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Best of ASCO in Gyn Oncology

Best of ASCO in Gyn Oncology. Adnan R Munkarah. Biologics in Recurrent Ovarian Ca. Cediranib - highly selective and potent oral TK inhibitor of VEGFR1, VEGFR2, VEGFR3 and c-Kit( Matulanis #5501, Hirte#5521 ) Sunitinib - multitargeted RTK inhibitor ( Biagi #5522 )

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Best of ASCO in Gyn Oncology

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  1. Best of ASCO in Gyn Oncology Adnan R Munkarah

  2. Biologics in Recurrent Ovarian Ca • Cediranib- highly selective and potent oral TK inhibitor of VEGFR1, VEGFR2, VEGFR3 and c-Kit(Matulanis #5501, Hirte#5521) • Sunitinib- multitargeted RTK inhibitor (Biagi #5522) • Pertuzumab- monoclonal ab prevents HER2 dimerization + CBDCA (Kaye #5520, Lalla #5550) • Sorafenib- oral TKI targeting raf & VEGFR, PDGFR, Flt3, c-kit ( Matei D, GOG #5537)

  3. Folate Receptor a (FRA) • Overexpressed in majority of EOC, absent in nomrla tissues • MORAb-003 humanized monoclonal ab to FRA • Armstrong D #5500 • 52 patients with platinum sensitive EOC in first relapse • Asymptomatic patients treated with single agent ab (SA) • Symptomatic patients or those with progression on SA receive ab with platinum & Taxane • MOAb-003 significantly increased overall response and duration of response

  4. Folate Receptor a (FRA) • Bell-McGuinn #5517 • Phase I trrial in platinum resistant EOC patients • Well tolerated • + response

  5. Belinostat • Histone deacetylase inhibitor • Preclinical studies • Synergy with carboplatinum and taxol • Effect in platinum resistant and sensitive EOC • Well tolerated in combination with taxol/carbo and clinical benefit in heavily pretreated patients (Finkler #5519) • Promising activity in LMP ovarian tumors (Mackay # 5518)

  6. Seiji Isonishi,1 Makoto Yasuda,1 Fumiaki Takahashi,2 Noriyuki Katsumata,3 Eizo Kimura, 1 Daisuke Aoki,4 Toshiko Jobo,5 Fumitoshi Terauchi,6 Hiroshi Tsuda,4 Toru Sugiyama7 1.The jikei UniversitySchool of Medicine, 2. Kitasato University,3. National Cancer CenterHospital, 3.Kousei General Hospital, 4. Keio University School of Medicine, 5. Social Insurance Sagamino Hospital, 6. Tokyo Medical University, 7.Iwate Medical University School of Medicine jgog0606@jgog.gr.jp

  7. Conventional administration of paclitaxel and carboplatin (c-TC) every 21 days is a standard therapy for advanced epithelial ovarian cancer. Several phase II clinical trials of dose-dense weekly administration of paclitaxel and carboplatin (dd-TC) in ovarian cancer have demonstrated promising efficacy and favorable tolerability (Gynecol Oncol 2005; 96: 296, Cancer Chemother Pharmacol 2008; 61: 243). Recent randomized phase III trials for breast cancer demonstrated weekly paclitaxel improved survival(NEJM 2008;358:1663-71, JCO 2008; 26:1642-1649).

  8. NewOvarianElaboratetrial:NOVEL trial Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube cancer FIGO Stage II-IV  Randomization Stratification; Residual disease: <1cm, > 1cm FIGO Stage： II vs. III vs. IV Histology： clear cell/mucinous vs.serous/others Conventional TC (c-TC) Paclitaxel 180mg/m2, day 1 Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80mg/m2, days 1,8,15 Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cycles

  9. Histologically or cytologically* confirmed stage II-IV ovarian epithelial, primary peritoneal, or fallopian tube cancer No prior chemotherapy Age: 20 and more Performance status: ECOG 0-3 1) Absolute neutrophil count at least 1,500/mm3 2) Platelet count at least 100,000/mm3 3) Bilirubin less than 1.5mg/dL 4) SGOT less than 100 IU/l 5) Serum creatinine less than 1.5mg/dL VI. Written informed consent *CA125/CEA >25, and GI cancer should be ruled out

  10. Primary endpoint: Progression-free Survival Secondary endpoints: Overall survival (OS) Response rate Adverse events Quality of life (FACT)

  11. Hypothesis: 5 months improvement in median PFS (from 16 to 21 months) Statistical test: 2 sided log-rank with α=0.05, β=0.2 Sample size: 380 patients initially on Apr. 2003 600 patients with one interim analysis after amendment on Jan. 2005 Progression defined as: appearance of any measurable or evaluable lesion OR CA125 level > 2 times UNL or nadir for 2 consecutive measurements at least 1 week apart

  12. 637 Patients enrolled and randomly assigned 320 Assigned to c-TC 317 Assigned to dd-TC 5 Ineligible 1 Ineligible 319 Eligible Patients 312 Eligible Patients 6 cycles of treatment Additional 3 cycles should be given if clinical responses were observed. Interval or secondary debulking surgery were allowed. 319 Primary intention to treat efficacy analysis 314 Safety analysis 312 Primary intention to treat efficacy analysis 312 Safety analysis

  13. Clinical Response P=0.72 Evaluated by WHO criteria

  14. Evaluated by NCI-CTC ver.2.0

  15. 0.0 0.5 1.0 1.5 2.0 dd-TC better c-TC better

  16. PFS was improved with dose-dense weekly TC compared to conventional TC in patients with advanced epithelial ovarian cancer. Analysis of overall survival is ongoing. Hematologic toxicity was increased in dose-dense TC. Neurotoxicity was similar in both groups.

  17. AZD2281 (KU-0059436), a PARP(poly ADP-ribose polymerase) inhibitorwith single agent anticancer activity in patients with BRCA deficient ovarian cancer:Results from a phase I study Peter C Fong1, David S Boss2, Craig P Carden1, Marja Mergui-Roelvink2, Jacques De Greve3, Charles M Gourley4, James Carmichael5,Johann S de Bono1, Jan H Schellens2, Stan B Kaye1 1The Royal Marsden Hospital and The Institute of Cancer Research, UK, 2The Netherlands Cancer Institute, The Netherlands, 3UZ Brussel Oncologisch Centrum, Belgium, 4Edinburgh Cancer Research Centre, UK, 5KuDOS Pharmaceuticals/AstraZeneca, UK

  18. PARP • Poly(ADP-ribose) polymerase-1- member of PARP enzymes • Abundant nuclear protein • Binds to DNA breaks • Activated PARP cleaves NAD+ into nictoinamide and ADP-ribose and polymerizes the latter onto nuclear receptor proteins including histones, transcription factors and PARP itself • Contributes to repair of single strand breaks in DNA

  19. Poly ADP-Ribose Polymerase (PARP)

  20. PARP inhibitors & BRCA

  21. BRCA2+/+ BRCA1+/+ BRCA2+/- BRCA1+/- BRCA1-/- BRCA2-/- Increased sensitivity of BRCA1-/- and BRCA2-/-cells to PARP inhibition No difference in sensitivity between heterozygous and wild-type BRCA cells Targeted inhibition  selective and less toxic therapy Farmer et al. Nature 2005; 434:917-21

  22. From targeted therapy to the AZD2281 Phase I study • Oral, small molecule PARP inhibitor • IC50 for PARP1 enzyme in the low nM range • Phase I trial began at RMH then NKI; later expanded to other centres • Escalation phase: All tumour types • Primary objectives of safety and tolerability • Expansion phase: BRCA mutation carriers (HR deficient) especially ovarian cancer • Further assessment of efficacy

  23. Overall recruitment • Escalation Phase (n=46)1,2 • Various tumour types; BRCA carrier status not mandatory • 10 dose level cohorts: • 10mg daily given for 2 out of 3 weeks • 600mg bid continuous dosing • 11 BRCA carrier ovarian cancer • Expansion phase (n=52) at 200mg bid continuous2 • Confirmed BRCA mutation carriers • 39 ovarian cancer 1Fong et al. Proceedings of ASCO 2006 2Yap et al. Proceedings of ASCO 2007

  24. Toxicities(first 60 patients, all tumour types) • Most toxicities were Grade 1-2 (≥95%) • Most common toxicities were: • nausea 28%, vomiting 18%, dysgeusia 13%, anorexia 12% • fatigue 28% • Grade 3-4 toxicities were rare: • myelosuppression (≤5%) • nausea and vomiting (2-3%) • CNS: dizziness or mood changes (2-3%) • Pattern of toxicity similar in BRCA mutation carriers

  25. Dose limiting toxicities (DLT) Maximum Tolerated Dose (MTD) = 400mg bid

  26. DemographicsBRCA-mutated ovarian cancer subpopulation • Includes primary peritoneal cancer (2 pts), fallopian tube carcinoma (1 pt) and 1 ovarian cancer pt with compelling family history for BRCA mutation • Excluded pts: • 1 pt died from disease-related non-neutropenic sepsis after 1 cycle • 1 pt had DLT on day 1 and again on day 8 with re-challenge of drug • 2 pts had PD within 2-3 weeks after commencement

  27. DemographicsBRCA-mutated ovarian cancer subpopulation

  28. 23 mm

  29. 21mm 16mm

  30. Response to AZD2281 byplatinum-free interval

  31. Response to AZD2281 byplatinum-free interval

  32. Response to AZD2281 byplatinum-free interval

  33. Response to AZD2281 byplatinum-free interval

  34. AZD2281 key messages • Well tolerated oral therapy not associated with the typical toxicities of chemotherapy • Clear evidence of beneficial tumour response in BRCA mutated ovarian cancer patients • 46% (21/46 pts) response rate (RECIST or GCIG CA125) • 13% meaningful disease stabilisation • Total clinical benefit rate of 59% • A randomised phase II trial in BRCA ovarian cancer pts with platinum-free interval of 0-12 months • AZD2281 vs pegylated liposomal doxorubicin

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