Case 1: Frontline Therapy
Transcription
Case 1: Frontline Therapy
Case 1: Frontline Therapy • A 67-year-old real estate agent presented to her PCP with early satiety and abdominal bloating for 6 weeks • Performance status = 0; no medical comorbidities with the exception of mild hypertension • Ultrasound revealed 6-8 cm bilateral adnexal masses with moderate to large volume ascites • Exploratory laparotomy with TAH / BSO, omentectomy, peritoneal stripping, and partial small bowel resection with primary reanastomosis was performed with optimal cytoreduction • Dx: poorly differentiated papillary serous adenocarcinoma 1 Case 2: Maintenance Therapy • A 62-year-old woman with an unremarkable PMH and excellent performance status presents to her gynecologist with progressive abdominal symptoms and pelvic mass by exam • CT scan reveals extensive mesenteric disease, multiple peritoneal implants, and ascites • Ultrasound-guided paracentesis revealed high-grade papillary serous adenocarcinoma consistent with a müllerian primary • Normal CEA, CA-125 = 8,433 • Treated with 3 cycles of neoadjuvant paclitaxel + carboplatin with good clinical response and CA-125 level falling to 89 • Undergoes an optimal interval cytoreduction (5 mm residuum) • Receives 3 additional cycles of carboplatin + paclitaxel and achieves a complete clinical remission by exam, CA-125 = 10, and CT scan • She expresses concern about the high risk for recurrence 2 Case 3: Late Recurrence • A 40-year-old patient presented with stage IIIC serous ovarian cancer and was optimally cytoreduced and treated with IP paclitaxel and cisplatin • Family hx: maternal aunt with ovarian cancer and 2 maternal cousins with premenopausal breast cancer • CA-125 was initially 456 U/mL and nadir was 11 U/mL after 6 cycles • Had grade 1 neuropathy that has resolved; PS = 0 • 24 months later her CA-125 = 118 U/mL and CT revealed small volume pelvic disease 3 Case 4: Early Recurrence • A 59-year-old florist presented with abdominal pain, bloating, and a pelvic mass. CA-125 was 1020 IU/mL • After an optimal cytoreduced (5 mm residuum) she randomized to Arm III of GOG-218 (paclitaxel and carboplatin 6 cycles with concurrent bevacizumab followed by maintenance bevacizumab) • Before starting maintenance bevacizumab she had a negative CA-125 and imaging (achieved complete clinical response) • Regimen was tolerated well except grade 1 neuropathy (mild numbness in her fingers and toes) • 5 months into maintenance bevacizumab she experienced abdominal pain and swelling develops • CA-125 has risen to 70 IU/mL and a CT scan reveals ascites and multiple pelvic masses causing intermittent moderate nausea and early satiety 4 Case 5: Treatment Toxicity • A 66-year-old woman with stage IIIC serous ovarian cancer recently underwent TAH / BSO and omentectomy resulting in suboptimal cytoreduction with small volume residual • PMH: – HTN treated with lisinopril, current BP 140/88 – DVT 20 years ago after elective cholecystectomy – PS = 1 • Surgical wound healing well and patient is without current complaint 5 CaseMat Home • • • • • • • • Introduction Patient Case 1: Frontline Patient Case 2: Maintenance Patient Case 3: Late recurrence Patient Case 4: Early recurrence Patient Case 5: Toxicity assessment Novel agents / developmental therapeutics Conclusion 6 Ovarian Cancer • 2nd most common gynecologic malignancy with the highest mortality – Estimated 21,880 new cases diagnosed in 2010 • Almost 75% of cases present with advanced stage disease – Risk of relapse in advanced stage disease is as high as 70% • No effective early diagnostic test available • The incidence increases with advancing age 7 American Cancer Society. Cancer Facts & Figures. 2010. Atlanta: American Cancer Society; 2010. Gynecologic Cancer Comparisons Estimated New Cancer Cases Ovarian Uterine Cervical Other 14% 7% 51% 28% Estimated Cancer Deaths Ovarian Cervical 14% Uterine Other 6% 54% 26% 8 American Cancer Society. Cancer Facts & Figures. 2010. Atlanta: American Cancer Society; 2010. Ovarian Cancer Staging Stage Description Stage I Confined to the Ovary IA Growth limited to one ovary, no ascites, capsule intact, no surface tumor extension IB Same as IA but involves both ovaries IC IA or IB but with positive washings or ruptured capsule Stage II Extends to True Pelvis IIA Involves fallopian tube or uterus IIB Extension to other pelvic tissues IIC Either IIA or IIB but with positive washings or ruptured capsule Stage III Extends Beyond the True Pelvis IIIA Tumor limited to true pelvis but microscopic positive biopsy outside the pelvis IIIB Abdominal implants up to 2 cm IIIC Positive lymph nodes or abdominal implants > 2 cm Stage IV Distant Disease Incidence Survival 20% 85% 5% 60% 58% 26% 17% 12% 9 Adapted from AJCC Cancer Staging Manual. 7th ed. New York, New York: Springer; 2010. Ovarian Cancer Symptomatology • Symptoms nonspecific and common • No difference in symptom frequency for late vs early stage Symptom(s) Early Stage Late Stage (n = 37) (n = 118) Odds Ratio (95% CI)* Unusual Bloating, Fullness, and Pressure in the Abdomen / Pelvis 65% 71% 1.3 (0.61-2.9) Unusual Abdominal or Lower Back Pain 49% 52% 1.1 (0.54-2.4) Frequent Urination, Urgency, or Burning 35% 32% 0.87 (0.40-1.9) Unusual Constipation 30% 21% 0.64 (0.28-1.5) 8% 22% 3.2 (0.96-10.7) Unusual Diarrhea 27% 14% 0.42 (0.18-1.0) Nausea 14% 11% 0.79 (0.26-2.4) Unusual Lack of Appetite *Late stage compared with early stage. Goff BA, et al. J Am Med Assoc. 2004;291:2705-2712; Olson SH, et al. Obstet Gynecol. 2001;98(2):212-217. 10 Historic Treatment Paradigm Diagnosis Symptoms Evaluation / Surveillance Chemotherapy #1 Surgery / Staging Progression Evaluation +/- Maintenance Chemo #2 Cure Progression Death Chemo #3+ Supportive Care 11 Secondary Response to Platinum Cleveland Clinic Experience • Retrospective review • ≥ 2 platinum-based recurrence regimens administered • 176 patients with 211 regimens reviewed • TFI2 > TFI1 in 4 pts (3%) • Length of TFI1 predictive of upper limit of response duration assuming same or similar regimen 13 Markman M, et al. J Clin Oncol. 2004;22(15):3120-3125. Chemotherapy Sensitivity End of FrontLine Therapy (Month 0) 6 Months 12 Months Primary Treatment Refractory Chemo Resistant Chemo Sensitive “IntermediateSensitive” “High-Sensitive” 14 CaseMat Home • • • • • • • • Introduction Patient Case 1: Frontline Patient Case 2: Maintenance Patient Case 3: Late recurrence Patient Case 4: Early recurrence Patient Case 5: Toxicity assessment Novel agents / developmental therapeutics Conclusion 15 Frontline Treatment 16 Primary Approach to Systemic Therapy: Landmark Phase III Studies GOG-111 – Cisplatin / cyclophosphamide vs cisplatin / paclitaxel 0.9 – Firstline paclitaxel ↑ 0.6 Paclitaxel / Cisplatin Cyclophos / Cisplatin 0.8 0.7 Proport ion PFS and OS in advanced disease OS 1.0 0.5 0.4 0.3 PFS 0.2 Paclitaxel / Cisplatin 0.1 Cyclophos / Cisplatin 0.0 0 6 12 18 24 30 36 42 48 Months After Entry into Study 17 McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. Primary Approach to Systemic . Therapy: Landmark Phase III Studies GOG-158 1.0 Carboplatin / paclitaxel OS 0.9 Cisplatin / paclitaxel 0.8 Proportion 0.7 0.6 0.5 PFS 0.4 0.3 0.2 Carboplatin / paclitaxel 0.1 Cisplatin / paclitaxel 0.0 0 12 24 36 Months ©2003 RF, by American of Clinical2003;21(17):3194-3200. Oncology Ozol et al. JSociety Clin Oncol. 48 60 18 Primary Approach to Systemic Therapy: Landmark Phase III Studies • GOG-172 – Paclitaxel + IV cisplatin vs paclitaxel + IP cisplatin – IP cisplatin ↑ OS in optimally debulked stage III disease CDDP = cisplatin. Armstrong DK, et al. N Engl J Med. 2006;354(1):34-43; Figure from GOG Intraperitoneal Chemotherapy Workshop, 2006. Available at: http://www.gog.org/ipchemoed/ipchemoed.html. Accessed March 11, 2011. 19 GOG-172: Treatment Regimens Every 21 Days Regimen 1 Intravenous 6 D1: IV Paclitaxel 135 mg/m2/24h D2: IV Cisplatin 75 mg/m2 D1 IV D2 IV Regimen 2 Intraperitoneal D1 IV D2 IP D8 IP D1: IV Paclitaxel 135 mg/m2/24h D2: IP Cisplatin 100 mg/m2 D8: IP Paclitaxel 60 mg/m2 20 Armstrong DK, et al. N Engl J Med. 2006;354(11):34-43. GOG-172: Survival Outcomes Progression-Free Survival 1.0 1.0 Rx Group PF Failed Total IV 50 160 210 IP 63 142 205 0.9 Proportion Progression-Free Overall Survival 0.8 0.7 IV: 18 mos IP: 24 mos HR: 0.80, P = 0.05 0.6 0.5 0.9 0.8 0.7 0.6 IV: 50 mos IP: 66 mos HR: 0.75, P = 0.03 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0 12 24 36 Months on Study 48 60 Rx Group Alive Dead IV 93 117 IP 117 88 Total 210 205 0.0 0 12 24 36 48 60 Months on Study 21 Armstrong DK, et al. N Engl J Med. 2006;354(11):34-43. GOG-172: Non-Hematologic Toxicity and Number of Courses Completed Grade 3 / 4 Adverse Events IV Gastrointestinal Event 24% 100 46% 90 2% Fatigue 4% 1% 7% 18% 11% % Completed 70 7% 27% 74 60 59 50 40 9% 19% 47 4 5 42 20 0 8 0 Neurologic Event 52 30 10 Metabolic Event 92 80 Renal or Genitourinary Event Pain IP 1 2 3 IP Courses 6 22 Armstrong DK, et al. N Engl J Med. 2006;354(11):34-43; Walker JL, et al. Gynecol Oncol. 2006;100(1):27-32. GOG-172: PFS Estimate by Total Cycles Administered 1.0 IP for 6 cycles superior to combination of IV/IP for 6 cycles 0.9 PFS Probability 0.8 No difference between routes if 1-2 or 3-5 cycles received 0.7 0.6 0.5 0.4 0.3 0.2 GOG 172-IP = 6 GOG 172-IP = 3-5 GOG 172-IP < 3 GOG 172-IV = 6 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months on Study 23 Tewari D, et al. J Clin Oncol. 2008;26(18S). Abstract 5549. GOG-172: Association of Survival With Reduced BRCA1 Expression • Archival tissue from 393 patients analyzed • Median follow-up 86 months BRCA1 Expression Median OS (mo) IP Arm IV Arm High (n = 204) 58 50 Low (n = 189) 84 48 Hazard ratio (95% CI) 0.689 (0.474-1.0) 1.299 (0.935-1.818) 24 Lesnock J, et al. Gynecol Oncol. 2010;116(3 suppl 1). Abstract 4. Moving the Bar: Primary Therapy • Dose-dense therapy • Biologics: anti-angiogenesis • Intraperitoneal chemotherapy 25 Dose-Dense Paclitaxel Ovarian Epithelial, PP, FT FIGO Stage II-IV DOSE DENSE Paclitaxel 80 mg/m2 over 1 hr day 1, 8, 15 Carboplatin AUC 6 day 1 q3w × 6-9 cycles Dose density: 80 mg/m2/wk n = 312 R Stratification: CONVENTIONAL Paclitaxel 180 mg/m2 over 3 hr day 1 Carboplatin AUC 6 day 1 q3w × 6-9 cycles Dose density: 60 mg/m2/wk n = 319 Residual disease: ≤ 1 cm, > 1 cm • FIGO stage II vs III vs IV • Histology: clear cell / mucinous vs serous / other • 26 Katsumata N, et al. Lancet. 2009;374(9698):1351-1363. Dose Dense: Survival Outcomes Progression-Free Survival 100 HR 0.714 (95% CI 0.58-0.88) P = 0.001 80 80 Patients surviving (%) Patients Surviving Progression-Free (%) 100 Overall Survival 60 40 20 Events Med PFS 160 28.0 mo 200 17.2 mo Dose dense Conventional 0 60 HR 0.75 (95% CI 0.57-0.98) P = 0.03 40 20 Dose dense Conventional Events 3-yr OS 96 72.1% 124 65.1% 0 0 6 12 18 24 30 36 42 48 Months From Randomization Katsumata N, et al. Lancet. 2009;374(9698):1351-1363. 0 6 12 18 24 30 36 42 48 54 60 66 Months From Randomization 27 Dose-Dense Therapy is Tougher to Maintain Dose Dense 76% Conventional P 67% 0.02 At least one dose reduction 48% 35% < 0.001 Carbo dose intensity 77% 79% NS Paclitaxel dose intensity 85% 86% NS At least one cycle delay 28 Katsumata N, et al. Lancet. 2009;374(9698):1351-1363. GOG-218 Primary Adjuvant and Maintenance Therapy RANDOMIZATION (n = 1873) Cycles 1-6* Cycles 7-22 Paclitaxel 175 mg/m2 Carboplatin AUC = 6.0 Placebo q3wk cycles Placebo cycles 2-62-6 Placebo q3w 16 Paclitaxel 175 mg/m2 Carboplatin AUC = 6.0 Bevacizumab 15 15 mg/kg q3wk cycles Bevacizumab mg/kg cycles 2-62-6 Placebo q3w 16 Paclitaxel 175 mg/m2 Carboplatin AUC = 6.0 Bevacizumab 15 15 mg/kg q3wk cycles Bevacizumab mg/kg cycles 2-62-6 Inclusion Criteria • EOC, FT, or primary peritoneal CA • Stage III with any gross (macroscopic or palpable) residual disease OR stage IV disease Burger R, et al. J Clin Oncol. 2010;28(18S). LBA1. Bevacizumab 15 mg/kg q3w 16 15 months total treatment Primary Endpoint: PFS *3-week cycles. 29 GOG-218: Patient Characteristics Arm I CP n = 625 Arm II CP + BEV n = 625 60 60 Arm III CP + BEV → BEV n = 623 60 Suboptimally debulked stage III disease 41% 41% 39% Stage IV disease 25% 26% 27% 11 (0-22) 12 (0-22) 14 (0-21) On treatment at time of analysis 14% 13% 19% Completed treatment regimen 16% 17% 24% Experienced disease progression while on treatment 48% 42% 26% Median age (years) Median number of cycles with bevacizumab or placebo (range) 30 Burger R, et al. J Clin Oncol. 2010;28(18S). LBA1. GOG-218 Investigator-Assessed PFS Arm I Arm II Arm III CP + PLA → PLA CP + BEV → PLA CP + BEV BEV (n = 625) (n = 625) (n = 623) Median follow-up: 17.4 months Proportion Surviving Progression-Free 1.0 Patients with event, n (%) 0.9 Median PFS, months 0.8 HR (stratified) (95% CI) 0.7 One-sided log-rank P value 375(60) 405(67) 363(71) 10.4 11.5 13.9 0.864 0.726 (0.759-0.996) (0.627-0.840) 0.0218 < 0.0001* 0.6 0.5 *P 0.4 value boundary = 0.0116. 0.3 0.2 CP (arm I) + BEV (arm II) 0.1 + BEV → BEV (arm III) 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Months Since Randomization 31 Burger R, et al. J Clin Oncol. 2010;28(18S). LBA1. Proportion Surviving Progression-Free GOG-218: Progression-Free Survival 1.0 Patients with event, n (%) 0.9 Median PFS, months 0.8 Arm I CP (n = 625) Arm II CP + BEV (n = 625) Arm III CP + BEV BEV (n = 623) 423 (67.7) 418 (66.9) 360 (57.8) 10.3 11.2 14.1 Stratified analysis HR (95% CI) 0.7 0.908 0.717 (0.759-1.040) (0.625-0.824) One-sided P value (log rank) 0.080* < 0.0001* 0.6 0.5 0.4 0.3 0.2 CP (Arm I) + BEV (Arm II) 0.1 + BEV BEV maintenance (Arm III) 0 0 12 24 Months Since Randomization 36 *P value boundary = 0.0116. 32 Burger R, et al. J Clin Oncol. 2010;28(18S). LBA1. GOG-218: Overall Survival 1.0 0.9 Proportion Alive 0.8 0.7 0.6 0.5 0.4 Patients with events, n (%) 0.3 Median, months Arm I CP (n = 625) Arm II CP + BEV (n = 625) Arm III CP + BEV BEV (n = 623) 156 (25.0) 150 (24.0) 138 (22.2) 39.3 38.7 39.7 HR* (95% CI) One-sided P value 0.2 0.1 1.036 0.915 (0.827-1.297) (0.727-1.152) 0.361 0.252 0 0 12 24 36 48 Months Since Randomization No at risk 625/625/623 442/432/437 173/162/171 46/39/40 *Stratified analysis. 33 Burger R, et al. J Clin Oncol. 2010;28(18S). LBA1. GOG 218: Toxicity Comparisons Arm I (CP) Arm II (CP + BEV) Arm III (CP + BEV --> BEV) P = NS; P = 0.03 if combined bev arms GI Perforation/fistula P < 0.036 Hemorrhage P < 0.005 Hypertension 0 5 10 15 20 34 Burger R, et al. J Clin Oncol. 2010;28(18S). LBA1. GOG-218: Prospective Analysis of Gastrointestinal Perforation • Overall incidence in 1759 patients Odds Ratio 14 12 Multivariate OR – Placebo: 1.7% – Concurrent bevacizumab: 3.4% – Concurrent + maintenance bevacizumab: 3.4% 16 10 8 6 4 2 0 IBD LBR SBR Bev Characteristic IBD = inflammatory bowel disease, LBR = large bowel resection SBR = small bowel resection, Bev = bevacizumab 35 Burger R, et al. Society of Gynecologic Oncologists 2011 Annual Meeting. Abstract 7. ICON-7 First-Line Bevacizumab RANDOMIZATION N = 1520 Cycles 1-6* Cycles 7-18* Paclitaxel 175 mg/m2 Carboplatin AUC = 6.0 Paclitaxel 175 mg/m2 Carboplatin AUC = 6.0 Bevacizumab 7.5 mg/kg q3w × 5-6† Inclusion Criteria • EOC, fallopian, or PPC • Optimal or suboptimal cytoreduction • Stage I-IV Bevacizumab 7.5 mg/kg q3w 12 12 months total Primary Endpoint: PFS Randomization closed Feb 2009 *3-week cycles; †Begin cycle 2, bevacizumab can be omitted from the first cycle if cytotoxic chemotherapy must be started within 4 weeks of surgery. 36 Primary Investigator: T Perren. Available at: http://www.icon7trial.org/. Accessed February 22, 2011. ICON-7: PFS Benefit Proportion Alive Without Progression From Date of Last CT or Last Clinical Follow-up, Whichever Was Later 1.00 Events, n (%) CP CPB 7.5+ 392 (51) 367 (48) 17.3 19.0 Median, months 0.75 Log-rank test P = 0.0041 HR (95% CI) 0.81 (0.70-0.94) 0.50 CP duration 0.25 Number at risk CP CPB 7.5+ CPB7.5+ duration 0 0 3 6 9 764 764 723 748 693 715 556 647 12 15 18 Time (months) 464 585 307 399 216 263 21 24 27 30 143 144 91 73 50 36 25 19 37 Perren T, et al. ESMO 2010. Abstract LBA4. Available at: http://www.icon7trial.org/. Accessed February 22, 2011. ICON-7: Preliminary Analysis of Overall Survival Proportion Surviving 1.00 0.75 0.50 Patients with event, n (%) Control Research 130 (17) 111 (15) P = 0.098 Log-rank test 0.25 Based on immature OS data (241 of 715 required events, 16% of all patients) as required by regulatory authorities (approved by IDMC and TSC) 0.81 (0.63-1.04) Hazard ratio (95% CI) 1-year survival rate, % Anti-VEGF after progression, n (%) 93 95 30 (4) 14 (2) 0 0 3 30 Number at risk Control 764 741 Research 764 753 6 724 737 9 701 716 12 652 678 15 486 525 368 404 18 252 259 21 24 159 162 27 83 89 Time (months) 33 40 38 Perren T, et al. 35th ESMO Congress Milan, Italy. October 2010. Abstract LBA4. 38 ICON-7: Selected Adverse Events (all grades) 45 40 Patients (%) Control (n=753) 39.6 Research (n=745) 35 30 29.1 28.3 25.9 25 20 15 10 5 0 12.5 11.6 6.2 5.0 4.4 2.5 2.1 1.31.7 0.41.3 6.7 4.1 9.2 3.6 1.5 0.4 0.4 0 0 2.8 2.0 ATE = arterial thromboembolism; CHF = congestive heart failure; RPLS = reversible posterior leukoencephalopathy syndrome; VTE = venous thromboembolism 39 Perren T, et al. ESMO 2010. Abstract LBA4. Available at: http://www.icon7trial.org/. Accessed February 22, 2011. Key Differences Between GOG-218 and ICON-7 Trial Setting / Design Patient Population Additional Endpoint GOG-218 • Double-blinded, placebo-controlled • Three-arm study • Bev for 15 months • Bev dose: 15 mg q3w • Stage III (suboptimal) • Stage III (optimal, visual / palpable) • Stage IV • OS analysis (formal testing at time of PFS) • IRC ICON-7 • • • • Open-label Two-arm study Bev for 12 months Bev dose: 7.5 mg q3w • Stage I or IIA (grade 3 / clear cell histology) • Stages IIB-IV (all) • Defined final OS analysis (end 2012) • No IRC 40 Phase III GOG-252 Schema Cycles 1-6* Cycles 7-22* IV Paclitaxel 80 mg/m2 days 1, 8, and 15 IV Carboplatin AUC 6 day 1 Bevacizumab 15 mg/kg q3w RANDOMIZATION N = 1100 Bevacizumab 15 mg/kg q3w† IV Paclitaxel 80 mg/m2 days 1, 8, and 15 IP Carboplatin AUC 6 day 1 Bevacizumab 15 mg/kg q3w Bevacizumab 15 mg/kg q3w† IV Paclitaxel 135 mg/m2 day 1 IP Cisplatin 75 mg/m2 day 2 IP Paclitaxel 60 mg/m2 day 8 Bevacizumab 15 mg/kg q3w Bevacizumab 15 mg/kg q3w † *Each cycle is 3 weeks; †Begin cycle 2. Walker JL. Am Soc Clin Oncol Ed Book. 2009:308-312. Primary endpoint: PFS 41 Case 1 Revisited: Frontline Therapy • A 67-year-old real estate agent presented to her PCP with early satiety and abdominal bloating for 6 weeks • Performance status = 0; no medical comorbidities with the exception of mild hypertension • Ultrasound revealed 6-8 cm bilateral adnexal masses with moderate to large volume ascites • Exploratory laparotomy with TAH / BSO, omentectomy, peritoneal stripping, and partial small bowel resection with primary reanastomosis was performed with optimal cytoreduction • Dx: poorly differentiated papillary serous adenocarcinoma 42 CaseMat Home • • • • • • • • Introduction Patient Case 1: Frontline Patient Case 2: Maintenance Patient Case 3: Late recurrence Patient Case 4: Early recurrence Patient Case 5: Toxicity assessment Novel agents / developmental therapeutics Conclusion 43 Maintenance Treatment 44 Historic Treatment Paradigm Diagnosis Symptoms Evaluation / Surveillance Chemotherapy #1 Surgery / Staging Progression Evaluation Progression Death +/- Maintenance Chemo #2 Cure Chemo #3+ Supportive Care What we know (maintenance): • 50% of CRs recur • 40% of PCRs recur • Reassessment is experimental 45 Maintenance Therapy Scorecard Maintenance Beneficial? Strategy No Prolonged Initial Therapy ✓ Short Duration / Non-Cross Resistant Chemotherapy ✓ High-Dose Chemotherapy ✓ Intraperitoneal P32 ✓ Interferon- ✓ Anti-CA-125 Ab ✓ Biologic Agent (MMPI, bevacizumab*) ✓ Paclitaxel (6 months) ✓ Paclitaxel (1 year) Yes ✓* ✓? 46 Maintenance Therapy: Phase III Trial N Maintenance Arms Median PFS Statistic (months) SWOG 9701 / GOG 1781,2 MITO-013 AGO-OVAR / GINECO4 AFTER-65 296 273 1308 200 Paclitaxel 175 mg/m2 × 3 vs Paclitaxel 175 mg/m2 × 12 Observation vs Topotecan 1.5 mg IV days 1-5 q3w × 4 Observation vs Topotecan 1.25 mg IV days 1-5 q3w × 4 Observation vs Paclitaxel 175 mg/m2 q3w × 6 14 HR 0.68 22 P = 0.004 28.4 HR 1.18 18.2 P = 0.83 18.5 HR 0.97 18.2 P = 0.688 30 2-year OS: 90% vs 87% P = NS 34 1Markman M, et al. J Clin Oncol. 2003;21(13):2460-2465; 2Markman M, et al. Gynecol Oncol. 2009;114(2):195-198; 3DePlacido S, et al. J Clin Oncol. 2004;22(13):2635-2642; 4Pfisterer J, et al. J Natl Cancer Inst. 2006;98(15):1036-1045; 5Pecorelli S, et al. J Clin Oncol. 2009;27:4642-4648. 47 MITO-1 AGO / GINECO EOC Stage IC-IV EOC Stage IIB-IV Paclitaxel 175 mg/m2 Carboplatin AUC 5 6 cycles RANDOMIZE (N = 1308) CR or PR Paclitaxel 175 mg/m2 Paclitaxel 175 mg/m2 Carboplatin AUC 5 Carboplatin AUC 5 6 cycles 6 cycles RANDOMIZE (N = 273) Topotecan 1.5 mg/m2 Days 1-5 4 cycles NFT De Placido S, et al. J Clin Oncol. 2004:22:2635-2642. Topotecan 1.25 mg/m2 Days 1-5 4 cycles Pfisterer J, et al. J Natl Cancer Instit. 2006;98:1036-1045. 48 Randomized Maintenance Trials: Topotecan MITO-1 AGO / GINECO PFS PFS Hazard Ratio 1.18 (0.86 - 1.63) De Placido S, et al. J Clin Oncol. 2004:22:2635-2642. Pfisterer J, et al. J Natl Cancer Instit. 2006;98:1036-1045. 49 Consolidation Therapy: GOG-178 EOC, Fallopian, PP Stage III-IV Prior chemo 5-6 cycles Register 3-8 weeks CCR Neuropathy ≤ Gr II N = 450 anticipated Accrual closed 9/6/2001 N = 277, 222 with follow-up 54 Progression events R A N D O M I Z E Paclitaxel (3-hour) 175 mg/m2 q 28 d 3 Paclitaxel (3-hour) 175 mg/m2 q 28 d 12 End points • PFS • OS 50 Markman M, et al. Gynecol Oncol. 2009;114(2):195-198. SWOG 9701 / GOG-178 Updated Progression-Free Survival 100% Hazard ratio 0.68 (P = 0.004) 80% At Risk Failed Median (mo) Paclitaxel 12 courses 150 104 22 Paclitaxel 3 courses 146 120 14 60% 40% 20% 0% 0 24 48 72 96 Months After Registration 51 Markman M, et al. Gynecol Oncol. 2009;114(2):195-198. Overall Survival (%) SWOG 9701 / GOG-178 Updated Overall Survival 100 Hazard ratio 0.88 (P = 0.34) 80 60 40 20 At Risk Deaths Paclitaxel 12 courses 150 76 Paclitaxel 3 courses 146 88 0 0 24 Median (months) 53 48 48 72 96 Months After Registration 52 Markman M, et al. Gynecol Oncol. 2009;114(2):195-198. GOG-178: Toxicity Result 3-Mos PFS 21 G4 Neut 9% G3 Myalgia 0% G2 Neuropathy 14% G3 Neuropathy 1% Adapted from Markman M, et al. Clin Adv Hem Onc. 2003. 12-Mos P 28 4% 1% 18% 5% 0.0023 NS NS NS NS 53 SWOG 9701 / GOG-178 Survival by CA-125 100% At Risk CA-125: 0 - 10 175 CA-125: >10 - 35 121 80% Median Death in Months 70 57 76 41 HR: 0.59, P = 0.03 60% 40% 20% 0% 0 24 Markman M, et al. J Clin Oncol.2006;24:1454. 48 Months After Registration 72 96 54 Phase III Maintenance Trials: AFTER-6 EOC, PP, FT cancer • N = 200 over 7+ yrs – Closed due to slow accrual Paclitaxel & Carboplatin cCR or pCR – Looking for 15% increase in absolute PFS • Violations – 14% of obs patients got treatment – 22% of pac patients stopped early Paclitaxel 175 mg/m2 q21d 6 mos No Treatment • Results – Median f/u: 44 mos – PFS: 34 vs 34.5 mos (NS) N = 250 patients PFS (Iº) Survival & Toxicity (IIº) endpoints – OS (3 yr): 88% (obs) vs 78% (pac) 55 Pecorelli S, et al. J Clin Oncol. 2009;27:4642-4648. Proportion Surviving Progression-Free GOG-218: Progression-Free Survival 1.0 Patients with event, n (%) 0.9 Median PFS, months 0.8 Arm I CP (n = 625) Arm II CP + BEV (n = 625) Arm III CP + BEV BEV (n = 623) 423 (67.7) 418 (66.9) 360 (57.8) 10.3 11.2 14.1 Stratified analysis HR (95% CI ) 0.7 0.908 0.717 (0.759-1.040) (0.625-0.824) One-sided P value (log rank) 0.080* < 0.0001* 0.6 0.5 0.4 0.3 0.2 CP (Arm I) + BEV (Arm II) 0.1 + BEV BEV maintenance (Arm III) 0 0 12 24 36 Months Since Randomization *P value boundary = 0.0116. 56 Burger R, et al. J Clin Oncol. 2010;28(18S). LBA1. GOG-218: Overall Survival 1.0 0.9 Proportion alive 0.8 0.7 0.6 0.5 0.4 Patients with events, n (%) 0.3 Median, months Arm I CP (n = 625) Arm II CP + BEV (n = 625) Arm III CP + BEV BEV (n = 623) 156 (25.0) 150 (24.0) 138 (22.2) 39.3 38.7 39.7 HR* (95% CI ) One-sided P value 0.2 0.1 1.036 0.915 (0.827-1.297) (0.727-1.152) 0.361 0.252 0 0 No at risk 625/625/623 12 24 36 Months since randomization 442/432/437 173/162/171 48 46/39/40 *Stratified analysis. 57 Burger R, et al. J Clin Oncol. 2010;28(18S). LBA1. GOG-218 and ICON-7: Restricted Means Estimate – Benefit During Exposure Only? 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 14 vs 17 3 months’ difference Research Arm 0 6 20 18 16 14 12 10 8 6 4 Research Arm 2 0 0 6 12 18 24 30 36 GOG-218 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 30 13.3 vs 16.5 3 months’ difference Research Arm 0 6 12 18 24 30 36 ICON-7 (III suboptimal and IV subgroup) 25 20 15 10 Research Arm 5 12 18 Time (months) 24 30 36 0 -5 0 6 12 18 24 30 36 Time (months) -10 Burger R, et al. J Clin Oncol. 2010;28(18S). LBA1; Perren T, et al. -15ESMO 2010. Abstract LBA4. 58 ICON-7 First-Line Bevacizumab RANDOMIZATION N = 1520 Cycles 1-6* Cycles 7-18* Paclitaxel 175 mg/m2 Carboplatin AUC = 6.0 Paclitaxel 175 mg/m2 Carboplatin AUC = 6.0 Bevacizumab 7.5 mg/kg q3w × 5-6† Inclusion Criteria • EOC, fallopian, or PPC • Optimal or suboptimal cytoreduction • Stage I-IV Bevacizumab 7.5 mg/kg q3w 12 12 months total Primary Endpoint: PFS Randomization closed Feb 2009 *3-week cycles; †Begin cycle 2, bevacizumab can be omitted from the first cycle if cytotoxic chemotherapy must be started within 4 weeks of surgery. 59 Primary Investigator: T Perren. Available at: http://www.icon7trial.org/. Accessed February 22, 2011. Phase III GOG-252 Schema Cycles 1-6* Cycles 7-22* IV Paclitaxel 80 mg/m2 days 1, 8, and 15 IV Carboplatin AUC 6 day 1 Bevacizumab 15 mg/kg q3w RANDOMIZATION N = 1100 Bevacizumab 15 mg/kg q3w† IV Paclitaxel 80 mg/m2 days 1, 8, and 15 IP Carboplatin AUC 6 day 1 Bevacizumab 15 mg/kg q3w Bevacizumab 15 mg/kg q3w† IV Paclitaxel 135 mg/m2 day 1 IP Cisplatin 75 mg/m2 day 2 IP Paclitaxel 60 mg/m2 day 8 Bevacizumab 15 mg/kg q3w Bevacizumab 15 mg/kg q3w † *Each cycle is 3 weeks; †Begin cycle 2. Walker JL. Am Soc Clin Oncol Ed Book. 2009;308-312. Primary endpoint: PFS 60 GOG Ovarian Strategy: 262 Paclitaxel 80 mg/m2 IV weekly Carboplatin AUC 6 IV q3wk Bevacizumab 15 mg/kg IV (beginning cycle 2; optional*) Suboptimal (> 1 cm Residual) Paclitaxel 175 mg/m2 IV q3wk Carboplatin AUC 6 IV q3wk Bevacizumab 15 mg/kg IV (beginning cycle 2; optional*) Bevacizumab q3wk (If chosen) Maintenance to Progression *Patient chooses whether to receive bevacizumab prior to enrolling in study. 61 Available at: http://www.clinicaltrials.gov/ct2/show/NCT01167712. Accessed April 12, 2011 Maintenance Therapy Scorecard Maintenance Beneficial? Strategy No Prolonged Initial Therapy ✓ Short Duration / Non-Cross Resistant Chemotherapy ✓ High-Dose Chemotherapy ✓ Intraperitoneal P32 ✓ Interferon- ✓ Anti-CA-125 Ab ✓ Biologic Agent (MMPI, bevacizumab*) ✓ Paclitaxel (6 months) ✓ Paclitaxel (1 year) Yes ✓* ✓? 62 Maintenance Trials: Ongoing GOG-212 EOC, PP, FT cancer • Bevacizumab • Abagovomab Paclitaxel Carboplatin • Erlotinib • Sorafenib • Pazopanib Paclitaxel CTI-2103 No 12 mos 12 mos Treatment • Intedanib (BIBF 1120) N = 1550 patients Survival primary endpoints QOL endpoints 63 Case 2: Maintenance Therapy • A 62-year-old woman with an unremarkable PMH and excellent performance status presents to her gynecologist with progressive abdominal symptoms and pelvic mass by exam • CT scan reveals extensive mesenteric disease, multiple peritoneal implants and ascites • Ultrasound-guided paracentesis revealed high grade papillary serous adenocarcinoma consistent with a müllerian primary • Normal CEA, CA-125 = 8,433 • Treated with 3 cycles of neoadjuvant paclitaxel + carboplatin with good clinical response and CA-125 level falling to 89 • Undergoes an optimal interval cytoreduction (5 mm residuum) • Receives 3 additional cycles of carboplatin + paclitaxel and achieves a complete clinical remission by exam, CA-125 = 10, and CT scan • She expresses concern about the high risk for recurrence 64 CaseMat Home • • • • • • • • Introduction Patient Case 1: Frontline Patient Case 2: Maintenance Patient Case 3: Late recurrence Patient Case 4: Early recurrence Patient Case 5: Toxicity assessment Novel agents / developmental therapeutics Conclusion 65 Late Recurrence 66 1000 100 900 90 800 80 700 70 600 60 500 50 400 40 300 30 200 20 100 10 0-3 Prog 0-3 Non PD 3-12 mos 12-18 mos Percentage Days Treatment-Free Interval and Survival 18+ mos PFS (days) 90 176 174 275 339 OS (days) 217 375 375 657 957 Response (%) 9 24 35 52 62 67 Pujade-Lauraine E, et al. Proc Am Soc Clin Oncol. 2002;21. Abstract 829. Recurrent Ovarian Cancer: Options A. Chemo Single Agent Combination Non-Platinum (novel agents) Platinum B. Surgery C. Other (biologics, radiation, hormones …) 68 Secondary Cytoreductive Surgery Goal of surgery: No gross residual disease DFI 6-12 mos 12-30 mos > 30 mos Single Site Suggest SC Suggest SC Suggest SC Multiple Sites: No Carcinomatosis Carcinomatosis Offer SC Suggest SC Suggest SC No SC Offer SC Suggest SC DFI = disease-free interval; mos = months; SC = secondary cytoreduction. 69 Chi DS, et al. Cancer. 2006;106(9):1933-1939. Phase III GOG-213 Recurrent Ovarian, PPT, or FT Cancer; TFI ≥ 6 months Surgical Candidate? Yes No Randomize Randomize Surgery No Surgery Chemotherapy Randomization Inclusion Criteria • EOC, fallopian, or peritoneal cancer • One prior therapy, platinum-free interval ≥ 6 months Carboplatin / Paclitaxel Carboplatin / Paclitaxel / Bevacizumab Bevacizumab Until Progression Primary Endpoint: OS Available at: http://www.cancer.gov/clinicaltrials/GOG-0213; Coleman R. Clinical Ovarian Cancer. 2008;1(1):78-80. 70 AGO-OVAR DESKTOP III A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer Platinum-sensitive recurrent cancer of the ovaries, fallopian tubes, or peritoneum PFI > 6 mos No prior chemotherapy for this 1st relapse Complete resection seems feasible and positive AGO score: • PS ECOG 0 • No ascites > 500 mL • Prior complete debulking or initial FIGO I/II (if data available) R A N D O M I Z E Cytoreductive surgery Platinum-based chemotherapy* recommended No surgery *Recommended platinum-based chemotherapy regimens: - Carboplatin / paclitaxel - Carboplatin / gemcitabine - Carboplatin / pegylated liposomal doxorubicin - or other platinum combinations in prospective trials 71 Available at: http://www.clinicaltrials.gov/ct2/show/NCT01166737. Accessed March 11, 2011. Recurrence Regimens NCCN Preferred Agents Platinum-Sensitive Combination* Platinum-Sensitive Single-Agent Platinum-Resistant Single-Agent Targeted Therapy Carboplatin / Paclitaxel (cat 1) Carboplatin Docetaxel Bevacizumab Carboplatin / Weekly Paclitaxel Cisplatin Oral etoposide Carboplatin / Docetaxel Gemcitabine Carboplatin / Gemcitabine Pegylated liposomal doxorubicin Cisplatin / Gemcitabine Weekly paclitaxel Carboplatin / Liposomal doxorubicin Topotecan *Platinum-based combination therapy should be considered for platinum-sensitive recurrences. NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer v.1.2011. Available at: http://www.nccn.org/professionals/physician_gls/PDF/ovarian.pdf. Accessed October 7, 2010. 72 Selected Positive Phase III Trials Recurrent Disease Trial ICON 4 AGOOVAR-2.5 OVA-301 CALYPSO Year 2003 2006 2010 2010 Platinum Sensitive Sensitive Sensitive and Resistant Intervention N No Prior Trt (%) Med PFS (mo) OS (mo) Platinum 410 57 9.0 24 Platinum + Paclitaxel 392 57 12.0 29 Carboplatin 178 33 5.8 17.3 Carboplatin + Gemcitabine 178 31 8.6 18 PLD 335 - 5.8 Trabectedin + PLD 337 - 7.3 Carboplatin + Paclitaxel 507 - 9.4 Carboplatin + PLD 466 - 11.3 Sensitive Data maturing Data maturing Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322; Parmar MK, et al. Lancet. 2003;361:2099-2106; Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707; Monk BJ, et al. J Clin Oncol. 2010;28(19):3107-3114; Pujade-Lauraine E, et al. J Clin Oncol. 2010;28(20):3323-3329. PLD = Pegylated liposomal doxorubicin. 73 Phase III CALYPSO International Randomized GCIG Intergroup Study Patients > 6 months post first- or secondline platinum-based therapy w / prior taxane exposure Paclitaxel 175 mg/m2 + Carboplatin AUC 5 q3w 6 n = 507 PLD 30 mg/m2 + Carboplatin AUC 5 q3-4w 6 n = 466 Primary Endpoint: PFS Secondary Endpoints: OS, safety, QOL PLD = pegylated liposomal doxorubicin. 74 Pujade-Lauraine E, et al. J Clin Oncol. 2010;28(20):3323-3329. Patient Characteristics and Treatment Exposure Carboplatin / PLD n = 466 Carboplatin / Paclitaxel n = 507 Stage III / IV 401 (86%) 427 (84%) Previous Lines of Therapy 1 2 408 (88%) 58 (12%) 421 (83%) 87 (17%) Treatment-Free Interval 6-12 m > 12 m 162 (35%) 304 (65%) 182 (36%) 326 (64%) Trial Treatment Exposure Median Treatment Duration (weeks) Patients With ≥ 6 Cycles* 21 16 85% 77% *P < 0.001. 75 Pujade-Lauraine E, et al. J Clin Oncol. 2010;28(20):3323-3329. Proportion not Progressing Primary Endpoint PFS Carbo / PLD Carbo / Pac 11.3 9.4 Median PFS (months) 1.0 0.8 C / PLD HR (95% CI) 0.82 (0.72-0.94) P Value (non-Inferiority)* < 0.001 0.6 C / Pac 0.4 0.2 0.0 0 Number at Risk 467 CD CP 509 6 12 18 24 30 Months From Randomization 397 405 188 152 60 45 20 10 4 2 *P value superiority = 0.005. Pujade-Lauraine E, et al. J Clin Oncol. 2010;28(20):3323-3329. 76 Randomized Phase III Study Comparing PLD and Trabectedin With PLD Alone in Subjects With Advanced Relapsed Ovarian Cancer (OVA-301) Advanced recurrent EOC 1 prior platinum-based tx regimen Evaluable / measurable dz Platinum sensitive or resistant ECOG PS ≤ 2 Primary Endpoint: PFS Secondary Endpoints: OS, RR, safety Pegylated Liposomal Doxorubicin 50 mg/m2 IV q4w n = 335 Pegylated Liposomal Doxorubicin 30 mg/m2 IV q4w Trabectedin 1.1 mg/m2 q3w n = 337 Translational Studies PK, PD, QOL, pharmacoeconomics, and circulating tumor cells 77 Monk B, et al. J Clin Oncol. 2010;28(19):3107-3114. OVA-301: Primary and Secondary Endpoints 30 28 PLD PLD+T PFS (mos) 19 20 HR: 0.79 P = 0.019 10 5.8 7.3 HR: 0.73 P = 0.017 7.5 HR: 0.95 P = 0.75 P = 0.008 9.2 15 10 3.7 4 5 20 % Response 25 25 15 30 5 0 0 ITT ITT-PS ITT-PR RR Data are for Independent Radiology Review PS = platinum-sensitive, PR = platinum-resistant ITT = intent-to-treat, RR = response rate Monk B, et al. J Clin Oncol. 2010;28(19):3107-3114. 78 RANDOMIZATION N = 450 Ovarian Cancer Evaluation of Bevacizumab and Safety (OCEANS) Phase III Second-Line Bevacizumab Trial Gemcitabine 1000 mg/m2 day 1 & 8 Carboplatin AUC = 4.0 day 1 Bevacizumab 15 mg/kg day 1 q3w 6 Bevacizumab to 51 weeks Gemcitabine 1000 mg/m2 day 1 & 8 Carboplatin AUC = 4.0 day 1 Placebo day 1 q3w 6 Placebo to 51 weeks Bevacizumab to PD Primary Endpoint: PFS Inclusion Criteria • Documented ovarian, PP, or fallopian tube carcinoma that has recurred • No prior chemotherapy in the recurrent setting (platinum sensitive) 79 Available at: http://clinicaltrials.gov/show/NCT00434642. Summary Recurrent Ovarian Cancer: Sensitive Chemotherapy Single-Agent Combination Options NonPlatinum (novel agents) Platinum 80 Case 3 Revisited: Late Recurrence • A 40-year-old patient presented with stage IIIC serous ovarian cancer and was optimally cytoreduced and treated with IP paclitaxel and cisplatin • Family hx: maternal aunt with ovarian cancer and 2 maternal cousins with premenopausal breast cancer • CA-125 was initially 456 U/mL and nadir was 11 U/mL after 6 cycles • Had grade 1 neuropathy that has resolved; PS = 0 • 24 months later her CA-125 = 118 U/mL and CT revealed small volume pelvic disease 81 Poly (ADP-Ribose) Polymerase (PARP) • Key regulator of DNA damage repair – Involved in DNA base-excision repair • Binds directly to DNA damage and produces large branched chains of poly (ADP-ribose) DNA damage PARP NAD+ nicotinamide + pADPr 82 Tutt A, et al. Lancet.2010;376(9737):235-244. PARP Inhibitors Suggested Mechanism of Action Chemotherapy inflicts DNA damage via adducts and DNA cross-linking PARP1 PARP Inhibitor PARP1 PARP1 Upregulation Base-excision repair of DNA damage Inhibition of PARP1 PARP1 Disables DNA base-excision repair Replication fork collapse Double strand DNA break BRCA1 BRCA2 CELL SURVIVAL CELL DEATH 83 O’Shaughnessy J, et al. J Clin Oncol. 2009;27(15S). Abstract 3. Phase I Trial of the PARP Inhibitor Olaparib 84 Fong PC, et al. N Engl J Med. 2009;361(2):123-134. Expansion Cohort of Phase I Olaparib Trial (200 mg BID) Characteristic BRCA1 mutation, n BRCA2 mutation, n Strong family history, n Mean age, years (range) 41 8 1 52 (37-80) Platinum status, n (%) Sensitive Resistant Refractory 13 (26) 24 (48) 13 (26) Number of prior therapies, n (%) 1 2 3 >4 5 (20) 11 (22) 11(22) 23 (46) 85 Fong PC, et al. J Clin Oncol. 2010;28(15):2512-2519. Olaparib Phase I Expansion Clinical Activity by RECIST + GCIG Total Platinum Sensitive Platinum Resistant Platinum Refractory 50 13 24 13 Responders by RECIST 14 (28%) 4 (46%) 8 (34%) 0 (0%) Responders by GCIG CA-125 17 (34%) 8 (62%) 7 (30%) 2 (15%) Responders by either RECIST or GCIG criteria 20 (40%) 8 (62%) 10 (42%) 2 (15%) SD (> 16 weeks) 3 (6%) 1 (7%) 1 (4%) 1 (8%) 28 (23-33) 28 (20-37) 28 (19-38) Not evaluable Number of evaluable patients Median duration of response in weeks (95% CI) 86 Fong PC, et al. J Clin Oncol. 2010;28(15):2512-2519. Olaparib Phase I Expansion Adverse Events > 8 % Incidence Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%) Lymphopenia 0 0 6 2 Anemia 0 6 8 0 Nausea 36 6 6 0 Vomiting 14 4 2 0 Diarrhea 4 2 2 0 Dyspepsia 6 10 0 0 Anorexia 12 4 0 0 Dysgeusia 8 2 0 0 Fatigue 8 32 4 0 Dizziness 4 2 2 0 87 Fong PC, et al. J Clin Oncol. 2010;28(15):2512-2519. Olaparib Phase I Expansion Correlation of Platinum-Free Interval and Best Response Platinum-Free Interval (months) 24 Sensitive Resistant Refractory 18 12 6 0 CR/PR SD > 4mos PD 88 Fong PC, et al. J Clin Oncol. 2010;28(15):2512-2519. Phase II Study of Olaparib of Patients With BRCA1 or BRCA2 Mutation • Two dosages tested in sequential cohorts of patients with recurrent, measurable disease • Primary endpoint: response rate 400 mg BID n = 33 ORR = 33% 100 mg BID n = 24 ORR = 13% • Adverse events: nausea, fatigue, anemia 89 Audeh MW, et al. Lancet. 2010;376(9737):245-251. Phase II Study of Olaparib vs PLD in Patients With BRCA1 or BRCA2 Mutation • BRCA1/2 germline carriers with ovarian cancer • Progressive or recurrent disease < 12 months after previous platinum-based chemotherapy RANDOMIZATION Open label Planned N = 90 Primary objective: Compare efficacy (PFS) of 2 dose levels of olaparib (OLA) with pegylated liposomal doxorubicin (PLD) OLA 200 mg bid in 28-day cycles OLA 400 mg bid in 28-day cycles PLD 50 mg/m2 IV every 4 weeks PD or withdrawal from treatment for other reason As above or max lifetime cumulative dose reached Patients in PLD group were allowed to cross over to olaparib 400 mg bid on confirmed PD 90 Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710. Phase II Study of Olaparib vs PLD in Patients With BRCA1 or BRCA2 Mutation Proportion of Patients Progression-Free Median PFS (80% CI) 1.0 OLA 200 mg OLA 400 mg 0.9 0.8 6.5 (5.6-8.0) months 8.8 (6.3-9.2) months PLD 50 mg/m2 7.1 (5.5-7.8) months 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 HR vs PLD (80% CI) OLA 200 mg: 0.91 (0.60-1.39); P = 0.78 OLA 400 mg: 0.86 (0.56-1.30); P = 0.63 OLA 200 mg + 400 mg: 0.88 (0.62-1.28); P = 0.66 0 Number of patients at risk: OLA 200 mg 32 OLA 400 mg 32 PLD 33 2 4 6 8 10 12 3 1 3 0 0 0 Time From Randomization (months) 24 28 25 21 21 18 Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710. 13 17 15 8 12 8 91 Phase II Study of Olaparib vs PLD in Patients With BRCA1 or BRCA2 Mutation RECIST Response OLA 400 PR SD ≥ 4 mos OLA 200 SD 2-4 mos PLD PD 0% 20% 40% 60% 80% 100% > Grade 3 toxicities OLA 200 (n = 32) OLA 400 (n = 32) PLD (n = 32) Any (%) 34 38 69 Anemia (%) 6 13 0 Fatigue (%) 3 9 9 PPE syndrome (%) 0 0 34 Rash (%) 0 0 9 92 Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710. Selection of PARP Inhibitors in Clinical Trials Agent Administration AZD-2281 (olaparib) Oral ABT-888 (veliparib) Oral BSI-201 (iniparib) IV KU59436 Oral AGO14699 IV INO-1001 IV MK4827 Oral GPI 21016 Oral 93 Adapted Ratnam K, et al. Clin Cancer Res. 2007;13:1383-1388; http://www.clinicaltrials.gov. CaseMat Home • • • • • • • • Introduction Patient Case 1: Frontline Patient Case 2: Maintenance Patient Case 3: Late recurrence Patient Case 4: Early recurrence Patient Case 5: Toxicity assessment Novel agents / developmental therapeutics Conclusion 94 Early Recurrence 95 Recurrence Regimens NCCN Preferred Agents Platinum-Sensitive Combination* Platinum-Sensitive Single-Agent Platinum-Resistant Single-Agent Targeted Therapy Carboplatin / Paclitaxel (cat 1) Carboplatin Docetaxel Bevacizumab Carboplatin / Weekly Paclitaxel Cisplatin Oral etoposide Carboplatin / Docetaxel Gemcitabine Carboplatin / Gemcitabine Pegylated liposomal doxorubicin Cisplatin / Gemcitabine Weekly paclitaxel Carboplatin / Liposomal doxorubicin Topotecan *Platinum-based combination therapy should be considered for platinum-sensitive recurrences. NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer v.1.2011. Available at: http://www.nccn.org/professionals/physician_gls/PDF/ovarian.pdf. Accessed October 7, 2010. 96 Select Phase II / III Single-Agent Trials Author N Treatment Median TTP (Weeks) Median OS (Weeks) ten Bokkel Huinink et al 226 Topotecan 23 61 Paclitaxel 14 43 Bolus Paclitaxel 12 42 Weekly Paclitaxel 14 37 Oxaliplatin 12 42 Paclitaxel 14 37 PLD 16 60 Topotecan 17 57 PLD 16 56* Gemcitabine 20 51* Rosenberg et al Piccart et al Gordon et al Ferrandina et al 208 86 474 153 *Statistically significant; P = 0.048. ten Bokkel Huinink W, et al. Ann Onc. 2004;15(1):100-103; Rosenberg P, et al. Acta Oncol. 2002;41:419-424; Piccart MJ, et al. J Clin Oncol. 2000;18(6):1193-1202; Gordon AN, et al. Gynecol Oncol. 2004;95(1):1-8; Ferrandina G, et al. J Clin Oncol. 2008;26:890-896. 97 GOG Single-Agent Trials GOG Resistant Population Treatment Response Rate 126-J 60 Docetaxel* 22% 126-N 48 Weekly paclitaxel* 21% 126-Q 51 Pemetrexed* 20% 126-M 50 Ixabepilone 14% 126-K 25 Oxaliplatin 4% 126-H 25 Topotecan (24H) 4% 126-L 57 Gemcitabine + paclitaxel 16% 126-R 51 Nab-paclitaxel* 23% *After paclitaxel. Rose P, et al. Gynecol Oncol. 2003;88:130-135; Markman M, et al. Gynecol Oncol. 2006;101:436-440; Miller DS, et al. J Clin Oncol. 2009;27(16):2686-2691; Fracasso P, et al. J Clin Oncol. 2003;21(15):2856-2859; Markman M, et al. Gynecol Oncol. 1999;75:444-446; Brewer C, et al. Gynecol Oncol. 2006;103(2):446-450. 98 Phase II Single-Agent Bevacizumab Recurrent Disease Dose / schedule Median age (Years) Primary endpoint Measurable disease Prior regimens Platinum DFI 1o Platinum DFI < 6 mo % Prior regimens (1 / 2 / 3 / 4) % GOG / ECOG PS (0 / 1 / 2) GOG-170-D Burger, et al. N = 62 Cannistra, et al.* N = 44 Bevacizumab 15 mg/kg q21d Bevacizumab 15 mg/kg q21d 57 (18-79) 59.5 (31-87) ORR + 6-month PFS ORR Yes (RECIST) Yes (RECIST) 1-2 2-3 Non-specified < 6 months (1st- or 2nd-Line) 36% 84% 34 / 66 / 0 / 0 0 / 52 / 48 / 0 73 / 27 / 0 59 / 41 / 0 *Trial terminated prematurely due to incidence of GI perforation. 99 Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5167; Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186. Phase II Single-Agent Bevacizumab Efficacy and Safety ORR 6-Month PFS GOG 170-D Burger, et al. N = 62 Cannistra, et al.* N = 44 13 (21%) 7 (15.9%) 40.3% 27.8% ≥ Grade 3 Toxicity GI perforation Thrombosis / embolism HTN - 5 (11.4%) 1 (1.6%) 4 (9.0%) (Venous) (3 Arterial 1 VTE) 6 (9.7%) 6 (13.6%) - 1 (2.3%) 1 (1.6%) - - 3 (6.8%) Cerebral ischemia Proteinuria Death suspected as related to bevacizumab *Trial terminated prematurely due to incidence of GI perforation. 100 Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5167; Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186. GOG-170-D Progression-Free Survival All Patients Proportion Progression-Free 1.0 0.9 Treatment PF Failed Total Historical Controls* 2 330 332 Pts on GOG-170-D 14 48 62 0.8 0.7 0.6 P < 0.0001 0.5 0.4 0.3 0.2 0.1 0 0 12 Months on Study 24 *The historical controls arm is comprised on agents found to be inactive in the GOG-126 series and does not represent active agents in this setting. 101 Burger RA, et al. J Clin Oncol. 2007;25:5165-5171. Summary Recurrent Ovarian Cancer: Resistant Chemotherapy Single-Agent Combination Options Non-Platinum (novel agents) Platinum 102 Case 4 Revisited: Early Recurrence • A 59-year-old florist presented with abdominal pain, bloating, and a pelvic mass. CA-125 was 1020 IU/mL • After an optimal cytoreduced (5 mm residuum) she randomized to Arm III of GOG-218 (paclitaxel and carboplatin 6 cycles with concurrent bevacizumab followed by maintenance bevacizumab) • Before starting maintenance bevacizumab she had a negative CA-125 and imaging (achieved complete clinical response) • Regimen was tolerated well except grade 1 neuropathy (mild numbness in her fingers and toes) • 5 months into maintenance bevacizumab she experienced abdominal pain and swelling develops • CA-125 has risen to 70 IU/mL and a CT scan reveals ascites and multiple pelvic masses causing intermittent moderate nausea and early satiety 103 CaseMat Home • • • • • • • • Introduction Patient Case 1: Frontline Patient Case 2: Maintenance Patient Case 3: Late recurrence Patient Case 4: Early recurrence Patient Case 5: Toxicity assessment Novel agents / developmental therapeutics Conclusion 104 Toxicity Assessment 105 Summary of Adverse Events in Early Randomized Trials Gordon 2001 PLD Topo ICON 4 2003 P P+Pac Pfisterer 2006 C C+G Sensory Neuropathy (grade 2-4) NR NR 1% 20% 5% 5% Alopecia 16% 49% 25% 86% 2% 14% Neutropenia (grade 3/4) 12% 77% NR NR 12% 70% Thrombocytopenia (grade 3/4) 1% 34% NR NR 11% 35% Hematologic (grade 3/4) NR NR 46% 29% NR NR PPE (grade 3/4) 23% 0% NR NR NR NR Gordon AN, et al. J Clin Oncol. 2001;19(14):3312-3322; Parmar MK, et al. Lancet. 2003;361(9375):2099-2106; Pfisterer J, et al. J Clin Oncol. 2006;24(29):4699-4707. 106 Calypso Trial Toxicity Carboplatin / PLD n = 466 Grade 2 (%) Grade 3 / 4 (%) Carboplatin / Paclitaxel n = 507 Grade 2 (%) P Value Grade 3 / 4 (%) Non-Hematologic Toxicity 31 4 20 4 < 0.001 Arthralgias / Myalgias 4 0 18 1 < 0.001 Hand-Foot Syndrome 11 2 2 0 < 0.001 Mucositis 13 2 6 1 < 0.001 Neuropathy 4 1 24 4 < 0.001 Alopecia 7 Nausea / Vomiting 84 < 0.001 Hematologic Toxicity Neutropenia 35 46 < 0.01 Thrombocytopenia 16 6 < 0.01 107 Pujade-Lauraine E, et al. J Clin Oncol. 2010;28(20):3323-3329. GOG-218 Toxicity Adverse Events, n (%) GI events* (grade ≥ 2) Hypertension (grade ≥ 2) Proteinuria (grade ≥ 3) Arm III Arm I Arm II CP CP + BEV (n = 601) (n = 607) 7 (1.2) 43 (7.2) † 4 (0.7) 17 (2.8) 100 (16.5) 4 (0.7) CP + BEV BEV (n = 608) 16 (2.6) † 139 (22.9) † 10 (1.6) Pain (grade ≥ 2) 250 (41.7) 252 (41.5) 286 (47.1) Neutropenia (grade ≥ 4) 347 (57.7) 384 (63.3) 385 (63.3) Febrile neutropenia 21 (3.5) 30 (4.9) 26 (4.3) Venous thromboembolic event 35 (5.8) 32 (5.3) 41 (6.7) Arterial thromboembolic event 5 (0.8) 4 (0.7) 4 (0.7) CNS bleeding 0 0 2 (0.3) Non-CNS bleeding (grade ≥ 3) 5 (0.8) 8 (1.3) 13 (2.1) RPLS 0 1 (0.2) 1 (0.2) RPLS = reversible posterior leukoencephalopathy syndrome; *Perforation / fistula / necrosis / leak; †P < 0.05. 108 Burger R, et al. J Clin Oncol. 2010;28(18S). LBA1. GOG-218: Prospective Analysis of Gastrointestinal Perforation • Overall incidence in 1759 patients Odds Ratio 14 12 Multivariate OR – Placebo: 1.7% – Concurrent bevacizumab: 3.4% – Concurrent + maintenance bevacizumab: 3.4% 16 10 8 6 4 2 0 IBD LBR SBR Bev Characteristic IBD = inflammatory bowel disease, LBR = large bowel resection SBR = small bowel resection, Bev = bevacizumab 109 Burger R, et al. Society of Gynecologic Oncologists 2011 Annual Meeting. Abstract 7. Summary of Bevacizumab Toxicity in Other Trials • Gastrointestinal perforation – 11% incidence in heavily pretreated recurrent disease patients – Management difficult due to risk of surgical complications • Thromboembolism (TE) – Pooled analysis found increased risk of arterial TE over chemotherapy alone (3.8% vs 1.7%) – Risk factors: prior arterial TE, age > 65 years 110 Stone RL, et al. Lancet Oncol. 2010;11(5):465-475. Summary of Bevacizumab Toxicity in Other Trials • Hypertension – Dose-related incidence • < 7.5 mg/kg: 3%-32% • > 7.5 mg/kg: 18%-36% – Requires medication manipulation in ~ 10% • Proteinuria – Grade 3/4 in 1%-4% – Urine dipstick should be monitored • If > 2 +, 24-hour collection obtained • If > 2 g/24-hour, hold bevacizumab until resolved 111 Stone RL, et al. Lancet Oncol. 2010;11(5):465-475. Case 5 Revisited: Treatment Toxicity • A 66-year-old woman with stage IIIC serous ovarian cancer recently underwent TAH / BSO and omentectomy resulting in suboptimal cytoreduction with small volume residual • PMH: – HTN treated with lisinopril, current BP 140/88 – DVT 20 years ago after elective cholecystectomy – PS = 1 • Surgical wound healing well and patient is without current complaint 112 CaseMat Home • • • • • • • • Introduction Patient Case 1: Frontline Patient Case 2: Maintenance Patient Case 3: Late recurrence Patient Case 4: Early recurrence Patient Case 5: Toxicity assessment Novel agents / developmental therapeutics Conclusion 113 Recurrent Ovarian Cancer Novel Biologics and Developmental Therapeutics Ovarian Cancer: Novel Targets Tumor Cell SURFACE MARKERS NUCLEAR TARGETS EGFR ER Her2 PDGFR Folate Receptor Integrins CA125 Erlotinib Gefitinib Trastuzumab Pertuzumab Lapatinib Imatinib Dasatinib Sorafenib XL 999 G706 Farletuzumab EC17 EC145 Volociximab Oregovomab Abagovomab PARP Tamoxifen Anastrozole Exemestane Letrozole LHRH Olaparib Iniparib Veliparib INO 1001 Microenvironment INTRACELLULAR SIGNALING ANGIOGENESIS VEGF PI3K/AKT mTOR RAS/RAF PKC Farnesyl IC486068 Haloquinone PX-316 Perifosine BX-795 BX-912 BX-320 CCI-779 Everolimus AP-23573 Sorafenib Enzastaurin Tipifarnib Bevacizumab Aflibercept VEGFR Sunitinib Sorafenib Cediranib XL999 Integrins Volociximab Angiopoietin AMG386 IMMUNE CELLS Cytokines Interferon Aldesleukin T-regs Denileukin diftitox 115 Adapted from Matei D, et al. Exp Opin Invest Drug. 2007;16:1227-1239. Phase II Oral Multi-Kinase Inhibitors in Relapsed Disease Agent Prior Treatment N % Platinum Resistant Cediranib ≤ 2 prior lines 46 55 Cediranib 1 prior line 60 57 Sunitinib ≤ 2 prior lines 30 27 Sorafenib ≤ 2 prior lines 71 - Pazopanib ≤ 2 prior lines 36 25 ORR (CR + PR) Grade 3 / 4 Toxicity 17% Hypertension, fatigue, diarrhea, CNS hemorrhage ≈ 7% (3 / 41 evaluable) 3% 3.4% (2 / 59 evaluable) 18%* (3 / 17 evaluable) Hypertension, fatigue Fatigue, hand-foot syndrome Rash, hand-foot syndrome, metabolic, GI, cardiovascular, pulmonary Diarrhea, ALT elevation *Primary endpoint CA-125 response. Matulonis UA, et al. J Clin Oncol. 2009;27(33):5601-5606; Hirte HW, et al. J Clin Oncol. 2008;26(suppl). Abstract 5521; Biagi JJ, et al. Ann Oncol. 2011;22(2):335-340; Matei D, et al. J Clin Oncol. 2011;29(1):69-75; Friedlander M, et al. Gynecol Oncol. 2010;119:32-37. 116 ICON-6 Phase III Second-Line Therapy Patients relapsed > 6 months post primary platinum-based chemotherapy RANDOMIZATION 2:3:3 N = 2000 Chemotherapy + Placebo 6 Placebo 18 months (max) or until progressive disease Chemotherapy 6 + Cediranib Placebo 18 months (max) or until progressive disease Chemotherapy 6 + Cediranib Cediranib 18 months (max) or until progressive disease 117 Available at: http://www.clinicaltrials.gov/ct2/show/NCT00544973?term=icon-6&rank=1. Accessed February 22, 2011. Poly (ADP-Ribose) Polymerase (PARP) • Key regulator of DNA damage repair – Involved in DNA base-excision repair • Binds directly to DNA damage and produces large branched chains of poly (ADP-ribose) DNA damage PARP NAD+ nicotinamide + pADPr 118 Tutt A, et al. Lancet.2010;376(9737):235-244. PARP Inhibitors Suggested Mechanism of Action Chemotherapy inflicts DNA damage via adducts and DNA cross-linking PARP1 PARP Inhibitor PARP1 PARP1 Upregulation Base-excision repair of DNA damage Inhibition of PARP1 PARP1 Disables DNA base-excision repair Replication fork collapse Double strand DNA break BRCA1 BRCA2 CELL SURVIVAL CELL DEATH 119 O’Shaughnessy J, et al. J Clin Oncol. 2009;27(15S). Abstract 3. Phase I Trial of the PARP Inhibitor Olaparib 120 Fong PC, et al. N Engl J Med. 2009;361(2):123-134. Expansion Cohort of Phase I Olaparib Trial (200 mg BID) Characteristic BRCA1 mutation, n BRCA2 mutation, n Strong family history, n Mean age, years (range) 41 8 1 52 (37-80) Platinum status, n (%) Sensitive Resistant Refractory 13 (26) 24 (48) 13 (26) Number of prior therapies, n (%) 1 2 3 >4 5 (20) 11 (22) 11(22) 23 (46) 121 Fong PC, et al. J Clin Oncol. 2010;28(15):2512-2519. Olaparib Phase I Expansion Clinical Activity by RECIST + GCIG Total Platinum Sensitive Platinum Resistant Platinum Refractory 50 13 24 13 Responders by RECIST 14 (28%) 4 (46%) 8 (34%) 0 (0%) Responders by GCIG CA-125 17 (34%) 8 (62%) 7 (30%) 2 (15%) Responders by either RECIST or GCIG criteria 20 (40%) 8 (62%) 10 (42%) 2 (15%) SD (> 16 weeks) 3 (6%) 1 (7%) 1 (4%) 1 (8%) 28 (23-33) 28 (20-37) 28 (19-38) Not evaluable Number of evaluable patients Median duration of response in weeks (95% CI) 122 Fong PC, et al. J Clin Oncol. 2010;28(15):2512-2519. Olaparib Phase I Expansion Adverse Events > 8 % Incidence Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%) Lymphopenia 0 0 6 2 Anemia 0 6 8 0 Nausea 36 6 6 0 Vomiting 14 4 2 0 Diarrhea 4 2 2 0 Dyspepsia 6 10 0 0 Anorexia 12 4 0 0 Dysgeusia 8 2 0 0 Fatigue 8 32 4 0 Dizziness 4 2 2 0 123 Fong PC, et al. J Clin Oncol. 2010;28(15):2512-2519. Olaparib Phase I Expansion Correlation of Platinum-Free Interval and Best Response Platinum-Free Interval (months) 24 Sensitive Resistant Refractory 18 12 6 0 CR/PR SD > 4mos PD 124 Fong PC, et al. J Clin Oncol. 2010;28(15):2512-2519. Phase II Study of Olaparib of Patients With BRCA1 or BRCA2 Mutation • Two dosages tested in sequential cohorts of patients with recurrent, measurable disease • Primary endpoint: response rate 400 mg BID n = 33 ORR = 33% 100 mg BID n = 24 ORR = 13% • Adverse events: nausea, fatigue, anemia 125 Audeh MW, et al. Lancet. 2010;376(9737):245-251. Phase II Study of Olaparib vs PLD in Patients With BRCA1 or BRCA2 Mutation • BRCA1/2 germline carriers with ovarian cancer • Progressive or recurrent disease < 12 months after previous platinum-based chemotherapy RANDOMIZATION Open label Planned N = 90 Primary objective: Compare efficacy (PFS) of 2 dose levels of olaparib (OLA) with pegylated liposomal doxorubicin (PLD) OLA 200 mg bid in 28-day cycles OLA 400 mg bid in 28-day cycles PLD 50 mg/m2 IV every 4 weeks PD or withdrawal from treatment for other reason As above or max lifetime cumulative dose reached Patients in PLD group were allowed to cross over to olaparib 400 mg bid on confirmed PD 126 Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710. Phase II Study of Olaparib vs PLD in Patients With BRCA1 or BRCA2 Mutation Proportion of Patients Progression Free Median PFS (80% CI) 1.0 OLA 200 mg OLA 400 mg 0.9 0.8 6.5 (5.6-8.0) months 8.8 (6.3-9.2) months PLD 50 mg/m2 7.1 (5.5-7.8) months 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 HR vs PLD (80% CI) OLA 200 mg: 0.91 (0.60-1.39); P = 0.78 OLA 400 mg: 0.86 (0.56-1.30); P = 0.63 OLA 200 mg + 400 mg: 0.88 (0.62-1.28); P = 0.66 0 Number of patients at risk: OLA 200 mg 32 OLA 400 mg 32 PLD 33 2 4 6 8 10 12 3 1 3 0 0 0 Time From Randomization (months) 24 28 25 21 21 18 Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710. 13 17 15 8 12 8 127 Phase II Study of Olaparib vs PLD in Patients With BRCA1 or BRCA2 Mutation RECIST Response OLA 400 PR SD ≥ 4 mos OLA 200 SD 2-4 mos PLD PD 0% 20% 40% 60% 80% 100% > Grade 3 toxicities OLA 200 (n = 32) OLA 400 (n = 32) PLD (n = 32) Any (%) 34 38 69 Anemia (%) 6 13 0 Fatigue (%) 3 9 9 PPE syndrome (%) 0 0 34 Rash (%) 0 0 9 128 Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710. Selection of PARP Inhibitors in Clinical Trials Agent Administration AZD-2281 (olaparib) Oral ABT-888 (veliparib) Oral BSI-201 (iniparib) IV KU59436 Oral AGO14699 IV INO-1001 IV MK4827 Oral GPI 21016 Oral 129 Adapted Ratnam K, et al. Clin Cancer Res. 2007;13:1383-1388; http://www.clinicaltrials.gov. ASCO 2010: Developmental Therapeutics • EC145 – Folate receptor / vinca alkaloid conjugate • Farletuzumab – Folate receptor alpha antagonist • NKTR-102 – Pegylated irinotecan • Nab-paclitaxel – Nanoparticle albumin bound paclitaxel • Voreloxin – DNA intercalation / topoisomerase II inhibitor • AMG-386 – Angiopoietin 1/2 inhibitor 130 ASCO 2011: Anticipated Presentations • OCEANS – Carboplatin / gemcitabine + bevacizumab • MIMOSA – Abagovomab (anti-idiotype antibody against CA-125) – After optimal response to initial surgery plus chemotherapy • Olaparib maintenance • OVA-301 final survival • CALYPSO final survival 131 CaseMat Home • • • • • • • • Introduction Patient Case 1: Frontline Patient Case 2: Maintenance Patient Case 3: Late recurrence Patient Case 4: Early recurrence Patient Case 5: Toxicity assessment Novel agents / developmental therapeutics Conclusion 132 Conclusion • Emerging clinical trials coupled with evolving basic science discoveries have changed the treatment of ovarian cancer – Historic treatment paradigms in ovarian cancer are being challenged – The safe and appropriate addition of new agents into the treatment paradigm is a priority – The development and incorporation of new therapeutic approaches are needed to improve patient outcomes 133 CaseMat Home • • • • • • • • Introduction Patient Case 1: Frontline Patient Case 2: Maintenance Patient Case 3: Late recurrence Patient Case 4: Early recurrence Patient Case 5: Toxicity assessment Novel agents / developmental therapeutics Conclusion 134