Novel Chemotherapy Agents for Metastatic Breast Cancer. Joanne L. Blum, MD, PhD Baylor-Sammons Cancer Center Dallas, TX

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1 Novel Chemotherapy Agents for Metastatic Breast Cancer Joanne L. Blum, MD, PhD Baylor-Sammons Cancer Center Dallas, TX

2 New Chemotherapy Agents in Breast Cancer New classes of drugs Epothilones Halichondrin B analogs New formulations of existing drugs Nab-paclitaxel Pegylated irinotecan (NKTR-102)

3 Overview: Mechanisms of Action of Vinca Alkaloids and Taxanes Vinca alkaloids Taxanes/Epothilones Destabilizers Stabilizers Polymerization Mitotic spindle formation blocked Polymerization MT Bundling Multipolar spindles

4 Epothilones: New Anti-tubulins Structurally unrelated to the taxanes Binding site on B tubulin differs from taxanes Epothilones appear to possess several advantages over paclitaxel Avoid development of resistance 4 Have greater polymerizing activity than paclitaxel Ixabepilone active against various taxane-sensitive and taxaneresistant cell lines More potent polymerizing agents compared to taxanes Computer model of beta-tubulin mutations Taxane Epothilone Image obtained from: Giannakakou et al. Proc. Natl. Acad. Sci. USA. 2000;97:2904.

5 Phase III Trials of Capecitabine with or without Ixabepilone in Anthracycline- and Taxane-Pretreated or Resistant Advanced Breast Cancer Eligibility criteria: Locally advanced or metastatic breast cancer CA Trial: Anthracyclinepretreated or resistant Taxane-resistant CA Trial: Anthracyclinepretreated Taxane-pretreated R A N D O M I Z E Ixabepilone 40 mg/m 2, day 1 q3w Capecitabine 2000 mg/m 2, days 1-14 q3w Capecitabine 2500 mg/m 2, days 1-14 q3w Resistance criteria for CA : Progression/recurrence: (Neo)adjuvant: < 6 months anthracycline, < 12 months taxane Metastatic: < 3 months anthracycline, < 4 months taxane Thomas et al., J Clin Oncol 2007; 25: Sparano et al., J Clin Oncol 2010; 28:

6 Phase III Trials of Capecitabine with or without Ixabepilone in Pretreated Advanced Breast Cancer Cape + ixa (n = 375) CA ,2 CA Cape (n = 377) Cape + ixa (n = 609) Cape (n = 612) ORR 35% 14% 43% a 29% a P <.0001 P <.0001 Median PFS 5.8 months 4.2 months 6.2 months b 4.4 months b HR; P value HR 0.75; P =.0003 HR 0.79; P =.0005 Median OS 12.9 months 11.1 months 16.4 months 14.4 months HR; P value HR 0.90; P =.1936 HR 0.90; P =.1162 a N = 462 for each arm b N = 480 for each arm Pooled analysis of patients with triple-negative breast cancer: 4 Combination showed 2.5 months improvement in median PFS (4.2 vs. 1.7 months) compared to capecitabine alone. Doubled ORR (31% vs. 15%) 1 Thomas et al., J Clin Oncol 2007; 25: Hortobagyi et al., Breast Cancer Res and Treat 2010; 122: Sparano et al., J Clin Oncol 2010; 28: Rugo et al. Cancer Res 2009; 69 (suppl): (abstract 3057).

7 Capecitabine Ixabepilone in MBC Patients: Pooled Analyses from Two Phase III Trials Overall pooled population (n = 1973) Efficacy Ixa + Cape (n = 855) Cape (n = 857) ORR 42% 25% CR 3% 2% PR 38% 24% Median PFS 5.6 mos 4.2 mos HR 0.80 P value <.0001 Median OS 14.6 mos (n = 984) HR 0.92 P value mos (n = 989) Selected Grade 3/4 AEs Ixa + Cape (n = 964) Cape (n = 971) Neutropenia 71% 9% Febrile neutropenia 6% < 1% Leukopenia 61% 7% Peripheral neuropathy Hand-foot syndrome 24% < 1% 20% 19% Fatigue 11% 3% Roche et al. SABCS 2008, Abstract 2015 Rugo et al. SABCS 2008, Abstract 3057 Vahdat et al. SABCS 2008, Abstract 6117

8 Capecitabine Ixabepilone in Triple Negative MBC Pooled triple negative subgroup (n = 443) Efficacy Ixa + Cape (n = 191) Cape (n = 208) ORR 31% 15% CR 3% 1% PR 28% 14% Median PFS 4.2 mos 1.7 mos HR 0.63 P value <.0001 Median OS 10.3 mos (n = 213) HR 0.87 P value mos (n = 230) Selected Grade 3/4 AEs Ixa + Cape (n = 209) Cape (n = 226) Neutropenia 70% 8% Febrile neutropenia 4% < 1% Leukopenia 63% 5% Peripheral neuropathy Hand-foot syndrome 23% < 1% 14% 16% Fatigue 11% 3% Rugo et al. SABCS 2008, Abstract 3057

9 Capecitabine Ixabepilone in Post-Adjuvant Rapidly Relapsing (PARR) MBC Patients Pooled PARR subgroup (n = 293): relapsed 12 months after neoadjuvant or adjuvant anthracyclines and taxanes Efficacy Ixa + Cape (n = 123) Cape (n = 111) ORR 46% 24% CR 7% 2% PR 39% 23% Median PFS 5.6 mos 2.8 mos HR 0.58 P value <.0001 Median OS 15.1 mos (n = 149) HR 0.84 P value mos (n = 144) Selected Grade 3/4 AEs Ixa + Cape (n = 142) Cape (n = 140) Neutropenia 74% 9% Febrile neutropenia 5% 1% Leukopenia 65% 9% Peripheral neuropathy Hand-foot syndrome 23% 0 22% 19% Fatigue 13% 2% Vahdat et al. SABCS 2008, Abstract 6117

10 Halichondrin B Analogue

11 Eribulin Mesylate: Mechanism of Action Microtubule dynamics Polymerize De-polymerize Paclitaxel Microtubule stabilization E7389 Inhibits Microtubule Assemby Non-productive aggregates

12 Eribulin phase II Trials in Breast Cancer 201 Trial: (N=103) Prior anthracycline & taxane therapy Progressed on or within 6 months of last chemotherapy If present, pre-existing neuropathy Grade 2 Eribulin 1.4 mg/m 2 over 1-4 min q 3 wks Assessments ORR with independent review Response duration PFS and OS Adverse Events 211 Trial (N=299) 2-5 prior chemotherapy regimens Prior anthracycline, taxane, and capecitabine therapy Progressed on or within 6 months of last chemotherapy If present, pre-existing neuropathy Grade 2 Vadhat L et al, JCO 2009;27: Cortes J et al, JCO :

13 Phase II studies of Eribulin in Breast Cancer 201 trial ( N= 103) 211 Trial (N= 299) Median # prior regimens 4 4 Response Rate (CR + PR) Clinical Benefit Rate (CR,PR,SD 6m) Median duration of response Primary toxicity neutropenia, fatigue, 5% PN 12% 9% 17% 17% 5.6 mos 3.5 mos Vadhat L et al, JCO 2009;27: Cortes J et al, JCO :

14 Phase III EMBRACE Trial: Eribulin Mesylate Versus Treatment of Physicians Choice for Heavily Pretreated Advanced Breast Cancer Eligibility criteria: Locally recurrent or metastatic breast cancer 2-5 prior chemotherapies: 2 for advanced disease Prior anthracycline and taxane Progression 6 months since last chemotherapy Neuropathy grade 2 R A N D O M I Z E 2:1 Eribulin mesylate 1.4 mg/m 2, days 1, 8 q 3 weeks Treatment of Physician s Choice (TPC) Any monotherapy approved for treatment of cancer or supportive care only N = 508 N = 254 Primary analysis based on 422 of 762 events Updated analysis based on 589 of 762 events Eribulin arm: 386 events/508 (76%) TPC arm: 203 events/254 (80%) Twelves et al., J Clin Oncol 2010; 28 (suppl): 958S (abstract CRA1004) Cortes J et al Lancet epub March 3, 2011

15 Phase III EMBRACE Trial: Initial Results and Updated Survival Analysis Initial Results from ASCO 2010 Eribulin (n = 508) TPC (n = 254) HR (95% CI) P value Survival Median OS (months) ( ).041 Median PFS (months) a ( ).14 a Independent review Updated OS Analysis Eribulin (n = 508) TPC (n = 254) HR (95% CI) P value Median OS (months) ( ) yr survival rate (%) NR NR 2-yr survival rate (%) NR NR Twelves et al., J Clin Oncol 2010; 28 (suppl): 958S (abstract CRA1004). Twelves et al. SABCS 2010; abstract P

16 Phase III EMBRACE Trial: Updated Safety Analysis Grade 3/4 Adverse Events (%) Eribulin (n = 503) TPC (n = 247) Neutropenia Leukopenia Asthenia/fatigue Peripheral neuropathy 8 2 Headache 5 <1 Dyspnea 4 3 Anemia 2 4 Nausea 1 2 Significant survival advantage for eribulin was maintained throughout the observation period No changes in safety profile of eribulin during observation period Twelves et al. SABCS 2010; abstract P

17 The Impact of Number of Prior Regimens on Overall Survival in the Phase III EMBRACE Trial Treatment history N Eribulin OS (months) N TPC OS HR (95% CI) P value 3 chemo regimens (404 days) (326 days) ( ).039 > 3 chemo regimens (355 days) (304 days) ( ).607 Overall survival benefit for eribulin was greatest in those who received 3 or fewer prior chemotherapy regimens Blum et al. SABCS 2010; abstract P

18 nab-paclitaxel

19 Phase III Trial: Standard Paclitaxel vs. nab Paclitaxel in MBC Eligibility criteria: Metastatic breast cancer No prior taxane N = 460 R A N D O M I Z E nab paclitaxel 260 mg/m 2, q3w No standard premedication Standard paclitaxel 175 mg/m 2, q3w Standard premedication given Efficacy nab Paclitaxel (n = 229) Paclitaxel (n = 225) P value ORR 33% 19%.001 TTP 23.0 wks 16.9 wks.006 Adverse events Grade 4 neutropenia 9% 22% <.001 Grade 3 sensory neuropathy 10% a 2% <.001 a Median time to improvement = 22 days Gradishar et al. J Clin Oncol 2005; 23:

20 Phase II Trial of nab Paclitaxel vs. Docetaxel as First-line Therapy for MBC Efficacy 300 mg/m 2 q3w (n = 76) nab Paclitaxel 100 mg/m 2 /week (n = 76) 150 mg/m 2 /week (n = 74) Docetaxel 100 mg/m 2 q3w (n = 74) ORR 37% 45% 49% 35% Median PFS 11.0 months 12.8 months 12.9 months a 7.5 months Adverse events Grade 4 neutropenia Grade 3 sensory neuropathy 5% 5% 9% 75% 17% 8% 14% 12% Grade 3 fatigue 5% 0 3% 19% a HR 0.495; P =.0065 compared to docetaxel arm Gradishar et al. J Clin Oncol 2009; 27:

21 PFS Investigator Assessment Proportion not progressed nab-paclitaxel 300 mg/m 2 q3w (A) nab-paclitaxel 100 mg/m 2 weekly (B) nab-paclitaxel 150 mg/m 2 weekly (C) docetaxel 100 mg/m 2 q3w (D) Regimen nab-paclitaxel (A) 300 mg/m 2 q3w nab-paclitaxel (B) 100 mg/m 2 3/4 weeks nab-paclitaxel (C) 150 mg/m 2 3/4 weeks (n = 74) Median PFS (mo) 10.9 NS 7.5 NS P value vs docetaxel 14.6 P = HR = A vs B; P = 0.076, HR = B vs C; P = 0.001; HR = Months docetaxel (D) 100 mg/m 2 q3w 7.8 PFS, progression free survival Gradishar et al. JCO 2009

22 Phase II Trial: nab Paclitaxel in MBC Previously Treated with a Taxane Efficacy nab Paclitaxel 100 mg/m 2 (n = 106) nab Paclitaxel 125 mg/m 2 (n = 75) P value ORR 15/106 (14%) 12/75 (16%).7309 Prior paclitaxel 4/30 (13%) 4/20 (20%) NR Prior docetaxel 7/34 (21%) 6/28 (21%) NR Prior pac and doce 2/29 (7%) 0 NR Median PFS 3.0 months 3.5 months NR Median OS 9.2 months 9.1 months NR Blum et al. Clin Breast Cancer 2007; 7:850-6.

23 40502: CALGB & NCCTG Phase III Trial Rugo H, Moreno A and Lyss A N=900 1 st line therapy for metastatic or locally advanced breast cancer Tumor biopsy on accessible tumor Correlative studies: tumor block for SPARC, Caveolin mutations, tubulin isoforms R A N D O M I Z E D Paclitaxel 90 mg/m 2 weekly* + *Bevacizumab 10 mg/kg q2w nab Paclitaxel 150 mg/m 2 weekly* + *Bevacizumab 10 mg/kg q2w Ixabepilone 16 mg/m 2 weekly* + Bevacizumab 10 mg/kg q2w Serial serum measurement of caveolin-1 Serial measurement of CTC and CEC Primary endpoint PFS (11 to 15 mths), Secondary endpoints ORR, toxicity, correlative studies, OS * D 1, 8, 15 q 28 days *Bev optional Circulating Tumor Cells, CTC; Circulating Endothelial Cells (CEC).

24 NKTR-102 Novel formulation of irinotecan, a topoisomerase 1 inhibitor 4 arm pegylated prodrug Synthesized to provide sustained release with reduced peak concentration of irinotecan and SN38 Given IV every 2-3 weeks Toxicity Most common grade 3/4 Diarrhea 14/6% Neutropenia 9/6% VERY low rate of alopecia More favorable with every 3 week dosing

25 NLTR-102: Metastatic Breast Cancer

26 New Agents: Goals Improved survival Better palliation Improved quality of life Better safety profile