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Nuove Prospettive Terapeutiche nel trattamento della paziente

con ca. mammella HER2+

P Pronzato

Torino, 3.10.2014

AIOM – CIPOMORETI ONCOLOGICHE PIEMONTE E LIGURIA

MBC: Survival Over Time/ HER2+

S Dawood, JCO 2010

HER2 positivity

N of Receptors

[TITLE]

Activation of HER2 pathway

[TITLE]

Adjuvant

• Estimation of the Residual Risk

• Estimate the Benefit (and the Risk) of a Toolable to Reduce the Risk of Clinically RelevantEvents (lifethreatening; within the Life Horizon)

• Estimate the impact for pts not included in the RCTs (very low risk of relapse; high risk of CVD)

• The Overall Best vs The Personalized Best

Risk Estimation (Relapse)

I Vas-Luiz, JCO 2014

Without CT or T5-yr DDFI 93% T1a

and 94% T1b

With CT +/- T5-yr DDFI 100% T1a

and 94% T1b

Risk Estimation (Relapse)

I Vas-Luiz, JCO 2014

Without CT or T5-yr DDFI 96% T1a

and 94% T1b

With CT +/- T5-yr DDFI 100% T1a

and 96% T1b

Risk Estimation (Cardiotoxicity)

E de Azambuja, JCO 2014

Risk Estimatiom (Cardiotoxicity)

M Chavez Mac Gregor, JCO 2013

Risk Estimation (Cardiotoxicity)

J Ajello Bowles, JNCI 2012

Overall Best vs Personalized Best

S Tolaney, SABCS 2013

A New Scenario with SC Trastuzumab

The (Breast) Med Oncol DH Points

• Acknowledgment

• Increasing Numbers (HER2+)

• Crowding

• Little Time for «Communication»

• High Clinical Risk

• Costs (HER2+)

Q&A (Patients & Caregivers)

• What about a new tool ensuring

– SC instead of IV

– Less Time in Hospital

• Good! Provided that efficacy and safety be the same or better!

PrefHer: A global, randomised, two-cohort cross-over preference study

Includes optional TaM sub-study in both cohorts* Remaining Herceptin administered by IV infusion unless patients participated in SID self-administrationIV, intravenous; PINT, Patient Interview; R, randomised; SC, subcutaneous; SID, single-use injection device; TaM, time-and-motion Pivot X, et al. Lancet Oncol 2013

Handheld syringe cohortSC handheld syringe

every 3 weeks x 4

IV

every 3 weeks x 4

SC handheld syringe

every 3 weeks x 4

IV

every 3 weeks x 4

HerceptinRemaining Herceptin

SC to complete 18 cycles in total

HER2-positive primary invasive

breast adenocarcinoma

(N = 240)

R

1:1

PINT1 PINT2

Cross-over period

HER2-positive primary invasive

breast adenocarcinoma

(N = 248)

R

1:1

SID

every 3 weeks x 4

IV

every 3 weeks x 4

SID

every 3 weeks x 4

IV

every 3 weeks x 4

Herceptin

SID cohort

Remaining Herceptinto complete

18 cycles in total

PINT1 PINT2

Cross-over period

Arm A

Arm B

Arm A

Arm B

PrefHer: Patients overwhelmingly preferred Herceptin SC over IV(evaluable ITT population)

0

10

20

30

40

50

60

70

80

90

100

Arm ASID→IVn = 117

Arm BIV→SIDn = 119

OverallN = 236

Percen

tag

e o

f p

ati

en

ts

IV No preference

n = 112 95.7%

n = 54.3% n = 0

0%

n = 119.2%

n = 104 87.4%

n = 43.4%

n = 166.8%

n = 216 91.5%

n = 41.7%

Pivot X, et al. Lancet Oncol 2013SC preferred (exact binomial): Overall = 91.5% (95% CI 87.2% to 94.7%)IV, intravenous; SC, subcutaneous; SID, single-use injection device

SC

PrefHer

• In PrefHer, patients very strongly preferredTrastuzumab SC using the SID or hand-held syringe,mainly because

– it saved time,

– caused them less pain/discomfort and was moreconvenient than IV administration

Q&A (Health Professionals)

• What about new tool ensuring

– To Spare Money

– Time Become Available for more FruitfulOperations

• Good! Provided that efficacy and safety be the same or better!

Items(Taken for granted pts Preference and

Advantages for the DH)

• Subcutaneous Administration

• Fixed Dose

• Lack of Loading Dose

• Efficacy and Safety

– Short vs Long Term

• Surrogacy for pCR

• Immunogenicity

FEC500/75/500

HER2-positive

EBC (N=596)

Safety, tumour response pCR Safety, EFS, OS

PK

Follow-up: 60 mo*(24 mo for EFS, OS)

trastuzumab IV

trastuzumab SC

Su

rg

ery

trastuzumab SCFixed dose of 600 mg(5 mL over 5 minutes)

trastuzumab IV8 mg/kg loading dose;6 mg/kg maintenancedose

Docetaxel75 mg/m2

R

1:1

1 year (18 cycles) trastuzumab

Primary endpoint

Show non-inferiority of SC vs. IV based on co-primary endpoints PK: observed trastuzumab Ctrough pre-dose Cycle 8 (pre-surgery) Efficacy: pathological complete response (pCR) in the breast

Randomised, open-label, Phase III, non-inferiority study to compare the PK, efficacy and safety of trastuzumab SC and IV in HER2-positive EBC

pCR, pathological complete response EFS, event-free survival; OS, overall survival Ismael G, et al. Lancet Oncol. 2012;13:869-78

* Clinicaltrial.gov NCT00950300

Graphical elaboration from text data

HannaH: Non-inferiority margins for co-primary endpoints

Ismael G, et al. Lancet Oncol 2012; 13:869–878

Pharmacokinetic co-primary endpoint:

Observed Ctrough at pre-dose Cycle 8

Prespecified non-inferiority marginfor geometric mean ratio SC vs. IV: 0.8

Efficacy co-primary endpoint:

Pathological complete response in the breast

Pre-specified non-inferiority marginfor pCR rate difference SCIV: 12.5%

HannaH: Primary and secondary pharmacokinetic endpoints

Pharmacokinetic per protocol population20 µg/mL is the therapeutic target threshold Ismael G, et al. Lancet Oncol 2012; 13:869–878

Ismael G, et al. Lancet Oncol 2012

Efficacy per protocol population; pathological tumour response was assessed locallypCR defined as absence of invasive neoplastic cells in the breastResidual ductal carcinoma in situ (DCIS) is acceptable for pCRCI, confidence interval; IV, intravenous; pCR, pathological complete response; SC, subcutaneous; tpCR, total pathological complete response (pCR in breast and axilla)

Herceptin IV (n=263) Herceptin SC (n=260)

Pati

en

ts a

ch

ievin

g a

pC

R(%

)

45.4

34.2

39.240.7

20

10

0

30

pCR tPCR

40

50

60

HannaH: pCR and tpCR rates

SC versus IV (Hannah & Prefer)

• Comparable Drug Exposure– Higher Ctrough & Lower Cmax for SC; Comparable

Exposure

• Comparable Efficacy– Not Correlated with Body Weight

• Comparable Safety Profile– Not Correlated with Body Weight

Items(Taken for granted pts Preference and

Advantages for the DH)

• Subcutaneous Administration

• Fixed Dose

• Lack of Loading Dose

• Efficacy and Safety

– Short vs Long Term

• Surrogacy for pCR

• Immunogenicity

HER2+ MBC

New Anti-HER2 Agents: First Line

S Swain, Lancet Oncology 2013

New Anti-HER2 Agents: Second Line

S Verma, NEJM 2012

New Anti-HER2 Agents: Beyond Second Line

IE Krop, Lancet Oncology 2014

• Aims of treatment of HER2+ MBC are the same as for HER2-

• Established/ Evidence Based First and Second Line

• Long Post-Progression Survival

• Sequential treatments as a Paradigm

Survival and Sequences: PPS after First Line

M Bonotto, Oncologist 2014

Survival and Sequences

DES Seah, J NCCN 2014

[TITLE]

Presented By Eric P. Winer, MD at 2013 Breast Cancer Symposium

4444

1st line Docetaxel + T+ Pertuzumab T-DM1

2nd line T-DM1 Lapatinib + Capecitabine

3rd line Lapatinib + Capecitabine Lapatinib + Trastuzumab

4th line Lapatinib + Trastuzumab Trastuzumab + Chemo

New Human Epidermal Growth Factor Receptor 2-Targeted Agents to Early and Metastatic Disease? – Martin J. Piccart-Gebhart, Jules Bordet Institute Optimizing the use of new HER2 targeted agents in advanced disease:

No known brain metastasesTrastuzumab (T) naive or T-

“sensitive” population (adj. T-free interval ≥ 1y)

Trastuzumab (T) pretreatedand doubt about T-

“sensitivity”(adj. T-free interval < 1 y)

*ASCO 2013: Education Session , Now What? Do We Optimize the Use of New Human Epidermal Growth Factor Receptor 2-Targeted Agents to Early and Metastatic Disease? – Martin J. Piccart-Gebhart, Jules Bordet Institute

[TITLE]

Presented By Eric P. Winer, MD at 2013 Breast Cancer Symposium

Adjuvant TCNS mtsDFISubgroups

Prior PertuzumabSubgroups

Role of LapatinibCT Alone

Lapatinib:Robustness of Results

RR PFS (*TTP) OS

EGF 151 (NEJM 2006/ Oncologist 2010)

22% *8.4 mos 87.3 wks

EAP (Ann Oncol 2009) - 21.1 wks 39.6 wks

EMILIA (NEJM 2012) 30.8% 6.4 mos 23 mos

CEREBEL (ESMO 2012) 27% 6.6 mos 22.7 mos

Neratinib randomized PhaseII Trial (SABCS 2011)

40% 6.8 mos 19.7 mos

Results for the Capecitabine + Lapatinib

HER2+ Role of Chemotherapy

Role of Combination in the Real Life

A Llombart-Cusac, ASCO 2014

Role of HT

S Johnston, JCO 2009

Role of HT

Table 1Adjusted PFS curves for patients with high HR expression receiving maintenance endocrine therapy (solid line), not receiving maintenance endocrine therapy (dashed line) and for patients with HR low/absent expression (dotted line)

F Montemurro, Cancer 2011

Neoadjuvant

Neoadjuvant Trials with Pertuzumab

Neoadjuvant Trials with Pertuzumab

ER+ and/or PgR + (%)

Operable(%)

Inflammatory(%)

Ref

NEOSPHERE 47-48 60-63 5-9 Schneeweiss,SABCS 2011

TRYPHAENA 46-53 63-72 5-7 Gianni,Lancet Oncol 2012

Lessons From Neoadjuvant Trials

Trial CT weeks Anti HER2

ypT0/is(%)

ypT0/is(%)HR+

ypT0/is(%)HR-

NEOSPHERE T 12 H 29.0 20.0 36.8 Gianni,Lancet Onc 2012

NEOSPHERE T 12 P 24.0 17.4 30.0 Gianni,Lancet Onc 2012

NEOSPHERE T 12 HP 45.8 26.0 63.2 Gianni,Lancet Onc 2012

NEOSPHERE no 12 HP 16.8 5.9 27.3 Gianni,Lancet Onc 2012

TRYPHAENA FEC/T 18 HP 61.6 46.1 79.4 Scheneeweiss, Ann Oncol 2013

TRYPHAENA FEC/T 18 HP* 57.3 48.5 65.0 Scheneeweiss, Ann Oncol 2013

TRYPHAENA TC 18 HP 66.2 50.0 83.7 Scheneeweiss, Ann Oncol 2013

(*) HP started after FEC

Lessons From Neoadjuvant TrialsTrials


ypT0/is(%)

ypT0/is(%)HR+

ypT0/is(%)HR-









Lessons From Neoadjuvant TrialsTrials: Anti-HER2 Agents


ypT0/is(%)

ypT0/is(%)HR+

ypT0/is(%)HR-









Lessons From Neoadjuvant TrialsTrials: CT


ypT0/is(%)

ypT0/is(%)HR+

ypT0/is(%)HR-









Lessons From Neoadjuvant TrialsHigh pCR Rate


ypT0/is(%)

ypT0/is(%)HR+

ypT0/is(%)HR-









Lessons From Neoadjuvant TrialsRelevance of Pertuzumab


ypT0/is(%)

ypT0/is(%)HR+

ypT0/is(%)HR-









Lessons From Neoadjuvant TrialsLonger CT


ypT0/is(%)

ypT0/is(%)HR+

ypT0/is(%)HR-









Lessons From Neoadjuvant TrialsWithout CT


ypT0/is(%)

ypT0/is(%)HR+

ypT0/is(%)HR-









Lessons From Neoadjuvant TrialsRelevance of HR


ypT0/is(%)

ypT0/is(%)HR+

ypT0/is(%)HR-









Conclusions

Clinical Needs- Personalization

• More potent treatment for Trastuzumab resistent

– Basing on specific mechanism of resistance

• Differentiated approaches for pts TrastuzumabCured

– Selecting the cases not needing treatment

– Different «lower profile» approaches : less CT, dualblockade, anti-HER2 + HT, different anti-HER2 agents

The Way to explore IntratumorHeterogeneity

• Consider the limits of Tumor Characterization• Consider the limits of newer and future drugs

• The «Old» paradigm about uncurability of advanced disease resists!

• Exploit the Neo-Adjuvant Setting• Value for Liquid Biopsy

Activation of HER2 pathway

Intrinsic Subtypes in Untreated HER2+ Disease (n=265)

Presented By Lisa Carey at 2014 ASCO Annual Meeting

pCR by Intrinsic Subtype (All Arms, n=265)


Residual Disease Before and After Therapy<br />(n=78 pairs)


Rexer BN, Artega CL; Crit Rev Oncog, 2012

Biomarkers Studies in Pertuzumab Trials (NEOSPHERE, TRYPHAENA, CLEOPATRA)

Extensively Studied

HER2 level of Expression

HER3

IGFR

PI3K (expression an mutations)

PTEN

MYC

…….

Predictive Effect only forHR

IMMUNE PROFILE

Tumor Evolution as a Paradigm:HER2+ and anti-HER2 Sensitivity

(Pertuzumab + Trastuzumab)

Treatment Stage ORR (%) cCR (%) pCR (%) Ref

PT LABC/EBC 67.6 - 18 Gianni,Lancet Onc 2013

PT+ Doce LABC/EBC 88.1 - 49 Gianni, Lancet Onc 2013

PT+FECPac LABC/EBC 91.8 59.7 61.6* TRYPHAENA,SABCS 2011

PT+ CarboPac LABC/EBC 89.6 40.3 66.2* TRYPHAENA,SABCS 2011

PT+Doce MBC 1 line 80.2 5.5 - Baselga,NEJM 2011

The Way to explore IntratumorHeterogeneity

Consider the limits of Tumor Characterization

Consider the limits of newer and future drugs

The «Old» paradigm about uncurability of advanceddisease resists!

Exploit the Neo-Adjuvant Setting

Value for Liquid Biopsy

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