New Developments in the Treatment of Recurrent Ovarian Cancer and Evolving New Therapies

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1 New Developments in the Treatment of Recurrent Ovarian Cancer and Evolving New Therapies Alexi Wright, MD Dana-Farber Cancer Institute Harvard Medical School

2 Outline Maintenance therapy Recurrent Ovarian Cancer Platinum-Sensitive Recurrence Platinum-Resistant Recurrence Biologic Therapies for Ovarian Cancer Anti-angiogenics PARP-inhibitors PI3 kinase inhibitors

3 Completion of Upfront Therapy Despite aggressive primary therapy and high initial response rates, most women with advanced ovarian cancer ultimately develop drug-resistant disease. In recurrent setting, chemotherapy response rates are substantially diminished. Need to develop better therapeutic agents and strategies.

4 Goals of Maintenance Therapy End of therapy: 1 st remission, 2 nd remission, or later remissions CA125 rising Documented Progression Documented Progression On Maintenance Maintenance agent: biologic, chemotherapy, immunotherapeutic, etc. Improvement in PFS due to maintenance therapy

5 Completion of Upfront Therapy Several drugs are being tested for maintenance therapy after 1 st -line therapy and subsequent lines. There is no standard of care for use of maintenance therapy. 1 1 Foster et al, Gyn Onc 115: , 2009.

6 Evidence: Maintenance Adding single agent topotecan has no benefit. Adding single agent paclitaxel x 1 year improves PFS by 7 months (21 versus 28). NO survival advantage (GOG 178). Neuropathy. GOG 212: Ongoing (taxol vs. CT-2103 vs. placebo) Several other biologics are being tested in the maintenance setting for either 1 st or 2 nd remission (PARP inhibitors, anti-angiogenics)

7 Approaches to Maintenance Rx: Biologics Anti-VEGF Bevacizumab Sorafenib BIBF1120 Cediranib Enzastaurin DNA repair inhibitors Olaparib (AZD2281) Hedgehog inhibitors GDC-0449 Anti-Folate drugs MORAb-003 EC145 HDAC inhibitors Vorinostat (ph Ib/II) Immunotherapies NY-ESO-1 OLP4 Oregovomab OPT-821 (adjuvant) DTA-H19 (plasmid containing gene for Dipth toxin A) EMD Others Chemotherapy IT-101 Anticoagulants: Fondaparinux

8 Upfront/Maintenance: 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.

9 Recurrent Ovarian Cancer Most women (>80%) with advanced ovarian cancer will recur within 6-24 months post-diagnosis. Recurrences often present as asymptomatic rises in CA125 Controversial whether to treat CA125 elevations. 1 Recurrent ovarian cancer is characterized by increasing platinum and chemotherapy resistance. Death occurs via recurring bowel obstructions and malnutrition, PE. 1 Rustin GJ et al, J Clin Oncol 27(18s):Abstr 1, 2009.

10 Choices of Treatment Time since diagnosis Platinum sensitivity Type of recurrence Asymptomatic vs. symptomatic Clinical trial availability Toxicities of prior chemotherapy Comorbidities Patients treatment preferences

11 Platinum Sensitivity P R E V I O U S Refractory T R E A T M E N T Resistant Sensitive Markman et al, JCO 1991

12 Treatment for Recurrent Disease Recurrence Platinum-sensitive Platinum doublets - liposomal dox - gemcitabine - taxane Platinum-resistant Single agent: - doxil - topotecan - gemcitabine - paclitaxel, weekly - bevacizumab - others: hexalan VP-15, cytoxan, IFF navelbine. NCCN guidelines, 2009

13 ICON IV: Carboplatin vs. Carbo/Tax Median PFS: 9 vs. 12 months Median survival: 29 vs. 24 months Median follow-up: 42 months OR: 54 vs. 66% (P =.06) Ledermann JA. Lancet. 2003;361:

14 AGO-OVAR-2.5: Carboplatin vs. Carboplatin and Gemcitabine Recurrent ovarian cancer 6+ months after platinum Strata PFI (6-12, > 12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs. evaluable Primary endpoint = PFS R A N D O M I Z E Gemcitabine 1,000 mg/m 2 days * Carboplatin AUC 4 day 1 Every 21 days 6 ( 10)( Carboplatin AUC 5 day 1 Every 21 days 6 ( 10)( Pfisterer J, et al. JCO 2006

15 AGO-OVAR Hazard ratio = 0.72 (95% CI: 0.57, 0.90) Log-rank P value = Progression-Free Probability Median = 5.8 mo ( mo) Median = 8.6 mo ( mo) Cb 178 pts / 162 evts GCb 178 pts / 163 evts months Pts at risk Cb GCb

16 AGO-OVAR-2.5 No overall survival benefit to Carboplatin + Gemcitabine vs. Carboplatin alone (18.0 months vs months, p=0.73) More bone marrow suppression (anemia 22.3% vs. 5.7%, neutropenia 41.7% vs. 10.9%, thrombocytopenia 30.3% vs. 10.3%)

17 CALYPSO Study Schema International, Intergroup, Open-label, Randomized Phase III Study Ovarian cancer in late relapse (> 6 months) after 1 st -or 2 nd -line platinum-based therapy (previous taxane required) R A N D O M I Z E Experimental arm: CD PLD 30 mg/m 2 IV d 1 Carboplatin AUC 5 d 1 Q 28 days x 6 courses* Control arm: CP Paclitaxel 175 mg/m 2 IV d 1 Carboplatin AUC 5 d 1 Q 21 days x 6 courses* *or progression in patients with SD or PR ASCO 2009

18 CALYPSO: PFS improved CD CP Median PFS, mo HR (95% CI) 0.82 (0.72, 0.94) Log rank p value (superiority) P value (non inferiority) <0.001 Carboplatin/liposomal dox Carboplatin/paclitaxel

19 CALYPSO: Toxicities (non-heme) CD (n=466) CP (n=501) Toxicity Grade 2 Grade 3/4 Grade 2 Grade 3/4 Nausea/vomiting* 31% 4% 20% 4% Constipation 19% 2% 20% 2% Diarrhea 4% 2% 6% 2% Arthralgia/myalgia* 4% 0% 18% 1% Hand-foot syndrome* 11% 2% 2% 0% Mucositis* 13% 2% 6% 1% Fatigue 31% 7% 34% 7% Grade 2 alopecia* 7% - 84% - Cardiac disorders 2% 1% 3% 1% *P< *P< 0.001

20 CALYPSO: Toxicities (Heme) Toxicity, grade Neutropenia, grade 3 CD (n=464) CP (n=500) Number of patients (%) 144 (31) 121 (24) P Value <0.01 grade 4 20 (4) 108 (22) Febrile neutropenia, gr (2) 21 (4) NS Infection, grade (3) 14 (3) NS Thrombocytopenia, grade (16) 31 (6) <0.01 Bleeding, grade (0.6) 0 (0) NS Anemia, grade (8) 27 (5) NS

21 Platinum Resistant Recurrence No best drug exists with regards to efficacy FDA approved ones are topotecan and liposomal doxorubicin (doxil) RR of non-platinum drug depends on degree of platinum sensitivity RR around 10-20% Problem with platinum re-use is accumulating toxicities and allergies. Duration of response <3 months

22 Platinum Resistant Recurrence VP-16 Navelbine Gemzar Taxanes Hexalan Cytoxan 5-FU Hormonal agents AI s, tam.

23 Biologic Therapies for Ovarian Cancer

24 Targeting Growth/Survival Pathways Mutations and amplifications send signals for abnormal growth and survival in cancer cells Targeted therapies are directed specifically against these signaling pathways Greater specificity against cancer cells Reduced toxicity to patients

25 Sub-classification of Ovarian Cancers All epithelial ovarian cancers BRCA+ cancers VEGF-driven tumors Low grade serous tumors PI3kinase Clear cell cancers All other ovarian cancers Thru 2008: all treated the same and moving forward:

26 VEGF-Directed Therapies Kowanetz, M. et al. Clin Cancer Res 2006.

27 Single Agent Bevacizumab Study # pts Plat status RR Burger et al, JCO % plat res 58% plat sens Median PFS Median OS Toxicities 21% 4.7 mos 17 mos No GI perforations Cannistra et al, JCO All resistant. 83.7% 1 plat resistant 15.9% 4.4 mos 10.7 mos 11.4% GI perforations

28 Bevacizumab Combination Therapies Study Trial design Eligibility # of pts/plat status Results Toxicities Garcia et al, JCO Phase II bevacizumab 10 mg/kg + cytoxan 50 mg/day PO Recurrent ovarian, up to 2 lines of tx for recurrence 40% plat resistant 60% plat sensitive 24% ORR 7.2 months PFS 16.9 months OS 4 GIP and 2 CNS events. Nimeiri et al, Gyn Onc, 2008 Ph II bevacizumab 15 mg/kg IV + erlotinib 150 QD Recurrent/refro varian, up to 2 lines for recurrence 13 patients 15% ORR 2 responses 7 SD 2 fatal GIP s and study was closed. Azad et al, JCO 26:3709 Ph I of bevacizumab + oral sorafenib PS of 0 or 1. no line limit. (Median=4). 39 pts; 13 ovarian cancer 46% PR 6/13 EOC pts 2 EOC pts developed fistulas. Fatal hemoptysis.

29 PARP Inhibitors: Synthetic Lethality PARP: poly (adenosine diphosphate ribose)(adp) polymerase PARP1 activity is required for base-excision repair (BER), a DNA-damage repair pathway that recognizes and eliminates DNA bases damaged by oxidation. BER is a process that occurs thousands of times during each normal cell cycle.

30 PARP Inhibitors: Synthetic Lethality BRCA1 and BRCA2 genes recognize and repair DNA double-stranded breaks, through Homologous Recombination. Cells that are deficient in BRCA1 and 2 proteins become genetically unstable. Single-stranded repair takes over and PARP is an enzyme that is important in this repair type. PARP inhibitors block single-strand repair causing tumor cells to undergo apoptosis.

31 PARP Inhibitors: Synthetic Lethality

32 PARP Inhibitors Ratnam, K. et al. Clin Cancer Res 2007

33 Olaparib: oral PARP inhibitor recurrent ovarian Total Platinum sensitive Platinum resistant # of patients Platinum refractory Response by RECIST 13 (28%) 5 (50%) 8 (32%) 0 GCIG CA (39%) 8 (80%) 8 (32%) 2 (18%) Either RECIST or CA (46%) 8 (80%) 11 (44%) 2 (18%) SD (> 4 mos) 6 (13%) 1 (10%) 4 (16%) 1 (9%) Median response 24 weeks (10-77 weeks) 23 weeks (16-77 weeks) 24 weeks (10-65 weeks) 26 (20-32 weeks) ASCO 2008; 5510, NEJM 2009

34 Common PARP Toxicities Toxicity Grade 1-2 Grade 3-4 Nausea 21 (64%) 2 (6%) Fatigue 17 (52%) 1 (3%) Diarrhea 12 (37%) 0 Vomiting 11 (33%) 2 (16%) Abdominal pain 9 (27%) 1 (3%) Audeh et al, abs 5500 ASCO 2009

35 PARP Inhibitors in Development Company Drug Name Clinical studies Kudos (Astrazeneca) AZD2281 (PO) Ph 1: carbo Ph 1: cisplatin Ph 2: 2281 versus liposomal doxorubicin Ph 2: maintenance Ph 2: carbo + taxol (plat-sens) MGI/Eisai E7016 (PO) Ph 1: drug alone in pts with BRCA-def breast and ovarian cancer Abbott ABT888 (PO) CTEP: carbo/paclitaxel + ABT888 CPT-11 + ABT-888 Pfizer AG Ph 2: AG for recurrent breast and ovarian cancer (non-brca-def pts) (UK sites only). BiPar BSI-201 (IV) BSI-401 (PO) Ph 1b: topotecan + BSI-201 Ph 2: BSI-201 in BRCA-def. recurrent ov cancer Ph2: carbo + gem + BS-201 (plat sens/resis)

36 PI3K/AKT pathway

37 PI3K/AKT pathway

38 PI3K/AKT pathway in gynecologic malignancies Lost in 50% uterine Mutation: 30% uterine 10% ovarian Amplification: 30% ovarian 70% cervical Activated in 70% ovarian

39 PI3K/AKT pathway inhibitors mtor inhibitors (Phase II trials) Active in uterine cancer 30-40% clinical benefit PI3K inhibitors (Phase I trials) Ovarian cancer Stable disease >6 months Response close to 12 months Uterine cancer Stable disease >3 months AKT inhibitors (Phase I trials) 3/3 ovarian cancer patients with decrease in CA125

40 Small molecule TKIs

41 Other Biologics Being Tested HER family inhibitors Hedgehog inhibitors Notch signaling pathway inhibitors Anti-folate receptor agents

42 Summary At diagnosis, ovarian cancer remains one of the most chemotherapy-sensitive cancers. After recurrence, ovarian cancer becomes more and more chemotherapy resistant. As our basic understanding of the disease (pathogenesis) and ovarian cancer subtypes improve, opportunities to develop more rationale drug strategies. Newer therapies are needed for both newly diagnosed cancer as well as recurrent ovarian cancer. Newer biologics are being tested.

43 HER Family Inhibitors Drug Target Mechanism Route Small molecule tyrosine kinase inhibitors CI-1033 HER1,HER2, HER3,HER4 acts directly with the ATP binding site of EGFR family and blocks activation/signaling of receptors. Lapatinib EGFR, HER2 Blocks activation/signaling of EGFR and HER2. Monoclonal Antibodies Trastuzumab HER2 signaling Pertuzumab HER2/HER3 signaling Heat shock protein inhibitors 17-AAG HSP90 HER2 Blocks HER2 dimer signaling Blocks HER2/HER3 signalling Reduces stability of HER2 leading to decreased signaling PO PO IV IV