Chemotherapy and Targeted Therapy for Metastatic Breast Cancer Part 1: HER 2 Negative Dr. Sonal...

Chemotherapy and Targeted Therapy for Metastatic Breast

Cancer Part 1: HER 2 Negative

Dr. Sonal GandhiSunnybrook 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;110:973-9.

From date of diagnosis of MBC, British Columbia, 1991–2001

n = 2150

Years

Impact of New Agents on MBC Survival

Cohort Median Survival (days)

1991–1992 Baseline 4361994–1995 Paclitaxel and vinorelbine 450

1997–1998 Docetaxel and aromatase inhibitors 564

1999–2001 Capecitabine and trastuzumab 661

• 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

• 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 symptomsQOL = 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)

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

Efficacy Toxicity

Drugs Currently Licensed for Breast Cancer

Chemotherapy Endocrine Therapy Biologics/Other

Cyclophosphamide Docetaxel Tamoxifen Clodronate

Methotrexate Paclitaxel Toremifene Pamidronate

Fluorouracil Vinorelbine Goserelin Zoledronate

Doxorubicin Cis/carboplatin Leuprorelin Ibandronate

Mitomycin C Capecitabine Megestrol Trastuzumab

Mitoxantrone Gemcitabine Anastrozole Lapatinib

Epirubicin Liposomal doxorubicin Letrozole Bevacizumab

nab-paclitaxel Exemestane

Fulvestrant

Approved for use in Canada as of April 2009

Single-Agent Response Rates in MBC

First Line (%) Second Line (%)

Doxorubicin 35–50 32–38

Epirubicin 52–68 28

Paclitaxel 29–63 19–57

Docetaxel 47–65 39–58

nab-paclitaxel 33–70

Capecitabine 15–35 20–27

Gemcitabine 15–40 13–41

Vinorelbine 25–53 17–36

Cyclophosphamide 10–60

Low-dose cyclophosphamide/methotrexate 10–30

Etoposide 10–50

Up To Date. 2009.

TAXANES: MONOTHERAPY

Randomized Phase III Study of Docetaxel Compared with Paclitaxel in

MBC

Jones SE et al. J Clin Oncol 2005;23:5542-51.

Docetaxel 100 mg/m2 over 1 h q 3 wkDexamethasone 8 mg po bid x 5 days

beginning the day prior to infusion

Paclitaxel 175 mg/m2 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

RANDOMIZATION

Jones et al. J Clin Oncol 2005

• No primary prophylactic growth factor support or antibiotics

Continueuntil

disease progression

Paclitaxel vs Docetaxel: Efficacy

Paclitaxel 175 mg/m2 q 3 wk

(n = 224)

Docetaxel 100 mg/m2 q 3 wk

(n = 225) RR (%) 25 32

TTP (months) 3.6 5.7OS (months) 12.7 15.4


RR = response rateTTP = time to progressionOS = overall survival


Intent-to-treat population

Paclitaxel vs Docetaxel:Toxicity

Docetaxel (n = 222) (%) Paclitaxel (n = 222) (%)

Overall Grade 3/4 Overall Grade 3/4

Neutropenia* 96 93 83 55

Febrile neutropenia† 15 2

Anemia 77 10 61 7

Thrombocytopenia 52 5 32 3

• Treatment-related deaths:– Docetaxel arm: 3 infection and 1 GI

bleed– Paclitaxel arm: 0


* P<0.0001 for both† P<0.001


How a Drug Is Given Matters…CALGB 9840: Weekly vs. q 3 wk

Paclitaxel

Weekly Paclitaxel80 mg/m2

q 3 wk Paclitaxel

175 mg/m2

P

Efficacy (n = 735; combined sample)

RR (%) 42 29 0.0004

Median TTP (months) 9 5 0.0001

Median OS (months) 24 12 0.0092

Toxicity (grades 3 + 4; %; n = 572; limited sample)

Neutropenia 9 15 0.017

Motor neuropathy 9 4 NR

Sensory neuropathy 24 12 NR

Seidman AD et al. J Clin Oncol 2008;26:1642-9.

RR = response rateTTP = time to progressionOS = overall survivalNR = 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;42:665-85.

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;23:7794-803.

nab-paclitaxel 260 mg/m2 iv over 30 min q 3 wk

No standard premedication(n = 233)

Paclitaxel 175 mg/m2 iv over 3 h q 3 wk

Standard premedication with dexamethasone and antihistamines

(n = 227)

RANDOMIZATION

(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)

Prop

ortio

n no

t pro

gres

sed

0.00

0.25

0.50

0.75

1.00

Weeks0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120

Median = 23.0 wk(19.4–26.1)

Median = 16.9 wk(15.1–20.9)

P = 0.006 (log rank)



Treatment-Related Grades 3 and 4 Adverse Events

Reported in ≥5% of Patients

GGT = gamma glutamyl transferase


Neutropenia

Elevated GGT

LeukopeniaFatigue

Arthralgia

Myalgia

Sensory neuropathy

* *

nab-paclitaxel - grade 3nab-paclitaxel - grade 4Paclitaxel - grade 3Paclitaxel - grade 4* P<0.05


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


RANDOMIZATION

Gradishar WJ et al. J Clin Oncol 2009 May 26, first-line treatment of MBC, N = 300

Arm A: nab-paclitaxel 300 mg/m2 q 3 wk

Arm B: nab-paclitaxel 100 mg/m2 weekly (3/4)

Arm C: nab-paclitaxel 150 mg/m2 weekly (3/4)

Arm D: docetaxel 100 mg/m2 q 3 wk

Comparison of Investigator and Independent Radiology Review Response Assessments

46

63

74

393745

49

35

0

10

20

30

40

50

60

70

80

Ove

rall r

espo

nse

rate

(%)

Investigator

IRR

nab-paclitaxel

Gradishar WJ et al. J Clin Oncol 2009 May 26.

300 mg/m2

q 3 wk (A: n = 76)

100 mg/m2

weekly (3/4) (B: n = 76)

150 mg/m2

weekly (3/4) (C: n = 74)

Docetaxel100 mg/m2 q 3 wk

(D: n = 74)

IRR = independent radiologist review


Progression-Free SurvivalInvestigator Assessments


Median PFS (months)10.97.514.67.8


Nab-paclitaxel: Toxicity

nab-Paclitaxel Arms Docetaxel Arm

Grade 4 neutropenia (%) 5–9 75

Febrile neutropenia (%) 1 8

Grade 3 fatigue (%) 0–5 19

Sensory neuropathy Incidence similar in all arms

Median time to improvement (to ≤ grade 1) in grade 3 sensory neuropathy (days) 19–22 37



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 #6. 2007 Jun 1.CED = Committee to Evaluate DrugsSOS = 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 Treatment n ORR (%) Response

Duration (months)

Docetaxel Paclitaxel 80 mg/m2 weekly ― Sawaki et al. (2004)* 44 31.8 6.1

Paclitaxel Docetaxel 100 mg/m2 q 3 wk ― Valero et al. (1998) 44 18.1 6.8

Taxane

nab-paclitaxel 100 mg/m2 106 14 3

or 125 mg/m2 q wk (3/4)― Blum et al. (2007)

75 16(21 with docetaxel

pretreatment†)

3.5

Sawaki M et al. Tumori 2004;90:36-9. Valero V et al. J Clin Oncol 1998;16:3362-8. Blum JL et al. Clin Breast Cancer 2007;7:850-6.

* 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/m2 daily for 14 of every 21 days; lower doses for patients >65 or those with renal dysfunction

Capecitabine

n CR + PR (%)

ORR + SD (%)

MedianTTP (months)

MedianOS (months)

Blum 162 20 60 3.1 12.8Blum 74 26 57 3.2 12.2

Reichardt 136 15 62 3.5 10.1Fumoleau 126 28 63 4.9 15.2

Miller 230 19.1* NR 7.6 14.5

Blum JL et al. J Clin Oncol 1999;17:485-93. Blum JL et al. Cancer 2001;92:1759-68. Reichardt P et al. Ann Oncol 2003;14:1227-33. Fumoleau P et al. Eur J Cancer 2004;40:536-42.Miller KD et al. J Clin Oncol 2005;23:792-9.

CR = complete responsePR = partial responseORR = overall response rateSD = stable diseaseTTP = time to progressionOS = overall survivalNR = not reported

* Investigator assessment; 9.1% by independent review facility

Capecitabine after Docetaxel Monotherapy

1.0

0.8

0.6

0.4

0.2

0.0

0 4 8 12 16 20 24 28 32 36 40

Months

Estim

ated

pro

babi

lity

12.3 21.0

Single-agent capecitabine (n = 28)All other chemotherapy (n = 128)

Log-rank P = 0.0046Hazard ratio = 0.500

Median overall survival

Miles D et al. Clin Breast Cancer 2004;5:273-8.

Miles et al. Clin Breast Cancer 2004

Vinorelbine

• 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 20 35 2.8 NRFazeny 14 0 NR NR

Zelek 40 25 6 (responding patients)

5 (patients with disease stabilization)6

Livingston 40 25 3.0 7.7

Udom DI et al. Eur J Cancer 2000;36:177-82. Fazeny B et al. Cancer Chemother Pharmacol 1996;39:150-6. Zelek L et al. Cancer 2001;92:2267-72. Livingston RB et al. J Clin Oncol 1997;15:1395-400.

CR = complete responsePR = partial responseTTP = time to progressionOS = overall survivalNR = not reported

13.5

1.0

0.8

0.6

0.4

0.2

0.0

Estim

ated

pro

babi

lity

0 4 8 12 16 20 24 28 32 36 40

12.6

Vinorelbine afterDocetaxel Monotherapy

Miles D et al. Clin Breast Cancer 2004;5:273-8.

Median overall survival

Log-rank P = 0.94Hazard ratio = 1.014

Vinorelbine-containing therapy (n = 50)All other chemotherapy (n = 106)

Months


Retrospective, Phase III, Post-study Comparison

of Capecitabine and Vinorelbine

Docetaxel 75 mg/m2 over 1 h q 3 wk

+ capecitabine1250 mg/m2 bid 14 days

O'Shaughnessy J et al. J Clin Oncol 2002;20:2812-23.Miles D et al. Clin Breast Cancer 2004;5:273-8.

O'Shaughnessy J et al. J Clin Oncol 2002

Docetaxel alone100 mg/m2 over 1 h q 3 wk

• Stratification by prior paclitaxel

RANDOMIZATION

Continueuntil

disease progression

Poststudy therapy

(not defined in protocol)

• Capecitabine• Vinorelbine

• Other


Gemcitabine

• 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

• 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 3rd/4th-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

• Etoposide– RR 25-50%, even in heavily pre-treated

patients– Continuous oral administration (50 mg/m2

daily) permits dose titration to toxicity, which is principally hematologic and gastrointestinal

– Oral etoposide is a reasonable 3rd/4th-line (or beyond) regimen.

COMBINATION CHEMOTHERAPY

Combination vs. Sequential Therapy: Lessons Learned from ECOG 1193

Doxorubicin (A)60 mg/m2

(n = 224)

Paclitaxel (T)175 mg/24 h

(n = 229)

Doxorubicin + Paclitaxel (AT)

50/150 mg/24 h(n = 230)

RR (%) 36 34 47*

Median TTF (months) 6 6 8*

Median survival (months) 19 22 22

QOL Similar in all groups

Sledge G et al. J Clin Oncol 2003;21:588-92.

• Primary end point was RRCrossover responses

A

T A

T = 22%

= 20%Not significant

* Statistically significant

RR = response rateTTF = time to treatment failureQOL = quality of life

Combination vs. Sequential Therapy ECOG 1193: Overall Survival

RR = response rateTTF = time to treatment failureOS = overall survivalTRMT = treatment

• Improved RR and TTF with combination• OS comparable

Sledge G et al. J Clin Oncol 2003;21:588-92.

Taxane Combinations in MBC:Efficacy

Study Regimens n ORR (%) PFS (months)

MedianOS (months)

O’Shaughnessy et al. (2002)

Capecitabine + docetaxel 255 42 6.1 14.5

Docetaxel 256 30 4.2 11.5

Albain et al. (2008)

Paclitaxel + gemcitabine 266 41.4 5.9 18.6

Paclitaxel 263 26.2 3.9 15.8

Chan et al. (2009)

Docetaxel + gemcitabine 153 32 8.05 19.29

Docetaxel + capecitabine 152 32 7.98 21.45

O'Shaughnessy J et al. J Clin Oncol 2002;20:2812-23. Albain KS et al. J Clin Oncol 2008;26:3950-7.Chan S et al. J Clin Oncol 2009;27:1753-60.

ORR = overall response ratePFS = progression-free survivalOS = overall survival

Taxane Combinations in MBC:Toxicity (Grades 3 and 4)

Study Regimens nNeutro-

penia (%)

Febrile Neutro-

penia (%)

Hand–Foot Syndrome

(%)

O’Shaughnessy et al. (2002)

Capecitabine + docetaxel 255 16* 16 24

Docetaxel 256 15* 21 1

Albain et al. (2008)

Paclitaxel + gemcitabine 266 47.9 5.0* NR

Paclitaxel 263 11.5 1.2* NR

Chan et al. (2009)

Docetaxel + gemcitabine 152 84 8† 0

Docetaxel + capecitabine 150 79 14† 26

NR = not reported* Required medical intervention; † includes neutropenic sepsis

O'Shaughnessy J et al. J Clin Oncol 2002;20:2812-23. Albain KS et al. J Clin Oncol 2008;26:3950-7.Chan S et al. J Clin Oncol 2009;27:1753-60.

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 SequentialBottom 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; 25:3399-3406: N = 66. RR 12%, SD 40%

• Perez EA et al. JCO 2007 Aug; 25:3407-3414: 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 monthsToxicity: median 4 cycles, 25% of patients received >/= 8 cyclesGrade 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; 25:5210-7

N= 652 MBC refractory to anthracycline and taxane: ixabepilone 40 mg/m2 IV + capecitabine 2,000 mg/m2 PO on days 1 through 14 of a 21-day cycle, VS capecitabine alone 2,500 mg/m2 on the same schedule

Efficacy: Median PFS 5.8 months vs C 4.2 months, HR 0.75, p=0.0003. RR 35% vs C 14% p<0.0001. 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 3....Sparano et al. JCO. June 2010.N = 1 221. 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/m2 2-5 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. 10.7 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

• 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 antibodyVEGF = vascular endothelial growth factor

Image: Hoffmann-La Roche Ltd. Miller K et al. N Engl J Med 2007;357:2666-76.

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: PFSMiller K et al. N Engl J Med 2007;357:2666-76.

DFI = disease-free intervalPFS = progression-free survival

RANDOMIZATION

Paclitaxel weekly (n = 354)

Paclitaxel weekly + bevacizumab

10 mg/kg q 2 wk (n = 368)

Continueuntil

disease progressio

n

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;357:2666-76.

HR for disease progression: 0.60

HR = hazard ratio

Prog

ress

ion-

free

sur

viva

l (%

)

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 2007Miles D et al. ASCO 2008:LBA1011.

PFS = progression-free survivalORR = overall response rateTTF = time to treatment failureOS = overall survivalQOL = quality of life

RANDOMIZATION

Docetaxel 100 mg/m2 q 3 wk + placebo

Docetaxel 100 mg/m2 q 3 wk + bevacizumab

7.5 mg/kg q 3 wk

Docetaxel 100 mg/m2 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)

Months Months0 6 12 18 0 6 12 18

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

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)

Placebo + docetaxel (n = 241)

8.0

HR + 95% CI (unstratified)

HR + 95% CI (stratified†) 0.69 (0.54–0.89)P = 0.0035

0.79 (0.63–0.98)P = 0.0318

Median 8.7

HR + 95% CI (stratified†) 0.61 (0.48–0.78)P<0.0001

Median 8.88.0

0.72 (0.57–0.90)P = 0.0099

HR + 95% CI (unstratified)

Bevacizumab + Taxanes: Increases in Response Rate*

48

Ove

rall

resp

ons

e ra

te (

%) Investigator

assessment(n = 525)

IRF assessment

(n = 472)

50

2223

Paclitaxel

Bevacizumab 10 mg/kg q 2 wk + paclitaxel

CR + PR P<0.0001

CR + PR P<0.0001

55(n = 201)

63(n = 206)

44(n = 207)

* In patients with measurable disease at baseline† vs. placebo + docetaxel* In patients with measurable disease at baseline† vs. placebo + docetaxel

CR + PR P = 0.0295†

CR + PR P = 0.0001†

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 2008:1036.2. Miles D et al. ASCO 2008:LBA1011.

100

80

60

40

20

0

100

80

60

40

20

0

E21001E21001

Investigator assessment

AVADO2AVADO2

IRF = independent review facilityCR = complete responsePR = partial response

100

80

60

40

20

0

100

80

60

40

20

0

Ove

rall

resp

ons

e ra

te (

%)

Bevacizumab + Taxanes: Increases in PFS

E21001

(Independent Review)AVADO2

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) 5.8 11.3 8.0 8.7 8.8

Unstratified HR(95% CI)

P

0.483 (NR)

<0.0001

0.79 (0.63–0.98)

0.0318

0.72 (0.57–0.90)

0.0099

1. Klencke BJ et al. ASCO 2008:1036.2. 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 intervalNR = not reported

SABCS 2009.

Phase III Trials E2100 and AVADO: Serious Adverse Events of Interest

E2100 1 (%) AVADO2 (%)

Taxane Taxane + Bevacizumab Taxane

Taxane + Bevacizumab

End Point* Low Dose High Dose

Thrombosis/embolism† 1.5 2.1 3.4 1.2 1.2

Hypertension 0 14.8 1.3 0.4 3.2

Bleeding 0 0.5 0.9 1.2 1.2

Fatigue 4.9 9.1 5.2 8.4 6.5

Infection 2.9 9.3 3.0 0.8 0.4

LV dysfunction/CHF 0.3 0.8 0 0.8 0

Sensory neuropathy 17.7 23.5 1.7 3.2 4.5

1. Miller K et al. N Engl J Med 2007;357:2666-76. 2. Miles D et al. ASCO 2008:LBA1011.

* Grade 3 or higher † No significant increase in bevacizumab arm in either study

LV = left ventricularCHF = congestive heart failure

RIBBON-1: Study Design

* 1000 mg/m2 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

Optionalsecond-line

chemo +bevacizumab

RANDOMIZATION

2:1

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 untilPD

Choice of chemo by investigator•Capecitabine*

•Taxane†

• Anthracycline‡

PF

S

Time (months)

Placebo

Bevacizumab


RIBBON-1: Capecitabine PFS by Investigator

Placebo (n = 206)

Bevacizumab (n = 409)

Median (months) 5.7 8.6

INVHR (95% CI) 0.69 (0.56–0.84)

P 0.0002

Median(months) 6.2 9.8

IRCHR (95% CI) 0.68 (0.54–0.86)

P 0.0011

PFS = progression-free survivalCI = confidence intervalHR = hazard ratioINV = investigatorIRC = independent review committee

PF

S

Time (months)

Bevacizumab

Placebo


RIBBON-1: Taxane/AnthracyclinePFS by Investigator

Placebo (n = 207)

Bevacizumab (n = 415)

Median (months) 8.0 9.2

INVHR (95% CI) 0.64 (0.52–0.80)

P <0.0001

Median(months) 8.3 10.7

IRCHR (95% CI) 0.77 (0.60–0.99

P 0.040

PFS = progression-free survivalCI = confidence intervalHR = hazard ratioINV = investigatorIRC = independent review committee

Event (%)

Capecitabine Taxane Anthracycline

Placebo (n = 201)

Beva(n = 404)

Placebo(n = 102)

Beva (n = 203)

Placebo(n = 100)

Beva (n = 210)

Bleeding events 0.5 0.2 0 5.4 0 0

Febrile neutropenia 0 0 2.0 7.9 5.0 3.8

GI perforation 0 0 1.0 2.0 0 0

Hypertension 1.0 9.4 2.0 8.9 0 10.0

LV systolic dysfunction 0.5 1.0 0 2.0 0 2.9

Neutropenia 1.0 1.2 4.9 9.4 4.0 4.3

Proteinuria 0 2.2 0 3.4 0 1.9

Sensory neuropathy 0.5 3.0 8.8 8.4 0 0.5

VTE 3.5 4.8 4.9 2.0 1.0 2.9

RIBBON-1: Selected Grade ≥3 Adverse Events


Beva = bevacizumabLV = left ventricularVTE = venous thromboembolism

AVASTIN in Second Line: RIBBON 2

SABCS 2009

SABCS 2009Benefit independent of chemotherapy EXCEPT VINO HR >1

Avastin in TN MBC

• ATHENA trial: Thomssen et al SABCS 2009. • 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: 10. 4 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 2009. • 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 2009. • 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=0.0002. Median PFS 6.9 vs 3.3 mos p < 0.0001. median OS: 9.2 vs 5.7 mos, p=0.0005 .

• SABCS 2009: FINAL RESULTS: MEDIAN OS 12.2 MOS VS 7.7 MOS P=0.005.

• 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....

Chemotherapy and Targeted Therapy for Metastatic Breast Cancer Part 1: HER 2 Negative Dr. Sonal...

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