Ovarian Cancer: A new look at an old veteran Sana Al-Sukhun, MD, MSc. Assistant Professor, Medical Oncology/ Hematology University of Jordan Best of ASCO July 11th 2009

Ovarian Cancer First line treatment: Relapsed setting: Standard Tx : Carboplatin / paclitaxel. Relapsed setting: Choice of relapsed disease treatment is dependent on interval since prior platinum-based therapy Relapse within 6 months: platinum-resistant disease Relapse over 6 months: platinum-sensitive disease Carboplatin-paclitaxel is standard in platinum-sensitive disease Ozols RF et al, J Clin Oncol 2003, 21: 3194-3200

Is carboplatin / liposomal doxorubicin a replacement doublet for carboplatin / paclitaxel?

Introduction Single-agent pegylated liposomal doxorubicin (PLD) is a standard option for platinum resistant relapsed ovarian cancer 1. Combination of carboplatin and PLD is highly active as second-line chemotherapy in patients with advanced ovarian cancer in late relapse 2-3 1Gordon AN et al, J Clin Oncol 2001, 19: 3312-3322 2Ferrero JM et al, Proc Am Soc Clin Oncol 2002 3Ferrero JM et al, Ann Oncol 2007, 18: 263-268 4Gordon AN et al, J Clin Oncol 2001, 19: 3312-3322

Carboplatin plus Paclitaxel versus Carboplatin plus Stealth Liposomal Doxorubicin in patients with advanced ovarian cancer: activity and safety results of the MITO-2 randomized multicenter trial S. Pignata1, G. Scambia2, A. Savarese3, R. Sorio4, E. Breda5, G. Ferrandina2, V. Gebbia6, P. Musso7, C. Gallo8, F. Perrone9 1Istituto Nazionale Tumori, Napoli; 2Università Cattolica del Sacro Cuore, Roma; 3Istituto Regina Elena, Roma; 4CRO, Aviano; 5Ospedale Fatebenefratelli, Isola Tiberina, Roma; 6Casa di Cura La Maddalena, Università di Palermo; 7Ospedale Oncologico M.Ascoli A.R.N.A.S., Palermo; 8Seconda Università di Napoli; 9Istituto Nazionale Tumori di Napoli,Italy.

Study design Control arm Random Experimental arm Carboplatin AUC 5, day 1 Paclitaxel 175 mg/m2, day 1 Treatment repeated every 21 days, for 6 cycles 1:1 Experimental arm Carboplatin AUC 5, day 1 PLD 30 mg/m2, day 1 Treatment repeated every 21 days, for 6 cycles Strata: Center PS (0-1, 2) Stage (IC, II, III, IV) Residual disease after surgery (absent, 1 cm, 1 cm, no surgery)

Study design Random Control arm Experimental arm Carboplatin AUC 5, day 1 Paclitaxel 175 mg/m2, day 1 1:1 Experimental arm Carboplatin AUC 5, day 1 PLD 30 mg/m2, day 1 Is carboplatin plus PLD more effective than carboplatin plus paclitaxel as first-line treatment of patients with advanced ovarian cancer? Objective : To demonstrate improvement in PFS from 18 to 22.5 months ( HR 0.8, 80% power).

Study population Inclusion criteria Main exclusion criteria Cyto/histological diagnosis of ovarian cancer FIGO Stage IC – II – III – IV Age  75 ECOG Performance Status 0-2 No previous chemotherapy Main exclusion criteria ANC  2000/L, platelets  100000/L Creatinine  1.25 x UNL, SGOT and SGPT  1.25 x UNL Life expectancy of less than 3 months

Study endpoints Primary endpoint Progression-free survival (PFS) Secondary endpoints Overall survival (OS) Objective response rate (RECIST) Toxicity (NCI – CTC v2.0) Quality of Life (EORTC QLQ C30)

Baseline characteristics Carbo + Paclitaxel Carbo + PLD (n = 410) (n=410) Age median (range) 57 (21-77) (25-77) ECOG Performance Status 0-1 398 (97%) 397 2 12 (3%) 13 FIGO Stage IC 38 (9%) II 40 (10%) 37 III 243 (59%) 247 (60%) IV 89 (22%) 88 Residual disease after surgery Absent 152 (37%) 150  1 cm 68 (17%) 69 (19%)  1 cm 117 (28%) 114 No surgery 73 (18%) 67 (16%)

Treatment compliance: delays Carboplatin + Paclitaxel Carboplatin + PLD Number of patients Delays due to non hematologic toxicity Delays due to hematologic toxicity Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Completed 6 cycles : 82% Carboplatinum / PLD Vs 88% receiving Carboplatinum / Paclitaxel P= 0.39

Toxicity (2) Any grade Severe (G3) C+P C+PLD p* Allergy 6% 5% 0.60 2% 0.86 Heart 4% 0.26 0.3% 0.06 Fatigue 44% 43% 3% 0.94 Constipation 32% 0.99 1% 0.73 Nausea 47% 51% 0.21 0.95 Vomiting 29% 30% 0.83 0.42 Diarrhoea 13% 0.001 - 0.25 Hair loss 63% 14% Skin toxicity 20% 0.01 Stomatitis 9% 0.5% 0.62 Neurotoxicity 15% 0.2% 0.004 C+P: carboplatin + paclitaxel, 399 patients; C+PLD: carboplatin + PLD, 386 patients *Chi square or Fisher exact test as appropriate

Objective response – RECIST Women with target lesions Carbo + Paclitaxel (n=156) + PLD (n=134) p (2)* Objective response 92 (59%) 76 (57%) 0.70 Complete response 24 (15%) 22 (16%) Partial response 68 (44%) 54 (40%) No response 64 (41%) 58 (43%) Stable disease 45 (29%) 41 (31%) Progressive disease 9 (6%) 7 (5%) Not evaluated 10 (6%) 10 (7%) *Objective response vs no response

Activity Women not eligible for RECIST Carbo + Paclitaxel + PLD p (2) Non-target lesions only Complete response (CR) 27 / 83 (33%) 29 / 99 (29%) 0.64* No CR / No PD 46 / 83 (55%) 48 / 99 (48%) Progressive disease 2 / 83 (2%) 4 / 99 (4%) Not evaluated 8 / 83 (10%) 18 / 99 (18%) Elevated Ca125 only Ca125 normalized 73 / 88 (83%) 69 / 80 (86%) 0.56** * Complete response vs not ** Ca125 normalized vs not

Primary endpoint Number of events required for final analysis (632) has not been reached yet As of May 4, 2009, with a median follow-up of 35 months, 531 progressions have been recorded Only overall curves are shown

Progression-free survival* Patients Events Median PFS (months) 1-yr PFS 2-yr 820 531 17.7 (95%CI 16.3-19.9) 65.0% 41.9% Patients at risk 820 531 258 134 69 21 - Months *May 2009

What have we learned? Three weekly Carboplatinum / PLD is associated with: More delays- mainly due to hematological toxicity. More skin toxicity and stomatitis. Less hair loss and neurotoxicity. RECIST response and complete remission – similar. PFS ?

What is the standard for platinum sensitive relapse? ICON 4 / OVAR 2.2 Platinum VS platinum / paclitaxel. Carboplatin VS carboplatin / gemcitabine. OVAR 2.5

on behalf of all GCIG collaborators CALYPSO trial Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine on behalf of all GCIG collaborators

Treatment continues longer CALYPSO Study Schema International, Intergroup, Open-label, Randomized Phase III Study R A N D O M I Z E Experimental arm: CD PLD 30 mg/m2 IV d 1 Carboplatin AUC 5 d 1 Ovarian cancer in late relapse (> 6 months) after 1st- or 2nd-line platinum-based therapy (previous taxane required) Q 28 days x 6 courses* Control arm: CP Paclitaxel 175 mg/m2 IV d 1 Carboplatin AUC 5 d 1 Stratification: Therapy-free interval (6-12 mo vs > 12 mo) Measurable disease (yes vs no) Center Treatment continues longer if SD or Responsive. Q 21 days x 6 courses* *or progression in patients with SD or PR

NON-INFERIORITY study design CALYPSO Study Schema NON-INFERIORITY study design International, Intergroup, Open-label, Randomized Phase III Study R A N D O M I Z E Experimental arm: CD PLD 30 mg/m2 IV d 1 Carboplatin AUC 5 d 1 Ovarian cancer in late relapse (> 6 months) after 1st- or 2nd-line platinum-based therapy (previous taxane required) Q 28 days x 6 courses* Control arm: CP Paclitaxel 175 mg/m2 IV d 1 Carboplatin AUC 5 d 1 - Primary endpoint: PFS. - Secondary endpoints: QOL OS Q 21 days x 6 courses* *or progression in patients with SD or PR

Baseline Characteristics (1) CD (n=466) CP (n=508) Number of patients (%) Age, median ECOG performance status* 1 2 Primary site of disease Ovarian Papillary/Serous histology Initial FIGO stage* I/II III/IV Number of previous lines One Two 60.5 286 (61) 159 (34) 13 (3) 415 (89) 334 (72) 52 (11) 401 (86) 408 (88) 58 (12) 61.0 317 (62) 164 (32) 15 (3) 451 (89) 366 (72) 59 (12) 427 (84) 421 (83) 87 (17) * Missing values to attain 100%.

Baseline Characteristics (2) CD (n=466) CP (n=508) Number of patients (%) Prior taxane Interval since prior therapy, median 6-12 months > 12 months Measurable disease Yes No Tumour size < 5 cm > 5 cm Number of sites 1 > 1 462 (99) 162 (35) 304 (65) 281(60) 185 (39) 377(81) 89(19) 217(47) 249 (53) 500 (99) 182 (36) 326 (64) 321 (63) 188 (37) 419 (82) 90 (18) 245(48) 264(52)

Treatment Feasibility CD (n=465)** CP (n=501)** Total treatment duration, median wk* 21 16 Relative dose intensity % Carbo: 99 PLD: 99 Carbo: 99 Paclitaxel: 98 Patients with ≥ 6 cycles, n (%)* 395 (85) 392 (78) Patients with ≥ 9 cycles, n (%) 36 (8) 36 (7) Treatment discontinuation 70 (15) 110 (22) Toxicity - related treatment discontinuation* 27 (6) 73 (15) Hypersensitivity reactions* (5) (19) Hypersensitivity - related discontinuation* (1) (4) * P< 0.001; ** Patients receiving at least one cycle

Progression-Free Survival (ITT) CD CP Median PFS, mo 11.3 9.4 HR (95% CI) 0.82 (0.72, 0.94) Log-rank p-value (superiority) 0.005 P-value (non-inferiority) <0.001

Combination chemotherapy for platinum sensitive disease

What have we learned? Four weekly Carboplatinum / PLD is associated with: Less hematologic toxicity. More skin toxicity and stomatitis. Less hair loss and neurotoxicity. The combination of PLD-carboplatin was not inferior in term of PFS to paclitaxel-carboplatin, BUT the question of superiority remains open. 18% reduction in risk of recurrence (HR 0.82; P=0.005). Overall survival data & QOL pending.

What’s the implication? What have we learned? What’s the implication? Carboplatinum / PLD is associated with different toxicity profile from carboplatin/ paclitaxel. More delays- mailnly due to hematologic toxicity. More skin toxicity and stomatitis. Less hair loss and neurotoxicity. First line setting … may be equivalent. RECIST response and complete remission – similar. PFS ? Relapsed setting …. Definitely not inferior. Discuss options with patient ! How does this compare to weekly Paclitaxel?

Randomized phase III trial of conventional paclitaxel and carboplatin (c-TC) versus dose dense weekly paclitaxel and carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Japanese Gynecologic Oncology. Print this page Sub-category:Ovarian Cancer Category:Gynecologic Cancer Meeting:2008 ASCO Annual Meeting Abstract No:5506 Citation:J Clin Oncol 26: 2008 (May 20 suppl; abstr 5506) Author(s):S. Isonishi, M. Yasuda, F. Takahashi, N. Katsumata, E. Kimura, D. Aoki, T. Jobo, F. Terauchi, H. Tsuda, T. Sugiyama Abstract:Background: Tri-weekly administration with paclitaxel and carboplatin (c-TC) is considered the standard of care for treatment of ovarian carcinoma. We compared the c-TC with dose dense weekly administration with TC (dd-TC) as first-line chemotherapy for stage II-IV epithelial ovarian, fallopian tube or primary peritoneal cancer. Methods: We randomly assigned patients to receive carboplatin to an area under the plasma concentration-time curve of 6 with either paclitaxel at 180 mg/m2 on day 1 or paclitaxel at 80 mg/m2 on days 1, 8, and 15. The treatments were repeated every 3 weeks for six cycles; in responding patients, additional three cycles were administered. Primary endpoint was progression-free survival (PFS) to be compared by log-rank test. Assuming 300 eligible patients in each arm, the study had 0.8 power to detect 5 months increase in median PFS at 0.05 two-sided alpha. Results: Of 637 patients who underwent randomization, 631 were eligible. After median follow-up of 29 months, median duration of PFS in the c-TC group and dd-TC group was 17.1 and 27.9 months, respectively (P=0.0014 by the log-rank test), and overall survival at 2 years was 77.7% and 83.6%, respectively (P=0.05). Among 282 patients with measurable disease, objective response rates were 53.3% and 55.8% in the c-TC and dd- TC groups respectively (P=0.91). Grade 3 and 4 anemia was reported more frequently in the dd-TC group, and other toxicities were similar in both groups. Conclusions: The dd-TC improves PFS as compared with c-TC in patients with advanced epithelial ovarian cancer. Abstract Disclosures Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy and are designated with a caret symbol (^) here and in the print version.   Associated Presentation(s): Isonishi et al, ASCO 2008

Thank You Sana Al Sukhun, MD, MSc.