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 BEV as single-agent showed promising activity in recurrent ovarian cancer in phase II studies 3,4 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 Clin Oncol 2007;25:2902–8 3 Burger et al. J Clin Oncol 2007;25:5165–71 4 Cannistra et al. J Clin Oncol 2007;25:5180–6 5 C Aghajanian, et al. ASCO Pujade-Lauraine et al. ASCO 2012

CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OC a Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo a Epithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m 2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m 2, d1 & 8 CG + BV C Aghajanian, et al ASCO 2011

OCEANS: PFS by IRC CG + PL (n=242) CG + BV (n=242) Events, n (%) 148 (61)119 (49) Median PFS, months (95% CI) 8.6 (8.3–10.2) 12.3 (10.7–14.6) Stratified analysis HR (95% CI) Log-rank p-value (0.351–0.580) < Proportion progression free CG + PL CG + BV Months No. at risk C Aghajanian, et al. ASCO 2011

OCEANS: Interim OS Proportion alive 0 Months No. at risk: CG + PL CG + BV14682 CG + PL (n=242) CG + BV (n=242) Events, n (%)78 (32)63 (26) Median OS, months (95% CI) 29.9 (26.4–NE) 35.5 (30.0–NE) Stratified analysis HR (95% CI) Log-rank p-value (0.537–1.052) a NE = not estimable a p-value does not cross pre-specified boundary of C Aghajanian, et al ASCO 2011

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

Progression-free survival Median duration of follow-up: 13.9 months (CT arm) vs 13.0 months (BEV + CT arm) CT (n=182) BEV + CT (n=179) Events, n (%) 166 (91%)135 (75%) Median PFS, months (95% CI) 3.4 (2.2 ‒ 3.7) 6.7 (5.7 ‒ 7.9) HR (unadjusted) (95% CI) Log-rank p-value (2-sided, unadjusted) 0.48 (0.38 ‒ 0.60) < Estimated probability Time (months) CT BEV + CT No. at risk: Pujade-Lauraine et al ASCO 2012

Ovarian Cancer : Why the Anti-Angiogenesis ? VEGF-associated tumor angiogenesis in ovarian cancer is associated with malignant behavior 1 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 1 st line treatment as maintenance: –GOG –ICON7 5 1 Hollingsworth et al. Am J Pathol 1995;147:33–41 2 C Aghajanian, et al. ASCO Pujade-Lauraine et al. ASCO Buerger et al ASCO, Perren, et al. NEJM 2011

9 GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Stratification variables: GOG performance status (PS) Stage/debulking status RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE 1:1:1 15 months Paclitaxel (P) 175 mg/m 2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Maintenance (16 cycles) (CP) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo BEV 15 mg/kg II (CP + BEV) BEV 15 mg/kg Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 III (CP + BEV  BEV) Buerger et al ASCO, 2010

CP (Arm I) Arm I CP (n=625) Patients with event, n (%) 423 (67.7) Median PFS, months10.3 Stratified analysis HR (95% CI) One-sided p-value (log rank) GOG-0218: PFS + BEV (Arm II) a p-value boundary = BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization Arm III CP + BEV  BEV (n=623) 360 (57.8) (0.625–0.824) < a 10 Arm II CP + BEV (n=625) 418 (66.9) (0.759–1.040) a

GOG-0218: OS Analysis At time of final PFS analysis Arm I CP (n=625) Arm II CP + BEV (n=625) Arm III CP + BEV  BEV (n=623) Patients with events, n (%) 156 (25.0) 150 (24.0) 138 (22.2) Median, months HR a (95% CI) (0.827–1.297) (0.727–1.152) One-sided p-value Proportion alive Months since randomization /625/623442/432/437173/162/17146/39/40 No. at risk

12 Adverse event (grade when limited), n (%) Arm I CP (n=601) Arm II CP + BEV (n=607) Arm III CP + BEV  BEV (n=608) Hypertension (grade ≥2)43 (7.2) b 100 (16.5) b 139 (22.9) b Proteinuria (grade ≥3) 4 (0.7) 10 (1.6) Neutropenia (grade ≥4)347 (57.7)384 (63.3)385 (63.3) Febrile neutropenia21 (3.5)30 (4.9)26 (4.3) Venous thromboembolic event35 (5.8)32 (5.3)41 (6.7) Arterial thromboembolic event 5 (0.8)4 (0.7) GOG-0218: Select Adverse Events Onset between cycle 2 and 30 days after date of last treatment RPLS = reversible posterior leukoencephalopathy syndrome a Perforation/fistula/necrosis/leak b p<0.05

GL/AVAO/1110/0027a RANDOMISERANDOMISE 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) Paclitaxel 175mg/m 2 Carboplatin AUC5 or 6* Paclitaxel 175mg/m 2 1:1 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) Bevacizumab 7.5mg/kg q3w 12 months CP CP + B7.5  B7.5 Perren, et al. NEJM 2011

GL/AVAO/1110/0027a ICON7: PFS CP CP + B7.5  B7.5 PFS estimate Number at risk CP CP + B  B7.5 CP CP + B7.5  B7.5 Events, n (%) 464 (61)470 (62) Median, months Log-rank testp=0.039 HR (95% CI)0.87 (0.77–0.99) Time (months) Perren, et al. NEJM 2011 Data cut-off date: November 30, 2010

GL/AVAO/1110/0027a ICON7: OS Number at risk CP CP + B  B Time (months) OS estimate CP CP + B7.5  B7.5 Events, n (%) 200 (26)178 (23) Median, months Not yet reached Log-rank testp=0.11 HR (95% CI)0.85 (0.69–1.04) 1-year OS rate (%)9295 Perren, et al. NEJM 2011 Data cut-off date: November 30, 2010

Pazopanib

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

[TITLE] Du Bois et al, ASCO 2013

[TITLE]

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

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

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

[TITLE]

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

Thank you For your attention