Focus sul carcinoma della mammella:Ruolo delle antracicline

La chemioterapia della malattia metastatica:

stato dell'arte

Prof. Corrado FicorellaMedical Oncology

San Salvatore Hospital University of l’Aquila

Consorzio InteruniversitarioNazionale per la Bio-Oncologia

Goals of CT for advanced breast cancer

• Relieve symptoms associated with advanced cancer, such as: pain, fatigue, or dispnea

• Prevent symptomatic progression of tumor

• Prolong survival

• Enhance quality of live

• Make advanced breast cancer a “chronic” condition

Treatment of HER2-Negative MBC

• Use of CT over OT

• Single vs combination therapy

• What chemotherapy options exist beyond first-line

treatment ?

• Continued treatment vs palliative care

Chemotherapy in Hormone-Receptor PositiveMetastatic Breast Cancer (MBC)

•First-line endocrine therapy generally used in the absence of:

Rapid clinical progressionHER2-positive disease (a,b)

Life-threatening visceral metastasis

• Predicted endocrine responsiveness

Recent literature suggest HER2-targeted therapy + endocrine therapy as reasonable option (trastuzumab + anastrozole; lapatinib + letrozole)

a) Kaufman B.JCO 2009

b) Johnston S. JCO 2009

Sistemic treatment of Recurrent or stage IV Disease: NCCN Guidelines

Preferred CT regimens for Recurrent/MBC

Preferred single agents Other Single Agents

• Anthracyclines • Cyclophosphamide

- Doxorubicin • Mitoxantrone

- Epirubicin • Cisplatin

- Pegylated liposomal doxo • Etoposide

• Taxanes • Vinblastine

- Paclitaxel • Fluorouracil

- Docetaxel • Ixabepilone

- Albumin-bound paclitaxel Preferred agents with Bevacizumab

• Anti-metabolites • Paclitaxel

- Capecitabine

- Gemcitabine

• Other microtubule inhibitors

- Vinorelbine

- Eribulin NCCN Guideline Version 2.2011

Preferred CT regimens for Recurrent/MBC

Preferred Chemotherapy Preferred First-Line Agents for

Combinations HER2-Positive Disease

• CAF/FAC • Trastuzumab with:

• FEC - Paclitaxel ± carboplatin

• AC - Docetaxel

• EC - Vinorelbine

• AT - Capecitabine

• CMF Preferred Agents for Trastuzumab-

• Docetaxel/capecitabine Exposed HER2 Positive Disease

• Gemcitabina/paclitaxel (GT) • Lapatinib + capecitabine

• Trastuzumab + other first-line agents

• Trastuzumab + capecitabine

• Trastuzumab + lapatinib (without Cytotoxic)

NCCN Guideline Version 2.2011

Single Agent vs Combination Therapy:Intergroup Phase III Trial (E1193) Doxorubicin and Paclitaxel and the Combination as Front-Line CT for MBC.

• PTS randomly assigned to:

doxorubicin (A) vs paclitaxel (T) vs combination (AT)

• Crossover permitted to the other monotherapy

• RR: 36% (A), 34% (T), 47% (AT) (A vs AT p=.007; T vs AT p= .004)

•TTF: 5.8 mo, 6.0 mo, 8.0 mo (A vs AT p= .003; T vs AT p=.009)

• OS: 18.9 mo (A), 22.2 mo (T), 22.0 mo (AT); p= not significant

• RR: pts crossing A to T 20% p= not significant

pts crossing T to A 22%

OS similar when crossover permittedSledge GW.JCO.2003;21:588

Intergroup Phase III Trial (E1193) Doxorubicin and Paclitaxel and the Combination as Front-Line CT for MBC.

Subsets Benefiting from Combination

Factors Associated with Overall Survival: Multivariate Analysis

Factor RR P

Er neg 1.7 .0001

Visceral dominant 1.4 .004

3 or more sites 1.4 .005

1-24 mo DFI 1.3 .03

Prior systemic therapy 1.1 .03

Sledge GW.JCO.2003;21:588

Single agent VS Combination Therapy

• Meta-analysis of 43 trials, ~ 10.000 women with MBC

• Combinations regimens associated with- Modest improvement in OS (HR 0.88; P<.00001)

- Favorable time-to-progression (HR 0.78; relative RR 1.29)

- Much more toxicity

Carrik S, et al. Cochrane Database Syst Rev. 2009

Single agent VS Combination Therapy

• Weakness of combination trial designs:

- Difficult to obtain homogeneous population

- Need for dose reductions to deliver combination regimens

- Survival advantage not seen in most individual trials;

when seen, often first line setting

“There is an unresolved question regarding the benefit of combination therapy vs single agents given sequentially”

Carrik S, et al. Cochrane Database Syst Rev. 2009

Duration of CT for MBC: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Gennari A. JCO 2011

11 randomized clinical trials (2.269 pts) comparing different CT

durations in the first-line treatment

Longer first-line CT duration resulted in to:

Marginally longer OS: HR 0.91; p=.046

Substantially longer PFS: HR 0.64; p< .001

Bevacizumab

13Rossari et al. J Oncol 2012;2012:417673

Bevacizumab

14

Rossari et al. J Oncol 2012;2012:417673

Bevacizumab

15 15

Rossari et al. J Oncol 2012;2012:417673

A meta-analysis of OS data from three randomized trials of Bev. and first-line CT as treatment for patients with MBC.(E2100, AVADO, RIBBON-1) Pooled Analysis

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Primary endpoint: PFS

Secondary endpoint: OS (trials not designed to show an OS benefit)

1 yr survival rate : 76.5% (control) vs 81.6% ( BV+chemo) p=0.003

O’Shaughnessy et al. JCO vol. 28, article 15s, 2010, abstract no. 1005

Quest for Biomarkers in HER2-Negative MBC: Results for Bevacizumab from phase III Trials

E2100 study

- VEGF-2578 AA genotype: superior mOS (HR 0.58; P=.023)

- VEGF-1154 A allele: superior mOS (HR 0.62; P=.001)

AVADO study

- 7.5 mg/kg Bev

• Higher plasma VEGF levels: longer PFS (HR 0.52; P=.01)

• Higher plasma VEGFR2 levels: longer PFS (HR 0.46; P=.03)

- 15 mg/kg Bev

• Higher plasma VEGF levels: longer PFS (HR 0.49; P=.08)

Schneider BP. JCO.2008

Miles DW.SABCS 2010

Review of Treatments in the third-line and Beyond

…evidence-based medicine provides some support for the use of

second-line and, to a lesser degree and in selected cases, third-line CT

in MBC

Beyond third-line treatment, however, there are no data that suggest a

clear benefit for such a therapeutic approachCardoso F.Ann Oncol.2002 - Review

Dufresne and colleagues demonstrated that 40% of patients achieve

disease control for more than 6 months with third-line chemotherapy

Dufresne. BCRT. 2008

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Cortes et al. Lancet 2011; 377: 914–23

ORR:Ind. rev. (12% vs 5%) – Invest.rev. (13% vs 7%) P=.002 - .028PFS: Ind. rev. (3.7 vs 2.2 mo) – Invest.rev. (3.6 vs 2.2 mo) p=.14 - .002OS: 13,12 mo vs 10,6 mo; HR 0.81, P .041) “Primary endpoint”

• Synthetic analogue of halichondrin:Bloks microtubule polymerization and forms nonfunctional tubulin aggregates

EMBRACE: Pros and Cons

• Limitations:

- not a blinded study

- TPC arm cuold receive treatments they have been exposed to previously

- Supportive care option, unfair comparison

- Bias regarding choice of therapy beyond progression

• Strengths

- heavily pretreated patient population (median 4 prior regimens)

- treatment choices reflect real-world-world options

- powered to look for OS with 2-sided log-rank test

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nab-Paclitaxel/ABI-007: Paclitaxel bound to nanoparticles of albumin, naturally occurring vehicle for hydrophobic molecules

ORR: 33% vs 19% p=.001 Nab: 260mg/mqPFS: 23 vs 17 weeks p=.006 Paclitaxel: 175 mg/mq

Neutropenia G4: 9% vs 22% p<.001 (despite 49% higher paclitaxel dose)Sensory neuropathy G3: 10% vs 2% p<.001 (reversible, short lived)No hypersensivity reactions

Administration time 30 m (vs 3 h), no premedication

CALGB 40502 – NCCTG N063H – CTSU 40502Open-Label Phase III Trial of First-Line Therapy for mBC:Nab-Paclitaxel 150/weekly + Beva 10mg/kg q 2 wks vsPaclitaxel 90/weekly + Beva 10 mg/kg q 2 wks

PFS

Paclitaxel (283): 10.6 mo vs Nab-Paclitaxel (271): 9.2 mo

HR 1.19; P = .12

OS

Paclitaxel (283): 26 mo vs Nab-Paclitaxel (271): 27 mo

HR 1.02; P= .92

Adverse Events G≥3 Nab Pac P

Hematologic 51% 21% <.0001

Nonhematologic 60% 44% .0002

Neuropathy 25% 16% .012Rugo et, al.ASCO 2012

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Nab-Paclitaxel vs Docetaxel: First-line Phase II Randomized Study

PFS: (Nab 150/W)13 mo vs 7.5 mo (Docetaxel/100 q3w) (p=.0065)

ORR: 45% (100/w), 49% (150/w) vs 35% (docetaxel/100 q3w) not significant

No difference in PFS e OS: Nab 300 q3w vs docetaxel (100 q3w)

G3/4 fatigue, neutropenia, febrile neutropenia less frequent in all nab-paclitaxel arms.

Malattia HER2-positiva

Ian Krop, SABCS 2011

Pivotal Combination Trial of First-Line Chemotherapy ± Trastuzumab in MBC: Efficacy/Toxicity

CT CT + T p value

ORR 32% 50% <.0001

TTP 4.6 mo 7.4 mo <.0001

Median OS 20.3 mo 25.1 mo .046

1 year OS 68% 79% .008

Cardiac Dysfunction

AC: 8%

AC-T: 27%

P: 1%

P-T: 13%

Slamon et al. NEJM 2001 Mar 15;344(11):783-92

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Trastuzumab: PFS

Slamon et al. NEJM 2001 Mar 15;344(11):783-92

Trastuzumab: OS

Slamon et al. NEJM 2001 Mar 15;344(11):783-92

Cardiac Disfunction (CD) in the Trastuzumab Clinical Trials Experience

Retrospective review from seven phase II/III trastuzumab clinical trials by Independent Cardiac Review and Evaluation Committee (CREC)

Seidman A,et al. JCO 2002

Treatment Cardiac Dysfunction % NYHA Functional Class III/IV %

Trastuzumab + AC 27 16

AC Alone 8 4

Trastuzumab + Paclitaxel 13 2

Paclitaxel Alone 1 1

Trastuzumab + CT 5 3

Trastuzumab Alone 3 to 7 4

Cardiac Disfunction (CD) in the Trastuzumab Clinical Trials Experience

Seidman A,et al. JCO 2002

Retrospective review from seven phase II/III trastuzumab clinical trials by Independent Cardiac Review and Evaluation Committee (CREC)

Study Treatment Prior Antrac. CD% NYHA Class III/IV %

H0551g Trastuzumab ? 7 4

H0552 Trast + CDDP ? 3 3

H0648g Trast + AC 1% 27 16

AC 1% 8 4

Trast + Paclitaxel 91% 13 2

Paclitaxel 97% 1 1

H0649g Trastuzumab ? 5 4

H0650g Trastuzumab ? 3 2

H0659g Trast ± other CT ? 6 3

H0693g Trast ± other CT ? 4 3

Most Trastuzumab treated pts developing CD were symptomatic (75%) and most improved

with standard treatment for CHF (79%)

Trastuzumab

Trastuzumab ha dimostrato una significativa attività in combinazione con molti agenti chemioterapici

In patients with MBC, loss of response to HER2-targeted therapy is the norm: Mechanism of resistance

• Barriers to antibody binding

Increased expression of p-95-HER2, Epitope masking

• Upregulation of downstream signaling

PTEN loss, PI3K muts, Increased Akt kinase activity

• Crosstalk

Increased IGF-IR signaling, Continued signaling from HER2/HER3

heterodimers, HER3 or EGFR upregulation, Increased c-Met

expression, Upregulation of ER signaling, Increased AXL signaling

• Failure of ADCC

Fc receptor polymorphisms

Optimizing the use of currently available agents, novel agents (Pertuzumab), trastuzumab emtansine conjugate, novel TKI (Afatinib, Neratinib)

Tsang et al. Br J Cancer 2012 Jan 3;106(1):6-13

HER2 Therapy: Horizons and Advances

Trastuzumab Beyond Progression

Primary end-point TTP

Secondary endpointsORR, OS

Duration of response

Safety

Von Minckwitz et al. JCO 2009 Apr 20;27(12):1999-2006

Trastuzumab Beyond Progression

Von Minckwitz et al. JCO 2009 Apr 20;27(12):1999-2006

TTP 8,2 mo vs 5,6 mo (p 0.0338)OS 25,5 mo vs 20,4 mo (p 0,257)ORR 48,1% vs 27% (p 0,0115)

ESMO Guidelines: evidence suggests continuing anti-HER2 therapyfor as long as possible (Ann Oncol 2012)

mBC: Lapatinib ± Trastuzumab (CT-free regimen)

Blackwell et al. 2010 Mar 1;28(7):1124-30

mBC: Lapatinib ± Trastuzumab

TTP 12 weeks vs 8,1 weeks (p 0.008)OS 51,6 weeks vs 39 weeks (p 0.106)ORR 10,3% vs 6,9% (p 0,46)CBR 24,7% vs 12,4% (p 0.01)

Median no. Prior CT regimens: 4 (L) , 5 (L+T); Prior trastuzumab regimens: 3 (L), 3 (L+T)

Dual Inhibition of HER2 is both safe and effective

Blackwell et al. 2010 Mar 1;28(7):1124-30

Overall Survival Benefit With Lapatinib + Trastuzumab for Patients with HEGFR2-Positive MBC: Final Results From The EGF104900 Study Kimberly L, et al. JCO 2012;30:2585-92

PFS 11.1 weeks vs 8,1 weeks (HR, 0.74; p= .011)

OS 14 mo vs 9.5 mo (HR, 0.74; p= .026) *

(*despite the fact that > 50% of pts crossed to combination therapy)

Median no. Prior CT regimens: 4 (L), 5 (L+T)

Median Prior trastuzumab regimens: 3 (L), 3 (L+T)

Continuing Trastuzumab Beyond Progression either + Ct or with

lapatinib/trastuzumab combination is both safe and effective

Geyer et al. NEJM 2006 Dec 28;355(26):2733-43

Progressive HER2+ MBC or LABC

Previously treated with anthracycline, taxane and trastuzumab(trastuzumab for metastatic disease)

No prior capecitabine

Lapatinib 1250 mg/diecontinuously

+Capecitabine 2000

mg/mq gg1-14 q21

Capecitabine 2000 mg/mq

gg1-14 q21

Primary end-point TTP

Secondary endpoints ORR, OS

Safety

Geyer et al. NEJM 2006 Dec 28;355(26):2733-43

TTP 8,4 mo vs 4,4 mo (p <0.001)OS 36 events vs 35 events (p 0,72)ORR 22% vs 14% (p 0,09)

Paclitaxel + Lapatinib vs Paclitaxel alone for first-line treatment of mBC

TTP by HER2 Status

HER2+ Paclitaxel + Lapatinib

(n = 52)

Paclitaxel + Placebo

(n = 39)

Median mo 8.1 5.8

HR (95% CI) / P value 0.57 0.011

HER2 - Paclitaxel + Lapatinib

(n = 199)

Paclitaxel + Placebo

(n = 202)

Median mo 5.8 5.3

HR (95% CI) / P value 1.04 .747

Di Leo JCO 2008

MA.31: Taxane based CT with Lapatinib or Trastuzumab

as First-Line Treatment for HER2+ mBC

HER2 mBC patients

Trastuzumab + Taxane x 24 weeks ➜ Trastuzumab until PD (TTAX/T)

VS

Lapatinib + Taxane x 24 weeks ➜ Lapatinib until PD (LTAX/L)

PFS (centrally Confirmed HER2+ Analysis)

Median PFS TTAX/T = 13.7 mo

Median PFS LTAX/L = 9.0 mo

HR = 1.48; P = .003

Gelmon K. ASCO 2012

Pertuzumab: “HER Dimerization Inhibitor”FDA-approved + trastuzumab and CT for treatment-naive, HER2-positive, MBC

World JCO 2011 February 10; 2(2): 125-134

Pertuzumab ± Trastuzumab in MBC progressing during prior trastuzumab therapy (Phase II Study)

Baselga J,et al.JCO 2010;28:1138-1144Cortés J, et al.JCO 2012;30:1594-1600

Cohorts 1/2: Cohort 3 Pertuzumab Pertuzumab

Trastuzumab

Cohort 3 *P➜ P+T

CR 7.6% 0.0% 0.0%

PR 16.7 3.4 17.6

CR+PR 24.24 3.4 17.6

SD≥ 6 mo 25.8 6.9 23.5

CR+PR+SD 50 10.3 41.2

PFS 5.5 mo 7.1 wks 17.4 wks

* Pts progressing while taking pertuzumab Adverse events mild to moderate

Phase III trial CLEOPATRA

Baselga J, et al. New Engl J Med 2012;366:109-19

CLEOPATRA: Docetaxel + Trastuzumab ± Pertuzumab (First-line treatment for MBC)

Baselga J, et al. New Engl J Med 2012;366:109-19

First-line HER2-positive

MBCI

Docetaxel (75mg) + Trastuzumab +

placebo

Docetaxel (75mg) + Trastuzumab +

Pertuzumab

N = 808

Pertuzumab:phase III studies (CLEOPATRA)

Baselga J, et al. NEJM 2012;366:109-19

Pertuzumab: phase III study (CLEOPATRA)

PFS 18,5 mo vs 12,4 mo (HR, 0.62; p <0.001)OS interim analysis: 96 events vs 69 (HR,0.64; P=.0053) ORR 80,2% vs 69,3% (p 0,001)

safety slight increase in Diarrhea, G≥3: 7.9% vs 5%and Febrile neutropenia, G≥3: 13.8% vs 7.6%)Left ventr. syst. dysf. G≥3 : 1.2% (PTD) vs 2.8% (TD)

Trastuzumab Emtansine (T-DM1)

Nel T-DM1 il Trastuzumab è legato ad un potente agente citotossico (emtansine)

Il DM1 è un inibitore dei microtubuli da 20 a 100 volte più potente della vincristina

A ciascun anticorpo si legano una media di 3,5 molecole di DM1

T-DM1 si lega a HER2 con un’affinità simile a quella del Trastuzumab

T-DM1: the antibody delivers a cytotoxic agent right to the cancer cell

Trastuzumab-DM1:single-arm Phase II TrialsBurris HA. JCO 2011Krop IE. JCO 2012

Study Burris, 2010 (TDM4258g)

Krop, 2012TDM437g)

No of patients 112 110

Prior treatments

- median no.of agents 8 8.5

% pts with prior

Trastuzumab 100 100

Taxanes 84 100

Antracyclines 71 100

Capecitabine 66 100

Lapatinib 60 100

RR,% 26 35

PFS (median), mo 4.6 6.9

T-DM1: phase I-II clinical trialsHurvitz et al. Ther Adv Med Oncol 2012 Sep:4(5):235-45

Hurvitz ESMO 2011 phase II first-line randomized study

Tolerability improved:G3/4 events less common (46.4% vs 89.4%)serious events less common (18.8% vs 25.8%)fewer discontinuation due to adverse events (7.2% vs 28.8%)

T-DM1:phase III clinical trials

Hurvitz et al. Ther Adv Med Oncol 2012 Sep;4(5):235-45

T-DM1: phase III study (EMILIA)

HER2-positive MBC previously treated with trastuzumab

and a taxane

T-DM1

Lapatinib+

Capecitabine

Verma et al. NEJM 2012 Nov 8;367(19):1783-91

T-DM1: phase III study (EMILIA)

PFS 9,6 mo vs 6,4 mo (p <0.001)OS 30,9 mo vs 25,1 mo (p <0.001)ORR 44% vs 30% (p <0.001)Safety Toxjcity G 3/4 more evident in Lap+Cap arm

(57% vs 41%)monitor platelet count (13%) and liver function

Progression-free Survival, as Assessed by an Independent Review

Committee

Second Interim Analysis of Overall Survival

Verma et al. NEJM 2012 Nov 8;367(19):1783-91

Cardiotossicità da antracicline

Smith et al. BMC Cancer 2010 Jun 29;10:337

Cardiotossicità da antracicline

Rispetto a regimi non contenenti antracicline, le antracicline

aumentano il rischio di:- cardiotox clinica di 5,43 - cardiotox subclinica di 6,25 - cardiotox qualsiasi di 2,27 - morte cardiaca di 4,94

Il rischio cardiaco si riduce del 61% con l'epirubicina

Il rischio cardiaco si riduce del 22% con la doxorubicina liposomiale.

Smith et al. BMC Cancer 2010 Jun 29;10:337

Cardiac event rate across NSABP B-31 and NCCTG N9831 trials that assessed the addition of trastuzumab to Adjuv. CT

Russell et al. JCO 2010 Jul 20;28(21):3416-21

Trastuzumab treated pts had a 2% incidence of symptomatic heart failure events vs 0.45% in the CT alone arm

Complete or partial recovery was observed in 86% of trastuzumab treated pts with symptomatic heart failure events

Independent predictors for cardiac events were:age older than 50

low FEV at the start of paclitaxel treatmenttrastuzumab treatment

Russell et al. JCO 2010 Jul 20;28(21):3416-21

Bowles et al. JNCI 2012;104:1293–1305

Women treated outside clinical trials

(Adjuvant setting)

Adjusted cumulative HF/CM incidence in antracycline only recipiens:

1.2% (Year 1) vs 4.3% (Year 5)

Trastuzumab only recipiens:

3.6% (Year 1) vs 12.1% (Year 5)

Antracycline + trastuzumab recipiens:

6.2% (Year 1) vs 20.1% (Year 5)

Bowles et al. JNCI 2012;104:1293–1305

Summary

HER2-negative mBC:

Multiple lines of effective treatment for late-stage disease

Longer duration of control with the first-line regimen

Predictive biomarkers for Beva for efficacy and safety are investigated

Nab-Paclitaxel: good for pts not tolerating steroids, having neuropathy

(first-line paclitaxel equivalent in efficacy and less expensive)

HER2-positive MBC:

Multiple lines of effective treatment

Trastuz. Beyond progression, T-DM1

The best treatment today for HER2 pts is dual HER2 blockade

Novel agents:

Next-generation TKIs (afatinib, neratinib)

PI3K pathway targeting

Other HER3 agents