Novel Chemotherapy Agents for Metastatic Breast Cancer Joanne L. Blum, MD, PhD Baylor-Sammons Cancer Center Dallas, TX
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)
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
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.
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 CA163-046 Trial: Anthracyclinepretreated or resistant Taxane-resistant CA163-048 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 CA163-046: 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: 5210-17. Sparano et al., J Clin Oncol 2010; 28: 3256-63.
Phase III Trials of Capecitabine with or without Ixabepilone in Pretreated Advanced Breast Cancer Cape + ixa (n = 375) CA163-046 1,2 CA163-048 3 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: 5210-17. 2 Hortobagyi et al., Breast Cancer Res and Treat 2010; 122: 409-18. 3 Sparano et al., J Clin Oncol 2010; 28: 3256-63. 4 Rugo et al. Cancer Res 2009; 69 (suppl): (abstract 3057).
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.086 13.6 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
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.18 9.0 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
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.21 12.5 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
Halichondrin B Analogue
Eribulin Mesylate: Mechanism of Action Microtubule dynamics Polymerize De-polymerize Paclitaxel Microtubule stabilization E7389 Inhibits Microtubule Assemby Non-productive aggregates
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: 2594-61 Cortes J et al, JCO 2010 28:3922-28
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: 2594-61 Cortes J et al, JCO 2010 28:3922-28
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
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) 13.12 10.65 0.81 (0.66-0.99).041 Median PFS (months) a 3.7 2.2 0.87 (0.71-1.05).14 a Independent review Updated OS Analysis Eribulin (n = 508) TPC (n = 254) HR (95% CI) P value Median OS (months) 13.2 10.5 0.805 (0.677-0.958).014 1-yr survival rate (%) 54.5 43 NR NR 2-yr survival rate (%) 22 19 NR NR Twelves et al., J Clin Oncol 2010; 28 (suppl): 958S (abstract CRA1004). Twelves et al. SABCS 2010; abstract P6-14-18.
Phase III EMBRACE Trial: Updated Safety Analysis Grade 3/4 Adverse Events (%) Eribulin (n = 503) TPC (n = 247) Neutropenia 46 17 Leukopenia 14 2.5 Asthenia/fatigue 8.5 10 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 P6-14-18.
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 362 13.3 (404 days) 162 10.7 (326 days) 0.774 (0.606-0.988).039 > 3 chemo regimens 106 11.7 (355 days) 51 10.0 (304 days) 0.899 (0.600-1.348).607 Overall survival benefit for eribulin was greatest in those who received 3 or fewer prior chemotherapy regimens Blum et al. SABCS 2010; abstract P6-13-01.
nab-paclitaxel
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; 23:7794-7803.
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; 27:3611-19.
PFS Investigator Assessment Proportion not progressed 1.00 0.75 0.50 0.25 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 = 0.012 HR = 0.568 0.00 0 3 6 9 12 15 18 21 24 A vs B; P = 0.076, HR = 0.702 B vs C; P = 0.001; HR = 1.972 Months docetaxel (D) 100 mg/m 2 q3w 7.8 PFS, progression free survival Gradishar et al. JCO 2009
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.
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).
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
NLTR-102: Metastatic Breast Cancer
New Agents: Goals Improved survival Better palliation Improved quality of life Better safety profile