Enfermedad con sobreexpresión de HER-2 neu · 2017. 5. 31. · – Pertuzumab/placebo: 840 mg loading → 420 mg maintenance – Trastuzumab: 8 mg/kg loading → 6 mg/kg maintenance

Enfermedad con sobreexpresión

de HER-2 neu

Elsa Dalmau

Parc Taulí Sabadell. Hospital Universitari.

Enfermedad con sobreexpresión de HER-2 neu

ÍNDICE

• Neoadyuvancia

• Adyuvancia

• Enfermedad avanzada


ÍNDICE

• Neoadyuvancia • Neo-ALTTO • Biomarcadores • Her2+/RH+

• Adyuvancia


Neoadyuvancia

EFS shown for the ITT population OS shown for the ITT population

Landmark analyses shown for the interaction between pCR and EFS in the ITT population

Landmark analyses shown for the interaction between pCR and OS in the ITT population

Neoadyuvancia

De Azambuja, Lancet Oncol 2014

Neoadyuvancia

PFS by tpCR: all treatment arms combined, ITT population

Gianni, ASCO 2015, Abst 505

• NeoALTTO1

– pCR was lower for patients with PI3KCA mutations. The difference was stadistically significant in the combination arm.

– EFS and OS not affected by PI3KCA status

• GeparQuattro, GeparQuinto and GeparSixto2

– The presence of a PI3KCA mutation was significantly associated with a lower pCR rate. The association was statistically significant in the G6 study (OR 0.357) in which patients received a dual anti-HER2 treatment.

– The HR +/ HER2 + tumors harboring the PI3KCA mutation have the lowest pCR in the dual anti-HER2 treatment arm.

– Neither DFS nor OS are statistically significantly different between pts with or without a PI3KCA mutation.

• CHER-LOB3

– PI3KCA WT status is related to a higher pCR rate following CT + dual blockades with T + L

– PI3KCA mutational status does not predict any differential sensitivity to CT + either T or L

Neoadyuvancia. Biomarcadores.

1Majewski, JCO 2015 (Baselga, ECCO 2013), 2Loibl, JCO 2014 (Loibl, SABS 2013), 3Guarneri, ESMO 2014

Presented By Sibylle Loibl at 2015 ASCO Annual Meeting



pCR Rates According to PI3KCA Mutation Status Overall and by HR Status

pCR Rates According to PI3KCA Mutation Status Overall and by anti-HER2 Treatment

Loibl, ASCO 2015

Disease Free Survival

HR-ve

HR+ve

Loibl, ASCO 2015



ÍNDICE

• Neoadyuvancia

• Adyuvancia • Tumores pequeños • Duración trastuzumab • Tratamiento extendido


Adyuvancia. Tumores pequeños.

SABCS 2013

DFS event Patients (N=406)

Any recurrence or death 3%

Local/regional Recurrence Ipsilateral axilla (HER2+) Ipsilateral breast (HER2+)

0.7% 0.2%

Distant recurrence 0.4%

New contralateral BC 0.9%

Death Non-breast cancer related

0.5%

Tolaney, NEJM 2015

3-year DFS 98.7% P<0.001

3-year RFS 99.2% P<0.001

Probabilites of Disease-free Survival and Recurrence-free Interval

Adyuvancia. Tumores pequeños.

Limitations!! • Lack of randomization • Inclusion of T1a tumors • 67% HR+ tumors (recurrence expectance beyond de

time of follow-up)

Adyuvancia

PLANNED JOINT ANALYSIS OF OVERALL SURVIVAL FROM NSABP B-31 AND NCCTG N9831

8-year incidence rate of deaths by cardiac causes: 0.2% (Trastuzumab regimen) and 0.1% (control arm)

• The HR >1 was observed independent of hormone receptor status of the tumor

• Patients who received trastuzumab had a 33% reduction in the hazard of a DFS event.

- HR 0.67, 95%CI (0.49-0.91)

• 2% pts with SNC metastasis as a first site of recurrence in all subgroups of treatment

Cardiac toxicity was lower in lapatinib arm but low in all treatment arms

Adyuvancia

ESMO 2014, Abst LBA7

Adyuvancia. Duración trastuzumab.

Six versus twelve months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: A

multicenter randomized study by the Hellenic Research Group (HORG) Mavroudis, Annals of Oncol 2015

481 pts with Early BC Her2+ 18-75y

Node-positive or high risk node-negative

Epirubicin 75mg/m2 + Cyclophosphamide

700mg/m2 + 5-fluouracil 700mg/m2

every 2w x 4 cycles

S

U

R

G

E

R

Y

Docetaxel 75mg/m2 + Trastuzumab 4mg/kg

every 2w

Trastuzumab 6mg/kg every

3w x 6 m

Trastuzumab 6mg/kg every

3w x 12 m Primary endpoint: DFS Secondary endpoints: OS and toxicity

HR 1.57 (95%CI 0.86-2.10); p=0.137

3-year DFS 95.7% (12m) and 93.3% (6m), p=0.436

PATIENT AND TUMOR CHARACTERISTICS 46% premenopausal 37% sequential trastuzumab 76% positive nodes 68% (Neo)Adjuvant chemotherapy with antracycline + taxane

Chan, ASCO 2015. Abst 508

Adyuvancia. Tratamiento extendido.



Neratinib

Placebo


Neratinib

Placebo

Neratinib

Placebo



No differences in LVEF ≥2 (N1.3% vs Pl 1.1%) Incidence of cardiac AEs similar in both arms

Grade 3: median duration 5 days Most occurred <30 days

Drug discontinuation 16.8%


• For patients with HER2+ small tumors the use of a less aggressive scheme of treatment with paclitaxel + trastuzumab achieves a low rate of cancer recurrence. – Should adjuvant CT with trastuzumab be considered in all patients with small,

node-negative tumors? T1a and T1b? – Which is the best (safest and most effective) regimen of treatment for these

patients?

• 1 year of adjuvant trastuzumab remains the current standard of care – 2 years of trastuzumab offers no additional efficacy but increase toxicity (HERA

trial) – 6 months of trastuzumab have NOT meet the non-inferiority criteria vs 12

months of trastuzumab (PHARE and HORG trials)

• Neratinib improves iDFS at the 2 year landmark analysis – We need longer F/U data to confirm sustained benefit and OS results. – Benefit or neratinib appears greater in ER+. – For lower risk patients, does the toxicity justify the small potential benefit? – Pertuzumab is an option in the neoadjuvant (adjuvant?) setting for high risk

patients, so would the neratinib benefit still persist in this group?

In summary...

Adyuvancia


ÍNDICE

• Neoadyuvancia

• Adyuvancia

• Enfermedad avanzada • 1ª línea • Líneas posteriores • Nuevos fármacos • M1 SNC

Lapatinib or Trastuzumab Plus Taxane Therapy for HER-2 Positive Advanced Breast Cancer: Final Results of NCIC CTG MA.31

Gelmon, JCO 2015

Kaplan-Meier estimates of intention-to-treat progression-free survival

Kaplan-Meier estimates of intention-to-treat overall survival

11.3m 9.0m

Enfermedad avanzada. Primera línea.


Swain, ESMO 2014 Swain, NEJM 2015

* < 6 cycles allowed for unacceptable toxicity or PD; > 6 cycles allowed at investigator discretion. Interval ≥ 12 months between neo(adjuvant) therapy and metastatic diagnosis was required

HER2-positive MBC centrally confirmed

(N = 808) Primary endpoint PFS

Placebo + trastuzumab

1:1

Docetaxel*

≥ 6 cycles

n = 406

n = 402

Pertuzumab + trastuzumab

Docetaxel*

≥ 6 cycles

PD

PD

• Randomization stratified by geographic region and

neo/adjuvant chemotherapy

• Study dosing q3w:

– Pertuzumab/placebo: 840 mg loading → 420 mg maintenance

– Trastuzumab: 8 mg/kg loading → 6 mg/kg maintenance

– Docetaxel: 75 mg/m2 → 100 mg/m2 escalation if tolerated

CLEOPATRA Study Design


Final OS Analysis Median follow-up 50 months (range 0–70 months)

OS

(%

)

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 70 60

Time (months)

HR 0.68

95% CI = 0.56, 0.84

p = 0.0002

Ptz + T + D

Pla + T + D

1 28 104 226 268 318 371

0 23 91 179 230 289 350

n at risk

Ptz + T + D

Pla + T + D

402

406

40.8

months

56.5

months Δ 15.7

months

Swain, ESMO 2014


AEs with ≥ 25% incidence or ≥ 5% difference between groups: •Diarrhea •Rash •Mucosal Inflammation •Pruritus •Febril neutropenia •Dry skin •Headache •Upper respiratory tract infection •Muscle spasms Left ventricular disfunction rate 6.6% (P) vs 8.6% (No P)

Swain, NEJM 2015


Phase III, randomized study of trastuzumab emtansine ± pertuzumab vs trastuzumab + taxane for first-line treatment of HER2-positive MBC: Primary results from the MARIANNE

study


Presented By Paul Ellis at 2015 ASCO Annual Meeting

MARIANNE Study Design


365

367

363

Ellis, ASCO 2015

Progression-Free Survival by IRF


ORR: HT 67.9%, T-DM1 59.7%, T-DM1+P 64.2% DURATION OF RESPONSE: HT 12.5m, T-DM1 20.7m, T-DM1-P 21.2m

Ellis, ASCO 2015

Maintenance of Health-Related Quality of Life


Ellis, ASCO 2015


Ellis, ASCO 2015

Hurvitz S6-01, SABCS 2014



Prespecified was <0.0044

TRASTYVERE: A Retrospective Analysis of Heavily Pretreated HER2-Positive MBC Patients treated in Spain with Lapatinib plus Trastuzumab as Compassive Therapy J Gavilá, SABCS 2014 (P5-19-21)

HER2+ metastatic or locally advanced BC ECOG status 0 – 2 Progression ≥ 1 prior line of trastuzumab for advanced disease Concomitant endocrine therapy, brain M1 and/or prior exposure to L was allowed.

Lapatinib + Trastuzumab

Primary outcome: Clinical Benefit Rate Secondary outcomes: TTP, OS, toxicity

L+T (n=115)

Median age (range) 60 (34-89)

RE Negative, % 36%

Prior lines of Trastuzumab 3

Prior treatment wih Lapatinib, % 64

Visceral disease, %

SNC MTS, %

77

32

Enfermedad avanzada. Múltiples líneas.

CBR 35% (95%CI, 26-44%) 6 CR, 19 PR, 15 SD ≥24w CBR L naïve 41.5% CBR L pretreated 31.5% p=0.285 CBR HR- 39% CBR HR+ 32.9% p=0.509 TTP 3.91m (95%CI 3.25-5.00) OS 21.6m (95%CI 17.1-27.2)

Enfermedad avanzada. Otros fármacos.

Safety and Efficacy of Neratinib in Combination With Capecitabine in Patients With Metastatic HER2-Positive Breast Cancer

Saura, JCO 2014

Phase I/II, open-label, two-part study. PART ONE: Modified 3+3 dose-escalation study to define the MTD of neratinib + capecitabine in pts with advanced solid tumors. PART TWO: Efficacy and safety of the MTD of neratinib + capecitabine in pts with advanced HER2-positive BC

Best OR to Study Treatment (part two evaluable for efficacy population; n=68)

Response No prior Lapatinib (n=61)

Prior Lapatinib (n=7)

ORR (63%) CR PR

64% 12% 53%

57% 14% 43%

CBR 72% 71%

Grade 3/4 AEs: diarrhea 26%, PPE 14%, asthenia 4%, vomiting 4%, elevated AST 3%

PFS in pts with no prior lapatinib treatment

PFS 40.3w

Neratinib 240mg/d vo + lapatinib 1500mg/m2/d

Enfermedad avanzada. M1 SNC.

CEREBEL (EGF111438): A Phase III, Randomized, Open-Label Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in

Patients With HER2-Positive MBC Pivot, JCO 2015

Study design

Primary endpoint: incidence of CNS M1 as site of first relapse (in the M-ITT population)

Only 475 pts included Closed prematurely on June 2011

CNS as first site of relapse 3% lapa+cape 5% trastu+cape OR 0.65, p.360 Overall incidence of CNS progression 7% lapa+cape 6% trastu+cape p.8646


CEREBEL (EGF111438): A Phase III, Randomized, Open-Label Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in

Patients With HER2-Positive MBC Pivot, JCO 2015

Progression-free survival in the ITT population

Progression-free survival in patients previously treated with trastuzumab


Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous

system metastases: a retrospective, exploratory analysis in EMILIA. Krop, Annals of Oncology 2015

Progression-free survival according to independent review committee Overall survival

2% and 0.7% of pts withouth M1 at baseline developed CNS progression in the TDM-1 and XL arms 22.2% and 16% of pts with M1 at baseline developed CNS progression in the TDM-1 and XL arms

• Although better tolerated, T-DM1 or T-DM1+P are not superior to TH, so THP remains the preferred first-line therapy for HER2+MBC.

– Can we extrapolate the same results with THP for high risk patients who will receive pertuzumab in the neoadjuvant (adjuvant) setting?

– Are the results of these trials applicable for patients developing metastatic disease after adjuvant treatment with trastuzumab?

– And the duration of targeted therapy for those responding?

• Can we combine Pertuzumab and Trastuzumab with other

partners?

– Other taxans? (PERUSE)

– Other chemotherapies? VNR? (VELVET, ORR 62.9 and 64%)

– Other biologics? TDM1? (MARIANNE negative)

Enfermedad avanzada

Unanswered questions...

• T-DM1 has been established as a second-line or first-line in early relapse demonstrating superiority in front of capecitabine + lapatinib.

– Has T-DM1 the same benefit in second-line setting in patients who have received pertuzumab and trastuzumab previously?

– Could neratinib replace lapatinib in the combination with capecitabine keeping in mind its toxicity?

• Trastuzumab + lapatinib might be an option from the third-line and beyond.

– Have we to restrict this treatment only for patients with HR negative?

• After treatment with a trastuzumab-containing regimen, 10-15% of patients will develop CNS metastases despite systemic control.

– Which the best treatment for these patients?

Enfermedad avanzada

Unanswered questions...

1st line

2nd line

3rd line Capecitabine +

Lapatinib

QT +

Trastuzumab

QT +

Trastuzumab

Capecitabine +

Lapatinib

Docetaxel + Trastuzumab +

Pertuzumab

TDM1

4rd line

and beyond

Lapatinib +

Trastuzumab

TDM1

Early relapse

TDM1

TDM1 Lapatinib +

Trastuzumab

TREATMENT SCHEME

Enfermedad avanzada

Seah, JNCCN 2014

Muchas gracias

[email protected]

Documents

Enfermedad con sobreexpresión de HER-2 neu · 2017. 5. 31. · – Pertuzumab/placebo: 840 mg loading → 420 mg maintenance – Trastuzumab: 8 mg/kg loading → 6 mg/kg maintenance