Contemporary Chemotherapy-Based Strategies for First-Line Metastatic Breast Cancer

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1 Contemporary Chemotherapy-Based Strategies for First-Line Metastatic Breast Cancer Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education University of California San Francisco Helen Diller Family Comprehensive Cancer Center

2 MBC Survival by Decade 2 Giordano S, et al. Cancer. 2004;100(1):44-52

3 3 Goals of Therapy Patient Goals Extend survival Minimize toxicity Improve or maintain QOL Other issues Hair loss IV access Frequency of visits Fatigue Clinical Trial Endpoints / Outcomes Response rate Response duration TTP / TTF / PFS OS Quality of life Safety

4 Treatment Considerations Treatment is based on: IHC markers ER+/HER2- HER2+ Triple negative Tumor biology Extent/sites of disease Disease free interval Response to prior therapy Patient related factors Preference Co-morbidity

5 Topics for Discussion When should we use combination chemotherapy? Is there a best microtubule inhibitor? Does increased dose increase efficacy? Is order of agents important? Role of maintenance chemotherapy

6 Combination Versus Single Agent Therapy: Considerations Combinations result in: Better RR, sometimes better PFS Improvement in OS dependent on subsequent therapy Increased toxicity Combination therapy should be reserved for: Rapidly progressive, visceral dominant disease Chemotherapy resistance Drop one agent after response to reduce impact on QOL Miles D, et al. J Clin Oncol. 2008;20(Suppl). LBA 1011; O Shaughnessy J, et al. N Engl J Med. 2005;353(16):

7 First-Line Chemotherapy for MBC (HER2-) Docetaxel and capecitabine (O Shaughnessy et al, 2002) Combination regimens Paclitaxel + carboplatin (Perez et al, 2000; Perez et al, 2005; Robert et al, 2006) Phase III: Paclitaxel + gemcitabine (Albain et al, 2004) E2100: Paclitaxel + bevacizumab (Miller et al, 2007) AVADO: Docetaxel + bevacizumab (Miles et al, 2008) Gemcitabine + carboplatin (O Shaughnessy et al, 2010)

8 NCCN-Recommended Single Agents for Metastatic Breast Cancer NCCN = National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. V

9 CALGB NCCTG N063H - CTSU An Open Label Phase III Trial of Firstline Therapy - - for Locally Recurrent or Metastatic Breast Cancer N = 900 (actual 799) Strata: Adj taxanes ER/PR status Median FU 12 mo. Exp 1 Control Exp 2 nab-paclitaxel 150 mg/m 2 weekly + bevacizumab 10 mg/kg q 2 wks paclitaxel 90 mg/m 2 weekly + bevacizumab 10 mg/kg q 2 wks ixabepilone 16 mg/m 2 weekly + bevacizumab 10 mg/kg q 2 wks Restage q 2 cycles until disease progression All chemotherapy was given on a 3 week on, one week off schedule Patients could discontinue chemotherapy and continue bevacizumab alone after 6 - cycles if stable or responding disease 98% received bevacizumab Primary endpoint: PFS of each experimental arm compared to control Rugo et al, ASCO 2012

10 CALGB Progression-Free Survival By Treatment Arm Proportion Progression-Free paclitaxel nab-paclitaxel ixabepilone Comparison HR P-value 95% CI nab vs. pac Pac ixa vs. pac 1.53 < Nab Ixa Months From Study Entry Agent N Median PFS paclitaxel nab-paclitaxel ixabepilone

11 Proportion Progression Free Proportion Progression Free Unplanned Subset Analysis of PFS 44% adjuvant taxanes, DFI > 1 year in 66% ER+ ER+ Disease Triple Triple Negative Disease Proportion Alive paclitaxel Pac nab-paclitaxel Nab Ixa ixabepilone Months From Study Entry Proportion Alive Pac Nab Ixa 28% of 799 ER/PR- = Months From Study Entry Comparison HR P-value 95% CI nab vs. pac ixa vs. pac Comparison HR P-value 95% CI nab vs. pac ixa vs. pac

12 Percent Dose Reductions by Cycle 3 uction All Cause Cumulative Discontinuation by Cycle 45% paclitaxel nab-paclitaxel ixabepilone 30 15% 15% nab Pac pac ixa Ixa Cycle Cycle number

13 CALGB Overall Survival Proportion Alive Comparison HR P-value 95% CI nab vs. pac ixa vs. pac Months From Study Entry Agent N Median OS paclitaxel nab-paclitaxel ixabepilone paclitaxel Pac nab-paclitaxel Nab ixabepilone Ixa

14 Toxicity Grade 3+ adverse events Hematologic: nab/pac/ixa 51% vs 21% and 12% Non hematologic: nab/pac/ixa 60% vs 44% and 56% Sensory neuropathy Grade 3+: nab/pac/ixa 25% vs 16% and 25% Other toxicities More common in both experimental arms

15 Conclusions Neither weekly nab or ixa are superior to weekly pac Weekly pac appears to offer better progression free survival than ixa Hematologic toxicity is greater with nab at this dose, sensory neuropathy is greater in both experimental arms At this dose and schedule, there is no advantage associated with either nabpaclitaxel or ixabepilone; most toxicities are increased

Implications Metastatic disease Ixabepilone should be given on a q 3 week schedule nab-paclitaxel should be dosed at 100 mg/m2 when given weekly Several trials will explore

16 Implications Metastatic disease Ixabepilone should be given on a q 3 week schedule nab-paclitaxel should be dosed at 100 mg/m2 when given weekly Several trials will explore high dose nab in the neoadjuvant setting in high risk or HER2+ disease, and in metastatic TNBC Eribulin will be compared to pac in an upcoming phase III trial (ACCRU, Liu PI)

17 Eribulin ACCRU Trial: Schema Eribulin 1.4 mg/m 2 on days 1 & 8 Q3W N = 810 Paclitaxel 90 mg/m 2 on days 1, 8, 15 Q4W ELIGIBILITY measurable disease 1 st or 2 nd line therapy stage IV, unresectable IIIB/C STRATIFICATION prior taxane line of therapy hormone receptor status PI: Minetta Liu

18 Weekly nab-paclitaxel + Gemcitabine as 1 st -Line Treatment of MBC Showed Clinical Activity N= 50 (10 pts were TNBC) PS 0-1 Prev taxane allowed if completed >6 mos No active CNS mets nab-paclitaxel 125 mg/m 2 Gemcitabine 1000 mg/m 2 day 1,8 q 21 days ORR: 50% Median PFS: 7.9 months Median OS: Not reached Roy V et al. Ann Oncol. 2009; 20:

RANDOMIZE nab-paclitaxel arm selected by combination of efficacy + safety RANDOMIZE tnacity: TNBC Registration Trial Phase 2 Phase 3 First Line TNMBC nab-paclitaxel 125

Carboplatin N = 275 Gemcitabine 1000 mg/m 2 + Carboplatin AUC2 d1 q3w N = 80 End Points phase 3 Primary PFS (central) Secondary ORR, OS, DCR, DOR, Safety End Points phase

19 RANDOMIZE nab-paclitaxel arm selected by combination of efficacy + safety RANDOMIZE tnacity: TNBC Registration Trial Phase 2 Phase 3 First Line TNMBC nab-paclitaxel 125 mg/m 2 + Carboplatin AUC2 d1/d8 q3w N = 80 nab-paclitaxel 125 mg/m 2 + Gemcitabine 1000 mg/m 2 N = 80 Winner of the 2 nab-paclitaxel arms N = 275 Gemcitabine + Carboplatin N = 275 Gemcitabine 1000 mg/m 2 + Carboplatin AUC2 d1 q3w N = 80 End Points phase 3 Primary PFS (central) Secondary ORR, OS, DCR, DOR, Safety End Points phase 2 Primary PFS (investigator) Secondary ORR, % of patients initiating cycle 6, OS, Safety Stratification Disease free interval Prior anthracycline/taxane adjuvant therapy (Ph 3 only) 19

20 Does the Choice of First Line Chemotherapy Matter? Interim analysis of the Turandot trial (Zielinski et al, ESMO 2012) HER2-negative measurable/nonmeasurable LR/mBC ECOG PS 0 2 No prior chemotherapy for LR/mBC Prior (neo)adjuvant chemotherapy and/or radiotherapy permitted only if completed 6 months before randomisation a R BEV PAC (n=285): BEV 10 mg/kg d1 & 15 + PAC 90 mg/m 2 d1, 8 & 15 q4w BEV CAP (n=279): BEV 15 mg/kg + CAP 1000 mg/m 2 bid d1 14 q3w Treat to PD or toxicity 564 patients randomized, primary objective non-inferiority for OS 20% exposure to adjuvant taxanes

21 Interim analysis did not meet criteria for noninferiority PFS and ORR significantly better with PAC-BEV 22 v 24% classified as TN Subset differences not presented/evaluated Treatment selection depends on tumor biology and individual priorities

22 Duration of Chemotherapy for MBC: Meta-analysis of RCTs Progression Free Survival Overall Survival Longer first-line chemotherapy duration is associated with a substantially longer PFS and marginally longer OS. Gennari A, et al. J Clin Oncol 29: , 2011

Study Design Prospective, phase III, multi-center, randomized study Enroll period: 2007.05 2010.

1,250 mg/m 2 Day 1 & 8 every 3 weeks Stratification 1. Visceral diseases 2. Prior adjuvant taxane 3. Response(CR/PR vs. SD) 4. HR(+) vs.

23 Study Design Prospective, phase III, multi-center, randomized study Enroll period: PD Off the study 324 MBC patients with no prior chemotherapy 6 cycles of PG CR/PR/SD R till PD PG regimen Paclitaxel 175 mg/m 2 Day 1 Gemcitabine 1,250 mg/m 2 Day 1 & 8 every 3 weeks Stratification 1. Visceral diseases 2. Prior adjuvant taxane 3. Response(CR/PR vs. SD) 4. HR(+) vs. HR(-) Observation till PD Primary Endpoint; PFS from Randomization Secondary Endpoints; OS, Toxicities, QoL, and Response Duration About 75% had HR+ disease, 20% had hormone therapy before PG Im et al, ASCO 2012

25 Summary Maintenance chemotherapy significantly prolonged PFS and OS compared with observation after an initial 6 cycles of treatment The majority of patients had hormone receptor positive disease Few received hormone therapy before chemotherapy in the metastatic setting None received hormone therapy as maintenance Toxicities in the maintenance arm were increased No QOL impairment or improvement observed in the maintenance arm There may be subsets in which continued chemotherapy results in improved outcome Triple negative disease?

Tailored Management of MBC Tumor Biology Tumor Aggressiveness Prior Adjuvant Treatments Feasibility of Multidisciplinary Treatments Patient Hormone receptor status HER2 status Duration of RFI since

26 Tailored Management of MBC Tumor Biology Tumor Aggressiveness Prior Adjuvant Treatments Feasibility of Multidisciplinary Treatments Patient Hormone receptor status HER2 status Duration of RFI since primary diagnosis Location of mets (visceral vs non-visceral) Extent of metastatic spread (oligo vs polymets) Endocrine, biologic or chemotherapy Combined treatments Oligometastatic disease Surgery, radiofrequency ablation, stereotactic radiotherapy Preferences Symptoms Comorbidities Individualize treatment to patient and tumor biology

New chemotherapy drugs in metastatic breast cancer. Guy Jerusalem, MD, PhD

New chemotherapy drugs in metastatic breast cancer Guy Jerusalem, MD, PhD MBC Patients survival over time Median survival increases over time, but is still measured in months This is not yet a chronic