La malattia metastatica La malattia HER2-positiva: strategia ... · Pondé N, et al. Cancer Treat...

La malattia HER2-positiva:

strategia terapeutica nella

pratica clinica e il futuro

G. RICCIARDI

UOC Oncologia Medica,

A.O. Papardo, Messina

Dir. Prof. V. Adamo

[email protected]

Sessione 4:

La malattia metastatica

Outline

HER2+ MBC: where are we now?

Emerging approaches in triple positive MBC

Role of pan-HER inhibitors

Emerging therapeutic strategies in pts with brain metastases

Which new anti-HER2 drugs are coming?

Is there a role for Immunotherapy?

Trastuzumab biosimilars

Final Remarks

Milestone of HER2/anti-HER2

Therapies in BC

Survival with HER2+ Metastatic Disease

Tolaney S, ASCO 2018

What is the optimal regimen in 1st line

regimen?

Pertuzumab-Trastuzumab-Docetaxel

the SOC in 1st line HER2+ MBC

Swain SM, et al. NEJM 2015

“...in patients with HER2-positive

metastatic breast cancer, the addition

of pertuzumab to trastuzumab and

docetaxel, as compared with the

addition of placebo, significantly

increased the median overall

survival to 56.5 months, an

improvement of 15.7 months over

survival in the control group...”

56.5 mos

40.8 mos 15.7 mos

Pertuzumab-Trastuzumab-Docetaxel

in a real world setting

“...There is some concern and debate about whether results obtained in clinical trials can be applied tout court to clinical practice.

(...) The most relevant differences between our population and patients enrolled in the CLEOPATRA trial was the presence of

brain metastases, the prevalence of HR positivity, visceral vs non-visceral pattern of metastasization and the prevalence of

(neo)adjuvant pretreatment with HT and trastuzumab. Importantly, as shown by our survival analyses, these differences did

not seem to affect efficacy. (...) Notably, mPFS was unexpectedly much greater in the RL setting than in the CLEOPATRA trial

(27.8 vs 18.5 months, respectively)...”

De Placido S, et al. Breast 2018

Pertuzumab: Key Clinical

Questions?

What is the efficacy of pertuzumab in trastuzumab – pre-

treated “real life” populations?

Can pertuzumab use be delayed until second line

setting?

Should pertuzumab be given beyond progression?

NO, but an important question to test in clinical

trial(s)

What is the efficacy of pertuzumab in

trastuzumab-pretreated “real life” populations?

Baseline characteristics of patients enrolled in the CLEOPATRA trial

Baselga J, et al. NEJM 2012

Only a minor fraction of patients

enrolled in the CLEOPATRA trial were

previously exposed to Trastuzumab

Are the results of the trial reproducible

in real practice?

Ricciardi GRR & Adamo V, et al. ASCO 2017

Population 35

Median age (range) 50 (20-71)

ECOG PS, median (range) 0 (0-1)

Menopausal Status, n (%)

Pre-menopausal 16 (45.7)

Post-menopausal 19 (54.3)

Surgery, n (%)

Mastectomy 17 (48.6)

Quadrantectomy 18 (51.4)

Lymphadenectomy n (%) 27 (77.1)

Sentinel Node Biopsy n (%) 7 (20)

Subtypes, n (%)

Luminal B 14 (40)

HER2-enriched 21 (60)

Metastatis sites (%)

Lung 20%

Lymph nodes 14.3%

Liver 11.4%

TRASTUZUMAB

Neoadjuvant,n(%) 12(34.3)

Adjuvant,n(%) 28(80)

Median PFS 12 mos

Median FU

55.6 mos

Median OS 15.2 mos

Safety and Efficacy of the combination of Pertuzumab plus Trastuzumab

plus Docetaxel for HER2-positive MBC in pretreated patients with

Trastuzumab in neo/adjuvant setting: a real-life study


Questions?




setting?



trial(s)

Is there a role for Pertuzumab-

Trastuzumab outside of 1st line?

Urruticoechea A, et al. ASCO 2018

Limitations:

H/X not the SOC in 2nd line

Open label design

No statistically-significant improvement in PFS

Benefit in OS, but less than observed in the CLEOPATRA trial (HR 0.76 vs. 0.68)


Questions?




setting?e be delayed until second line setting?



trial(s)

What is the optimal regimen in 2nd and

other lines?

Overview of improvements in OS brought

by anti-HER2 agents in T-pretreated pts

1Cameron D, et al. Oncologist 2010; 2 Geyer CE, et al. NEJM 2006; 3Blackwell KL, et al. JCO 2012; 5Verma S, et al. NEJM 2012; 6 Krop IE, et al.

Lancet Oncol 2014; 7Wildiers H, et al. SABCS 2015.

0 10 20 30

CAPE 14,88

CAPE + LAP 17,25

Cameron D, 2011 [1, 2]

TPC 25,1

T-DM1 30,9 EMILIA [5]

CAPE + LAP 15,8

T-DM1 22,7 TH3RESA [6, 7]

EGF 104900 [3]

LAP

LAP + T

9,5

14,0

T-DM1 vs. capecitabine plus lapatinib previously

treated HER2-positive MBC: the EMILIA trial

Verma S, et al. NEJM 2012; Dieras V, et al. Lancet Oncol 2017

“...T-DM1 significantly prolonged progression-free and overall survival with less

toxicity than lapatinib plus capecitabine in patients with HER2-positive

advanced breast cancer previously treated with trastuzumab and a taxane...”

Questions regarding T-DM1

What is the efficacy of T-DM1 in pertuzumab –

pre-treated “real life” populations?

Should T-DM1 only be used in the second line

setting?

What is the efficacy of T-DM1 in pertuzumab-

pretreated “real life” populations?

Fabi A, et al. Fut Oncol 2017

P + T: mPFS 5.0 months (95% CI: 4.3–5.7);

T only: mPFS 11.0 months (95% CI: 7.8–14.2)

Overall response rate was 33.3% in

patients with prior pertuzumab and

57.1% in the remaining subjects.

Disease control rate was 47 and 43%,

respectively, and clinical benefit rate was

43.3 and 71.1%, respectively.

Median progression-free survival was

5.0 months in patients with prior

pertuzumab and 11.0 months in those

without (hazard ratio: 2.02; 95% CI:

1.14–3.58; p = 0.01).

Patients treated with T-DM1 who

previously received pertuzumab have

poorer clinical outcomes compared

with those receiving a trastuzumab-only-

based regimen in the first-line setting.

Questions regarding T-DM1

What is the efficacy of T-DM1 in pertuzumab –

pre-treated “real life” populations?

Should T-DM1 only be used in the second line

setting?

Is there a role for T-DM1 in 1st line

HER2-positive MBC?

Perez EA, et al. JCO 2017 & ASCO 2017

T-H= T-DM1 = T-DM1 + P

T-DM1 remains the SoC in 2nd

line

Possible option for first line in

pts unsuitable for TPH

What would be the role of T-

DM1 if P (APHINITY trial) will

be moved in the adjuvant

setting in high risk pts?

What is the role of lapatinib in the

pertuzumab/T-DM1 era?

Baez-Vallecillo L, et al. SABCS 2016

Lapatinib remains a therapeutic

option for pts with HER2-positive MBC

despite being previously treated with

multiple anti-HER2 therapies.

≥50% of pts obtained clinical benefit for

over 6 mos with no significant toxicity

Lapatinib shows a partial

lack of cross-resistance

with pertuzumab and T-DM1

thus further emphasizing the

benefit of using beyond the

2nd line setting

1. Of the 34 pts identified as the target cohort with

prior pertuzumab and/or T-DM1 exposure, 29

were available for outcome analysis

2. In the comparison cohort (n= 536) who had

received lapatinib without prior pertuzumab

and/or T-DM1 exposure, 445 pts were

available for outcome analysis

Current advanced HER2-positive

breast cancer treatment guidelines

Pondé N, et al. Cancer Treat Rev 2018

Outline








Final Remarks

25

Johnston S R Clin Cancer Res 2010;16:1979-1987

pTEN cbl

Cross-talk between different signal transduction

is the best studies cause of resistance

Kaufman B, et al. JCO 2009, Johnston S, et al. JCO 2009; Burstein HJ, et al. JCO 2014

TAnDEM EGF30008

Anastrazole

vs.

Anastrazole + Trastuzumab

Letrozole

vs.

Letrozole + Lapatinib

Fulvestrant

vs.

Fulvestrant + Lapatinib

Single Agent HER2 Targeted Therapy

Adds Modestly To Endocrine Therapy

CALGB 40302

mPFS: 4.8 vs. 2.4 mos mPFS: 8.2 vs. 3.0 mos mPFS: 5.9 vs. 3.3 mos

1st line Trastuzumab + AI ± Pertuzumab:

the PERTAIN study

Rimawi M, et al. JCO 2018

Rimawi M, JCO 2018

P + T significantly

improved PFS

compared with

trastuzumab alone

in all population

Among patients who did

not receive induction

chemotherapy: mPFS

was 21.72 mo in the

pertuzumab+

trastuzumab arm and

12.45 mo in the

trastuzumab arm

PERTAIN efficacy results

ALTERNATIVE: efficacy results

“…Dual HER2 blockade with LAP +

TRAS + AI showed superior PFS

benefit versus TRAS + AI in pts with

HER2-positive/HR-positive MBC.This

combination offers an effective and

safe chemotherapy-sparing

alternative treatment regimen for this

pts population…”

Johnston SR, et al. JCO 2018

Study Ph. Design Population n. Arm(s) Objectives

DETECT

V/CHEVENDO III

Randomized,

open-label

1st-3rd line therapy

HER2+/ER+ MBC 270

CHT + T + P

vs.

ET + T + P

AEs (primary);

Quality-adjusted survival,

ORR, OS, PFS (secondary)

CDK4/6 inhibitors in HER2+ BC

Ongoing clinical trials with anti-HER2

agents + ET+ CDK4/6 inhibitors

Study Ph. Design Population n. Arm(s) Objectives

PATINA II Randomized,

open-label

HER2+/ER+ MBC,

prior anti-HER2 +

CHT induction

therapy

496

Palbociclib + T + P + ET

vs.

T + P + ET

PFS (primary);

OS, 3-yr/5-yr OS, ORR,

DOR, CBR, PROs

(secondary)

PATRICIA II Randomized,

open-label

HER2+ MBC, 2-4

prior anti-HER2

therapy lines

138

ER-: T + Palbociclib

ER+: T + Palbociclib ±

Letrozole

PFS (primary);

CBR, ORR, safety

(secondary)

MonarcHER II Randomized,

open-label

HER2+/ER+ MBC,

postmenopausal,

≥2 prior anti-HER2

therapies

225

Abemaciclib + T + Fulvestrant

vs.

Abemaciclib + T

vs.

T + SoC CHT

PFS (primary);

OS, ORR, DOR, CBR

(secondary)

Adapted from Brandao M, et al. Exp Rev Anticancer Ther 2018

Legend: CHT, chemotherapy; T, Trastuzumab; P, Pertuzumab; ET, endocrine therapy.

Outline








Final Remarks

pan-HER inhibitors in HER2-positive MBC

STUDY Phase Drug(s) Population ORR PFS OS

LUX-Breast-1 [1] III

Afatinib + VNB

vs.

VNB + H

HER2+ MBC,

prior

trastuzumab

46.1%

vs.

47.0%

5.5 mos

vs.

5.6 mos

19.6 mos

vs.

28.6 mos

LUX-Breast-3 [2] II

Afatinib

vs.

Afatinib + VNB

vs.

TPC

HER2+ BC with

progressive BMs

prior Trastzumab

and/or Lapatinib

0%*

vs.

8%*

vs.

14%*

2.74 mos

vs.

2.83 mos

vs.

4.23 mos

13.27 mos

vs.

8.58 mps

vs.

11.98 mos

Martin M, 2013 [3] II

Neratinib

vs.

Lap-Cape

HER2+ MBC,

prior

trastuzumab

29%

vs.

41%

4.5 mos

vs.

6.8 mos

19.7 mos

vs.

23.6 mos

Saura C, 2014 [4] I/II Neratinib + Cape

HER2+ MBC,

prior

trastuzumab

and lapatinib

64% (no prior

lapatinib)

57% (prior

lapatinib)

9.27 mos (no

prior lapatinib)

8.26 mos (prior

lapatinib)

N.R.

TBCRC 022 [5] II Neratinib HER2+, BMs 8%* 1.9 mos N.R.

NEfERT-T [6] II

Neratinib-Tax

vs.

H-Tax

HER2+, 1st line

74.8%

vs.

77.6%

12.9 mos

vs. 12.9 mos N.R

1Harbeck N, et al. Lancet Oncol 2016; 2Cortes J, et al. Lancet Oncol 2015; 3Martin M, et al. Eur J Cancer 2013; 4 Saura C, et al. JCO 2014; 5Freedman RA, et al.

JCO 2016; 6 Awada A, et al. JAMA Oncol 2016

* Intracranial ORR

Outline








Final Remarks

CNS tropism

Limited systemic options

In the RegisHER study 37% of pts

with HER2+ BC had brain mts

detected over the study

7% of diagnosis

30% over course of their disease

Worse outcome with presence of

brain mts

median survival 26.3 months

with vs 44.6 months without

Sperduto PW, et al. J Neurooncol. 2013; Brufsky AM, et al. Clin Cancer Res 2011

Brain Metastases from Breast Cancer

HER2-positive Breast Cancer With Brain Metastases in

the era of HER2-targeted therapy

Morikawa A, et al. Clin Breast Cancer 2018

“...Significantly better

survival from BM was

noted for patients with

higher performance status,

fewer BM lesions,

continued use of HER2-

targeted therapy after BM

diagnosis, and better

controlled extracranial

metastatic disease.

…Systemic Treatment

anti-HER2 play an

important role especially in

HER2+ patients: Median

OS from BMs onset can

now exceed 2 years .”

Adapted from Duchnowska R, et al. Cancer Treat Rev 2018

Completed prospective clinical trials of TKIs in HER2+

BC with established brain metastases

Study Phase n previous

CHT/anti-HER2

Previous

WBRT Arm(s)

CNS

ORR

TTP/PFS

(mos)

OS

(mos)

EGF105084 [1] II 237

50 yes/yes 100%

Lapatinib

Lapatinib + Capecitabine

6%

20%

2.4

3.6

6.4

N.R.

LANDSCAPE [2] II 45 yes/no 0% Lapatinib + Capecitabine 66% 5.5 91% at

6 mos

EMILIA [3] III 95* yes/yes 60%

51%

T-DM1

Lapatinib + Capecitabine N.R.

5.6

5.7

26.8

12.9

Shawky et al. [4] II 21 yes/yes 76% Lapatinib + Capecitabine 33% 5.5 11.0

TBCRC [5] II 37 yes/yes 65% Neratinib + Capecitabine 49% 5.5 13.5

LUX-Breast 3 [6] II 121 yes/yes

65%

74%

60%

Afatinib

Afatinib + Vinorelbine

TPC

0%

8%

14%

2.6

2.7

4.1

13

8

12

*Subset analysis

[1] Lin NU, et al. Clin Cancer Res 2009; [2] Bachelot T, et al. Lancet Oncol 2013; [3 ]Krop IE, et al. Ann Oncol 2015; [4] Shawsky H, et al. J Egypt Natl

Cancer Inst 2014; [5] Freedman RA, et al. JCO 2016; [6] Cortes J, et al. Lancet Oncol 2015.

“...The triplet combination of tucatinib, capecitabine, and

trastuzumab demonstrated preliminary activity in pretreated

HER2-positive pts with MBC, including patients previously

treated with pertuzumab, T-DM1 and lapatinib.

The mPFS in pts with brain metastases of 6.7 months was

encouraging when compared with other systemic therapies used

in a similar patient population....”

Murthy R, et al. Lancet Oncol 2018; Borges VF, et al. JAMA Oncol 2018

“...The combination of tucatinib and T-DM1 demonstrated

preliminary activity in pretreated pts with ERBB2/HER2-

positive MBC as reflected by a mPFS of 8.2months

(95%CI, 4.8-10.3 months). The mPFS among pts with

brain metastases was 6.7 months (95% CI, 4.1-10.2

months), which is encouraging compared with other

systemic therapies used to treat a similar pts population...”

Phase II study of Tucatinib vs. Placebo in Combination

with Capecitabine & Trastuzumab in HER2+ MBC

Outline








Final Remarks

New combination strategies in

HER2-positive MBC

Pondé N, et al. Cancer Treat Rev 2018

Antibody-drug conjugates

Tolaney S. ASCO 2018

SYD985: preliminary data from HER2-positive

MBC expansion cohort of the phase 1 study

Saura C, et al. ASCO 2018

FDA granted Fast Track Designation

Novel Anti-HER2 Antibodies: Margetuximab

Novel Anti-HER2 Antibodies: Other

Outline








Final Remarks

The prevalence of somatic mutations

across human cancer types

Alexandrov LB, et al. Nature 2013

Lower median rate of somatic mutations detected compared to most immune

sensitive cancers

HER2+ Breast Cancer are higly infiltrated with T

cells

Quantity is prognostic and TIL biomarker is robust

surrogate

Trastuzumab has know immune MOA

Trastuzumab elicits antitumor immunity producing

antibody-dependent cellular cytotoxicity (ADCC)

Rationale for immunotherapy in HER2-

positive breast cancer

Solinas C, et al. ESMO Open. 2017; Denkert C, et al. Lancet Oncol 2017; Stagg J, et al. Proc Natl Acad Sci U S A. 2011

Pembrolizumab + Trastuzumab in HER2-

positive MBC: the phase I/II PANACEA study

Loi S, et al. SABCS 2017

Higher stromal TILs (sTILs) associated

with better response and disease control

Loi S, et al. SABCS 2017

sTILs ≥5% as potential predictive marker

Outline








Final Remarks

HERITAGE: EFFICACY RESULTS

Rugo HS, et al. ASCO 2018

Outline








Final Remarks

Final Remarks

Pertuzumab and T-DM1 led to improved outcomes with favorable toxicity in 1st and

2nd line HER2+ MBC, respectively, and are the preferred regimens in these settings; However, some important clinical questions (Pertuzumab in T-pretreated pts? Pertuzumab outside 1st line?

T-DM1 in pertzumab-pretreated pts?) are still open.

Endocrine therapy + dual-blockade HER2 therapy is associated with significant

improvement in PFS and can be considered for selected triple positive pts;

In 3rd and later lines of therapy (or where pertuzumab/TDM1 are not available), the

addition of a HER2-directed agent improves outcomes compared to chemotherapy

alone and thus should be continued whenever possible;

Several different agents are under development in HER2-positive MBC, trying to

overcome mechanisms of resistance to currently approved anti-HER2 agents;

For HER2-disease, Immunotherapy development still lagging behind due to effective

anti-HER2 therapies.

The use of T biosimilars may reduce cancer care costs, with similar outcomes and

safety profile to originator T.

Grazie!

La malattia metastatica La malattia HER2-positiva: strategia ... · Pondé N, et al. Cancer Treat...

Documents

Transcript of La malattia metastatica La malattia HER2-positiva: strategia ... · Pondé N, et al. Cancer Treat...