, paclitaxel – neuropathy, all: myelosuppression) • Toxicity may relate to exposure (longer on experimental arms) • Bevacizumab augments outcomes (response, PFS) of standard chemotherapy • Paclitaxel may benefit to greater degree • Await OS data • CAVEATS • Not placebo-controlled • Pretreatment characteristics: 80% measurable, 30% ascites, 8% prior AA therapy • Each arm is equivalent to RP2

  40. Bottom Line… • For platinum-resistant disease, I like: • Weekly paclitaxel ± bevacizumab • PLD • Gemcitabine + cisplatin (q 2 wk infusion) • Try HARD to get onto clinical trial • Lots of options with interesting new agents

  41. NCCN Guidelines Version 2013 Therapy for Relapse > 6 months NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer v.1.2013. Available at: http://www.nccn.org

  42. DESKTOP-I: Surgical Endpoint of Surgery at Relapse 1.0 0.9 0.8 no residuals median OS 45.2 mo 0.7 0.6 Survival probability 0.5 0.4 residuals > 10 mm 0.3 0.2 residuals 1-10 mm 0.1 0 0 12 36 48 24 Months from Randomization

  43. Secondary Cytoreduction: Multivariate Analysis Who Benefits? Tay, ObstetGynecol 99:1008, 2002

  44. Secondary Cytoreductive Surgery Goal of surgery: No gross residual disease DFI = disease-free interval; mos = months; SC = secondary cytoreduction. Chi DS, et al. Cancer. 2006;106(9):1933-1939.

  45. AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) • EOC, FT, PP • PFI > 6 • No priorrecurrencechemotherapy • Completeresectionseemsfeasible and positiveAGO score: • PS ECOG 0 • No ascites > 500 ml • Prior completedebulkingorinitial FIGO I/II Secondary Cytoreduction R Chemo No surgery • Regimenspost-randomization • Carboplatin/paclitaxel • Carboplatin/gemcitabine • Carboplatin/PLD N = 150/408 planned

  46. GOG-213 Recurrent Ovarian, PPT and FT Cancer TFI ≥ 6 mos Surgical Candidate? Yes No Randomize Randomize Surgery No Surgery Carboplatin Paclitaxel or Gemcitabine Carboplatin Pac or Gem Bevacizumab To Chemotherapy Randomization Bevacizumab PI: Coleman

  47. SOC I Shanghai Gynecologic Oncology Group A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer Platinum-sensitive, first relapserecurrent cancer of theovaries, fallopian tubes, orperitoneum PFI > 6 mosNo prior chemotherapyfor this 1st relapse Complete secondary cytoreduction predicting score (iMODEL) • FIGO stage • Residual disease after primary surgery • PFI • PS ECOG • CA125 • Ascites at recurrence N=420 Cytoreductivesurgery RAN D OMIZ E Platinum-basedchemotherapy* No surgery Primary outcome: OS Secondary outcome: PFS, QoL, Complications Available at: http://www.clinicaltrials.gov/ct2/show/NCT01611766 Accessed March 04, 2013.

  48. Outcomes in Recurrent Ovarian Cancer: PS • Take home messages: • PFS appears to be impacted from combination therapy • No OS effect to date • Post progression survival is dramatically increasing *Data still maturing.

  49. Bottom Line… • For Platinum-sensitive disease, I like: • Secondary cytoreduction if small volume and remote recurrence • However, I try HARDto get on clinical trial as this is a very biased situation • Platinum-based doublets • PLD, Gemcitabine and Paclitaxel with carboplatin • If I give gemcitabine doublet I give with bevacizumab • Lots of new trials coming online here as well

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