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ASCO 2010: Metastatic Breast Cancer New Data & Expert Clinical Insights

ASCO 2010: Metastatic Breast Cancer New Data & Expert Clinical Insights. Edith A. Perez, MD Serene M. and Frances C. Durling Professor of Medicine Deputy Director, Mayo Clinic Cancer Center Mayo Clinic . Mayo Clinic Today. 3 million patients a year from USA & 150 countries

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ASCO 2010: Metastatic Breast Cancer New Data & Expert Clinical Insights

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  1. ASCO 2010: Metastatic Breast CancerNew Data & Expert Clinical Insights Edith A. Perez, MDSerene M. and Frances C. Durling Professor of Medicine Deputy Director, Mayo Clinic Cancer CenterMayo Clinic

  2. Mayo Clinic Today • 3 million patients a year from USA & 150 countries • 56,800 total personnel Mayo Clinic in Minnesota Mayo Clinic in Arizona Mayo Clinic in Florida

  3. Phase II/III Trials in Metastatic Breast Cancer: What is New? HER2 positive Triple negative General

  4. A Phase Ib/II Trial of Trastuzumab-DM1 (T-DM1) with Pertuzumabfor Women with HER2+ MBC Previously Treated with Trastuzumab K. Miller, L. Gianni, F. Andre, V. Dieras, R. L. Mahtani, N. Harbeck, J. E. Huang, T. Shih, Y. Choi, H. A. Burris III Miller K, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1012)

  5. Study Design: HER2+ Locally Advanced or Metastatic Breast Cancer • 58 patients added into expanded Phase II at established dose* Cohort 2 Expand T-DM1 3.6 mg/kg* dose level to 60 evaluable pts Yes† 0/3 or 1/6 DLTs T-DM1 3.6 mg/kg + Pertuzumab* Cohort 1 Yes 3-6 patients Expand T-DM1 3.0 mg/kg dose level to 60 evaluable pts No 0/3 or 1/6 DLTs T-DM1 3.0 mg/kg + Pertuzumab* No Expand T-DM1 2.4 mg/kg dose level to 60 evaluable pts 0/3 or 1/6 DLTs Yes T-DM1 2.4 mg/kg + Pertuzumab* No DLT=dose-limiting toxicity: T-DM1=trastuzumab-MCC-DM1. * Full-dose pertuzumab=Cycle 1 loading dose (840 mg); 420 mg all subsequent cycles. † Patients enrolled to the initial cohort may now receive 3.6 mg/kg T-DM1 in subsequent cycles along with full-dose pertuzumab. ‡ 20 first-line and 40 relapsed (second-line and beyond) patients were to be included in this phase. No Further Enrollment Dose-Escalation Phase Expansion Phase‡ Miller K, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1012)

  6. Preliminary Efficacy Promising with T-DM1 + Pertuzumab • 67 patients enrolled • 44 evaluable relapsed pts (2nd line or beyond) • 22 pts with newly diagnosed HER2+ MBC (first-line) • 1 pt without safety data, excluded from analysis • Median 5 doses T-DM1 received • ORR 35.7% (10/28 partial responses) ORR data from 28 pts who received ≥4 cycles, or progressed or died Miller K, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1012)

  7. HER2+ Breast Cancer:what is next in MBC? • TDM4550 1st-line trial --- ESMO Oct 2010 (Perez et al) • T-DM1 vs (Docetaxel + Trastuzumab) • CLEOPATRA • Docetaxel + Trastuzumab +/- Pertuzumab • COMPLETE (MA.31) • 1st line: Taxane + (Trastuzumab or Lapatinib) • EMILIA study ongoing; refractory • T-DM1 vs (Lapatinib + Capecitabine) • Phase III Capecitabine + Trastuzumab or Lapatinib; refractory • MARIANNE to be initiated; 1st-line • Phase III of T-DM1 vs (T-DM1 + Pertuzumab) vs taxane+ Trastuzumab

  8. Safety and Efficacy of the Oral PARP Inhibitor Olaparib (AZD2281) + Paclitaxel as 1st or 2nd-line Rx of Metastatic Triple-negative Breast Cancer: Results From the Safety Cohort of A Phase I/II Multicenter Trial R. A. Dent, G. J. Lindeman, M. Clemons, H. Wildiers, A. Chan, N. J. McCarthy, C. F. Singer, E. S. Lowe, K. Kemsley, J. Carmichael Dent RA, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1018)

  9. Olaparib + Paclitaxel Well Tolerated Except for Dose-Limiting Neutropenia • Olaparib 200 mg po BID continuous + paclitaxel 90mg/m2 IV weekly for 3/4 weeks • 1st-line TN breast cancer • N=19, about 70% first-line • Toxicities • Neutropenia Grade 1/2 (26%), Grade ≥3 (32%) • Acceptable dose intensity not achieved due to neutropenia • Protocol amended to allow treatment with GSCF as secondary prophylaxis, additional cohort (n=10) added • Diarrhea Grade 1/2 (63%) • Nausea Grade 1/2 (58%) • Fatigue Grade 1/2 (47%), Grade 3 (5%) Dent RA, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1018)

  10. Response Data of Olaparib + Paclitaxel in TNBC • No complete responses, 33-40% partial responses • Median PFS >5 months in both cohorts • 6.3 months (no GCSF) • 5.2 months (GCSF) • Regimen will not be pursued due to neutropenia Dent RA, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1018)

  11. Triple Negative Breast Cancer: What is next for MBC? • Evaluate role of PARP expression on sensitivity to PARP inhibitors • Pending data of the phase III gem/carbo +/- iniparib • Evaluate role of platinum agents, anti-angiogenic Rx, brostacillin Rx

  12. A Phase III Study (EMBRACE) of Eribulin Mesylate Versus Treatment of Physician's Choice in Patients With Locally Recurrent or Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane C. Twelves, D. Loesch, J. L. Blum, L. T. Vahdat, K. Petrakova, P. J. Chollet, C. E. Akerele, S. Seegobin, J. Wanders, J. Cortes Twelves C, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr CRA1004^)

  13. Eribulin in Heavily Pretreated Metastatic Breast Cancer • Global, randomized, open-label Phase III trial (Study 305, EMBRACE) • Final analysis after 422 deaths • Median age 55.2 yrs, 16% HER2+, 19% TNBC, median 4 prior agents Eribulin mesylate 1.4 mg/m2, 2-5 min IV Day 1, 8 q21 days • Primary • endpoint • Overall survival • Patients (N = 762) • Locally recurrent or MBC • 2-5 prior chemotherapies • ≥2 for advanced disease • Prior anthracycline and taxane • Progression ≤6 monthsof last chemotherapy • Neuropathy ≤ grade 2 • ECOG ≤2 • Secondary • endpoints • PFS • ORR • Safety Randomization 2:1 Treatment of Physician's Choice (TPC) Any monotherapy (chemotherapy,hormonal, biological) orsupportive care only Twelves C, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr CRA1004^)

  14. EMBRACE: Treatments of Physician’s Choice 96% of patients treated with chemotherapy 50 Total patients = 247 40 30 n=61 % of patients n=46 n=44 20 n=38 n=24 n=25 10 n=9 0 Taxanes Hormonal Vinorelbine Gemcitabine Other chemo Capecitabine Anthracyclines No patient received best supportive care or "biological" therapies only Twelves C, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr CRA1004^)

  15. EMBRACE: Significant Improvement in OS with Eribulin vs Physicians’ Choice 1 year survival Eribulin (n=508) 53.9% TPC (n=254) 43.7% 1.0 0.8 Eribulin Median 13.12 months 0.6 HR* 0.81 (95% Cl 0.66, 0.99) p-value†=0.041 Survival Probability TPC Median 10.65 months 0.4 0.2 2.47 months 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Overall Survival (months) ITT population, *HR Cox model including geographic region, HER2/neu status, and prior capecitabine therapy as strata † p value from stratified log-rank test (pre-defined primary analysis); TPC, treatment of physicians’ choice, HR, hazard ratio; Cl, confidence intervals Twelves C, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr CRA1004^)

  16. 1.0 1.0 0.8 0.8 Eribulin (n=508) Eribulin (n=508) 0.6 0.6 TPC (n=254) TPC (n=254) Proportion progression-free Proportion progression-free 0.4 0.4 0.2 0.2 0.0 0.0 0 0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 16 16 18 18 20 20 Time (months) Time (months) EMBRACE: PFS by Independent and Investigator Review Investigator review (ITT) Independent review (ITT) TPC, treatment of physicians’ choice Twelves C, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr CRA1004^)

  17. EMBRACE: ORR and Safety • AEs • Grade 3/4 asthenia/fatigue (7.6%), neutropenia (44%), peripheral neuropathy (8.4%) with eribulin • 10% of pts experienced SAEs (eribulin 12%, physician choice 7%) Twelves C, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr CRA1004^)

  18. Sunitinib (SU) in Combination With Docetaxel (D) Versus D Alone For the First-line Treatment of Advanced Breast Cancer (ABC) Phase III Trial of Sunitinib (SU) in Combination With Capecitabine (C) Versus C in Previously Treated Advanced Breast Cancer (ABC) J. Bergh, R. Greil, N. Voytko, A. Makhson, J. Cortes, A. Lortholary, X. Huang, C. Giorgetti, K. A. Kern, M. Lichinitser J. Crown, V. Dieras, E. Staroslawska, D. A. Yardley, N. Davidson, T. D. Bachelot, V. R. Tassell, X. Huang, K. A. Kern, G. Romieu Bergh J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr LBA1010) Crown J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr LBA1011)

  19. SUN 1064 and 1099 Study Designs SUN 1064 SUN 1099 R A N D O M I Z ATION R A N D O M I Z ATION CAP 2,000 mg/m2po days 1-14 q3w+Sunitinib 37.5 mg po CDD N=221 Docetaxel 75 mg/m2 IVday 1 q3w+Sunitinib 37.5 mg podays 2-15 q3w N=296 Docetaxel 100 mg/m2 IV q3w N=297 CAP 2,500 mg/m2po days 1-14 q3wN=221 • No prior chemotherapy for ABC • 17% no chemotherapy • 28% <12 month DFI • 20% TNBC • 78% previous rx for ABC • Prior anthracycline and taxane • 27% TNBC Bergh J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr LBA1010) Crown J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr LBA1011)

  20. Sunitinib in Combination with Docetaxel or Capecitabine Not Recommended for Advanced Breast Cancer • Trials did not meet endpoints of prolonging PFS or OS • Bergh (N=593) • Median PFS 8.6 mo for SU + D vs 8.3 mo with D alone • Median OS 24.8 mo for SU + D vs 25.5 mo with D alone • Crown (N=442) • Median PFS 5.5 mo for SU + C vs 5.9 mo for C alone • Median OS 16.4 mo for SU + C vs 16.5 mo for C alone • Sunitinib + docetaxel or + capecitabine not recommended as combination in advanced breast cancer Bergh J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr LBA1010) Crown J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr LBA1011)

  21. Progression-free Survival (PFS) in Patient Subgroups in RIBBON-2, a Phase III Trial of Chemotherapy +/- Bevacizumab for 2nd-line Rx of HER2-negative MBC A. Brufsky, R. R. Rivera, S. A. Hurvitz, I. N. Bondarenko, V. Smirnov, V. Valero, H. S. Rugo, R. Swamy, H. Mu, E. A. Perez Brufsky A, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1021)

  22. RIBBON-2: BV in Combination ProvidesPFS Benefit to HER2- Patients • Bevacizumab added to variety of chemo agents in 2nd line HER2- stage IV breast cancer • 684 patients randomized to chemo + placebo (n=225) or chemo + BV (n=459) • Addition of BV improved median PFS (5.1 mo with placebo vs 7.2 mo with BV, P=0.0072) PFS by subset Brufsky A, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1021)

  23. A Meta-analysis of Overall Survival Data From 3 Randomized Trials of Bevacizumab (BV) and 1st-line Chemotherapy as Treatment for Patients with MBC J. O'Shaughnessy, D. Miles, R. J. Gray, V. Dieras, E. A. Perez, R. Zon, J. Cortes, X. Zhou, S. Phan, K. Miller O’Shaughnessy J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1005)

  24. OptionalSecond-line Chemo + BV(AVADO and RIBBON-1 only) E2100Paclitaxel Chemo +No BV Previously Untreated MBC Treat until PD AVADO Docetaxel RANDOMIZE Chemo +BV RIBBON-1 Capecitabine, Taxane,orAnthracycline 1st-line Chemotherapy +/- Bevacizumab Meta-analysis • Meta-analysis of OS in 2,447 patients from 3 trials • Control (n=1,008); BV + chemo (n=1,439) O’Shaughnessy J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1005)

  25. ChemoRx +/- Bevacizumab Meta-analysis: Progression-Free Survival (pooled analysis) O’Shaughnessy J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1005)

  26. Chemotherapy +/- Bevacizumab Meta-analysis: Overall Survival (pooled analysis)

  27. Summary (PFS, ORR, 1 yr survival, OS) of Meta-analysis with Bevacizumab as 1st-line • PFS • HR=0.64, 36% reduction in risk of PD or death • 2.5 month improvement in median PFS (P<0.0001) • Improvements across key clinical subpopulations • ORR • 17% increase vs controls • 1-year survival rate greater in BV + chemo arms (P=0.003) • OS • No statistically significant difference O’Shaughnessy J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1005)

  28. A Meta-analysis of Results from Two Randomized, Double-blind Studies of Denosumab vs Zoledronic Acid (ZA) for Treatment of Bone Metastases A. Lipton, A. Stopeck, R. von Moos, D.H. Henry, G.E. Richardson, G.I. Rodriguez, H.P. Bourgeois, C. Ke, S. Jun, R.D. Dansey Lipton A, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 565)

  29. Denosumab vs Zoledronic Acid: Meta-analysis of Two Pivotal Trials Denosumab 120 mg SC andPlacebo IV every 4 weeks (N=1912) • Key Inclusion • Adults with confirmed bonemetastases from advancedcancer (except prostate) and multiple myeloma Supplemental Calcium and Vitamin D • Key Exclusion • Current or prior intravenousbisphosphonateadministration Zoledronic acid 4 mg IV andPlacebo SC every 4 weeks (N=1910) Primary Endpoint ■Time to first on-study SRE (non-inferiority) Secondary Endpoints ■ Time to first on-study SRE (superiority)■ Time to first and subsequent on-study SRE (superiority) Lipton A, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 565)

  30. 17% Median Months to 1st SRE Zoledronic acid 21.1 Denosumab Not reached Denosumab vs Zoledronic Acid:Time to First On-Study SRE • Significantly longer for denosumab vs zoledronic acid • Separation between treatments begins around 3 months 1.0 HR 0.83 (95% CI: 0.74, 0.92) P < 0.001 (Superiority) RiskReduction 0.8 0.6 Proportion of Patients Without SRE 0.4 0.2 0 0 6 12 18 24 30 Study Month Lipton A, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 565)

  31. Denosumab Superior to Zoledronic Acid in Delaying or Preventing SREs • Denosumab reduced mean skeletal morbidity rate (SREs/year) (0.64 vs 0.80 for zoledronic acid, P=0.0006) • Similar rates in both groups for overall rates of • Disease progression (HR 1.00; 95% CI: 0.92, 1.08; P=0.90) • Survival (HR 0.95; 95% CI: 0.86, 1.05; P=0.35) • AEs (AEs; 96% denosumab, 97% ZA) • Serious AEs (53% denosumab, 56% ZA) • Increased rates with zoledronic acid • AEs potentially associated with renal toxicity (9.6% vs 6.5% with denosumab) • Acute phase reactions at 3 days (21.4% vs 8.8% with denosumab) Lipton A, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 565)

  32. Summary of MBC Data at ASCO 2010 • Feasibility of T-DM1 + Pertuzumab • Eribulin • Improved overall survival vs. standard of care • Sunitinib • No benefit when added to docetaxel or capecitabine • Bevacizumab • Improvement in RR and PFS, not OS in 1st-line setting • PFS benefit of bevacizumab in 2nd line setting, efficacy across subgroups • Denosumab for bone metastases • Improved bone events vs zoledronic acid

  33. Thank you Sunday Feb 13, 2011 Jacksonville, FL www.breastcancermarathon.com

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