Chemotherapy and Targeted Therapy for Metastatic Breast Cancer Part 1: HER 2 Negative Dr. Sonal Gandhi Sunnybrook Odette Cancer Centre March 18, 2011 Thanks to R Dent for use of some slides.

OUTLINE Overview of MBC survival Taxanes in MBC Sequential monotherapy vs combination chemotherapy Other chemotherapeutics: classic and novel Targeted Agents for HER 2 negative MBC

Chemotherapy Appropriate for: (1) ER/PR negative disease (2) hormone-resistant disease (3) rapidly progressive, predominantly symptomatic visceral disease and (4) pts with short disease-free interval (<1-2 years) MBC is chemosensitive. Active agents: anthracyclines, taxanes, alkylating agents, antimetabolites, and vinorelbine

Overall Survival in MBC Chia SK et al. Cancer 2007;110: From date of diagnosis of MBC, British Columbia, 1991–2001 Overall survival n = 2150 Years

Impact of New Agents on MBC Survival Cohort Median Survival (days) 1991–1992Baseline –1995Paclitaxel and vinorelbine –1998Docetaxel and aromatase inhibitors –2001Capecitabine and trastuzumab661 Access to new therapeutic agents for MBC significantly improved survival Chia SK et al. Cancer 2007;110:973-9.

MBC Is Not One Disease “Chronic lymphocytic leukemia” of breast cancer “Acute leukemia” of breast cancer Rapid disease progression Extensive visceral involvement Resistance to hormonal therapy Resistance to chemotherapy Death within weeks of diagnosis Rapid disease progression Extensive visceral involvement Resistance to hormonal therapy Resistance to chemotherapy Death within weeks of diagnosis Long, indolent course Bone and soft tissue disease Sensitive to hormonal therapy Sensitive to chemotherapy Extended survival (many years) Long, indolent course Bone and soft tissue disease Sensitive to hormonal therapy Sensitive to chemotherapy Extended survival (many years) Median survival from diagnosis of MBC is at least 2–3 years Newly available treatments are changing the disease’s natural history Two Ends of the Spectrum With permission from Dr. Shailendra Verma, Ottawa

Goals of Therapy for MBC Prolong life Control disease over long term Maintain/improve QOL Minimize toxicities Palliate symptoms QOL = quality of life

Factors Determining Choice of Treatment in MBC Prior adjuvant therapy HER2 receptor status Pace of disease ER/PR receptor status Performance status Patient preferences (e.g. oral vs. iv treatment) Patient preferences (e.g. oral vs. iv treatment) Choice of treatment

Efficacy vs. Toxicity Treatment of systemic recurrence of breast cancer prolongs survival and enhances QOL but is not curative Therefore treatments with minimal toxicity are preferred QOL = quality of life EfficacyToxicity

Drugs Currently Licensed for Breast Cancer ChemotherapyEndocrine TherapyBiologics/Other CyclophosphamideDocetaxelTamoxifenClodronate MethotrexatePaclitaxelToremifenePamidronate FluorouracilVinorelbineGoserelinZoledronate DoxorubicinCis/carboplatinLeuprorelinIbandronate Mitomycin CCapecitabineMegestrolTrastuzumab MitoxantroneGemcitabineAnastrozoleLapatinib EpirubicinLiposomal doxorubicinLetrozoleBevacizumab nab  -paclitaxelExemestane Fulvestrant Approved for use in Canada as of April 2009

Single-Agent Response Rates in MBC First Line (%)Second Line (%) Doxorubicin35–5032–38 Epirubicin52–6828 Paclitaxel29–6319–57 Docetaxel47–6539–58 nab  -paclitaxel33–70 Capecitabine15–3520–27 Gemcitabine15–4013–41 Vinorelbine25–5317–36 Cyclophosphamide10–60 Low-dose cyclophosphamide/methotrexate10–30 Etoposide10–50 Up To Date

TAXANES: MONOTHERAPY

Randomized Phase III Study of Docetaxel Compared with Paclitaxel in MBC Jones SE et al. J Clin Oncol 2005;23: Docetaxel 100 mg/m 2 over 1 h q 3 wk Dexamethasone 8 mg po bid x 5 days beginning the day prior to infusion Docetaxel 100 mg/m 2 over 1 h q 3 wk Dexamethasone 8 mg po bid x 5 days beginning the day prior to infusion Paclitaxel 175 mg/m 2 over 3 h q 3 wk Dexamethasone 20 mg po 12 h + 6 h prior to infusion + diphenhydramine 50 mg iv + cimetidine 300 mg or ranitidine 50 mg iv 30–60 min prior to infusion Paclitaxel 175 mg/m 2 over 3 h q 3 wk Dexamethasone 20 mg po 12 h + 6 h prior to infusion + diphenhydramine 50 mg iv + cimetidine 300 mg or ranitidine 50 mg iv 30–60 min prior to infusion RANDOMIZATIONRANDOMIZATION Jones et al. J Clin Oncol 2005 No primary prophylactic growth factor support or antibiotics Continue until disease progression

Paclitaxel vs Docetaxel: Efficacy Paclitaxel 175 mg/m 2 q 3 wk (n = 224) Docetaxel 100 mg/m 2 q 3 wk (n = 225) RR (%)2532 TTP (months) OS (months) Jones SE et al. J Clin Oncol 2005;23: RR = response rate TTP = time to progression OS = overall survival Jones et al. J Clin Oncol 2005 Intent-to-treat population

Paclitaxel vs Docetaxel: Toxicity Docetaxel (n = 222) (%)Paclitaxel (n = 222) (%) OverallGrade 3/4OverallGrade 3/4 Neutropenia* Febrile neutropenia † 152 Anemia Thrombocytopenia Treatment-related deaths: –Docetaxel arm: 3 infection and 1 GI bleed –Paclitaxel arm: 0 Jones SE et al. J Clin Oncol 2005;23: * P< for both † P<0.001 Jones et al. J Clin Oncol 2005

How a Drug Is Given Matters… CALGB 9840: Weekly vs. q 3 wk Paclitaxel Weekly Paclitaxel 80 mg/m 2 q 3 wk Paclitaxel 175 mg/m 2 P Efficacy (n = 735; combined sample) RR (%) Median TTP (months) Median OS (months) Toxicity (grades 3 + 4; %; n = 572; limited sample) Neutropenia Motor neuropathy94NR Sensory neuropathy2412NR Seidman AD et al. J Clin Oncol 2008;26: RR = response rate TTP = time to progression OS = overall survival NR = not reported

Limitations of Conventional, Solvent-Based Taxane Therapy Most taxanes, similar to many cancer drugs, are hydrophobic and require solvents Solvents cause hypersensitivity reactions that necessitate –Corticosteroid premedication –Prolonged infusion Since solvents leach plasticizers, specialized IV tubing is needed Solvents alter bioavailability of the active drug ten Tije AJ et al. Clin Pharmacokinet 2003;42:

How a Drug is Packaged Matters… Albumin Bound-Paclitaxel (Abraxane®) Nonsoluble drug becomes water soluble No Cremophor  or other solvents Rapid bioavailability Potential for more selective tumour uptake via gp60 albumin receptor on endothelial cells Protein (albumin) 130-nm diameter Drug (paclitaxel) Robinson DM et al. Drugs 2006:66:941-8.

Phase III Randomized Trial of nab  -Paclitaxel vs. Paclitaxel in MBC Gradishar WJ et al. J Clin Oncol 2005;23: nab  -paclitaxel 260 mg/m 2 iv over 30 min q 3 wk No standard premedication (n = 233) nab  -paclitaxel 260 mg/m 2 iv over 30 min q 3 wk No standard premedication (n = 233) Paclitaxel 175 mg/m 2 iv over 3 h q 3 wk Standard premedication with dexamethasone and antihistamines (n = 227) Paclitaxel 175 mg/m 2 iv over 3 h q 3 wk Standard premedication with dexamethasone and antihistamines (n = 227) RANDOMIZATIONRANDOMIZATION (1:1) n = 460 Gradishar et al. J Clin Oncol 2005

Significantly Prolonged Time to Disease Progression nab  -paclitaxel (n = 229) Standard paclitaxel (n = 224) Proportion not progressed Weeks Median = 23.0 wk (19.4–26.1) Median = 16.9 wk (15.1–20.9) P = (log rank) Gradishar et al. J Clin Oncol 2005 Gradishar WJ et al. J Clin Oncol 2005;23:

Treatment-Related Grades 3 and 4 Adverse Events Reported in ≥5% of Patients GGT = gamma glutamyl transferase Gradishar et al. J Clin Oncol 2005 Neutropenia Elevated GGT Leukopenia Fatigue Arthralgia Myalgia Sensory neuropathy ** nab  -paclitaxel - grade 3 nab  -paclitaxel - grade 4 Paclitaxel - grade 3 Paclitaxel - grade 4 * P<0.05 Gradishar WJ et al. J Clin Oncol 2005;23:

Nab-Paclitaxel: Randomized Phase II Trial nab  -paclitaxel vs. docetaxel (A, B, C vs. D) Weekly vs. q 3 wk nab  -paclitaxel (B, C vs. A) Low- vs. high-dose weekly nab  -paclitaxel (B vs. C) Arms A, C, and D administered at the maximum tolerated dose Gradishar WJ et al. J Clin Oncol 2009;27: RANDOMIZATIONRANDOMIZATION Gradishar WJ et al. J Clin Oncol 2009 May 26, first-line treatment of MBC, N = 300 Arm A: nab  -paclitaxel 300 mg/m 2 q 3 wk Arm B: nab  -paclitaxel 100 mg/m 2 weekly (3/4) Arm C: nab  -paclitaxel 150 mg/m 2 weekly (3/4) Arm D: docetaxel 100 mg/m 2 q 3 wk

Comparison of Investigator and Independent Radiology Review Response Assessments nab  -paclitaxel Gradishar WJ et al. J Clin Oncol 2009 May mg/m 2 q 3 wk (A: n = 76) 100 mg/m 2 weekly (3/4) (B: n = 76) 150 mg/m 2 weekly (3/4) (C: n = 74) Docetaxel 100 mg/m 2 q 3 wk (D: n = 74) IRR = independent radiologist review Gradishar WJ et al. J Clin Oncol 2009;27:

Progression-Free Survival Investigator Assessments Gradishar WJ et al. J Clin Oncol 2009 May 26. Median PFS (months) Gradishar WJ et al. J Clin Oncol 2009;27:

Nab-paclitaxel: Toxicity nab  -Paclitaxel ArmsDocetaxel Arm Grade 4 neutropenia (%)5–975 Febrile neutropenia (%)18 Grade 3 fatigue (%)0–519 Sensory neuropathy Incidence similar in all arms Median time to improvement (to ≤ grade 1) in grade 3 sensory neuropathy (days) 19–2237 Gradishar WJ et al. J Clin Oncol 2009 May 26. Gradishar WJ et al. J Clin Oncol 2009;27:

Cancer Care Ontario Recommendation CED-SOS advice report #6: section 1 (June 1, 2007) The role of albumin-bound paclitaxel (Abraxane  ) in the treatment of MBC Recommendation: –Women with metastatic breast cancer and no previous taxane chemotherapy who are candidates for first- or second-line single-agent paclitaxel could be offered nab  -paclitaxel Qualifying statement: –nab  -paclitaxel may be equivalent or superior to docetaxel in terms of tumour response rate with a decrease in neutropenia and no increase in neuropathy –Overall survival with nab  -paclitaxel does not differ from paclitaxel in first- line therapy, but nab  -paclitaxel is superior in second-line therapy Hamm C et al. CED-SOS advice report # Jun 1. CED = Committee to Evaluate Drugs SOS = Standing Oncology Subcommittee

Case: What If the Patient Had Previously Been Treated with a Taxane as Part of the FEC-D Regimen? Optimal therapy for taxane-pretreated populations: –Taxanes in taxane-pretreated MBC –nab  -paclitaxel in taxane-pretreated MBC

Evidence for Taxane Retreatment Previous Treatment Study TreatmentnORR (%) Response Duration (months) Docetaxel Paclitaxel 80 mg/m 2 weekly ― Sawaki et al. (2004)* Paclitaxel Docetaxel 100 mg/m 2 q 3 wk ― Valero et al. (1998) Taxane nab  -paclitaxel 100 mg/m or 125 mg/m 2 q wk (3/4) ― Blum et al. (2007) 7516 (21 with docetaxel pretreatment † ) 3.5 Sawaki M et al. Tumori 2004;90:36-9. Valero V et al. J Clin Oncol 1998;16: Blum JL et al. Clin Breast Cancer 2007;7: * Retrospective study † Both nab  -paclitaxel doses ORR = overall response rate

Taxanes: Clinical Implications Increasing use of docetaxel in the adjuvant setting Consider a taxane rechallenge for patients with MBC who have had previous adjuvant taxanes –If they have had previous docetaxel then consider nab  -paclitaxel (where funded) or paclitaxel

NON TAXANE CHEMOTHERAPY

Fluoropyrimidines 5-FU: give with leucovorin. Benefit even if progress on FU containing regimens like CMF. “Lower” toxicity but diarrhea/mucositis. Capecitabine: ph 2 data –Blum et al, Cancer 2001; capecitabine in taxane-pretreated MBC –Reichardt et al, Ann Oncol 2003; capecitabine in MBC relapsing after treatment with a taxane-containing therapy –Fumoleau et al, Eur J Cancer 2004; capecitabine monotherapy in anthracycline- and taxane-pretreated MBC RR 15-28%, ORR+SD 57-63%, median TTP 3.0 to 4.9 mo., median OS 10.4 to 15.2 mo. Dose: 2000 to 2500 mg/m 2 daily for 14 of every 21 days; lower doses for patients >65 or those with renal dysfunction

Capecitabine n CR + PR (%) ORR + SD (%) Median TTP (months) Median OS (months) Blum Blum Reichardt Fumoleau Miller *NR Blum JL et al. J Clin Oncol 1999;17: Blum JL et al. Cancer 2001;92: Reichardt P et al. Ann Oncol 2003;14: Fumoleau P et al. Eur J Cancer 2004;40: Miller KD et al. J Clin Oncol 2005;23: CR = complete response PR = partial response ORR = overall response rate SD = stable disease TTP = time to progression OS = overall survival NR = not reported * Investigator assessment; 9.1% by independent review facility

Capecitabine after Docetaxel Monotherapy Months Estimated probability Single-agent capecitabine (n = 28) All other chemotherapy (n = 128) Log-rank P = Hazard ratio = Median overall survival Miles D et al. Clin Breast Cancer 2004;5: Miles et al. Clin Breast Cancer 2004

Vinorelbine – Prevent assembly of microtubules, thereby inhibiting DNA replication – Monotherapy particularly useful for the treatment of MBC in older women who have significant comorbidity – Side effects: mild nausea, vomiting and hair loss – RR 25-53%, median TTP 2.8 to 3.0 mo., median OS 6.0 to 7.0 mo., even in heavily pre-treated patients – Combination regimens with vinca alkaloid often have higher RR but no better OS when compared to anthracycline or a taxane alone

Vinorelbine n CR + PR (%) Median TTP (months) Median OS (months) Udom NR Fazeny140NR Zelek (responding patients) 5 (patients with disease stabilization) 6 Livingston Udom DI et al. Eur J Cancer 2000;36: Fazeny B et al. Cancer Chemother Pharmacol 1996;39: Zelek L et al. Cancer 2001;92: Livingston RB et al. J Clin Oncol 1997;15: CR = complete response PR = partial response TTP = time to progression OS = overall survival NR = not reported

Estimated probability Vinorelbine after Docetaxel Monotherapy Miles D et al. Clin Breast Cancer 2004;5: Median overall survival Log-rank P = 0.94 Hazard ratio = Vinorelbine-containing therapy (n = 50) All other chemotherapy (n = 106) Months Miles et al. Clin Breast Cancer 2004

Retrospective, Phase III, Post-study Comparison of Capecitabine and Vinorelbine Docetaxel 75 mg/m 2 over 1 h q 3 wk + capecitabine 1250 mg/m 2 bid  14 days Docetaxel 75 mg/m 2 over 1 h q 3 wk + capecitabine 1250 mg/m 2 bid  14 days O'Shaughnessy J et al. J Clin Oncol 2002;20: Miles D et al. Clin Breast Cancer 2004;5: O'Shaughnessy J et al. J Clin Oncol 2002 Docetaxel alone 100 mg/m 2 over 1 h q 3 wk Stratification by prior paclitaxel RANDOMIZATIONRANDOMIZATION Continue until disease progression Poststudy therapy (not defined in protocol) Capecitabine Vinorelbine Other Poststudy therapy (not defined in protocol) Capecitabine Vinorelbine Other Miles et al. Clin Breast Cancer 2004

Gemcitabine – As monotherapy : RR 15-40% depending on whether they have received prior chemotherapy Little N/V, minimal hair loss, but myelosuppression can be severe, particularly in heavily pre-treated patients or those who have received radiation to large areas of marrow-containing bone Idiopathic and unpredictable pulmonary toxicity occur uncommonly – In combination: Can be combined occasionally to taxanes (refer to above), cisplatin, vinorelbine RR 36-70% even in heavily pre-treated patients Acceptable toxicity

Cyclophosphamide – Most widely used alkylating agent – Older: RR 10-60% in previously untreated MBC – Side effects: nausea, vomiting, alopecia, myelosuppression as well as bladder inflammation and hematuria – Increased risk of secondary AML, related drug exposure and cumulative dose * Low dose Cyclo (50 mg/d) with Methotrexate (2.5mg bid d 1, 2 weekly, Goldhirsh regimen) – N = 63 ph 2: RR 19%, CB- 32%. Decreases serum VEGF levels… Colleoni et al. Annals 2002

Platinums Cisplatin and carboplatin –Combinations with other drugs, including taxanes, capecitabine, etoposide, vinorelbine, and gemcitabine may be considered for 3 rd /4 th -line (or beyond) therapy in pts who maintain a good ECOG and adequate marrow reserve –Evolving role in TN MBC (plus or minus Parp-i)…

Etoposide –RR 25-50%, even in heavily pre-treated patients –Continuous oral administration (50 mg/m 2 daily) permits dose titration to toxicity, which is principally hematologic and gastrointestinal –Oral etoposide is a reasonable 3 rd /4 th -line (or beyond) regimen.

COMBINATION CHEMOTHERAPY

Combination vs. Sequential Therapy: Lessons Learned from ECOG 1193 Doxorubicin (A) 60 mg/m 2 (n = 224) Paclitaxel (T) 175 mg/24 h (n = 229) Doxorubicin + Paclitaxel (AT) 50/150 mg/24 h (n = 230) RR (%)363447* Median TTF (months)668* Median survival (months)1922 QOLSimilar in all groups Sledge G et al. J Clin Oncol 2003;21: Primary end point was RR Crossover responses A A T T A A T T = 22% = 20% Not significant * Statistically significant RR = response rate TTF = time to treatment failure QOL = quality of life

Combination vs. Sequential Therapy ECOG 1193: Overall Survival RR = response rate TTF = time to treatment failure OS = overall survival TRMT = treatment Improved RR and TTF with combination OS comparable Sledge G et al. J Clin Oncol 2003;21:

Taxane Combinations in MBC: Efficacy StudyRegimensnORR (%) PFS (months) Median OS (months) O’Shaughnessy et al. (2002) Capecitabine + docetaxel Docetaxel Albain et al. (2008) Paclitaxel + gemcitabine Paclitaxel Chan et al. (2009) Docetaxel + gemcitabine Docetaxel + capecitabine O'Shaughnessy J et al. J Clin Oncol 2002;20: Albain KS et al. J Clin Oncol 2008;26: Chan S et al. J Clin Oncol 2009;27: ORR = overall response rate PFS = progression-free survival OS = overall survival

Taxane Combinations in MBC: Toxicity (Grades 3 and 4) StudyRegimensn Neutro- penia (%) Febrile Neutro- penia (%) Hand–Foot Syndrome (%) O’Shaughnessy et al. (2002) Capecitabine + docetaxel25516*1624 Docetaxel25615*211 Albain et al. (2008) Paclitaxel + gemcitabine *NR Paclitaxel *NR Chan et al. (2009) Docetaxel + gemcitabine152848†8† 0 Docetaxel + capecitabine † 26 NR = not reported * Required medical intervention; † includes neutropenic sepsis O'Shaughnessy J et al. J Clin Oncol 2002;20: Albain KS et al. J Clin Oncol 2008;26: Chan S et al. J Clin Oncol 2009;27:

Combination vs. Sequential Soto et al. ASCO abstract 2006 Anthracycline pretreated MBC: xeloda (X)  Taxotere (T) versus XT, versus XP (paclitaxel). RR higher with combo (60-70% vs 40% for sequential) but after 15mos f/u, median OS similar (about 30 mos all arms.) Carrick S et al. Cochrane Database 2005 A meta-analysis of 37 trials: single agent versus combination chemotherapy for MBC There was a relative survival advantage from combination therapy of only 12%, but combination therapy caused significantly worse leukopenia, nausea, and vomiting

Combination vs Sequential Bottom Line Sequential single agents are preferred for most patients –Variety of options; no single gold standard –Limit toxicity –Supported by clinical trial data Combinations are appropriate for rapidly progressive symptomatic disease –Symptom reduction outweighs potential toxicity –Important to discuss this option with patient –Consider anthracycline + taxane if high burden and did not receive adjuvantly

NOVEL CHEMOTHERAPEUTICS

Ixabepilone Epothilone, a new class of non-taxane tubulin polymerizing agents Ph 2 data: 40mg/m2 iv, q 21 days. Thomas E et al. JCO 2007 Aug; 25: : N = 66. RR 12%, SD 40% Perez EA et al. JCO 2007 Aug; 25: : N= 126, anthracycline, taxane, capecitabine refractory (88% > prior 2 regimens) Efficacy: RR 18.3% for all patients (range 11.9 to 26.1%), 50% SD; 14.3% achieved SD for >/= 6 mo. Median duration of response 5.7 months Median PFS = 3.1 months. Median OS = 8.6 months Toxicity: median 4 cycles, 25% of patients received >/= 8 cycles Grade 3 or 4: peripheral sensory neuropathy (14%), fatigue/asthenia (13%), myalgia (8%), and stomatitis/mucositis (6%). Resolution of grade 3/4 neuropathy median 5.4 weeks

Ixabepilone (cont’d) Ph 3: Thomas E et al. JCO 2007 Nov; 25: N= 652 MBC refractory to anthracycline and taxane: ixabepilone 40 mg/m 2 IV + capecitabine 2,000 mg/m 2 PO on days 1 through 14 of a 21-day cycle, VS capecitabine alone 2,500 mg/m 2 on the same schedule Efficacy: Median PFS 5.8 months vs C 4.2 months, HR 0.75, p= RR 35% vs C 14% p< OS not reported. Toxicity Grade 3/4 sensory neuropathy: I+C 21% vs C 0%; Neutropenia: I+C 68% vs C 11%. Death from toxicity: I+C 3% vs C 1% where patients with liver dysfunction [>/= grade 2 liver function tests] had greater risk Capecitabine-related toxicities were similar in both groups

More phase Sparano et al. JCO. June N = Same design.  Median OS: 16.4 v 15.6 months; HR = 0.9; 95% CI, 078 to 1.03; P =.1162).  Cox regression analysis adjusted for performance status and other prognostic factors, OS improved for the combination (HR = 0.85; 95% CI, 0.75 to 0.98; P =.0231).  In 79% of patients with measurable disease, I + C impmroved PFS; median 6.2 v 4.2 months; HR = 0.79; P =.0005) and response rate (43% v 29%; P <.0001).  Grade 3 to 4 neuropathy in 24% treated with the combination, but was reversible. SO: Ixabepilone active for anthracycline and taxane-refractory MBC. ixabepilone is approved in US for: –In combination with capecitabine for locally advanced or MBC who are resistant to anthracycline and taxane, or taxane-resistant (anthra contra.) –As monotherapy for locally advanced or MBC whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine

Eribulin Mesylate A nontaxane microtubule dynamics inhibitor with a novel mode of action Ph 3: ASCO 2010 Twelves et al. 2-5 prior CT for BC (>2 for MBC), prior anthracycline and taxane unless contraindication. randomized 2:1 to E 1.4 mg/m IV d1, 8 q 3ks, or treatment of physician's choice (TPC). TPC=any monotherapy (cytotoxic, hormonal, biologic) or supportive care only (but all got chemo). 16% were HER2-positive, 19% triple-negative, 73% received prior capecitabine, median no. of prior CT was 4. Median OS was 13.1 months (mo) for E vs mo for TPC, p=0.04. toxicities: fatigue, neutropenia (44%), neuropathy (8%). 12 % vs 7% TPC had adverse reaction.  Eribulin had 2.5 mos survival benefit in heavily pretreated MBC.

TARGETED TREATMENT

Mechanism of Action of Bevacizumab Bevacizumab is a humanized mAb directed against VEGF VEGF is the main angiogenic factor expressed by invasive breast cancer – Stimulates endothelial proliferation and migration – Inhibits endothelial apoptosis – Induces remodelling of extracellular matrix – Increases vascular permeability and vasodilation mAb = monoclonal antibody VEGF = vascular endothelial growth factor Image: Hoffmann-La Roche Ltd. Miller K et al. N Engl J Med 2007;357: Early Effects Later Effects

E2100: Study Design Stratification: –DFI: ≤24 vs. >24 months –Metastatic sites: <3 vs. ≥3 –Adjuvant chemotherapy: yes vs. no –ER status: positive vs. negative vs. unknown No crossover Primary end point: PFS Miller K et al. N Engl J Med 2007;357: DFI = disease-free interval PFS = progression-free survival RANDOMIZATIONRANDOMIZATION Paclitaxel weekly (n = 354) Paclitaxel weekly + bevacizumab 10 mg/kg q 2 wk (n = 368) Paclitaxel weekly + bevacizumab 10 mg/kg q 2 wk (n = 368) Continue until disease progression MBC not previously treated with chemotherapy for metastatic disease (n = 722) MBC not previously treated with chemotherapy for metastatic disease (n = 722) 28-day cycle: –Paclitaxel 90 mg/m² day 1, 8, and 15 –Bevacizumab 10 mg/kg day 1 and 15 until progression

E2100: Progression-Free Survival Miller K et al. N Engl J Med 2007;357: HR for disease progression: 0.60 HR = hazard ratio Progression-free survival (%) Months

AVADO: Phase III Trial of Bevacizumab + Docetaxel in MBC Randomized, double-blind, placebo-controlled, multicentre Primary end point: PFS Secondary end points: ORR, response duration, TTF, OS, safety, QOL Recruitment commenced March 2006; closed April 2007 Miles D et al. ASCO 2008:LBA1011. PFS = progression-free survival ORR = overall response rate TTF = time to treatment failure OS = overall survival QOL = quality of life RANDOMIZATIONRANDOMIZATION Docetaxel 100 mg/m 2 q 3 wk + placebo Docetaxel 100 mg/m 2 q 3 wk + bevacizumab 7.5 mg/kg q 3 wk Docetaxel 100 mg/m 2 q 3 wk + bevacizumab 7.5 mg/kg q 3 wk Docetaxel 100 mg/m 2 q 3 wk + bevacizumab 15 mg/kg q 3 wk Docetaxel 100 mg/m 2 q 3 wk + bevacizumab 15 mg/kg q 3 wk All patients given option to receive bevacizumab with second- line therapy Placebo or bevacizumab until disease progression Previously untreated MBC (n = 736) Previously untreated MBC (n = 736)

Months AVADO: Progression-Free Survival * mg/kg q 3 wk † Data censored for nonprotocol therapy before progressive disease Miles D et al. ASCO 2008:LBA1011. Intention-to-treat population Bevacizumab 15 * + docetaxel (n = 247) Bevacizumab 7.5 * + docetaxel (n = 248) Placebo + docetaxel (n = 241) 8.0 HR + 95% CI (unstratified) HR + 95% CI (stratified † ) 0.69 (0.54–0.89) P = (0.63–0.98) P = Median 8.7 HR + 95% CI (stratified † ) 0.61 (0.48–0.78) P< Median (0.57–0.90) P = HR + 95% CI (unstratified)

Bevacizumab + Taxanes: Increases in Response Rate* 48 Overall response rate (%) Investigator assessment (n = 525) IRF assessment (n = 472) Paclitaxel Bevacizumab 10 mg/kg q 2 wk + paclitaxel CR + PR P< (n = 201) 63 (n = 206) 44 (n = 207) * In patients with measurable disease at baseline † vs. placebo + docetaxel CR + PR P = † CR + PR P = † CR + PR Placebo + docetaxel Bevacizumab 7.5 mg/kg q 3 wk + docetaxel Bevacizumab 15 mg/kg q 3 wk + docetaxel 1. Klencke BJ et al. ASCO 2008: Miles D et al. ASCO 2008:LBA E Investigator assessment AVADO 2 IRF = independent review facility CR = complete response PR = partial response Overall response rate (%)

Bevacizumab + Taxanes: Increases in PFS E (Independent Review) AVADO 2 Paclitaxel (n = 354) Bevacizumab 10* + Paclitaxel (n = 368) Placebo + Docetaxel (n = 241) Bevacizumab 7.5 † + Docetaxel (n = 248) Bevacizumab 15 † + Docetaxel (n = 247) Median PFS (months) Unstratified HR (95% CI) P (NR) < (0.63–0.98) (0.57–0.90) Klencke BJ et al. ASCO 2008: Miles D et al. ASCO 2008:LBA1011. * mg/kg q 2 wk † mg/kg q 3 wk PFS = progression-free survival HR = hazard ratio CI = confidence interval NR = not reported

SABCS 2009.

Phase III Trials E2100 and AVADO: Serious Adverse Events of Interest E (%)AVADO 2 (%) Taxane Taxane + Bevacizumab Taxane Taxane + Bevacizumab End Point* Low DoseHigh Dose Thrombosis/embolism † Hypertension Bleeding Fatigue Infection LV dysfunction/CHF Sensory neuropathy Miller K et al. N Engl J Med 2007;357: Miles D et al. ASCO 2008:LBA1011. * Grade 3 or higher † No significant increase in bevacizumab arm in either study LV = left ventricular CHF = congestive heart failure

RIBBON-1: Study Design * 1000 mg/m 2 bid x 14 days † Docetaxel q 3 wk or nab  -paclitaxel q 3 wk ‡ AC, EC, FAC, FEC § 15 mg/kg q 3 wk Chemo + bevacizumab § q 3 wk Chemo + placebo q 3 wk Optional second-line chemo + bevacizumab Optional second-line chemo + bevacizumab R A N D O M I Z A T I O N 2:1 Previously untreated MBC (n = 1237) Stratification Factors Disease-free interval Previous adjuvant chemo Number of metastatic sites Capecitabine, taxane, or anthracycline Previously untreated MBC (n = 1237) Stratification Factors Disease-free interval Previous adjuvant chemo Number of metastatic sites Capecitabine, taxane, or anthracycline Robert NJ et al. ASCO 2009:1005. PD = progressive disease Treat until PD Choice of chemo by investigator Capecitabine* Taxane † Anthracycline ‡

PFS Time (months) Placebo Bevacizumab Robert NJ et al. ASCO 2009:1005. RIBBON-1: Capecitabine PFS by Investigator Placebo (n = 206) Bevacizumab (n = 409) Median (months) INV HR (95% CI)0.69 (0.56–0.84) P Median (months) IRC HR (95% CI)0.68 (0.54–0.86) P PFS = progression-free survival CI = confidence interval HR = hazard ratio INV = investigator IRC = independent review committee

PFS Time (months) Bevacizumab Placebo Robert NJ et al. ASCO 2009:1005. RIBBON-1: Taxane/Anthracycline PFS by Investigator Placebo (n = 207) Bevacizumab (n = 415) Median (months) INV HR (95% CI)0.64 (0.52–0.80) P< Median (months) IRC HR (95% CI)0.77 (0.60–0.99 P0.040 PFS = progression-free survival CI = confidence interval HR = hazard ratio INV = investigator IRC = independent review committee

Event (%) CapecitabineTaxaneAnthracycline Placebo (n = 201) Beva (n = 404) Placebo (n = 102) Beva (n = 203) Placebo (n = 100) Beva (n = 210) Bleeding events Febrile neutropenia GI perforation Hypertension LV systolic dysfunction Neutropenia Proteinuria Sensory neuropathy VTE RIBBON-1: Selected Grade ≥3 Adverse Events Robert NJ et al. ASCO 2009:1005. Beva = bevacizumab LV = left ventricular VTE = venous thromboembolism

AVASTIN in Second Line: RIBBON 2 SABCS 2009

Benefit independent of chemotherapy EXCEPT VINO HR >1

Avastin in TN MBC ATHENA trial: Thomssen et al SABCS N= 2251, MBC first line, TN patients 26% (n=577). Bev10mg/kg q2w or 15mg/kg q3w combined with the physician's choice of taxane regimen (or investigator's standard of care, excluding anthracyclines). Prelim (2008), median PFS 9 mos. TTP: TN: 7.2 mos, non TN: mos. ORR: TN: 47%, non TN: 53%. Median OS: TN-19.7 mos, non TN-28.7 mos. Therefore, activity in TN, although worse outcomes compared to non TN so far.

Bevacizumab: Clinical Implications There is a small benefit seen with the addition of bevacizumab in first and second line: PFS Need to identify group that benefits most from antiangiogenic therapy FDA Approval for Bevacizumab in MBC revoked in Dec/2010. Health Canada status so far unchanged.

HER 2 NEGATIVE MBC: TARGETED AGENTS

SORAFENIB SORAFENIB: SOLTI-0701 trial- Baselga et al SABCS Locally advanced or metastatic breast cancer patients (with one or less prior treatments) randomized to capecitabine (1000mg/m2 po bid, 14 days on in 21 day cycle), plus either placebo or sorafenib 400mg po bid. 60% of patients had prior taxane therapy. Improved PFS with combination of capecitabine + sorafenib compared to capecitabine alone (6.4 vs. 4.1 mos, HR 0.58 p=0.0006). hand foot syndrome significantly increased with the combination (89% vs. 63%); 45% were grade 3+ events Ph 3 pending.

IMC-1121B IMC-1121B: TRIO-012 trial, Mackey et al: double-blind phase III study of IMC-1121B (amucirumab, VEGFR-2i) plus docetaxel versus placebo plus docetaxel in previously untreated patients with HER2-negative, unresectable, locally recurrent or metastatic breast cancer. ONGOING.

PARP-inhibitors BSI-201 (PARP-inhibitor). O’Shaughnessy, SABCS Randomized ph 2. N=123.1 prior chemo for TN allowed, no prior gem, parp-I, or platinum. Randomized to gem 1000mg/m2 d 1, 8 + carbo AUC 2 d 1,8 q 21 day +/- BSI-201 at 5.6mg/kg d 1, 4, 8, 11. Primary endpoint CBR and safety, secondary survival. ASCO 2009: BSI arm vs chemo alone: ORR- 48% vs 16% p = 0.02, CBR 62% vs 21% p= Median PFS 6.9 vs 3.3 mos p < median OS: 9.2 vs 5.7 mos, p= SABCS 2009: FINAL RESULTS: MEDIAN OS 12.2 MOS VS 7.7 MOS P= TN tumours expressed higher parp levels on pcr. GR 2-4 toxicities similar.

Summary HER 2 negative MBC is also a heterogeneous disease Chemotherapy options are myriad, but taxanes remain cornerstone of first line therapy in most cases. Sequential monotherapy is preferred in most patients New chemotherapeutic agents are on the horizon (Eribulin) Targeted treatments continue to evolve....

Cases....