Otimizando a terapia anti-HER2 no câncer de mama inicial

José Bines, MD PhD

Instituto Nacional de Câncer

Clínica São Vicente

Rio de Janeiro ▪︎ Brasil

Disclosures

Clinical study: Roche

Travel expenses: AstraZeneca, Roche

Consultant: Abbvie, Genomic Health, Libbs, Lilly, Pfizer, Roche

Personal opinion may not reflect the Instituto Nacional de Câncer orientation

The evolution of HER2-positive breast cancer natural history

Docetaxel Docetaxel + carboplatin

Doxorubicin + cyclophosphamide Herceptin Paclitaxel

Chemotherapy +/- sequential radiotherapy

HERA (ex-US)1,2

IHC/FISH N = 5102

Observation

1 year

2 years

NCCTG N9831 (US)4

IHC/FISH N = 1944

1 year

1 year

NSABP B-31 (US)4

IHC/FISH N = 2101

1 year

•

1. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353:1659–1672; 2. Gianni L, et al. Lancet Oncol 2011; 12:236-244; 3. Slamon D, et al. N Engl J Med 2011; 365:12731283; 4. Perez EA, et al. J Clin Oncol 2011; 29:33663373.

BCIRG-006 (global)3

FISH N = 3222 1 year

1 year

Four pivotal trials (>12,000 patients) that showed 35% reduction in the risk of death established adjuvant Trastuzumab as the SoC for HER2-positive eBC

Failure of 3 trials of shorter Trastuzumab duration The PERSEPHONE trial still unpublished

N %

Age, years <50 50–70 ≥70

132 233 41

33 57 10

Size of primary tumour, cm

T1a: 0.5 T1b: >0.5–1.0 T1c: >1.0–2.0 T2: >2.0–3.0

77

124 169 36

19 31 42 9

Histologic grade I: Well-differentiated II: Moderately differentiated III: Poorly differentiated

44

131 228

11 32 56

Hormone receptor status (ER and/or PR) Positive Negative

272 134

67 33

7-year analysis of APT study: Adjuvant paclitaxel and Herceptin for node-negative, HER2-positive breast cancer

APT: Patients with node-negative small tumors may receive sufficient benefit from Trastuzumab + paclitaxel

Tolaney SM, et al. ASCO 2017 (Abstract 511) Jones SE. Lancet Oncol 2013

Distant recurrence 4 (1%)

BCIRG-006: Despite efficacy improvements with Trastuzumab, 1 in 4 patients still experience recurrence or death after 10-years follow-up

Slamon D, et al. SABCS 2015; abstract S5-04

BCIRG-006: DFS final analysis (10.3 years median follow-up)

74.6%

73.0%

67.9%

0 12 24 36 48 60 72 84 96 108 120 132

DFS

(%)

Time (months)

100

90

80

70

60

50

40

AC-T

AC-TH

TCH Trastuzumab-containing arms

25% have experienced

events at 10 years’ follow up

1 in 4 patients with

HER2-positive eBC will

still experience recurrence or

death despite 1 year of

adjuvant Herceptin +

chemotherapy

ExteNET: Phase III trial of Neratinib in the extended ‘post-adjuvant’ showed 33% reduction in the risk of recurrence

IDFS, invasive disease-free survival; ITT, intent-to-treat. 1. Chan A, et al. Lancet Oncol 2016; 17:367–377; 2. Chan A, et al. ASCO 2015; Abstract 508; Oral presentation.

Neratinib x 1 year 240 mg/day

Placebo x 1 year

HER2-positive eBC with prior adjuvant Trastuzumab

+ chemotherapy (N = 2840)

R* 1:1

ExteNET: Phase III trial of Neratinib in the extended ‘post-adjuvant’ showed 33% reduction in the risk of recurrence

IDFS, invasive disease-free survival; ITT, intent-to-treat. 1. Chan A, et al. Lancet Oncol 2016; 17:367–377; 2. Chan A, et al. ASCO 2015; Abstract 508; Oral presentation.

Neratinib x 1 year 240 mg/day

Placebo x 1 year

HER2-positive eBC with prior adjuvant Tratsuzumab

+ chemotherapy (N = 2840)

R* 1:1

0

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24

IDFS

(%

)

Months after randomisation

Neratinib Placebo

Hormone-receptor positive (n = 1631)

4.2% HR 0.51;

95% CI 0.33–0.77; p = 0.001

97.9%

96.0%

95.4%

91.2%

tpCR

9

5% C

I (%

)

tpCR†

NeoSphere

HT PHT PH PT 0

10

20

30

40

50

60

21.5

39.3

11.2 17.7

Benefit of dual anti-HER2 therapy with Pertuzumab plus Trastuzumab has been demonstrated in 1L mBC and neoadjuvant settings

1. Gianni L, et al. Lancet Oncol 2012; 13:25–32; 2. Schneeweiss A, et al. Ann Oncol 2013; 24:2278–2284.

0 10 20 30 40 50 60 70

0

10

20

30

40

50

60

70

80

90

100

Ove

rall

surv

ival

(%)

∆ 15.7 months

.

Swain SM, et al. N Engl J Med 2015; 372:724–734.

CLEOPATRA

APHINITY: Phase III study to assess Pertuzumab plus Trastuzumab in the adjuvant setting showed 19% reduction in the risk of recurrence

von Minckwitz G, et al. N Engl J Med 2017; 377:122–131.

Chemotherapy* + Trastuzumab + placebo

Chemotherapy* + Trastuzumab + Pertuzumab

Randomisation and treatment within 8 weeks

of surgery

Anti-HER2 therapy for a total of 1 year (52 weeks) (concurrent with start of taxane)

Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy

Central confirmation of HER2 status

(N = 4805)

R

S U R G E R Y

Pertuzumab–Trastuzumab (n = 2400) Placebo–Trastuzumab (n = 2404)

1.0

0.9

0.8

0.7

0.0

Prop

ortio

n ev

ent-

free

0 6 12 18 24 30 36 42 48 Time (months)

93.2% 94.1%

3 years

95.7% 96.4% 98.8%

98.6%

90.6% 92.3%

4 years

1 year 2 years

0.5

0.6

APHINITY: Subgroups with more pronounced benefit

Node-positive subgroup Hormone receptor negative subgroup

von Minckwitz G, et al. N Engl J Med 2017; 377:122–131.

KATHERINE: T-DM1 decreased the risk of recurrence by 50% when compared with Trastuzumab among patients with residual disease after neoadjuvant treatment

Patients that are cured without anti-HER2 treatment

More T1a, T1b being treated

Too much double blockade?

Post-neoadjuvant treatment for those that will not relapse

Are we overtreating?

Attempts to identify biomarkers beyond HER2 Tumor infilitrating lymphocytes (TILs) may be predictive of trastuzumab benefit

Loi S. Ann. Oncol 2014.

Standardized Uptake Value (SUV) may be predictive of pathologic complete response to pertuzumab and trastuzumab

Connoly RM. J Clin Oncol 2019

HER2-positive early-stage breast cancer Take-Home I

T1N0 Surgery

T1N0

> T1N0

Paclitaxel + Trastuzumab

Chemotherapy + Trastuzumab OR

dual HER2-blockade

HER2-positive early-stage breast cancer Take-Home II

> T1N0 Neoadjuvant

chemotherapy + dual HER2-blockade

Continue anti-HER2 Rx

TDM-1

PCR

No PCR

Grato!

jose_bines@yahoo.com

ALLTO study: Trastuzumab + Lapatinib showed no significant increase in PFS

Moreno-Aspitia A. ASCO 2017

Surgery

Completion of all (neo)adjuvant anthracycline-

based chemotherapy

(≥4 cycles)

Design 1 no concurrent

taxane

Design 2

concurrent taxanes

(12 weeks)

Trastuzumab q3w

Lapatinib

Lapatinib

Trastuzumab qw Wash-

out

Lapatinib + Trastuzumab q3w

Ran

do

mis

atio

n

52 weeks

12 weeks 6 weeks 34 weeks*