Background. TAP, Paclitaxel + Doxorubicin + Cisplatin

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1 A randomized phase II study of paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus and ixabepilone/carboplatin/bevacizumab as initial therapy for measurable stage III or IVA; stage IV or recurrent endometrial cancer, GOG-86P C Aghajanian, VL Filiaci, DS Dizon, J Carlson, MA Powell, AA Secord, KS Tewari, D Bender, DM O Malley, A Stuckey, J Rotmensch, DA Levine, HA Lankes, KN Moore

2 Background Paclitaxel/carboplatin (PC) is a standard initial therapy for advanced endometrial cancer (EC) GOG209, a randomized noninferiority trial of initial therapy (n=1381), showed that PC was not inferior to TAP in terms of PFS and OS Bevacizumab, temsirolimus and ixabepilone have shown single agent activity in recurrent EC TAP, Paclitaxel + Doxorubicin + Cisplatin Gynecol Oncol 2012,125(3) Suppl 1:S2-188, page 771; J Clin Oncol 2011;29: ; Gyn Oncol 2013;129:22-7; J Clin Oncol 2011;29: ; Gynecol Oncol 2014;132:585-92; J Clin Oncol 2009;27:3104-8

3 GOG86P: Schema One Cycle = 3 weeks Open: 9/14/09 Closed: 1/9/12 6 cycles Maintenance Paclitaxel 175 mg/m 2 IV 3 hours Carboplatin AUC 6 IV Bevacizumab 15 mg/kg IV* Bevacizumab 15 mg/kg IV Endometrial Cancer No prior chemotherapy -Stage III or IVA (measurable disease) -Stage IVB (measurable disease or not) -Recurrent (measurable disease or not) Paclitaxel 175 mg/m 2 IV 3 hours Carboplatin AUC 5 IV Temsirolimus 25 mg IV days 1 & 8* Temsirolimus 25 mg IV days 1, 8 and 15 Stratification: performance status (< 1 vs 2) recurrent disease (yes/no) measurable disease (yes/no) prior EBRT (yes/no) Ixabepilone 30 mg/m 2 IV 1 hour Carboplatin AUC 6 IV Bevacizumab 15 mg/kg IV* Bevacizumab 15 mg/kg IV Treatment until disease progression or adverse events prohibit further therapy *Starting cycle 2 when within 12 weeks of surgery EBRT, External Beam Radiation Therapy

4 GOG86P: Statistical Design Primary endpoint: PFS Secondary endpoints: ORR, OS, safety Matched group from GOG209 PC Arm used as historical control 3 experimental Arms of GOG86P are compared individually to historical control RECIST 1.1 Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Planned sample size: 330 PFS: 35% decrease (HR=0.65) considered significant 12 month PFS from 39% to 54% 58 PFS events in an experimental arm, 85% power, 3.9% type I error 6, 18 week time intervals evaluated to lessen bias (as comparisons made to matched group from GOG209)

5 GOG86P: Patient Characteristics PC + Bevacizumab PC + Temsirolimus IC + Bevacizumab Enrolled (n=349) Eligible and Treated (n=329) Median Age, years (range) 62 (36-87) 63 (38-82) 65 (37-89) Performance Status (91%) 109 (95%) 113 (96%) Stage III (measurable disease) 12 (10%) 13 (11%) 10 (9%) IV 58 (50%) 58 (51%) 62 (52%) Recurrent 46 (40%) 44 (38%) 46 (39%) Histology (Central pathology review) Endometrioid, grade 1 17 (15%) 13 (11%) 15 (13%) Endometrioid, grade 2 36 (31%) 24 (21%) 27 (23%) Endometrioid, grade 3 30 (26%) 30 (26%) 22 (19%) Serous 16 (14%) 26 (23%) 31 (26%) Clear Cell 6 (5%) 4 (3%) 6 (5%) Other 11 (9%) 18 (16%) 17 (14%) PC, paclitaxel + carboplatin; IC, ixabepilone + carboplatin

6 GOG86P: Patient Characteristics PC + Bevacizumab PC + Temsirolimus IC + Bevacizumab Eligible and Treated (n=329) Prior EBRT No 99 (85%) 95 (83%) 98 (83%) Yes 17 (15%) 20 (17%) 20 (17%) Measurable Disease No 27 (23%) 30 (26%) 33 (28%) Yes 89 (77%) 85 (74%) 85 (72%)

7 GOG86P: Treatment Exposure Treatment Delivered PC + Bevacizumab (n=116) PC + Temsirolimus (n=115) IC + Bevacizumab (n=118) Chemotherapy Median number of cycles, range Paclitaxel/Ixabepilone Median number of cycles, range Carboplatin 6 (0-6) 6 (0-6) 6 (0-6) 6 (0-6) 6 (0-6) 6 (0-6) Bevacizumab/Temsirolimus Median number of cycles, range 12 (0-78) 8 (0-62) 9 (0-53)

8 GOG86P: Overview of AEs Patients, % PC + Bevacizumab n=112 PC + Temsirolimus n=113 IC + Bevacizumab n=114 Any AE, Any grade Any AE, Grade > Any AE, Grade AE Leading to Study Drug Discontinuation 26.8 (bev) 23 (tem) 24.6 (bev) 15.8 (ixa) SAE

9 GOG86P: AEs of Special Interest Patients, % PC + Bevacizumab n=112 PC + Temsirolimus n=113 IC + Bevacizumab n=114 Fisher s Exact Test (2 sided)* ATE, grade > p=0.554 VTE, grade > p=0.681 Non-CNS Bleeding, grade > p=0.281 GI Fistula, Leak, Perforation, Any grade p=0.505 HTN, grade > p<0.001 Proteinuria, grade > p=0.018 Pneumonitis, any grade p=0.002 Mucositis, oral, grade > p<0.001 Rash, grade > p<0.001 Hypertriglyceridemia, grade > p=0.004 *Test comparing PC or IC + bevacizumab vs PC + temsirolimus

10 GOG86P: PFS Comparison to Historical Reference Hazard 92.2% Hazard Ratio Ratio Confidence Limits Arm Hazard 92.2% Hazard Ratio Ratio Confidence Limits Arm Hazard 92.2% Hazard Ratio Ratio Confidence Limits Arm

11 GOG86P: Objective Response Rate Measurable Disease Patients PC + Bevacizumab (n=116) PC + Temsirolimus (n=115) IC + Bevacizumab (n=118) GOG209 PC Historical Reference (n= 462) Complete Response (CR) 22 (24.7%) 14 (16.5%) 9 (10.6%) 40 (10.8%) Partial Response (PR) 31 (34.8%) 33 (38.8%) 36 (42.4%) 149 (40.4%) Objective Response Rate (CR + PR) 53 (59.5%) 47 (55.3%) 45 (52.9%) 189 (51.2%)

12 GOG86P: OS Arm Median Point Estimate (p<0.039) Reference 22.7

13 Translational science 25 most commonly mutated genes from TCGA endometrial cancer project sequenced to a minimum mean depth of 600X Top mutated genes by histology (primary samples only, n=219) Endometrioid, G1 Endometrioid, G2 Endometrioid, G3 Serous Gene (n=37) (n=69) (n=59) (n=45) PTEN 73% 71% 58% 9% PIK3CA 38% 54% 53% 29% TP53 14% 20% 44% 87% ARID1A 38% 48% 39% 2% CTNNB1 57% 32% 31% 2% PIK3R1 27% 26% 19% 7% KRAS 19% 20% 24% 2% CHD4 27% 12% 20% 11% PPP2R1A 11% 4% 5% 29% FBXW7 0% 6% 10% 16% MTOR 5% 9% 14% 4% POLE 11% 6% 8% 2% Profile of serous cases (n=45) Douglas A. Levine, Fanny Dao

14 Conclusions PFS is not significantly increased in any Arm OS is significantly increased in the PC + Bevacizumab Arm when compared with historical controls No new safety signals Integration of the translational research findings and clinical endpoints is ongoing

15 Thank you We gratefully acknowledge: All the patients and their caregivers who participated in this trial, All the Investigators and staff who contributed their time and effort to this study, and NRG Oncology