seoul national university hospital tae-yong kim

Recent insight into clinic in HER2+mBC

Seoul National University HospitalTae-Yong Kim

*Disclaimer : All the contents in the presentation is owned by the speaker and does not necessarily represent the views and opinions of Roche Korea. It may contain therapies currently under clinical development for the purpose of scientific discussion and the company does not recommend any off-label uses. Physicians should refer to the approved PI before prescription.

Case# Breast cancers/p wide excision, lt (2004.12.22.) patho) IDCa, sup. T2N0M0, E/P/H +/+/-s/p RTx ( 2005. 2. 7 ~ 4. 1 ) s/p FAC #6 (750-75-750) 2005. 4. 8 ~ 2005. 8. 11. s/p tamoxifen (2005.9.15. - 2010.9) s/p letrozole (2010.9.28 - 2015.9)

<RFS 11Y6M> F/U BS(16.6.30): R/O bone meta in T8 liver CT(16.7.11): Multiple low attenuated nodular lesions in both lobe of the liver more likely, hepatic metastasis. * liver Bx: c/w metastatic carcinoma from breast, E/P/H (90%/2%/3+), ki-67 2%

Case

What would you like to choose the followings?

Taxane+trastzumab+pertuzumab

Taxane+trastuzuamb

Trastuzumab+anastrozole

1

2

3

CLEOPATRA

Docetaxel (≥ 6 cycles recommended)Trastuzumabplacebo

R

• Centrally confirmed HER2-positive locally recurrent, unresectable or MBC

• ≤ 1 hormonal regimen for MBC• Prior (neo)adjuvant

systemic Rx, including trastuzumab and/or taxane allowed if followed by DFS ≥ 12 mos

• Baseline LVEF ≥ 50%; no CHF

Docetaxel (≥ 6 cycles recommended)Trastuzumabpertuzumab

N = 406

N = 402

Primary endpoint: Independently assessed PFS

Baselga J, et al. N Engl J Med. 2012;366:109-119.

Study Design

CLEOPATRA

Overall survival Subgroup analysis

Swain SM, et al., N Engl J Med. 2015;372(8):724-34

DHP HP

56.5 months 40.8 months

The addition of pertuzumab to HP improved mOS

CLEOPATRA

Subgroup analysis


DHP HP

18.7 months 12.4 months

DHP also improved PFS, compared with HP

PFS

Brief summary of CLEOPATRA

• Pertuzumab+trastuzumab+docetaxel• significantly prolonged PFS and OS• showed the efficacy independent of subgroups• could been established as standard treatment


Case

1. Normal LV cavity size and mildly decreased systolic

function; Visually EF : 48%

2. No regional wall motion abnormality

3. Normal LV wall thickness

4. Normal valves

5. No intracardiac mass, thrombi or pericardial effusion

Echocardiography

Criteria for cardiac functions in pivotal trials

Trial Eligible criteria for cardiac fuction

Slamon DJ et al. Not described

CELOPATRA A left ventricular ejection fraction of 50% or more at baseline

EMILIA A left ventricular ejection fraction of 50% or more

TH3RESA A left ventricular ejection fraction (LVEF) of 50% or higher

EGF100151 A left ventricular ejection fraction (LVEF) within the institution’s normal range

Slamon DJ et al., N Engl J Med, 2001;344(11)Swain SM, et al., N Engl J Med. 2015;372(8):724-34Verma S, et al., N Engl J Med. 2012;367(19):1783-91Krop IE et al., Lancet Oncol. 2014;15(7):689-99Geyer C, et al. N Engl J Med 2006;355:2733-2743.

Case

What would you like to choose the followings?

Taxane+trastzumab+pertuzumab

Taxane+trastuzuamb

Taxane

Aromatase inhibitor +/- CDK4/6i

1

2

3

4

Consultation to cardiologist5

Cardiac AEs from CLEOPATRA

Cardiac disorders (NCI-CTCAE v3.0, grades 1–5)

Swain SM, et al. Oncologist 2013; 18:257–264.

Placebo+DH Pertuzumab+DH

All grade cardiac AEs 16.4% (n=65) 14.5% (n=59)

≥Gr3 cardiac AE 3.8% (n=15) 1.5% (n=6)



Mean LVEF over time.



LVSD (grading according to NCI-CTCAE v3.0)

aAll symptomatic LVSD events (n11) were reported as LVSD grade3. However, there were five patients with LVSD grade 3 (placebo arm: n=4; pertuzumab arm: n=1) that was not deemed to be symptomatic by the investigator.bAssessment of NCI-CTCAE grade was missing for one patient.Abbreviations: LVSD, left ventricular systolic dysfunction; NCI-CTCAE, National Cancer Institute common terminology criteria for adverse events



• Prior anthracycline exposure : HR, 2.21; 95% CI, 1.27 to 3.86; p.0053)• prior radiotherapy : HR, 2.43; 95% CI, 1.37 to 4.31; p.0025

Comparison of risk factors between patients who developed symptomatic LVSD and the overall patient population

MANTICORE 101–Breast

Perindopril 2mg dailyN=33• HER2+ EBC

• 18 years• Stage I-IIIA• planned adjuvant

treatment with trastuzumab

R Bisoprolol 2.5mg dailyN=31

Placebo dailyN=30

Pituskin E. et al., J Clin Oncol 2016;35:870-877.

double-blinded, placebo-controlled trial,

The primary objective was cardiac remodeling expressed as the change in indexed left ventricular end diastolic volume (LVEDVi) on cardiac MRI from baseline to completion of trastuzumab therapy

MANTICORE 101–Breast

Pituskin E. et al., J Clin Oncol 2016;35:870-877.

Abbreviations: LVEDVi, indexed left ventricular end diastolic volume; LVEF, left ventricular LV MASSi, indexed left ventricular mass.

Perindopril and bisoprolol protected against cancer therapy–related declines in LVEF; however, not trastuzumab-mediated left ventricular remodeling (the primary outcome)

Case

I’m very concerned about the additional toxicity of pertuzumabExplain the additional toxicity of

pertuzumab in detail

Safety of pertuzumab

59Y/FRt. Breast Ca with M/axilla, liver, bone at the time of diagnosisPathology) IDCa, E/P/H (2%/-/3+)Adequate cardiac function

Safety of pertuzumab: Diarrhea

Factors Comments

Incidence • All grade: 46-72.4% in DHP• Gr3-4: 6-11.8% in DHP

Comparison of trastuzumab alone(in the CLEOPATRA)

When? • During cycle 1 of treatment and decreasing in subsequent cycles

• In the CLEOPATRA trial, the first episode occurred 8 days after receiving their first treatment.

Prevention Loperamide and opiates are the most commonly used agents


All grade 184/397 (46.3%) 272/407 (66.8%)

Gr 3-4 20/397 (5.0%) 32/407 (7.9%)

Baselga J, et al. N Engl J Med. 2012;366:109-119.Gao J, et al., Expert Opin Drug Saf. 2016;15(6):853-63.

Safety of pertuzumab: NeutropeniaFactors Comments

Incidence • All grade: 50-53% in DHP• Gr3-4: 45-49% in DHP

Comparison of trastuzumab(in the CLEOPATRA)

Neutropenia Placebo+DH Pertuzumab+DH

All grade 49.6% 52.8%

Gr 3-4 45.8% 48.9%

Febrileneutropenia


Gr 3-4 7.6% 13.8%


Safety of pertuzumab: Skin

Factors Comments

Comparison of trastuzumab alone(in the CLEOPATRA)

When? • The median time to onset: 20 days after first treatment• Median duration: 96 days

Management • steroids used for rash• antibiotics for nail disorders• antihistamines for pruritus

In addition to breast and cardiac cells, HER2 is also expressed in keratinocytes.

Rash Placebo+DH Pertuzumab+DH

All grade 24.2% 33.7%

Gr 3-4 Not reported Not reported


Safety of pertuzumab: Skin

Acneiform (papulopustular) rash (grade 1) on the face (a) and chest (b) of patients on pertuzumab

Drucker AM et al. Breast Cancer Res Treat. 2012;135(2):347-54.

Safety of pertuzumab: pregnancy


Studies in monkeys • pertuzumab can cause oligohydramnios,

delayed kidney development, and even death.• classified as a category D drug • contraception recommended while taking

pertuzumab is highly advised.

Major AEs for dual anti-HER2 agents

Meta-analysis from 9 clinical trials containing dual anti-HER2 therapy

Hao S et al, Oncotarget. 2017 Feb 10.

Case

45Y/F Rt. breast cancer pathology) IDC, NG/HG 3/III, E/P/H(-/-/2+) FISH(+)(6.31)

I don’t want hair loss. I’m not sure I can

stand toxicity.

Case

Anti-HER2 targeted therapy without chemotherapy

Anti-HER2 therapy without chemotherapyNeoALTTO NeoSphere

Trastuzumab+docetaxel

Pertuzumab+trastuzumab+docetaxel

Pertuzumab+trastuzumab

Pertuzumab+docetaxel

Lapatinib

Trastuzumab

Trastuzumab+lapatinib

Baselga J et al., Lancet. 2012;379(9816):633-40Gianni L, et al. Lancet Oncol. 2012;13:25-32.

Disclaimer : All the contents in the presentation is owned by the speaker and does not necessarily represent the views and opinions of Roche Korea. It may contain therapies currently under clinical development for the purpose of scientific discussion and the company does not recommend any off-label uses. Physicians should refer to the approved PI before prescription.

EGF104900

patients with ErbB2-positive MBC who had

experienced progression on prior trastuzumab-

based therapy

RTrastuzumab

Lapatinib

Lapatinib

a phase III, randomized, multicenter, open-label study

Lapatinib in combination with trastuzumab significantly improved PFS versus lapatinib alone in previously heavily treated patients

* Disclaimer : All the contents in the presentation is owned by the speaker and does not necessarily represent the views and opinions of Roche Korea. It may contain therapies currently under clinical development for the purpose of scientific discussion and the company does not recommend any off-label uses. Physicians should refer to the approved PI before prescription.

* Blackwell KL. et al, J Clin Oncol. 2010 Mar 1;28(7):1124-30.

T-DM1 and pertuzumab

synergistic reduction of cell viability antitumor activity of T-DM1 and pertuzumab in xenograft model

Enhanced anti-tumor effect in combination of T-DM1 with pertuzumab in preclinical models

Phillips GD et al., Clin Cancer Res. 2014;20(2):456-68.

* Disclaimer : All the contents in the presentation is owned by the speaker and does not necessarily represent the views and opinions of Roche Korea. It may contain therapies currently under clinical development for the purpose of scientific discussion and the company does not recommend any off-label uses. Physicians should refer to the approved PI before prescription.

MARIANNE

Trastuzumab+docetaxelTrastuzumab+paclitaxel

RN=1095

• HER2+ LABC or MBC• No prior chemotherapy for

LABC/MBC• >6 months from prior neo-

/adjuvant chemotherapy

T-DM1+placebo

Study Design

T-DM1+pertuzumab

• Primary end point: PFS by independent review facility, non-inferiority and superiority• Secondary end point: OS, PFS by investigator, ORR, safety, pt-reported outcomes

Perez EA, et al., J Clin Oncol. 2017;35(2):141-148


MARIANNE: safety and ORRORR

Perez EA, et al., J Clin Oncol. 2017;35(2):141-148


PFS

Anti-HER2 therapy without chemotherapy

Case

• 47/F• LABC, cT2(3.9cm)N1M0 E/P/H (-/-/3+)s/p AC#4DH#4s/p MRM with SLNBx Final pathology: T1(1.2cm)N0M0s/p herceptin#5-18

• 4M after completion of last herceptin, palpable lt. SCN• Bx: metastatic Ca, from breast, E/P/H (-/-/3+)s/p lapatinib+capecitabine #18 PR after #3PD after #18 (lt. SCN, lt. IMN, pleura)s/p navelbine #3 PD(lt. SCN)

Strategies of anti-HER2 therapy

Taxane+trastuzumab

Taxane+Trastuzumab+Pertuzumab(CLEOPATRA)

T-DM1+pertuzumab(MARIANNE)

T-DM1(MARIANNE)

T-DM1(EMILIA)

Lapatinib+Capecitabine(EGF100151)


* Off label shown in dotted line and red background

GBG26/BIG03-05

Patients with HER-2–positive

breast cancer that progresses during

treatment with trastuzumab

International, intergroup, open-label, phase III

von Minckwitz G., et al., J Clin Oncol. 2009;27(12):1999-2006.

RTrastuzumabCapecitabine

Capecitabine

Primary endpoint: Time to progression

Trastuzumab+Cape Cape HR; P-value

PFS(months) 8.2 5.6 0.69; P=0.0338

RR 48.1% 27.0% 2.50; P=0.0115

DCR 75.3% 54.1% 2.59; P=0.0068

Brief summaryContinuation of trastuzumab plus capecitabineA significant improvement in overall response and time to progression compared with capecitabine alone.


EGF104900

Blackwell KL. et al, J Clin Oncol. 2010 Mar 1;28(7):1124-30.

patients with ErbB2-positive MBC who had

experienced progression on prior trastuzumab-

based therapy

RTrastuzumab

Lapatinib

Lapatinib

a phase III, randomized, multicenter, open-label study

Lapatinib in combination with trastuzumab significantly improved PFS versus lapatinib alone in previously heavily treated patients



Taxane+trastuzumab



T-DM1(MARIANNE)

T-DM1(EMILIA)


Capecitabine+Trastuzumab

(GBG26/BIG03-05)

Lapatinib+Trastuzumab(EGF104900)



TH3RESA

Krop IE et al., Lancet Oncol. 2014;15(7):689-99.

RN=602

• HER2+ MBC• ≥prior 2 HER2-directed

therapies (trastuzumab and lapatinib) in the advanced setting

• Taxane in any setting

T-DM13.6mg/kg iv every 3 weeks

TPC• Chemotherapy• Endocrine therapy• HER2-directed therapy

404

198

A randomised, multicentre, openlabel, phase 3 trial

• The co-primary endpoints: investigator-assessed PFS and OS in the intention-to-treat population

• The secondary endpoints: ORR, duration of objective response, 6-month survival, 1-year survival and safety

TH3RESA

PFS

Krop IE et al., Lancet Oncol. 2014 Jun;15(7):689-99.

OS

TPC(n=198)

T-DM1(n=404)

PFS 3.3 mos 6.2mos

HR 0.528 (95% CI 0.422-0.661)P<0.0001

TPC(n=198)

T-DM1(n=404)

OS 14.9 mos NE

HR 0.552 (95% CI 0.369-0.826)P=0.0034

TH3RESA

Krop IE et al., Lancet Oncol. 2014 Jun;15(7):689-99.

Brief summary• T-DM1 significantly improved PFS compared with TPC in patients

who previously received trastuzumab and lapatinib• Trastuzumab emtansine should be considered as a new standard

T-DM1 showed consistent efficacy even in patients who received TPC containing trastuzuamb


Taxane+trastuzumab



T-DM1(MARIANNE)

T-DM1(EMILIA)


Capecitabine+Trastuzumab

(GBG26/BIG03-05)

Lapatinib+Trastuzumab(EGF104900)



T-DM1(TH3RESA)

I read articles related to palbociclib in the newspaper. And I’d like to receive it

• 59 year-old patient• mBC with liver meta at diagnosis• IDCa with E/P/H 80%/5%/3+s/p docetaxel+trastuzumab #24 (trastuzumab after #13)s/p T-DM1#15s/p FEC#6s/p lapatinib+capecitabine #12 PD in lung

1 YES

2No, palbociclib has been approved in only HR+ and HER- BC

3Um, I’m going to looking for clinical trials

Key characteristics of CDK inhibitors

Sherr CJ, et al., Discov. 2015 Dec 11.

Summary of CDK4/6 inhibitors

Trial Treatment patients PFS OS

PALOMA-2 Letrozole+palbociclib vs. letorozole

• HR+/HER- 24.8 mo vs. 14.5 mo, HR 0.58 (95% CI 0.46-0.72) P<0.001

Immature at the time of analysis

PALOMA-3 Fulvestrant+palbociclib vs.

• HR+/HER-• Prior one-line

9.2 mo vs. 3.8 moHR 0.42 (95% CI 0.32-0.56) p<0.01

NE vs. 3.7 moHR 0.27 (95% CI 0.16-0.46) p<0.001

MONALEESA-2 Letrozole + Ribociclib vs. letrozole

• HR+/HER-• not received

previous sys-temic therapy

NE vs. 14.7 moHR 0.56 (95% CI 0.43-0.72) p<0.0001

Not mature at the time of the interim analysis

Finn RS, et al., N Engl J Med. 2016;375(20):1925-1936Turner NC, et al., N Engl J Med 2015; 373: 1672-1673Hortobagyi GN, et al., N Engl J Med. 2016;375(18):1738-1748.

CDK pathway and HER2

Corona SP, et al., Crit Rev Oncol Hematol. 2017;112:208-214.

Inter-communication between CyclinD1-CDK4/6 and HER2

Intrinsic subtype and CDK4/6 inhibitor

luminal

HER2 amplified

Nonluminal/EMTnonluminal

Finn, R.S., et al., Breast Cancer Res. 2009;11(5), R77.

Palbociclib can inhibit growth of luminal ER-positive as well as HER2-amplified breast cancer cell lines

CDK4/6 inhibitor in HER2+ BC

Palbociclib+trastuzumabPalbociclib alonetrastuzumab alone

Combinations of palbociclib plus trastuzumab showed synergistic effect in HER2- amplified breast cancer cells.

Finn, R.S., et al., Breast Cancer Res. 2009;11(5), R77.

MDA EFM 192A


CDK4/6 inhibition has potent cytostatic effect in HER2-positive models

PD-0332991 also had potent cell cycle inhibitory activityin lapatinib-resistant cell lines

Witkiewicz AK, et al., Genes Cancer. 2014;5(7-8):261-72.


Witkiewicz AK, et al., Genes Cancer. 2014;5(7-8):261-72.

CDK4/6 has additive activity with HER2/EGFR kinase inhibitors


The Cyclin D1-CDK4 Axis Mediates Resistance to HER2-Targeted Therapy

IC50 of lapatinib or trastuzumab highly increased in HER2+ BC cell lines overexpressing CCDN1

Goel, S., et al., Cancer Cell 2016;29(3): 255–269.


The Effects of Combined CDK4/6- HER2 Inhibition on Cellular Viability, Proliferation, and Apoptosis

Goel, S., et al., Cancer Cell 2016;29(3): 255–269.

Clinical trials for CDK4/6i+anti-HER2 therapy in HER2+ mBC

• Palbociclib can inhibit growth of luminal ER-positive as well as HER2-amplified breast cancer cell lines.

• Combinations of palbociclib plus trastuzumab showed synergistic effect in HER2-amplified breast cancer cells.

• CDK4/6 inhibition has potent cytostatic effect in HER2-positive models.

I read articles like this.


I read articles like this.


1 YES

2No, immune checkpoint has not been yet approved in HER2+ mBC

3Um, I’m going to looking for clinical trials

Target and immune checkpoint

Márquez-Rodas I et al. Ann Transl Med. 2015 Oct;3(18):267

Immune therapy in mBCKEYNOTE-012

Previously heavily treated pts with PD-L1(+) TNBC

• RR: 18.5%• the median time to response: 17.9

weeks (range, 7.3 to 32.4 weeks)

TIL in the CELOPATRA

No association b/w sTIL and PFS. Significant association with longer overall survival in terms of sTIL

PFS OS

Higher TIL values are significantly associated with improved overall survival

Luen SJ, et al., Lancet Oncol. 2017;18(1):52-62.

Immune therapy in HER2+BC

I-O and trastuzumab in preclinical model

Anti–ErbB-2 mAb Therapy Synergizes with Anti–PD-1 mAb

H2N113 tumor cells (5 × 105 cells) were injected s.c. into BALB/c mice and treated with 50 μg anti–ErbB-2 mAb (clone 7.16.4)

Vanneman M, et al., Nat Rev Cancer 2012; 12: 237-251.Stagg J, et al. Proc Natl Acad Sci U S A 2011; 108: 7142-7147.

Immune therapy in HER2+BC T-DM1 renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade

Percentage of stromalTILs in human breast cancerbefore and after T-DM1

Müller P et al., Sci Transl Med. 2015;7(315):315ra188

Anti-HER2+CD3 bispecific mAb

HER2-BsAb was effective against HER2+ xenografts

Junttila TT et al., CancerRes. 2014;74(19):5561-71.

Lopez-Albaitero A et al., Oncoimmunology. 2017;6(3)

Anti-HER2+CD3 bispecific mAb

Breast cancer HCC-1954-resistant to anti-HER2 agents

HER2-BsAb-mediated cytotoxicity against HER2+ cell lines that were resistant to other HER2-targeted therapies

Lopez-Albaitero A et al., Oncoimmunology. 2017;6(3)

Clinical trials for I-O plus anti-HER2 therapy in HER2+ mBC

• sTIL could be associated with prognosis in HER2+ BC like TNBC • Trastuzumab can prime anti-tumor CTLs and boost NK cell.• Anti–ErbB-2 mAb Therapy can synergize with Anti–PD-1.• T-DM1 can make HER2+ BC highly susceptible to anti-PD-1

blockade.• Anti-HER2 plus CD3 bispecific mAb can boost T-cell activity and

improve the efficacy of anti-HER2 agents by cell immunity

HER2+ mBC could be good candidate in immune therapy. Anti-HER2 therapy combined with I-O can be one of treatment options in anti-HER2 refractory BC

Summary of guidelines in HER2+ mBC

Taxane+Trastuzumab+Pertuzumab

ASCOguideline

NCCNguideline

T-DM1

ET+trastuzumab

Lapatinib+capecitabine

Taxane+Trastuzumab+Pertuzumab

T-DM1T+P±carboT+docetaxelT+chemo

Lapatinib+capecitabineTrastuzumab+capecitabine

Trastuzumab+lapatinibTrastuzumab+other agents


* Off label shown in grey letter

Selection of anti-HER2 agents

Adjuvant trastuzumab

1Y

6Mo 12Mo0

ASCO guideline

T-DM1

Korean regulation

End of last administration of

trastuzuamb

T-DM1

DHP

DHP

Recurrence 0-12m

Summary

Cardiac toxicity of anti-HER2 therapy• Pertuzumab in addition to DH did not increase cardiac toxicity• ACE-I or beta blocker can help reduce cardiac toxicity of anti-HER2 therapy

Additional toxicity of pertuzumab• Diarrhea, febrile neutropenia and skin rash are more frequently observed

in combination of pertuzumab than in DH alone• Appropriate prophylaxis should be needed to prevent the additional

toxicity of pertuzumab

Anti-HER2 targeted therapy without chemotherapy• Dual anti-HER2 targeted therapy without chemotherapy showed

comparable results with target+chemotherapy.• However, Anti-HER2 targeted therapy without chemotherapy as first-line

has not been yet approved.

Summary

Treatment beyond trastuzumab (±pertuzumab)• T-DM1 or lapatinib+capecitabine are recommended as appropriate

treatment after trastuzumab (±pertuzumab)

Anti-HER2 targeted therapy combined with other targeted agents• CDK4/6 inhibitor or immune checkpoint inhibitor showed promising results

in preclinical studies.• However, further studies should be warranted to introduce real practice.

seoul national university hospital tae-yong kim

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