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PierFranco Conte University of Modena and Reggio Emilia

AZIENDA OSPEDALIERO-UNIVERSITARIA DI MODENA. Mediterranean School of Oncology New Drugs in Cancer Therapy Rome, May 13 th , 2011. PierFranco Conte University of Modena and Reggio Emilia. MBC. HR +. HR –. BRCA mutated. HER2+. HER2+. HER2–. HER2–. SERM SERD

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PierFranco Conte University of Modena and Reggio Emilia

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  1. AZIENDA OSPEDALIERO-UNIVERSITARIA DI MODENA Mediterranean School of Oncology New Drugs in Cancer Therapy Rome, May 13th, 2011 PierFranco Conte University of Modena and Reggio Emilia

  2. MBC HR + HR – BRCA mutated HER2+ HER2+ HER2– HER2– SERM SERD AI OFS Trastuzumab + anastrozole lapatinib+ letrozole PolychemoRx Paclitaxel + Beva DNA damaging CT Trastuzumab + taxanes ChemoRx +PARPi Paclitaxel + Beva Single agent chemo Lapatinib + capecitabine Trastuzumab+ capecitabine TDM-1, Pertuzumab, Neratinib, mTORi Metastatic Bone Disease: Bisphosphonates, Denosumab Treatment Algorithm for MBC Olaparib

  3. The Taxanes: Paclitaxel and Docetaxel • Efficacy • Breast, lung, ovarian, prostate, head and neck, bladder, and esophageal cancer1 • Taxane resistance is common2 • P-glycoprotein (P-gp) efflux pump • Tubulin mutation/overexpression • Tau protein-dependent mechanism • Toxicity1,2 • Myelosuppression • Neurotoxicity • Myalgia • Major hypersensitivity 1Dumontet C and Sikic BI. J Clin Oncol. 1999;17:1061-1070. 2Rowinsky EK. Annu Rev Med. 1997;48:353-374.

  4. Microtubulesastherapeutictargets • Microtubules composed of: • Tubulindimers (primarily a and ) • Microtubule-associated proteins • Dynamic microtubule assembly/disassembly vital for: • Mitosis • Maintenance of cell shape • Intracellular transport • Microtubule-targeted agents • Inhibit tubulin polymerization (eg, vincristine) • Stabilize and/or induce polymerization (eg, taxanes, epothilones) • Stabilization of microtubule dynamics results in • G2/M-phase arrest • Aberrant spindle formation during mitosis • Apoptotic cell death

  5. Beyond Taxanes: Anti-Microtubule Agents Morris et al. Clin Cancer Res. 2008;14:7167-7172.

  6. Paclitaxel Epothilones Eleutherobin Sarcodictyins Discodermolide Laulimalide Taccalonolide Taxus brevifolia Sorangium cellulosum Eleutherobin aurea Sarcodictyon roseum Discodermia dissoluta Fasciospongia rimosa Cacospongia mycofijiensis Tacca plantaginea Tacca chantrieri Pacific yew Myxobacteria Corals Corals Sponge Sponge Sponge Plant Plant Microtubule Stabilizing AgentsNatural Products Morris et al. Clin Cancer Res. 2008;14:7167-7172.

  7. Epothilones – a new class of cytotoxics • Epothilones were isolated from the soil-dwelling myxobacteriumSorangiumcellulosum • S. cellulosum is a unique bacterial species • Largest known bacterial genome • Unique capability to respond to adverse environmental conditions by producing fruiting bodies containing resistant spores • Believed epothilones confer competitive advantage in the natural environment Sorangium cellulosum Fruiting body Nettles JH, et al. Science. 2004;305:866-869.

  8. The natural epothilones and their analogs Ixabepilone Epothilone B S. cellulosum • Low susceptibility to tumor resistance mechanisms • MRP-1 and P-gp efflux pumps • b (III) tubulin overexpression • b tubulin mutations • Activity in multiple tumor models • Demonstrated pre-clinical synergy with capecitabine

  9. Paclitaxel Epothilone A Epothilones Bind Specifically and Uniquely to Beta-Tubulin • Thiazole side-chain occupies the region of binding site not occupied by taxanes • Only 1 polar contact point (C7-OH) is shared with taxanes EpoA and paclitaxel bound to beta-tubulin Nettles. Science. 2004;305:866-869.

  10. Potential Advantages of Epothilones: summary • Bind specifically and uniquely to beta-tubulin • Epothilone B has 2- to 10-fold greater polymerizing activity than paclitaxel • No steroid premedication needed • Less susceptible to multidrug resistance (MDR) • Poor substrates for MDR proteins • MDR expression not altered in epothilone-resistant cell lines • Low susceptibility to tumor resistance mechanisms • MRP-1 and P-gp efflux pumps • b (III) tubulinoverexpression • btubulin mutations

  11. 4.8 4.5 2 1.3 0.4 0.3 0.2 0.2 PAT-7MDR/MRP Ixabepilone In Vivo Efficacy Epothilone A Epothilone B 6 Paclitaxel Ixabepilone 5 4 3.1 Log cell kill at MTD 3 2.5 2 1.6 1 0.8 1 0.4 0.3 0.3 0 A2780 Normal Sensitive A2780/TAXTubulin mutation HCT/VM46MDR PAT-21Unknown M5076Unknown (non-MDR) MTD = maximum tolerated dose.

  12. Novel Microtubule-Stabilizing Agents Under Evaluation Name Derivative Developer Phase Ixabepilone Epothilone B BMS III Patupilone Epothilone B Novartis III KOS-862 Epothilone D Kosan/ROCHE II ZK-EPO Epothilone B Schering AG II BMS-310705 Epothilone B BMS I

  13. Phase II metastatic breast cancer trials Ixabepilone/capecitabine combination Ixabepilone monotherapy 100 90 80 SD 70 ORR 60 % of patients with clinical benefit 50 40 30 20 10 0 Anthracycline pretreated Progressing on taxane Taxane pretreated/resistant Anthracycline/taxane pretreated/resistant CA163010 CA163009 NCI-0229 CA163031 n=65 n=49 n=37 n=62 BMS, data on file.

  14. Ixabepilone safety profile in metastatic breast cancer % of patients experiencing each adverse event according to study *Low JA, et al. J Clin Oncol. 2005;23:2726-2734. BMS, data on file.

  15. IxabepiloneBreast Cancer Registrational Trials Ixabepilone + capecitabine Prior therapy with anthracycline and taxane Capecitabine End points: RR (IRC) TTP Prior therapy with anthracycline , taxane and capecitabine Ixabepilone End points: TTP (IRC) OS RR

  16. 1.0 0.8 0.6 0.4 0.2 0.0 OS mos 8.7 2nd line therapy after anthra-failure 304 trial Mitomycin C + vinblastine Probability 0 6 12 18 24 30 Ixabepilonein triple refractory MBC • 126 pts, previously treated with doxorubicin, taxane and capecitabine • The majority of the patients had PD within 8 weeks since last course of chemotherapy • Ixabepilone 40 mg/m2 q 3 wks • PR (IRF): 12%, SD: 50% • Median PFS: 3.1 mos, Median OS: 8.6 mos • In 2006, 4th line chemotherapy can assure the same survival obtained with 2nd line treatment before taxane availability X. Pivot, ESMO 2006

  17. Ixabepilone +capecitabine Resistant to anthracycline and taxane in MBC patients Primary End Point: 046 PFS 046 Study N=752 capecitabine Ixabepilone +capecitabine 048 Study N=1221 Pretreated with an anthracycline and taxane in MBC patients Primary End Point: 048 OS capecitabine - Phase III trials of Ixabepilone plus Capecitabine versus Capecitabine in metastatic breast cancer - Thomas ES et al.: J Clin Oncol, 2007 Sparano JA et al.: J Clin Oncol, 2010

  18. Key inclusion criteria (including definition of resistance)

  19. Stratification • Visceral metastases • Prior chemotherapy for MBC • Anthracycline resistance • Study site Study Design: International, Randomized, Open-label, Phase III Trial 046 Thomas ES et al.: J Clin Oncol, 2007

  20. 046 Trial - Study Endpoints - • Primary • Progression-free survival by blinded Independent Radiologic Review (IRR) • Secondary • Response rate • Time to response • Duration of response • Survival (pending 631 events) Thomas ES et al.: J Clin Oncol, 2007

  21. 046 TRIAL - Results: Response Rate Thomas ES et al.: J Clin Oncol, 2007

  22. 046 TRIAL - Results: Progression-free Survival - 1. Indipendent radiology review progression-free survival HR: 0.75 (95%CI, 0.64–0.88) Thomas ES et al.: J Clin Oncol, 2007

  23. 046 Trial – G ¾ toxicities - Thomas ES et al.: J Clin Oncol, 2007

  24. Grade 3/4 Peripheral Neuropathy • Primarily sensory • Cumulative • Reversible Proportion Not Resolved Median time to resolution of 6 weeks* Weeks *Resolution = return to baseline or grade 1 24 Thomas ES et al.: J Clin Oncol, 2007

  25. Study Design: Multinational, Randomized, Open-label, Phase III Trial 048 Sparano JA et al.: J Clin Oncol, 2010

  26. 048 Trial - Study Endpoints - • Primary • - Overall Survival • Secondary • - Progression-free Survival • (pts with measurable disease) • - Response rate • - Time to response • - Duration of response Response-evaluable patients Sparano JA et al.: J Clin Oncol, 2010

  27. 048 TRIAL - Results: Response Rate Sparano JA et al.: J Clin Oncol, 2010

  28. 048 TRIAL - Progression-free Survival patients with measurable disease (79%) p=0.0005 HR=0.79; 95%CI, 0.69-0.90 Sparano JA et al.: J Clin Oncol, 2010

  29. 048 TRIAL - Results: Overall Survival p=0.1162 HR=0.9; 95%CI, 0.78-1.03 OS adjusted for age, KPS, number of organ sites, ER status, liver impairment, time for diagnosis, visceral disease: HR 0.85; 95%CI, 0.75-0.98; p=0.0231 Sparano JA et al.: J Clin Oncol, 2010

  30. 048 - Grade 3/4 Toxicities Sparano JA et al.: J Clin Oncol, 2010

  31. Ixabepilone and EribulinCross Trial Comparison

  32. 046 and 048 trials - POOLED ANALYSIS BY PERFORMANCE STATUS - Kaplan-Meier analysis of PFS (A) and OS (B) in POOLED KPS 90-100 PTS p=0.009 HR=0.82; 95%CI, 0.73-0.92 p=0.8110 HR=0.98; 95%CI, 0.87-1.12 Roché et al.: Breast Cancer Res Treat, 2011

  33. 046 and 048 trials - POOLED ANALYSIS BY PERFORMANCE STATUS - Kaplan-Meier analysis of PFS (A) and OS (B) in POOLED KPS 70-80 PTS p=0.0021 HR=0.76; 95%CI, 0.64-0.90 p=0.0015 HR=0.75;95%CI, 0.63-0.90 Roché et al.: Breast Cancer Res Treat, 2011

  34. Epothilones: summary • A new class of microtubule stabilizers active in paclitaxel-sensitive and resistant tumor models • Most common AEs are peripheral neuropathy (ixabepilone) and diarrhea (patupilone) • Premedication not required • Ixabepilone is active in “difficult” breast tumors (triple refractory, triple negative) • Ixabepilone + capecitabine is significantly superior to capecitabine in anthra/taxane resistant/refractory patients • Patupilone is active in platinum/taxane resistant/refractory ovarian cancer and can be active in other tumor types

  35. Challenges in the development of new cytotoxics for breast cancer • Chemotherapy has still a role in the management of breast cancer • Hurdles in the development of new cytotoxics include: • - Prolonged post-progression survival • - Tolerability • - Difficulty to develop reliable predictive biomarkers • New cytotoxics should be developed in clearly defined patient population: • - multiple refractory • - triple negative • - high risk after neoadjuvant chemotherapy

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