1 / 27

Pazopanib in Advanced Ovarian Cancer: A new galloping horse.

Pazopanib in Advanced Ovarian Cancer: A new galloping horse. Dr. Raafat Ragaie, MD,FRCR. Ovarian Cancer: Why the Anti-Angiogenesis ?. Tumor angiogenesis is associated with malignant behavior in ovarian cancer 1,2

rgaddy
Download Presentation

Pazopanib in Advanced Ovarian Cancer: A new galloping horse.

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Pazopanib in Advanced Ovarian Cancer: A new galloping horse. Dr. Raafat Ragaie, MD,FRCR

  2. Ovarian Cancer:Why the Anti-Angiogenesis ? • Tumor angiogenesis is associated with malignant behavior in ovarian cancer 1,2 • BEV as single-agent showed promising activity in recurrent ovarian cancer in phase II studies3,4 • BEV combined with chemotherapy showed positive results in phase III randomized clinical trials in both platinum sensitive (OCEANS)5 as well as platinum resistant ovarian cancer (AURELIA)6 1 Hollingsworth et al. Am J Pathol 1995;147:33–41 2 Burger et al. J ClinOncol 2007;25:2902–8 3 Burger et al. J Clin Oncol 2007;25:5165–71 4 Cannistra et al. J ClinOncol 2007;25:5180–6 5 C Aghajanian, et al. ASCO 2011 6 Pujade-Lauraine et al. ASCO 2012

  3. OCEANS: Study schema C AUC 4 CG + PL • Platinum-sensitive recurrent OCa • Measurable disease • ECOG 0/1 • No prior chemo for recurrent OC • No prior BV • (n=484) G 1000 mg/m2, d1 & 8 PL q3w until progression C AUC 4 G 1000 mg/m2, d1 & 8 CG + BV BV 15 mg/kg q3w until progression • Stratification variables: • Platinum-free interval (6–12 vs >12 months) • Cytoreductive surgery for recurrent disease (yes vs no) CG for 6 (up to 10) cycles BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer C Aghajanian, et al ASCO 2011

  4. OCEANS: PFS by IRC 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Months No. at risk CG + BV 242 195 73 22 7 0 CG + PL 242 168 31 8 3 0 C Aghajanian, et al. ASCO 2011

  5. OCEANS: Interim OS 1.0 0.8 0.6 0.4 0.2 0 Proportion alive 0 6 12 18 24 30 36 42 Months No. at risk: CG + BV 242 238 200 146 82 42 8 0 CG + PL 242 235 195 131 77 26 8 0 NE = not estimable ap-value does not cross pre-specified boundary of 0.001 C Aghajanian, et al ASCO 2011

  6. AURELIA trial design • Platinum-resistant OCa • ≤2 prior anticancer regimens • No history of bowel obstruction/abdominal fistula, or clinical/ radiological evidence of rectosigmoid involvement Chemotherapy Treat to PD/toxicity Optional BEV monotherapyc R BEV 15 mg/kg q3wb+ chemotherapy Treat to PD/toxicity Investigator’s choice(without BEV) 1:1 Stratification factors: • Chemotherapy selected • Prior anti-angiogenic therapy • Treatment-free interval (<3 vs 3‒6 months from previous platinum to subsequent PD) Chemotherapy options (investigator’s choice): • Paclitaxel 80 mg/m2 days 1, 8, 15, & 22 q4w • Topotecan 4 mg/m2 days 1, 8, & 15 q4w (or 1.25 mg/m2, days 1–5 q3w) • PLD 40 mg/m2 day 1 q4w Pujade-Lauraine et al ASCO 2012

  7. Progression-free survival 1.0 0.8 0.6 0.4 0.2 0 Estimated probability 3.4 6.7 0 6 12 18 24 30 Time (months) No. at risk: CT 93 1 0 182 37 8 1 0 20 140 4 1 179 88 18 1 0 49 BEV + CT Pujade-Lauraine et al ASCO 2012 Median duration of follow-up: 13.9 months (CT arm) vs 13.0 months (BEV + CT arm)

  8. Ovarian Cancer :Why the Anti-Angiogenesis ? • VEGF-associated tumor angiogenesis in ovarian cancer is associated with malignant behavior1 • BEV as single-agent showed promising activity in phase II recurrent ovarian cancer studies • BEV combined with chemotherapy showed positive results in phase III randomized clinical trials in both platinum sensitive (OCEANS)2 as well as platinum resistant ovarian cancer (AURELIA)3 • Two Phase III randomized clinical trials studied BEV in 1st line treatment as maintenance: • GOG 2184 • ICON7 5 1 Hollingsworth et al. Am J Pathol 1995;147:33–41 2 C Aghajanian, et al. ASCO 2011 3 Pujade-Lauraine et al. ASCO 2012 4 Buerger et al ASCO, 2010 5 Perren, et al. NEJM 2011

  9. GOG-0218: Schema Arm Carboplatin (C) AUC 6 I • Front-line: Epithelial OV, PP or FT cancer • Stage III optimal (macroscopic) • Stage III • suboptimal • Stage IV • n=1800 (planned) Paclitaxel (P) 175 mg/m2 (CP) Placebo Carboplatin (C) AUC 6 1:1:1 II RANDOM I Z E Paclitaxel (P) 175 mg/m2 (CP + BEV) BEV 15 mg/kg Placebo Carboplatin (C) AUC 6 III • Stratification variables: • GOG performance status (PS) • Stage/debulking status Paclitaxel (P) 175 mg/m2 (CP + BEV  BEV) BEV 15 mg/kg Cytotoxic (6 cycles) Maintenance (16 cycles) 15 months Buerger et al ASCO, 2010

  10. GOG-0218: PFS + BEV → BEV maintenance (Arm III) ap-value boundary = 0.0116 10 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Proportion surviving progression free CP (Arm I) + BEV (Arm II) 0 12 24 36 Months since randomization

  11. GOG-0218: OS Analysis At time of final PFS analysis 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Proportion alive 0 12 24 36 48 Months since randomization No. at risk 625/625/623 442/432/437 173/162/171 46/39/40

  12. GOG-0218: Select Adverse EventsOnset between cycle 2 and 30 days after date of last treatment RPLS = reversible posterior leukoencephalopathy syndrome aPerforation/fistula/necrosis/leak bp<0.05

  13. ICON7: scheme • Stratification variables: • Stage and extent of debulking: I–III debulked ≤1cm vs stage I–III debulked >1cm vs stage IV and inoperable stage III • Timing of intended treatment start: ≤ vs > 4 weeks after surgery • GCIG group (*also choice of AUC dose 5 [AGO, NSGO, GINECO] or 6) Carboplatin AUC5 or 6* Stage I–IIa (grade 3 or clear cell) or Stage IIb–IV (all grades/ histologic types) debulked ≤1 cm or >1 cm OC, PP, FTC (n=1,528) RANDOMISE CP Paclitaxel 175mg/m2 1:1 Carboplatin AUC5 or 6* CP + B7.5  B7.5 Paclitaxel 175mg/m2 Bevacizumab 7.5mg/kg q3w 12 months Perren, et al. NEJM 2011

  14. ICON7: PFS 1.0 0.8 0.6 PFS estimate 0.4 0.2 CP CP + B7.5  B7.5 0 0 6 12 18 24 30 36 42 48 Time (months) Number at risk CP 764 474 221 39 0 CP + B7.5 764 599 229 27 0  B7.5 Perren, et al. NEJM 2011 Data cut-off date: November 30, 2010

  15. ICON7: OS 1.00 0.75 0.50 0.25 0 OS estimate 0 6 12 18 24 30 36 42 48 Time (months) Number at risk CP 764 724 672 623 421 212 71 6 0 CP + B7.5 764 737 702 657 459 228 69 4 0  B7.5 Perren, et al. NEJM 2011 Data cut-off date: November 30, 2010

  16. Pazopanib

  17. Targeting Angiogenesisby targeting VEGFR and PDGFR Bevacizumab ↑ VEGF ↑ PDGF VEGF PDGF VEGFR PDGFR Pericyte/Fibroblast/ Vascular Smooth Muscle Vascular Endothelial Cell Pazopanib Sorafenib Sunitinib Axitinib Vascular permeability Cell survival, proliferation Vascular formation, maturation Inhibition of progression

  18. [TITLE] Du Bois et al, ASCO 2013

  19. [TITLE]

  20. [TITLE]

  21. PFS: AGO-OVAR 16 Du Bois et al, ASCO 2013

  22. [TITLE] • AGO-OVAR 16 :OS Du Bois et al, ASCO 2013

  23. [TITLE] • AGO-OVAR 16 :Adverse Events Du Bois et al, ASCO 2013

  24. [TITLE]

  25. KASO INTERPRETATION • Anti-Angiogenesis will PROBABLY CLICK In Ovarian Cancer • Pazopanib provided the best data set for improvement of PFS ? YES • However: no OS gain ? Yet • Toxicity / including financial toxicity

  26. Thank you For your attention

More Related