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Angiogenesis Inhibitors and Novel Targeted Agents in Ovarian Cancer

Angiogenesis Inhibitors and Novel Targeted Agents in Ovarian Cancer. Robert L. Coleman, MD Professor & Deputy Chair Vice Chair, Clinical Research Department Gynecologic Oncology & Reproductive Medicine M.D. Anderson Cancer Center. Disclosures. Research Funding:

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Angiogenesis Inhibitors and Novel Targeted Agents in Ovarian Cancer

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  1. Angiogenesis Inhibitors and Novel Targeted Agents in Ovarian Cancer Robert L. Coleman, MD Professor & Deputy Chair Vice Chair, Clinical Research Department Gynecologic Oncology & Reproductive Medicine M.D. Anderson Cancer Center

  2. Disclosures • Research Funding: • OCRF, CPRIT, NCI (P50, N01) • Regeneron, sanofi-aventis, Novartis, Morphotek, Merck, GSK, Esperance, Genentech/Roche • Marcus Foundation • Scientific Steering Committee/Advisory: • Regeneron, sanofi-aventis, GSK, Esperance, Boehinger-Ingleheim, Genentech/Roche, Morphotek/Eisai, Merck, Nektar, Endocyte, Medimmune, AstraZeneca

  3. Today’s Focus • New therapeutics update • Angiogenesis targeting • FR-alpha targeting • Rare ovarian tumors

  4. Today’s Focus • New therapeutics update • Angiogenesis targeting • FR-alpha targeting • Rare ovarian tumors

  5. Cancer is a Disease of Tissues Joyce JA, et al. Nat Rev Cancer. 2009;9(4):239-252.

  6. AURELIA: A randomized phase III trial evaluating bevacizumabplus chemotherapy for platinum-resistant recurrent ovarian cancer R A N D O M I Z E Non-Platinum Chemotherapy • Recurrent EOC • Platinum resistant • ≤ 2 prior therapies • No clinical or radiologic evidence of bowel involvement 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.

  7. Baseline Characteristics CT = chemotherapy; ECOG PS = Eastern Cooperative Oncology Group performance status; PFI = platinum-free interval aStratification factor. bFrom last platinum to subsequent PD

  8. Baseline Characteristics CT = chemotherapy; ECOG PS = Eastern Cooperative Oncology Group performance status; PFI = platinum-free interval aStratification factor. bFrom last platinum to subsequent PD

  9. aTwo-sided chi-square test with Schouten correction Summary of Overall Response Rates p<0.001a p<0.001a p=0.001a Patients (%)

  10. 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.

  11. AURELIA: QoL

  12. OS: ITT population 1.00 0.75 Estimated probability 0.50 0.25 0 0 6 12 18 24 30 36 42 Time (months) No. at risk: CT 182 130 98 63 29 12 1 0 179 148 106 75 39 13 1 0 BEV + CT Data cut-off: 25 January 2013. Median duration of follow-up: 27.4 months in both arms ITT = intent to treat a2-sided log-rank, unadjusted

  13. Exploratory Subgroup Analysis Of OS aUnstratified. bMissingN=3 0.2 0.3 0.5 1 2 3 4 5

  14. Paclitaxel Cohort: OS 100 75 50 Overall survival (%) 25 0 0 6 12 18 24 30 36 42 Time (months) No. at risk: CT 55 40 32 22 13 3 0 60 52 43 34 19 4 1 BEV + CT

  15. Conclusions • PFS, was significantly improved with bevacizumab • OS HR was 0.85 (95% CI 0.66‒1.08) (ITT population) • Median OS: 16.6 months (BEV + CT) vs 13.3 months (CT) • Interpretation of OS is complicated by bevacizumab crossover (40%) and the lack of information on post-progression therapy • Exploratory subgroup analyses suggested: • Generally consistent effects on OS • More pronounced OS treatment effect in the weekly paclitaxel subgroup

  16. Beyond VEGF: FGF and PDGF Expression in Ovarian Cancer • After blockade of the VEGF pathway, there is a compensatory upregulationof FGF and PDGF Casanovas O, et al. Cancer Cell. 2005;8(4):299-309.

  17. VEGFs FGFs PDGFs Endothelialcells (VEGFRs, FGFRs) Pericytes (PDGFRs) Smooth musclecells (FGFRs, PDGFRs) Ligands Stimulation Cell types (proliferation, survival) Nintedanib (BIBF 1120): A Triple Angiokinase* Inhibitor Nintedanibblocksthreecriticalfactorsinvolved in angiogenesis *Angiokinase refers to tyrosine receptor kinases involved in promoting angiogenesis. Hilberg F, et al. Cancer Res. 2008;68(12):4774-4782. Stopfer P, et al. Ann Oncol. 2008;19(S8):Abstract 478P.

  18. AGO-OVAR-12 Carboplatin AUC 5/6 • Front-line EOC, PP or FT cancer • Stage IIB-IV • Primary max. surgery • N = 1366 Arm A Paclitaxel 175 mg/m² Placebo po BID 2:1 Arm B Primary endpoint: PFS Carboplatin AUC 5/6 Paclitaxel 175 mg/m² BIBF 1120a 200 mg po bid • Stratification variables: • FIGO stage: II/III vs IV • residual tumor: 0 cm vs >0 cm (no macroscopic vs macroscopic 2 years National Institutes of Health. Available at: http://clinicaltrials.gov/show/NCT01015118. Accessed: February 12, 2013.

  19. Primary Endpoint: Progression-Free Survival RECIST 1.1 and CA-125 in conjunction with Clinical MBO Criteria All patients (N=1366) – Cut-off date: 29 April 2013 Time from randomization (months) 542 352 160 1 0 911 761 17 381 257 168 76 3 0 0 455 *Stratified for macroscopic residual postoperative tumour, FIGO stage and carboplatin dose

  20. Exploratory Subgroup Analysis “ICON 7 defined low-risk patients subgroup” (FIGO II or FIGO III and ≤ 1cm residual postoperative tumor) Estimated percentage alive and progression-free Median PFS difference: + 6.3 months Time from randomization (months) Patients at risk Nintedanib 556 478 380 270 124 9 0 248 Placebo 2 0 283 186 123 52

  21. Trebananib (AMG 386) – Peptibody That Binds and Neutralizes Ang1 and Ang2 • Trebananib is an investigational recombinant peptide-Fc fusion protein (peptibody) • In clinical studies trebananib has shown: • Single-agent activity in relapsed ovarian cancer in a phase 1 study1 • Prolongation of PFS in a randomized phase 2 study in combination with paclitaxel in recurrent ovarian cancer2 • Herbst RS, et al. J Clin Oncol. 2009;27:3557‒3565. • Karlan BY, et al. J Clin Oncol. 2012;30:362‒371.

  22. TRINOVA-1: Trial Design • Recurrent EOC • ≤ 3 prior anticancer regimens • Evaluable or measurable disease • GOG Performance Status of 0 or 1 • PFI < 12 months Treat to PD/toxicity Weekly Paclitaxel+ Placebo R Treat to PD/toxicity Weekly Paclitaxel+Trebananib 1:1 Paclitaxel 80 mg/m2 IV on days 1, 8, 15 Q4W Trebananib 15 mg/kg IV QW ClinicalTrials.gov Identifier: NCT01204749 • Stratification factors • Platinum-free interval (PFI) (≤ 6 vs. > 6 months) • Measurable disease (Yes/No) • Region (North America, Western Europe/Australia, Rest of World) EOC = epithelial ovarian cancer including primary peritoneal, or fallopian tube cancer; PD = progressive disease

  23. TRINOVA-1: Demographics *Three patients had 4 or unknown lines of prior therapy (protocol deviation); †Four patients were “refractory” (protocol deviation)

  24. TRINOVA-1: PFS Primary Analysis

  25. TRINOVA-1: Overall Survival(Interim Analysis)

  26. TRINOVA-3 Maintenance Carboplatin AUC 5-6 IV d 1 Paclitaxel 175 mg/m2 IV d 1 Placebo weekly Weekly Placebo x 18 months • Previously untreated • epithelial ovarian, primary peritoneal, or fallopian tube cancer • Post operative • Stage III, IV • Neoadjuvant R (2:1) Carboplatin AUC 5-6 IV d 1 Paclitaxel 175 mg/m2 IV d 1 Trebananib (AMG 386) weekly Trebananib x 18 months N = 1000 (rev) Available at: http://clinicaltrials.gov/ct2/show/NCT01493505. Accessed Feb 2014.

  27. Randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: Results of the ICON6 trial. Ledermann JA, Perren T, Raja FA, Embleton AC, Rustin GJS, Jayson G, Kaye SB, Swart AM, Vaughan M, Hirte H on behalf of the ICON 6 Collaborators (NCRN, NCIC-CTG, ANZGOG, GEICO) • An academic sponsored GCIG trial

  28. Arm A (Chemo only) Arm B (Concurrent) Arm C (Maintenance) Chemotherapy + placebo Chemotherapy + cediranib Chemotherapy + cediranib Switch to placebo Continue placebo Maintenance cediranib Study schema Relapse > 6 months after completion of first line platinum-based chemotherapy • ICON6: Cediranib with platinum-based chemotherapy in ‘platinum-sensitive’ relapsed ovarian cancer • Cediranib targets: VEGFR-1/2/3 Randomise 2 : 3 : 3 • 6 Cycles platinum-based • Chemotherapy • Carboplatin/paclitaxel • Carboplatin/gemcitabine • Single agent platinum Maintenance phase Treatment continued to 18 months or until progression (>18 for patients continuing to benefit)

  29. Progression-free survival – arms A vs. C Maintenance Chemotherapy Restricted mean survival time increases by 3.1 months with maintenance treatment Chemo. Maint.

  30. Progression-free survival – all three arms Maintenance Chemotherapy Concurrent Chemo. Conc. Maint.

  31. Overall survival Maintenance Restricted mean survival time increases by 2.7 months with maintenance treatment (over two years) Chemotherapy Chemo. Maint.

  32. Angiogenesis as a Target: Ovarian Burger RA et al. N Engl J Med. 2011;365:2473‒2483. Perren TJ et al . N Engl J Med. 2011;365:2484‒2496. du Bois A et al. J ClinOncol. 2013;31(18suppl):LBA5503. du Bois A et al. LBA ESGO 2013 Liverpool, UK Pujade-Lauraine E et al. J ClinOncol. 2012;30(18suppl):LBA5002. Monk BJ, et all., LBA ESGO, Liverpool, UK AghajanianC et al. J ClinOncol. 2012;30:2039‒2045. Ledermann JA et al . Eur J Cancer. 2013;49(suppl):LBA

  33. Bottom Line… • Anti-angiogenesis agents in ovarian cancer • PFS appears to be enhanced by biological targeting • The menu of available agents is expanding • Toxicity and impact of therapy is needed to adjudicate use • Intervention is extending post treatment life expectancy • Better and selected therapy is needed for OS

  34. Today’s Focus • New therapeutics update • Angiogenesis targeting • FR-alpha targeting • Rare ovarian tumors

  35. Folate Metabolism: MoA Increases DNA synthesis Inhibits apoptosis Increases anoikis Increases cell motility Vergote, Marth, Coleman. Cancer Met Rev 2014

  36. Folate Receptor Expression

  37. Utilizing the Folate Receptor: EC145 • Folate-Vinca conjugate • Relevant for imaging targeting and therapy

  38. EC145: Novel Folate Receptor Targeted Therapeutic • Randomized Phase II, Platinum-resistant ovarian • Prior therapy: no more than 2 priors • Regimen: • PLD 50 mg/m2 IBW q 28 days • PLD 50 mg/m2 IBW q 28 days + EC145 2.5 mg weeks 1 and 3 (cycle: 28 days) • Toxicity similar in both arms: total AEs, SAEs, TETs Naumann W, et al. J ClinOncol (2013)

  39. PROCEED: Randomized Phase III PLD +/- EC145 (Vintafolide) in Platinum-Resistant Ovarian Cancer EC145 (vintafolide) + PLD Receptor scan N = 640 patients Platinum resistant ovarian cancer patients (failed first or second platinum therapy <6 months) EC145 = 2. 5mg TIW weeks 1, 3 PLD = 50 mg/m2 (IBW) every 28 days 2:1 PLD + placebo 50 mg/m2 (IBW) every 28 days • Primary endpoint: PFS • Co-primary analysis • EC20 (++/+): 85% power to detect HR = 0.70 • EC20 (++): 85% power to detect HR = 0.56 • Secondary endpoints • OS (no crossover) • ORR • Duration of Response • Quality of Life Assessment

  40. Farletuzumab: Pre-Clinical Data • Humanized MoAb to FRa • Mechanism: • Blocks Lyn kinase phosphorylation • Induces cytotoxicity via ADCC & CDC • Active in xenograft model • Favorable toxicity profile in primate studies

  41. Farletuzumab Phase 2: Design Patients with EOC experiencing first platinum sensitive relapse After first remission of 6-18 months duration Evaluable disease by CA125 Asymptomatic relapse Symptomatic relapse Combination Therapy: Original Carbo/Taxane regimen Plus farletuzumab 6 cycles Single agentFarletuzumab Until progression Combination ORR Farletuzumab maintenance Rx For responders Single Agent ORR Compare lengths of first and second remissions Armstrong, et al. GynecolOncol (2013) 129:452

  42. Target Lesion Response by RECIST(Combination Therapy) Best Response • CR = 7% • PR = 63% • SD = 23% • PD = 7% ORR = 70% Patient Benefit 93% Armstrong, et al. GynecolOncol (2013) 129:452

  43. EOC in first relapse> 6months or < 24 months Randomize 1:1:1 6 Cycles Carboplatin & Taxane Plus: Farletuzumab 1.25 mg/kg N =300 Farletuzumab 2.5 mg/kg N=300 Placebo (Saline) N=300 Single Agent Maintenance Key Secondary Endpoint: Overall Survival Farletuzumab Phase 3 in platin-sensitive ovarian cancer first recurrence Primary endpoint: PFS (each Farletuzumab arm vs control 2 sided 0.05 level, power 95% Median PFS control group 12 months HR: 0.70, 43% improvement to 17.1 months* Primary Endpoint: Progression-Free Survival *accrual was increased from 900 to 1080 to account for non-progression based discontinuation

  44. Farletuzumab Phase 3 in platin-sensitive ovarian cancer first recurrence Strata - characteristics

  45. Farletuzumab Phase 3 in platin-sensitive ovarian cancer first recurrence Progression Free Survival (ITT)

  46. Farletuzumab Phase 3 in platin-sensitive ovarian cancer first recurrence Overall Survival (ITT) (2013 April Update)

  47. Neither FAR dose met the study’s primary PFS endpoint in the ITT population Most commonly reported adverse events across arms were those known to be associated with the study chemotherapy agents Higher dose and exposure of FAR seems to be correlated with PFS improvement Hypotheses: CA125may inhibit the potential ADCC effect of FAR Hence, FAR in adequate dosing may have a potential effect in lower CA125 populations Farletuzumab Phase 3 in Platinum Sensitive Ovarian Cancer First Recurrence Conclusions

  48. Today’s Focus • New therapeutics update • Angiogenesis targeting • FR-alpha targeting • Rare ovarian tumors

  49. Relevant Mutations in Ovarian Cancer

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