her2-positive metastatic breast cancer · 1- m v dieci; 186o tumor-infiltrating lymphocytes (tils)...

ESMO PRECEPTORSHIP PROGRAM – BC ZUERICH, 28 JUNE 2019

Evandro de Azambuja, MD, PhD

with the help of Daniel Eiger, Medical Fellow

Institut Jules Bordet, Université Libre de Bruxelles (ULB)

ESMO Council Member

Chair of the Fellowship Committee

HER2-Positive

Metastatic Breast

Cancer

Disclosure information

◆ Honoraria and advisory board from Roche/GNE

◆ Travel grants from Roche/GNE and GSK/Novartis

◆ Research grant from Roche/GNE (my institution)

◆ Research grant from Astra-Zeneca (my institution)

◆ Research grant from GSK/Novartis (my institution)

◆ Research grant from Servier (my institution)

IntroductionLife expectancy from HER2 + ABC diagnosis according to year analyzed - a consistent shift toward better survival

Roth J et al ESMO 2017 Abstract 263P

The management of ABC is complex and, therefore, involvement of all appropriate

specialties in a multidisciplinary team is crucial

Decisions should always take into account patient preferences, values and needs as

essential to optimal cancer care

Time-line of approval of anti-HER2 drugs

1997 1998 … 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

1st mAB trastuzumab

approved for HER2+

ABC

Trastuzumab moves to adjuvant

therapy: node + HER2+ EBC

1st TKI approved for HER2+ ABC: lapatinib

Trastuzumab indication

expanded to adjuvant therapy of

node-negative disease

2nd mAB approved for HER2-dual blockade w/

trastuzumab for metastatic disease:

pertuzumab

T-DM1 is the 1st

ADC approved for

trastuzumab-resistant HER2+

ABC

Neoadjuvant trastuzumab/pertuzumab

Neratinib, a pan-HER TKI, approved for adjuvant use

Dual HER2-blockade w/ trastuzumab/pertuzumab

moves to adjuvant scenario

T-DM1 as post-neoadjuvant

therapy for non-pCR cases

Dual Blockade as First-Line: CLEOPATRA TRIAL

Previously untreated HER2-positive LR/mBC

• Centrally confirmed IHC 3+ or IHC 2+ and FISH/CISH+

• Measurable or evaluable disease• ECOG PS 0/1• No CNS metastases

Trastuzumab (8 mg/kg→6 mg/kg)Docetaxel (75 mg/m2)

Placeboq3w

Trastuzumab (8 mg/kg→6 mg/kg)Docetaxel (75 mg/m2)

Pertuzumab (840→420 mg) q3w

R

Stratification variables

• Prior treatment status (prior adjuvant or neoadjuvant chemotherapy vs none)

• Geographic region (Asia, Europe, North America, or South America)

Baselga J et al, New Engl J Med 2012 Swain SM et al, Lancet Oncol 2013

Swain SM et al, New Engl J Med 2015Swain SM et al, ASCO 2019

Presented By Olwen Hahn at 2019 ASCO Annual Meeting

Dual blockade as 1st line: CLEOPATRA TRIAL

Avoiding ChT w/

trastuzumab/pertuzumab – is it safe?

Annals of Oncology (2019) 30 (suppl_3): iii47-iii64. 10.1093/annonc/mdz100

Annals of Oncology (2019) 30 (suppl_3): iii47-iii64. 10.1093/annonc/mdz100

Monoclonal antibody: trastuzumab

Target expression: HER2

Highly potent chemotherapy

(maytansine derivative)

Cytotoxic agent: DM1

Systemically stableBreaks down in target cancer cell

LinkerT-DM1

Receptor-T-DM1 complex is internalised into HER2-positive cancer cell

Potent antimicrotubule agent is released once inside the HER2-positivetumour cell

T-DM1 binds to the HER2 protein on cancer cells

Courtesy of Martine Piccart

Trastuzumab-DM1(T-DM1)

Trastuzumab-DM1 (T-DM1) as First-Line?

Dual Blockade with Pertuzumab

HER2-positive(Centrally confirmed) ABC, First-line➢ 6 months

from prior (neo)adjuvant taxanes

➢ (N=1,095)

Trastuzumab + Taxane

T-DM1 + Placebo

T-DM1 + Pertuzumab

The MARIANNE Study

Perez EA et al, J Clin Oncol 2016

Trastuzumab-DM1 (T-DM1) as First-Line:

Dual Blockade with Pertuzumab

Perez EA et al, J Clin Oncol 2016

Progression-Free Survival

Trastuzumab-DM1 (T-DM1) as 2nd Line: EMILIA Trial

• Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral

disease

• Primary end points: PFS by independent review, OS, and safety

• Key secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression

1:1

HER2+ (central)

LABC or MBC

(N=980)

• Prior taxane and

trastuzumab

• Progression on

metastatic tx or

within 6 mos of

adjuvant tx

T-DM1

3.6 mg/kg q3w IV

Capecitabine1000 mg/m2 orally bid, days 1–14, q3w

+

Lapatinib 1250 mg/day orally qd

Verma S et al, New Engl J Med 2012

496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0

495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0

Cap + Lap

T-DM1

No. at risk by independent review:

Median (mos) No. events

Cap + Lap 6.4 304

T-DM1 9.6 265

Stratified HR=0.65 (95% CI, 0.55-0.77)

P<0.0001

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Pro

po

rtio

n p

rog

ress

ion

-fre

e

Time (mos)


Progression-Free Survival by Independent Review

Trastuzumab-DM1(T-DM1) as 2nd Line: EMILIA Trial


Overall Survival: 2nd Interim Analysis

Trastuzumab-DM1 (T-DM1) as 2nd Line: EMILIA Trial

Also PFS and OS improvement when used as ≥ 2

lines in the TH3RESA Trial

Investigational treatment optionsTargeting HER2 and beyond New anti-HER2 agents

Margetuximab

Patritumumab

ProliferationInvasivenessMigrationAngiogenesis

DNA

HER-1/EGFR

HER-2

HER-3

HER-4

TK-domainTransmembrane domain

Ligand domain

Growth factor

heterodimerization

Cellular membrane

Cytoplasm

Nucleous

Lymphocyte

Tumor Cell

PD-1

PDL-1 ER

E2

mTO

R<-

AK

T <-

PI3

K

Cyclin

New TKIsAfatinib

NeratinibPyrotinibPoziotinibTucatinib

Bi-antibodiesZW25 (HER2/HER2)

MCLA128 (HER2/HER3) GBR 1302 (CD3/HER2)PRS343 (CD137/HER2)

CDK 4/6 inhibitorsPalbociclib

AbemaciclibRibociclib

PI3K inhibitorsBuparlisibPilaralisibAlpelisibTaselisib

ICBsPembrolizumab

AtezolizumabDurvalumab

ADCsTrastuzumab vc-seco-DUBA

Trastuzumab deruxtecanXMT1522

MM302 (terminated due to futility)MEDI4276

Why Immunotherapy in HER2 + ABC?

◆ Higher TILs, a surrogate marker of immunological activity against the tumor, are associated with better outcomes in HER2 + EBC treated with trastuzumab (ultimately, an immunotherapy itself)1

◆ Immune evasion may play an important role in trastuzumab resistance2

◆ Pre-clinical studies demonstrated improved trastuzumab therapeutic activity with anti-PD13

1- M V Dieci; 186O Tumor-infiltrating lymphocytes (TILs) as an independent prognostic factor for early HER2+ breast cancer patients treated with adjuvant chemotherapy and trastuzumab in the randomized shortHER trial, Annals of Oncology, Volume 29, Issue suppl_8, 1 October 2018, mdy270.183, https://doi.org/10.1093/annonc/mdy270.1832- Vanessa G. Martinez; ONCOIMMUNOLOGY 2017, VOL. 6, NO. 12, e1362530 (10 pages) https://doi.org/10.1080/2162402X.2017.13625303- Stagg J. Anti–ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti–PD-1 or anti-CD137 mAb therapy. Proceedings of the National Academy of Sciences Apr 2011, 201016569; DOI:10.1073/pnas.1016569108

https://doi.org/10.1093/annonc/mdy270.183

https://doi.org/10.1080/2162402X.2017.1362530

PANACEA study design and results

Central testing

HER2 by IHC

Central PD-L1 testing

Non Eligible

Enroll

Non Eligible

PD-L1 -

Phase Ib (dose finding Pembrolizumab in 3+3 design) /Phase II at RP2DTreatment in 3 weeks cycles

Trastuzumab 6 mg/kg q 3 w

Pembrolizumabat R2PD q 3 w

PD or Txor 2y

PD or Txor 2y

ABCPrior progression while

on trastuzumab

S. Loi et al Lancet Oncol 2019

*

* PDL1 negative cohort added later

HER2 -

Phase I: dose escalation with 18 PD-L1 + pts; Pembrolizumab RP2D = 200mg q3w

• ORR: 15% (met primary endpoint)

• DCR at 6 months.: 25%

Phase II: 58 patients enrolled

• ORR: 39%

• DCR at 6 months.: 47%

Subset of PD-L1 + and TILs > 5%:

40 pts

• ORR: 0%Subset of PD-L1 negative: 12 pts

HER2 +

PD-L1 +

PANACEA study results

S. Loi et al Lancet Oncol 2019

KATE-2 study

Trial Design

LA Emens, F Esteva, M Beresford, C Saura, M De Laurentiis, S-B Kim, S-A Im, M Patre, Y Wang, A Mani, H Liu, S de Haas and S LoiDOI: 10.1158/1538-7445.SABCS18-PD3-01 Published February 2019

KATE-2 studyResults – ITT patients

LA Emens, F Esteva, M Beresford, C Saura, M De Laurentiis, S-B Kim, S-A Im, M Patre, Y Wang, A Mani, H Liu, S de Haas and S LoiDOI: 10.1158/1538-7445.SABCS18-PD3-01 Published February 2019

Serious AEs (SAEs): 33% (Atezo) vs. 19% (Placebo)

KATE-2 study

Results – PD-L1 positive patients

LA Emens, F Esteva, M Beresford, C Saura, M De Laurentiis, S-B Kim, S-A Im, M Patre, Y Wang, A Mani, H Liu, S de Haas and S Loi DOI: 10.1158/1538-7445.SABCS18-PD3-01 Published February 2019

New Anti-Body Drug Conjugates

The success of T-DM1 has created a lot of excitement around ADCs

Drug Name Antibody Chemotherapy

SYD- 0985 Trastuzumab Duocarmycin

DS – 8201a Humanized anti-HER2 antibody

Exatecan

MM - 302 Humanized anti-HER2 antibody

Lipossomaldoxorrubicin

XMT - 1522 HT-19 (Humanized anti-HER2 antibody )

Auristatin

1. Barok M. Breast Cancer Res. 2014; 16(2): 209; 2. Dokter W. et al Mol Cancer Ther 2014;13(11):2618–29; 3. Ogitani Y et Al Clin Cancer Res 2016 22 (20) 5097-5108; 4. Espelin CW et al Cancer Res 2016 76(6):1517-27; 5. Bergstrom DA et al AACR Abstract 6716.

Destiny Breast Phase 3

trials designs

Trastuzumab deruxtecan5.4mg/kg IV q21d

T-DM1 3.6mg/kg IV q21d

HER2-positive ABC previously treated w/ trastuzumab + taxane

N = 500

1:1Primary

endpoint:

PFS

Trastuzumab deruxtecan5.4mg/kg IV q21d

Trastuzumab/cape or lapatinib/cape*

HER2-positive ABC previously treated w/

T-DM1N = 600

1:1Primary

endpoint:

PFS

NCT03529110 and NCT03523585 at clinicaltrials.gov

Why target PI3K? ◆ Signaling to PI3K-Akt as a result

of HER2-HER3 dimerization is the most important survival pathway downstream of HER2 1

◆ Resistance to anti-HER2 treatment may arise from persistence or reactivation of PI3K signaling, via mutations on its components 2

◆ Preclinical data suggests that trastuzumab resistance is overcome by PI3K pathway inhibitors 3

3

1- Junttila TT. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. May 5; 2009 15(5):429–40.2- Eichhorn PJA. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. Nov 15; 2008 68(22):9221–30. 3- Chakrabarty A. Trastuzumab-Resistant Cells Rely on a HER2-PI3K-FoxO-Survivin Axis and Are Sensitive to PI3K Inhibitors. Cancer Res. Feb 1; 2013 73(3):1190–200.

Phase I study of alpelisib (BYL-719) and T-DM1 in HER2 + ABC after trastuzumab and taxane therapy

• Phase 1 dose de-escalation

• Alpelisib orally daily plus T-DM1 3.6mg/kgMethods

• MTD and toxicity of alpelisib combined with T-DM1

Primary endpoints

• 17 pts enrolled

• 3 median lines of therapies, 54% previous T-DM1

• MTD: 250mg/day

• AEs: hyperglycemia 53%, fatigue 53%, rash 47%, nausea 35%

Results

Breast Cancer Research and Treatment (2018) 171:371–381 https://doi.org/10.1007/s10549-018-4792-0

Phase I study of alpelisib (BYL-719) and T-DM1 in HER2 + ABC after trastuzumab and taxane therapy

Breast Cancer Research and Treatment (2018) 171:371–381 https://doi.org/10.1007/s10549-018-4792-0

A mouse-human phase I co-clinical trial of

taselisib in combination with T-DM1 in

advanced HER2-positive BC

Journal of Clinical Oncology 36, no. 15_suppl (May 20 2018) 1036-1036.

A mouse-human phase I co-clinical trial of

taselisib in combination with T-DM1 in

advanced HER2-positive BC

Journal of Clinical Oncology 36, no. 15_suppl (May 20 2018) 1036-1036.

• ORR according to T-DM1 (yes 30%, no 36%)

• ORR according to PIK3CA mut status (mut 40%, WT 22%)

• mPFS 7.6 months

CDK 4/6 and anti-HER2 Resistance

Corona SP et al Crit Rev in Oncol/Hematol 2017 112: 208-2014; Goel S et al Cancer Cell 2016 29 (3):255-269

Palbociclib Phase 2 designPATRICIA

N = 225

N = 138

R

Ciruelos E, Villagrasa P, Paré L, Oliveira M, Pernas S, Cortés J, Soberino J, Adamo B, Vazquez S, Martínez N, Perelló A, Bermejo B, Martínez E, Garau I, Melé M, Morales S, Galván P, Pascual T, Canes J, Nuciforo P, Gonzalez X, Prat A. SOLTI-1303 PATRICIA phase II trial (STAGE 1) --Palbociclib and trastuzumab in postmenopausal patients with HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-03

Arm A

Arm B1

Arm B2

PATRICIA stage 1 results

N = 225

N = 138

Ciruelos E, Villagrasa P, Paré L, Oliveira M, Pernas S, Cortés J, Soberino J, Adamo B, Vazquez S, Martínez N, Perelló A, Bermejo B, Martínez E, Garau I, Melé M, Morales S, Galván P, Pascual T, Canes J, Nuciforo P, Gonzalez X, Prat A. SOLTI-1303 PATRICIA phase II trial (STAGE 1) -- Palbociclib and trastuzumab in postmenopausal patients with HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-03

• 45 pts (15 per arm)

• mAge = 59.5y

• N of prior therapies = 3Population

• PFS6R: arm A 33.3%, arm B1 40%, arm B2 53.3%

• Luminal-disease PFS 12.4 months vs non-luminal-disease PFS 4.1 months (p = 0.052)

• 80% G3-4 neutropenia, 17% thrombocytopenia

Results

Investigational treatment optionsNew TKIs: a niche for patients with CNS involvement?

Drug/target Trial name Phase Population Regimen Sample Size

Pyrotinib NCT02973737 Phase 3 Failed up to 2 lines, including taxane/trastuzumab

Pyrotinib + Cape vs Placebo + Cape

279

Neratinib NCT01808573 Phase 3 Failed at least 2 lines of anti-HER2 therapy

Neratinib + Cape vs Lapatinib + cape

621

Tucatinib NCT02614794 Phase 2 Failed at least 2 lines of anti-HER2 therapy (including T and L)

Cape+T+Tucatinibvs Cape+T+placebo

480

Poziotinib NCT02418689 Phase 2 Failed at least 2 lines of anti-HER2 therapy (including T, L, P, T-DM1)

Poziotinib 104

Poziotinib NCT02544997 Phase 2 HER2+ (or EGFR/AR+) failed at least two lines of therapy including useof Anthra and taxane

Poziotinib 30

Poziotinib NCT02659514 Phase 2 Failed at least 2 lines of anti-HER2 therapy (including T and T-DM1)

Poziotinib 70

PHENIX Study Design<br /> Pyrotinib combined with capecitabine in women with HER2+ metastatic breast caNcer prevIously treated with trastuzumab and taXanes: a randomized

phase 3 study<br />

Presented By Zefei Jiang at 2019 ASCO Annual Meeting

• No pts previously pre-treated with T-DM1 or Pertuzumab


• AE profile consistent with the class of TKIs: G3 diarrhea and hand-foot syndrome of 30.8% and 15.7% in experimental arm vs 12.8% and 5.3% in placebo arm, respectively

NALA study design

Presented By Cristina Saura at 2019 ASCO Annual Meeting

• Only ≈ 34% pre-treated with trastuzumab/pertuzumab and afterwards T-DM1

Centrally confirmed PFS (co-primary endpoint)


PFS: Forest plot


• No OS benefit (HR 0.88; p = 0.2086)

Time to intervention for CNS metastases


Most frequent grade 3/4 adverse events


Margetuximab: Fc-engineered to Activate Immune Responses

Presented By Hope Rugo at 2019 ASCO Annual Meeting

Study CP-MGAH22-04 (SOPHIA) Design1,2


ITT Population: Prior Cancer Therapy


PFS Analysis in ITT Population


PFS Subgroup Analyses


AEs Regardless of Causality<br /><br />


Conclusions (I)◆ We walked a long path during the last 15 years.

◆ There is a better understanding of the optimal sequencing in metastatic disease:

◆ So far, more data is needed to safely eliminate ChT in 1° line, although frail patients may benefit from this strategy.

1st line: Trastuzumab + Pertuzumab + Taxane (ChT) →maintenance Trastuzumab + Pertuzumab (± ET)

2nd line: TDM-1

3rd line: Capecitabine + Lapatinib or Lapatinib + Trastuzumab (±AI) or Chemotherapy + Trastuzumab

New treatment options for 3rd and latter lines of therapy are on the rise (special consideration for neratinib and margetuximab).

▪ Newer treatment combinations are eagerly awaited.

1st line: Trastuzumab + Pertuzumab + Taxane (ChT) →maintenance Trastuzumab + Pertuzumab (± ET)

2nd line: TDM-1

3rd line: Capecitabine + Lapatinib or Lapatinib + Trastuzumab (+AI) or Chemotherapy + Trastuzumab

3rd line: Cap + Neratinib or ChT + Margetuximab or lapatinib + trastuzumab (±AI)

Conclusions (II)

Capecitabine+ Neratinib or Lapatinib + Trastuzumab

ChT + margetuxi

mab

ChT + margetuximab

Capecitabine + Neratinib or Lapatinib + Trastuzumab + ET

Acknowledgments

her2-positive metastatic breast cancer · 1- m v dieci; 186o tumor-infiltrating lymphocytes (tils)...

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