Systemic Therapy of HER2-positive Breast Cancer...Systemic Therapy of HER2-positive Breast Cancer Tanja Cufer, MD, PhD. University Clinic Golnik, Medical Faculty Ljubljana, Slovenia.

Systemic Therapy of HER2-positive Breast Cancer

Tanja Cufer, MD, PhDUniversity Clinic Golnik,

Medical Faculty Ljubljana, Slovenia

ESO ESMO Masterclass, Belgrade 2018

HER2-positive Breast CancerAdjuvant trastuzumab trials: Relative risk reduction of death

00.10.20.30.40.50.60.70.80.9

11

0.66 0.67 0.67

0.41

0.590.66

Rel

ativ

eR

isk

Risk od death

33-59%

HER2-directed therapy is the largest achievements in medical treatment of breast cancer, during the last decade!

HER2 is a molecular driver of approx. 20% of BC. EBC: Uniform efficacy, 30 – 40 % improvement in DFS and OS. MBC: Doubling of overall survival time.

HER2-directed therapy in ABC: Survival rates

Courtesy of M. Piccart

Analysis Year

Expected: 5-year Survival (%)

Expected: Mean Per-Patient Survival

(Months)1995 9.1 26.6

2000 10.9 28.7

2005 14.2 32.6

2010 18.2 37.3

2015 34.0 50.8

Roth J, et al. ESMO 2017.

Adjuvant HER2-directed Therapy

Adjuvant Trastuzumab: Pivotal Phase 3 Trials

Trial Study Design

No. of Patients Treatment Arm

DFSAbsolute valuesHR (95% CI; p)

OSAbsolute valuesHR (95% CI; p)

HERAPiccart-Gebhart M, et al. NEJM 2015 Cameron D, et al. Lancet 2017.

Phase 3

1,698 Observation 11-year DFS: 63.0% 12-year OS: 72.9%

1,703 Sequential trastuzumab 1 yr 11-year DFS: 69.3%0.76 (0.68-0.86; <0.0001)

12-year OS: 79.4%0.74 (0.64-0.86; <0.0001)

1,701 Sequential trastuzumab 2 yrs 11-year DFS: 68.5%0.77 (0.69-0.87; <0.0001)

12-year OS: 79.5%0.72 (0.62-0.83; <0.0001)

NCCTG N9831 and NSABP-B31Perez EA, et al. J Clin Oncol 2014.

Phase 32,018 CT 8-year DFS: 62.0% 8-year OS: 75.2%

2,028 CT +trastuzumab 1 yr

8-year DFS: 73.7%0.60 (0.53-0.68; <0.001

8-year OS: 84.0%0.63 (0.54-0.73; <0.001)

BCIRG 006Slamon DJ, et al. SABCS 2015.

Phase 3

1,073 AC -> T 10-year DFS: 67.9% 10-year OS: 78.7%

1,074 AC -> TH -> trastuzumab 1 yr 10-year DFS: 74.6%0.72 (0.62-0.85; <0.0001)

10-year OS: 85.9%0.63 (0.62-0.79; <0.0001)

1,075 TCH -> trastuzumab 1 yr 10-year DFS: 73.0%0.77 (0.65-0.90; 0.0011)

10-year OS: 83.3%0.76 (0.62-0.93; 0.0075)

FNCLCC-PACS 04Spielmann M, et al. J Clin Oncol 2011.

Phase 3260 Observation 3-year DFS: 77.9% 3-year OS: 96.0%

268 Sequential trastuzumab 1 yr 3-year DFS: 80.9%0.86 ( 0.61-1.22; 0.41)

3-year OS: 95.0%1.27 (0.68-2.38; NS)

Subgroup (no. patients) HR (95% CI)Nodal status

Not assessed (neoadjuvant chemotherapy) (372) 0.66 (0.43, 1.00)Negative (1099) 0.59 (0.39, 0.91)1–3 positive nodes (976) 0.61 (0.43, 0.87)≥4 positive nodes (953) 0.64 (0.49, 0.83)

Hormone receptor statusER negative + PgR negative (1627)ER negative + PgR positive (172)ER positive + PgR negative (460)ER positive + PgR positive (984)

All patients (3401)

Favours observationFavours trastuzumab

0.0 0.5 1.0 1.5

HR

0.63 (0.50, 0.78)0.77 (0.34, 1.74)0.82 (0.50, 1.34)0.63 (0.43, 0.93)

0.64 (0.54, 0.76)

Untch, et al. Ann Oncol 2008.

Trastuzumab is Effective Regardless Nodal and/or HR Status: HERA Trial

Concurrent Trastuzumab Performs Better than Sequential: NCCTG N9831Trial

Perez, et al. Cancer Res 2009.

Benefit of Trastuzumab in Small ≤ 2cm N0 Disease: Meta-Analysis

O’Sullivan C, et al. J Clin Oncol 2015

HR +

HR -

Trastuzumab is recommended for patients with T1c (> 1cm) tumors, while its role in tumors ≤ 1 cm is still debatable.

Only smal number (n=75) pts with T1a/b (≤ 1 cm) included!

No Benefit of Trastuzumab in HER2-low Disease: NSABP B-47 Trial (HER2 IHC 1+/2+ and ISH-negative)

Fehrenbacher L, et al. SBCS 2017.

There is no benefit of adjuvant trastuzumab in HER2-negative disease.

Cardiac Safety of 1 year Adjuvant HER2-directed TherapyTrial Arm Any CHF (%) Any LVEF drop (%)

HERA, de Azambuja, et al. (2014) ChemoChemo T 1y

00.8

0.97.2

NSABP B-31, Romond, et al. (2012) AC PAC PT

1.23.8

NR12.0

NCCTG N9831, Advani, et al. (2016) AC PAC P TAC PT

0.92.63.5

9.616.723.8

BCIRG 006, Slamon, et al. (2015) AC DAC DTDCarboT

0.82.00.4

11.219.19.4

APT, Tolaney, et al. (2015) PT 0.5 3.2

ALLTO, Piccart M, et al. (2016) Chemo T 1yChemo T Lapa 1yChemo T + Lapa 1y

1.0<1.01.0

5.03.05.0

APHINITY, von Von Minckwitz, et al. (2017)

Chemo T 1yChemo T + Pertuz 1y

0.30.7

2.82.7

Risk factors for CHF: low LVEF, age, obesity, hypertension. LVEF is mandatory before initiation of trastuzumab and during treatment.

Escalation and De-escalation of Adjuvant Anti-HER2 Therapy

Adoped from Lambertini M, et al. Expert Rev Cancer Ther 2017.

Non-anthracycline-based CT BCIRG 006: TCH regimen (positive) APT: weekly P + H (positive)

Reducing duration of adjuvant H PHARE: H for 6 months (negative) HORG trial: H for 6 months (negative) SHORT-HER: H for 3 months (negative) PERSEPHONE: H for 6 months (positive) SOLD: H for 9 weeks (on-going)

„CT-free“ regimen ATEMPT: T-DM1 (on-going)

ANTHRACYCLINE AND TAXANE BASED CHEMOTHERAPY WITH TRASTUZUMAB

FOR ONE YEAR

Escalating targeted agents BETH: H + Bevacizumab (negative) ExteNET: H -> neratinib (positive) ALTTO: H -> L or H+L (negative) APHINITY: H + pertuzumab (positive) KAITLIN: T-DM1 + pertuzumab (on-going)

Prolonging duration of adjuvant H HERA: H for 2 years (negative)

Adjuvant treatment if no pCR KATHERINE: T-DM1 (on-going)

ExteNET: 1 year Neratinib after 1 year of Trastuzumab vs 1 year Trastuzumab alone

Chan A, et al. Lancet Oncology 2016.

Positive DFS data persist with longer FU (5-year DFS, Martin M, Lancet Oncol 2017).

OS data are still pending!

Substantial toxicity (40% G3/4 diarrhea) Diarrhea prophylaxis key!

Subsets HR iDFSNode-negative 0.83 (ns)1 – 3+ nodes 0.75 (ns)4+ nodes 0.67*ER+ 0.60*ER- 0.95 (ns)

5yr DFS absolute benefit = 2.5%

APHINITY: 1 year Trastuzumab plus Pertuzumab vs 1 year Trastuzumab plus Placebo

von Minckwitz G, et al. N Engl J Med 2017.

4yr iDFS absolute benefit = 1.7%

Number needed to treat: 112

Expected: 89.2%

Statistically significant, but is it clinically meaningful ?

Δ 2.3%

von Minckwitz G et al. N Engl J Med 2017.

Δ 3.2%

Node-positive Subgroup

HR-negative Subgroup

Δ 2.3%

APHINITY: 1 year Trastuzumab plus Pertuzumab vs 1 year Trastuzumab plus Placebo

De-escalating HER2-directed Adjuvant Therapy

Trial Study Design

No. of patients

Treatment Arm

DFSAbsolute ValuesHR (95% CI; p)

OSAbsolute ValuesHR (95% CI; p)

Non-anthracycline- based Cht

BCIRG 006Slamon DJ, et al. SABCS, 2015.

Phase 3 1,073 AC -> T 10-year DFS: 67.9%

10-year OS: 78.7%

1,074 AC -> TH -> Trastuzumab for 1 year

10-year DFS: 74.6% 0.72 (0.62-0.85; <0.0001)

10-year OS: 85.9% 0.63 (0.51-0.79; <0.0001)

1,075 TCH -> Trastuzumab for 1 year

10-year DFS: 73.0% 0.65 (0.65-0.90; <0.0011)

10-year OS: 83.3%0.76 (0.62-0.93; <0.0075)

APTTolaney SM, et al. N Engl J Med 2015;ASCO 2017, Abstr 511

Phase 2(T1/2 N0)

406 Weekly paclitaxel x 12 + Trastuzumabfor 1 year

7-year iDFS: 93.3%

7-year OS: 95.0%

No significant difference in DFS or OS between Trastuzumab arm; hiowever, trails was not powered to detect equivalence.

De-escalating HER2-directed Adjuvant Therapy

TrialNo. of

patients Treatment ArmDFSAbsolute ValuesHR (95% CI; p)

OSAbsolute ValuesHR (95% CI; p)

Cardiac Events Shorter vs Longer Trastuzumab

Shorter duration of adjuvant Trastuzumab

PHARE Phase 3Pivot X, et al. Lancet Oncol 2013.

1690 CT + trastuzumab for 1 year 2-year DFS: 93.8% NR 5.7%

1690 CT + trastuzumab for 6 months 2-year DFS: 91.1% 1.28 (1.05-1.56; 0.29)

NR1.46 (1.06-2.01; 0.03)

1.9%

HORG Phase 3Mavroudis D, et al. Ann Oncol2015.

241 ddFEC -> ddDocetaxel + trastuzumab for 1 year

3-year DFS: 95.7% NR 2 cases

240 ddFEC -> ddDocetaxel + trastuzumab for 6 months

3-year DFS: 93.3% 1.57 (0.86-2.10; 0.137)

NR1.45 (0.57-3.67; 0.438

0 cases

Short-HER Phase 3Conte PF, et al., ASCO 2017, Abstr 501.

627 CT + trastuzumab for 1 year 5-year DFS: 87.5.% NR 16%

626 CT + trastuzumab for 9 weeks 5-year DFS: 85.4% 1.15 (0.91-1.46; ns)

NR 6%

PERSEPHONE Phase 3Earl H, et al. ASCO 2018, Abstr 506

2045 CT + trastuzumab for 1 year 4-year DFS: 89.8% NR 12%

2043 CT + trastuzumab for 6 months 4-year DFS: 89.4%1.07 (0.93-1.24; 0.01)

NR 9%

PERSEPHONE and SHORT-HER Subgroups AnalysisSHORT-HER: Subgroups for which 6 m might be non-inferior

Earl H, et al ASCO 2018, Abstr 506; Conte PF, et al. ASCO 2017, Abstr 501.

PERSEPHONE: Subgroups for which 12 m might be superior

ER-

Taxane

Stage I, II

N0-1

Neoadjuvant Cht

Concomitant T

Shorter trastuzumab treatment duration might be equally effective in low stage, ER + disease.

However, in all other scenarios 1 year of trastzumab remains the gold standard!

Take Home Messages: Adjuvant HER2-directed Therapy

1 year of trastuzumab remains standard in adjuvant therapy of HER2-positive EBC.

A dual HER2 blockade with pertuzumab or extended neratinib might be considered in specific populations, higher risk HER2-positive patients, i.e. patients multiple-node positive disease or ER+ disease, respectively.

Shorter duration of trastuzumab may be considered in selected, low risk patients who can not tolerate 12 months of therapy.

Anthracycline based Cht followed by taxane with concurrent trastuzumab or TCH are proposed regimens.

Trastuzumab plus paclitaxel seems to be appropriate therapy patients with T1/2 N0, disease.

Additional biomarkers to identify HER2-positive patients suitable for escalation or de-escalation of adjuvant therapy are urgently needed.

HER2- directed Therapy for Advanced Breast Cancer (ABC)

Cardoso F, et al The Breast 2011.

HER2+ Advanced Breast Cancer: Currents Standards of Care in 2018

Adopted from Piccart M , SABC Symposium 2017; Cardoso F, et al. Ann Oncol 2016.

First line Second line* Later lines** . . . .

Pertuzumab Lapatinib

Trastuzumab

Lapatinib

TrastuzumabTrastuzumab

Taxane Vinorelbine CapecitabineTDM1

Superior to trastuzumab + docetaxel

(CLEOPATRA)

Superior to capecitabine + lapatinib

(EMILIA) or to physicians choice

(TH3RESA)

Pertuzumab

Capecitabine

Trastuzumab

Superior to lapatinib alone (EGF 104900)

Superior to lapatinib plus capecitabine

(MA.31)

If patients relapse ≤ 12 mos start as first line; ** Combination of trstuzumab plus either capecitabine, eribulin, gemciatbine, platinum agents or metronomic Cht might be used as well as per ABC3!

Swain S, et al. NEJM 2015.

CLEOPATRA: First-line Trastuzumab and Docetaxel +/-Pertuzumab in HER2+ MBC

Pertuzumab + trastuzumab+docetaxel

Placebo + trastuzumab+docetaxel

Hazard ratio P-value

ORR1 80.2% 69.3% 0.0001

PFS2 18.7 months 12.4 months 0.68 <0.0001

OS2 56.5 months 40.8 months 0.66 0.0001

Long term cardiac safety maintained, with favorable LVEF and CHF in experimental arm !

Verma S, et al. NEJM 2012.

13www.esmo2012.org

Progression-Free Survival by Independent Review

496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0

Cap + LapT-DM1

No. at risk by independent review:

Median (months)

No. of events

Cap + Lap 6.4 304T-DM1 9.6 265Stratified HR=0.650 (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

Prop

ortio

n pr

ogre

ssio

n-fr

ee

Time (months)

Unstratified HR=0.66 (P<0.0001). 16www.esmo2012.org

Overall Survival: Confirmatory Analysis

496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5

Cap + LapT-DM1

No. at risk: Time (months)

78.4% 64.7%

51.8%

85.2%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 360.0

0.2

0.4

0.6

0.8

1.0

Prop

ortio

n su

rviv

ing

Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).

Median (months) No. of eventsCap + Lap 25.1 182T-DM1 30.9 149Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006

Efficacy stopping boundary P=0.0037 or HR=0.727

T-DM1 Lapatinib + capecitabine Hazard ratio P-valuePFS 9.6 months 4.6 months 0.65 <0.001OS 30.9 months 25.1 months 0.68 <0.001

EMILIA: T-DM1 vs Lapatinib Plus Capecitabine in HER+ MBC

HER2+ Advanced Breast Cancer: Standards of Care for “Triple Positive “ Disease in 2018

First line Second line Later lines . . . .

Pertuzumab Lapatinib

Trastuzumab

Lapatinib

TrastuzumabTrastuzumab

EndocrineTherapy

EndocrineTherapy

VinorelbineTDM1

Superior to trastuzumab + ET

(PERTAIN); Induction Cht in 57%

Superior to lapatinib or trastuzumab + ET

(ALTERNATIVE)

Trastuzumab

Adopted from Piccart M, SABC Symposium 2017. Cardoso F, et al. Ann Oncol 2016.

Superior to lapatinib alone (EGF 104900)

• Trials comparing HER2 plus ET vs HER2 plus Cht in ABC are ongoing (Detect V, CHEVENDO, PERNETTA,…)• Despite absence of EBD, HER2 plus ET might be considered as maintenance therapy as per ABC3.

Trial Treatment arm No. ptsMedian

PFS(months)

Overall Response Rate (ORR)

Overall Survival (months)

First-line setting PERTAIN*Arpino G et al., SABCS 2016.

AI + Trastuzumab +/-

Pertuzumab**

258 15.8

18.9*

56%

63%

NR

Second-line settingALTERNATIVEGradishar WJ et al., ASCO 2017, Abstr1004.

AI + TrastuzumabAI + Lapatinib

AI + Trastuzumab + Lapatinib

355 5.78.3

11.0*

14%19%32%*

NR

HER2- directed plus ET in First-line Therapy of HR+/HER2+, ”Triple positive” MBC

Gradishar WJ, et al. ASCO 2017, Abstr 1004.

Dual HER2 blockade plus ET performs better than mono HER2 plus ET; however; therefore, it is a reasonable option in selected HR+/HER2+ patients, used as induction or as maintenance therapy.

* PERTAIN: Induction Cht in 57%.

Treatment of CNS Metastases in HER2+ MBC

Trastuzumab Improves Survival in Patients with CNS Disease: Retrospective Analysis

Kirsch DG, et al. JCO 2005

OS (ITT population)

Surv

ival

(%

)

Time from randomisation (months)Subjects at riskLap + CapTras + Cap

271 194 129 79 48 27 7269 207 140 97 61 29 6 1

Lap + Cap (N=271) Tras + Cap (N=269)

Median OS, months 22.7 27.3

Hazard ratio (95% CI) 1.34 (0.95, 1.90)

Stratified log-rank p-value 0.095

Early closure!

Low number of brain metastses

Trastuzumab + capecitabinebetter OS

CEREBEL: Capecitabine plus Lapatinib or Trastuzumab in HER2+ MBC without CNS mets

Lapatinib + capecitabine

(N=251)Trastuzumab + capecitabine

(N=250)OR

(95% CI) P-value

CNS at first site of relapse, n (%) 8 (3) 12 (5) 0.65(0.26-1.63) 0.360

Incidence of CNS progression at any time, n (%) 17 (7) 15 (6) 1.14(0.52-2.51) 0.8646

Time to first CNS progression, median (range) 5.7 (2-27) 4.4 (2-27) - -

Pivot X, et al. J Clin Oncol 2015.

Efficacy of Pertuzumab + Trastuzumab and of T-DM1 in CNS metastases

0

10

20

30

40

50

60

70

80

90

100

Time (months)

Prog

ress

ion-

free

pro

babi

lity

(%)

0 5 10 15 20 25 30 35 40

11.9 15.0

Pertuzumab, trastuzumab, docetaxel Trastuzumab, docetaxel, placebo

HR 0.5895% CI 0.39, 0.85

p = 0.0049

No. at risk 0PHT 016101727425455

0HT 0034616284551

45

Median time to progression, CNS as first site of progression

Patients without prior chemotherapy or biologic therapy for HER2-positive MBC were included; patients with evidence of CNS metastases were excluded

Swain S, et al. Ann Oncol 2014. Krop I, et al. Ann Oncol 2015.

Post-hoc Analyses of CLEOPATRA, EMILIA

Novel Treatment Strategies for HER2+ Breast Cancer in Clinical Research

New predictive markers for better tailoring of HER2-directed therapy are urgently needed! So far, we only have additional prognostic markers (HER2 mRNA, PIK3CA, TIL), while HER2

status remains the only predictive biomarker, after decades of research in HER2+ breast cancer! At least we should take into consideration that triple positive breast cancer is a distinctive subtype!

New HER2-directed AgentsNew anti-HER TKIs (tucatinib, poziotinib)Antibody Drug Conjugates (ADCs)New anti-HER AntibodiesBi-specific Antibodies

New CombinationsAnti-HER2 + mTOR InhibitorsAnti-HER2 + PI3K InhibitorsAnti-HER2 + CDK 4/6 InhibitorsAnti-HER2 + PD-1/PD-L1 Inhibitors

Trastuzumab plus pertuzumab plus taxane represents the standard first-line therapy for ABC pts, not receiving previous HER2-directed therapy. When pertuzumab is not given (available) trastuzumab plus taxane or

vinorelbine should be given in first-line setting! T-DM1 represents the standard second-line therapy in ABC pts receiving

previous HER2-directed therapy. T-DM1 can be considered as alternative to trastuzumab/taxane combination

in the first-line setting, mainly for patients with short DFI (< 12 mos) after neo-/adjuvant HER2-directed therapy. For later lines of therapy trastuzumab plus Cht, lapatinib plus capecitabine

or trastuzumab plus lapatinib remain viable options.

Take Home Messages: HER2-directed Therapy of ABC

For selected “triple positive”, especially elderly patients with a low burden of disease, a combination of ET and dual HER2-directed therapy with trastuzumab plus pertuzumab in first-line or with trastuzumab plus lapatinib in second-line can be considered, as upfront or as maintenance therapy. Optimal duration of HER2-directed therapy in ABC patients achieving CR is

not yet known. Stopping HER-2 therapy might considered if re-challenge is available in case of progression. Patients with CNS disease benefit from HER2-directed therapy: trastuzumab

plus capecitabine, trastuzumab plus pertuzumab plus taxane or T-DM1 are viable options. Intrathecal trastuzumab might be considered in patients with leptomeningeal

disease (Zagouri, et al. BCRT 2013.).

Take Home Messages: HER2-directed Therapy of ABC