Current state of upfront treatment for newly diagnosed advanced ovarian cancer

Current state of upfront treatment for newly diagnosed advanced ovarian cancer Ursula Matulonis, M.D. Associate Professor of Medicine, HMS Program Leader, Medical Gyn Oncology Dana-Farber Cancer Institute Boston, MA Email: umatulonis@partners.org Phone: 617 632-2625

Agenda Review trials for upfront management of newly diagnosed advanced ovarian cancer Review ongoing studies Review new therapies being tested

Ovarian cancer 2010 22,500 cases diagnosed per year in the United States and 16,500 deaths per year 1. Most patients are diagnosed in late stages; no screening test exists. Pathology: 4 different types (serous, endometrioid,, clear cell and mucinous) 1 Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2009. CA: Cancer J Clin 59(4):225-49, 2009

Unique aspects of newly diagnosed advanced ovarian cancer Upfront surgical management is standard of care: allows access to tissue OC is very chemotherapy sensitive at diagnosis; >80% of cancers will respond to platinum- and taxane-based chemotherapy upfront at dx. Cancer becomes more treatment-refractory refractory following recurrence. Few but some CTC s. Outcomes for newly diagnosed ovarian cancer have reached a plateau with platinum/taxane taxane combinations.

Ovarian cancer staging Stage I: confined to ovary(ies) Stage II: local spread to pelvis Stage III: Stage IIIA: microscopic upper abdominal spread Stage IIIB: upper abd implants <2 cm Stage IIIC: 2cm implants and/or +nodal involvement Stage IV: spread outside the abdominal cavity. Definition of extent of debulking is what is residual post surgical debulking: optimal cytoreduction/debulking: 1cm residual suboptimal debulking: : > 1cm residual cancer

Advanced ovarian cancer

PFS and OS for newly diagnosed advanced ovarian cancer Study Median PFS Median OS Comments GOG 111 NEJM 1996 18 mos 38 mos Suboptimally and stage IV GOG 158 JCO 2003 21 mos 57.4 mos Optimally cytoreduced only GOG 172 NEJM 2006 24 mos 65 mos Optimally cytoreduced only. Longest survival observed in advanced ovarian cancer GOG 182 JCO 2009 16 mos 44 mos Both optimal and suboptimal. Study compared 5 arms of treatment Weekly pac vs q21 d Lancet 09 28 mos (vs. 17 mos) Not reached Both optimal and suboptimal EORTC neoadjuvant IGCS 2008 Both 12 mos 29/30 mos Neoadjuvant vs. upfront debulking GOG 218: ASCO 2010

GOG111: Survival By Treatment Pac + cis (38 mos) Cy + cis (24 mos) Treatment Alive (N) Died (N) Median PFS Survival (mo) Relative Risk Cisplatin/ cyclophosphamide 28 174 13.0 Cisplatin/paclitaxel 45 138 18 0.69 McGuire WP, et al. N Engl J Med. 1996;334:1-6.

GOG0182-ICON5: Schema I Carboplatin AUC 6 (d1) Paclitaxel 175 mg/m2 (d1) x8 R A N D O M I Z E II III IV V Carboplatin AUC 5 (d1) Paclitaxel 175 mg/m 2 (d1) Gemcitabine 800 mg/m 2 (d1,8) Carboplatin AUC 5 (d1) Paclitaxel 175 mg/m 2 (d1) Doxil 30 mg/m 2 (d1, every other cycle) Carboplatin AUC 5 (d3) Topotecan 1.25 mg/m 2 (d1-3) Carboplatin AUC 6 (d8) Gemcitabine 1 g/m 2 (d1,8) x4 x4 x8 x8 Carboplatin AUC 6 (d1) Paclitaxel 175 mg/m 2 (d1) x4 JCO 2008

GOG0182-ICON5: Progression-Free Survival

GOG0182-ICON5: Overall Survival

Primary Therapy IP Median PFS, months Hazard ratio Median OS, months Hazard ratio GOG 104 1 GOG 114 2 GOG 172 3 IV 22 18.3 IP 28 23.8 0.78 (P =.01) 0.80 (P =.05) IV 41 52 50 IP 49 63 66 0.76 (P =.02) 0.81 (P =.05) 0.75 (P =.03) PFS = Progression-free survival; OS = Overall survival; IV = Intravenous; IP = Intraperitoneal. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK, et al. N Engl J Med. 2006;354:34-43.

GOG #172 Armstrong et.al. N Engl J Med 2006;354:34-43 BRCA Analysis DNA Banking Second look Laparotomy (if chosen) Ovarian cancer Optimal (<1cm) Stage III Stratify: Gross residual Planned 2 nd look R A N D O M I Z E Paclitaxel 135 mg/m 2 /24h Cisplatin 75 mg/m 2 q 21 days x 6 Paclitaxel 135 mg/m 2 /24h Cisplatin 100 mg/m 2 IP D2 Paclitaxel 60 mg/m 2 IP D8 q 21 days x 6

GOG #172: outcomes Regimen 1 Intravenous Regimen 2 Intraperitoneal Progression-free 18.3 mos 23.8 mos Overall Survival 49.5 mos 66.9 mos

Figure 1 By Treatment Group (GOG 172) 1.0 Proportion Progression-Free 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 18.3 months for IV Rx Group PF Failed Total IV 50 160 210 IP 63 142 205 23.8 months for IP group (Δ = 6 months) 0.1 0.0 0 12 24 36 48 60 Months on Study

GOG Protocol 172 By Treatment Group 1.0 0.9 0.8 IP median overall survival = 66 months (Δ = 16 months) Proportion Surviving 0.7 0.6 0.5 0.4 0.3 IV median overall survival = 49.5 months 0.2 0.1 0.0 Rx Group Lost to Alive Dead Total Follow-up Rx IV Group 5 Alive Dead 78 Total 127 210 IV 93 117 210 IP 11 117 93 88 205 101 205 0 12 24 36 48 60 Months on Study N Engl J Med. 2006;354:34-43. Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P =.03

GOG Protocol 172 Toxicity G3/4 G3/4 G3/4 G3/4 G3/4 G3/4 G3/4 G3/4 G3/4 Leukopenia* Platelet GI* Renal* Neurologic Event* Fatigue* Infection* Metabolic* Pain* IV, % (N = 210) 64 4 24 2 9 4 6 7 1 IP, % (N = 201) 76 12 46 7 19 18 16 27 11 *P 0.05

Modulating Toxicity of IP Therapy New approaches to improve toxicity profile Timing of catheter placement Timing of chemotherapy relative to surgery relative to catheter placement Agents used Supportive care (anti-emetics, IV fluids, myeloid growth factor) Successful use of IP therapy requires: Training Skill Experience Dedication

GOG 252: Newest upfront IP study

IGCS Bangkok October 25 th 2008

Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) Randomisation Primary Debulking Surgery Neoadjuvant chemotherapy 3 x Platinum based CT 3 x Platinum based CT Interval debulking (not obligatory) Interval debulking if no PD > 3 x Platinum based CT > 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications

Randomised EORTC-GCG/NCIC GCG/NCIC-CTG CTG trial on NACT + IDS versus PDS Statistical considerations 704 patients were required in order to show noninferiority with respect to survival between PDS and NACT, with a one-sided type I error of 0.05 and a power of 80%.

Randomised EORTC-GCG/NCIC GCG/NCIC-CTG CTG trial on NACT + IDS versus PDS Baseline Characteristics (ITT) PDS NACT -> > IDS FIGO Stage IIIc IV 77% 23% 77% 23% Serous 64% 58% Age 62 (25-86) 62 (33-81) CA125 > 30 KU/L 98% 99% Largest metastasis (mm) 80 (0-400) 80 (0-389)

Randomised EORTC-GCG/NCIC GCG/NCIC-CTG CTG trial on NACT + IDS versus PDS Surgical findings and results (PP1) PDS (n = 329) NACT -> > IDS (n = 339)* Metastases before > 2 cm 95% 68% Metastases before > 10 cm 62% 27% No residual after surgery 21% 53% 1 cm after surgery 46% 82% * % calculated on the 306 patients who underwent IDS.

Randomised EORTC-GCG/NCIC GCG/NCIC-CTG CTG trial on NACT + IDS versus PDS Surgical characteristics (PP1) Postoperative mortality (< 28 days) PDS (n = 329) NACT -> > IDS (n = 339)* 2.7% 0.6% Postoperative fever Gr 3-43 8% 2% Fistula (bowel/gu) 1.2% / 0.3% 0,3% / 0.6% Operative time (minutes) 180 180 Red blood cell transfusion 51% 53% Hemorhage Grade 3/4 7% 1% Venous Gr 3/4 2.4% 0.3%

NACT + IDS versus PDS: ITT 100 90 80 70 60 50 40 30 20 10 Progression-free survival Median PFS PDS: 12 months IDS: 12 months HR for IDS:0.99 (0.87, 1.13) 0 (years) 0 1 2 3 4 5 6 7 8 O N Number of patients at risk : Treatment 320 360 168 60 39 26 17 7 2 Upfront debu 320 357 177 60 36 20 13 3 1 Neoadjuvant

NACT + IDS versus PDS: ITT Overall survival 100 90 80 70 60 50 Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) 40 30 20 10 0 (years) 0 2 4 6 8 10 O N Number of patients at risk : Treatment 259 361 183 68 16 2 Upfront debulking s 251 357 191 56 11 1 Neoadjuvant chemo

NACT + IDS versus PDS: ITT Survival time: Figo stage EORTC 55971 Events / Patients Statistics Upfront debulkingneo-adj. Chemo (O-E) Var. HR & CI* (Upfront debulking : Neo-adj. Chemo) 1-HR % ± SD III 190 / 276 191 / 273-1.8 94.7 IV 68 / 81 59 / 83 4 31.4 Total 258/ 357 250/ 356 2.2 126.1 (72.3 %) (70.2 %) 2% ±9 increase Test for heterogeneity Chi-square=0.5, df=1: p>0.1 0.25 0.5 1.0 2.0 4.0 Upfront debulking Neo-adj. Chemo better better Treatment effect: p>0.1 *90% CI everywhere

NACT + IDS versus PDS: ITT Survival time: Age EORTC 55971 Events / Patients Upfront debulkingneo-adj. Chemo Statistics (O-E) Var. HR & CI* (Upfront debulking : Neo-adj. Chemo) 1-HR % ± SD <50 34 / 46 31 / 56 6.1 15.5 50-70 172 / 244 161 / 221 0 82.7 >70 53 / 71 59 / 80-2.6 26.9 Total 259/ 361 251/ 357 3.5 125.1 (71.7 %) (70.3 %) 3% ±9 increase Test for heterogeneity Chi-square=2.59, df=2: p>0.1 0.25 0.5 0.81.0 2.0 4.0 Upfront debulking Neo-adj. Chemo better better Treatment effect: p>0.1 *90% CI everywhere

Multivariate analysis for OS(PP1) P values Optimal debulking 0.0001 Histological type (9 categories) 0.0003 Largest tumor size at randomisation 0.0008 Figo Stage (IIIc vs IV) 0.0008 Country (14 categories) 0.0014 Age 0.0020 WHO PS Differentiation Grade Treatment arm NS NS NS

Conclusions 1. In Stage IIIc-IV IV OVCA, NACT followed IDS produces similar OS and PFS outcomes compared to standard primary debulking followed by chemotherapy in FIGO Stage IIIc-IV IV ovarian carcinoma. 2. There does not seem to be a subgroup based on 1. Stage IIIc or IV 2. Age 3. WHO performance 4. Histological type ovarian cancer 5. Countries with high or low optimal debulking rate for which PDS or NACT -> > IDS result in better survival. Because of the overall poorer PFS and OS compared to other studies, the use of neoadjuvant chemotherapy is not considered the standard of care in the United States, but is reserved for patients who are too ill to undergo initial surgery or those patients who have clearly non-debulkable cancer.

PFS and OS for newly diagnosed advanced ovarian cancer Study Median PFS Median OS Comments GOG 111 NEJM 1996 18 mos 38 mos Suboptimally and stage IV GOG 158 JCO 2003 21 mos 57.4 mos Optimally cytoreduced only GOG 172 NEJM 2006 24 mos 65 mos Optimally cytoreduced only. Longest survival observed in advanced ovarian cancer GOG 182 JCO 2009 16 mos 44 mos Both optimal and suboptimal. Study compared 5 arms of treatment Weekly pac vs q21 d Lancet 09 28 mos (vs. 17 mos) Not reached Both optimal and suboptimal EORTC neoadjuvant IGCS 2008 Both 12 mos 29/30 mos Neoadjuvant vs. upfront debulking GOG 218: ASCO 2010

Dose dense paclitaxel versus q 3 week paclitaxel for newly diagnosed ovarian cancer 631 eligible patients were enrolled Eligibility: stage II to IV epithelial ovarian cancer Pts could have upfront or interval debulking surgery Primary endpoint was PFS Treatment 1 : Paclitaxel 180 mg/m2 + carboplatin AUC 6 day both day 1 or Paclitaxel 80 mg/m2 days 1, 8, 15 + carboplatin AUC 6 day 1 (dose dense group) 1 Creatinine clearance calculated by Jelliffe and treatment given for 6 cycles Katsumata et al, Lancet 2009

Progression-free survival PFS for: DD Pac: 28 months q3 week: 17.2 mos HR 0.75 (95% CI: 0.58-0.88) p=0.015 Katsumata et al, Lancet 2009

Overall survival 3 year OS for: DD Pac 72% q3 week: 65% HR 0.75 (95% CI: 0.57-0.98) p=0.03 Katsumata et al, Lancet 2009

Progression-free survival according to baseline characteristics Lancet, 2009

Grade 3/4 anemia was higher in the dose dense group From: Katsumata et al, Lancet 2009

GOG Frontline Trials GOG-218 Optimal or Suboptimal EOC, PPC, FT cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Placebo 15 months Placebo 15 months Bevacizumab 15 months Survival, PFS primary endpoints Biologic & QOL endpoints EOC = Epithelial ovarian cancer; PPC = Primary peritoneal cancer; FT = Fallopian tube; PFS = Progression-free survival; QOL = Quality of life.

GOG 218 results To be presented at ASCO 2010 Preliminary results were released via press release in March 2010 (www.gene.com( www.gene.com). Patients receiving carboplatin/taxol/bevacizumab + bevacizumab maintenance did better than carbo/taxol alone. Patients receiving carboplatin/taxol/bevacizumab (no maintenance) did equally well as patients receiving carboplatin/taxol alone. At this point, our group is not using bevacizumab off study. www.gene.com

Newer biologics being added to upfront treatment PARP inhibitors Src inhibitors Other anti-angiogenics angiogenics besides bevacizumab Notch inhibitors

Protocol 10-065 065 Pilot study screening for druggable mutations in both recurrent and newly diagnosed advanced ovarian cancer. Opened March 2010; 28 pts enrolled thus far. CLIA-approved PIK3CA, KRAS,, and BRAF testing at LMM (for clinical decision making). OncoMap platform used thereafter to test for 1100 mutations in 100 oncogenes (for research).

Standard of Care for pts with advanced epithelial ovarian cancer: 2010 Upfront debulking surgery by a gynecologic oncologist. If optimally cytoreduced (i.e. 1cm tumor remaining), options are: Placement of an IP port and IP/IV tx 1, IV carboplatin/paclitaxel,, or clinical trial. If suboptimally cytoreduced,, options are: IV carboplatin/paclitaxel (q3 week or weekly paclitaxel) 3 or clinical trial Neoadjuvant chemotherapy 2 has demonstrated equivalent results to upfront cytoreduction chemotherapy, but this appears more popular in Europe than the U.S. with lower OS and PFS overall compared to other studies. 1 Armstrong DK, et al, N Engl J Med 354(1):34-43, 2006. 2 Vergote I et al. IGCS 2008 Meeting: Abstract #2008_1767. Available at: http://www.igcs.org/abstract/meeting_2008_1767.html. 3

Following completion of upfront chemotherapy CA125 monitoring every 3 months; although off study, controversy exists whether or not this is of benefit 1 Several drugs are being tested in the first maintenance setting. There is no standard of care for use of maintenance therapy 2 1 Rustin GJ et al, J Clin Oncol 27(18s):Abstr 1, 2009. 2 Foster et al, Gyn Onc 115:290-301, 2009

Conclusions Standard of care for newly diagnosed advanced ovarian, tubal or peritoneal cancer remains a platinum and taxane combination New options for patients include dose dense administration of paclitaxel Results of GOG 218 asking question of role of bevacizumab in newly diagnosed patients to be presented at ASCO 2010