Treatment of Metastatic HER2-positive Breast Cancer

Albert GrinshpunSharett Institute of Oncology

Hadassah-Hebrew University Medical Center

October 2018

Disclosures

• Honoraria:– Roche

– Astra Zeneca

Metastatic HER2+ breast cancer,You know how it starts but you can’t predict

the future…

Two Tikvah(s)…

48 y.o, D+2

No family history

Ashkenazi

Right breast mass + enlarged axillary lymph node

Referred to MRI, systemic evaluation & biopsy

55 y.o, M+7

Mother had BC at 70 y.o.

Ashkenazi

Left breast mass + enlarged axillary lymph node

Referred to MRI, systemic evaluation & biopsy

Biopsy

• Invasive ductal carcinoma (breast & axilla)

• G3

• ER\PR negative

• HER2 +3

• KI67- 50-60%

Which systemic evaluation would you prefer?

1. 18-FDG PET-CT

2. Total body CT

3. Chest x-ray & abdominal US

4. HER2 PET-CT

What is the preferred systemic staging modality?

Imaging results

Will you biopsy the metastasis?

1. Yes

2. No

What will be the 1st line?

1. Pertuzumab + Trastuzumab + Vinorelbine

2. Pertuzumab + Trastuzumab + Paclitaxel (Q7D)

3. Pertuzumab + Trastuzumab + Docetaxel

4. Pertuzumab + Trastuzumab + Paclitaxel (Q21D)

What is the preferred 1st line regimen?

CLEOPATRA Study Design

12

HER2-positive MBCcentrally confirmed

(N = 808)

Placebo + trastuzumab

1:1

Docetaxel*≥ 6 cycles

n = 406

n = 402

Pertuzumab + trastuzumab

Docetaxel*≥ 6 cycles

PD

PD

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

• Randomization stratified by geographic region and neo/adjuvant chemotherapy

• Study dosing q3w:

– Pertuzumab/placebo: 840 mg loading → 420 mg maintenance

– Trastuzumab: 8 mg/kg loading → 6 mg/kg maintenance

– Docetaxel: 75 mg/m2 → 100 mg/m2 escalation if tolerated

Final OS Analysis – Raising the survival standard for HER2+ mBC to 56.5 months

Median follow-up 50 months (range 0–70 months)

1313

OS

(%)

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 7060

Time (months)

HR 0.68 95% CI = 0.56, 0.84

p = 0.0002

Ptz + T + D

Pla + T + D

128104226268318371

02391179230289350

n at risk

Ptz + T + D

Pla + T + D

402

406

40.8 months

56.5months

Δ 15.7 months

•Primary endpoint: Safety, tolerability

•Secondary objectives: PFS, OS, BOR

PERUSE: 1st line Pertuzumab + Trastuzumab + Taxane therapy in metastatic HER2-positive breast cancer

Adapted from T Bachelot, et al. Poster presentation, SABCS 2016

Male or female patients with HER2-positive mBC

(N = 1436)

Pertuzumab + trastuzumab + taxane*

(docetaxel or paclitaxel or nab-paclitaxel)

PERUSE tests the safety and efficacy of pertuzumab and trastuzumab when combined with investigator’s choice of taxane in 1L HER2-positive mBC

Median PFS = 21.2 months in all patients who received at least one dose of study treatment

PERUSE- Efficacy of 1st line Pertuzumab and Trastuzumabwith Taxane therapy

Median follow-up: 17.2 months

Docetaxel 775 751 721 672 603 544 485 439 406 373 327 280 235 204 161 118 87 67 39 18 12 8 3 0

Paclitaxel 589 574 557 524 473 429 395 365 338 315 290 264 222 184 149 124 93 75 41 27 11 1 0 0

Nab-paclitaxel 65 63 60 55 47 43 40 36 34 32 28 27 26 24 23 19 15 10 3 2 1 1 0 0

n at risk

I Censored0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

gre

ssio

n-f

ree

su

rviv

al

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46

Months

ITT population by taxane

Total Censored Events Median (95% CI)

Docetaxel 775 333 (43.0%) 442 19.71 (17.45, 22.87)

Paclitaxel 589 261 (44.3%) 328 24.67 (20.67, 26.25)

Nab-paclitaxel 65 25 (38.5%) 40 18.07 (12.22, 34.23)

Adapted from T Bachelot, et al. Poster presentation, SABCS 2016

Median PFS was 14.3 months (95% CI 11-17.3)

M. Anderson et al, velvet trial, presented as poster at ESMO 2014

M. Anderson et al, velvet trial, presented as poster at ASCO 2015

Two Tikvah(s)…

After 10 months of Paclitaxel, Trastuzumab, PertuzumabNew liver lesions

After 3 months of Paclitaxel, Trastuzumab, PertuzumabComplete response

How would you proceed with patient ?

1. Switch to Vinorelbine, continue Pertuzumab + Trastuzumab

2. Continue current treatment (Pertuzumab + Trastuzumab + Paclitaxel)

3. TDM-1

4. Lapatinib + Capecitabine

How would you proceed with patient ?

1. Stop chemo, continue Pertuzumab + Trastuzumab alone

2. Continue current treatment (Pertuzumab + Trastuzumab + Paclitaxel) indefinitely

3. Continue current treatment (Pertuzumab + Trastuzumab + Paclitaxel) for additional 3 months

4. Stop everything, just follow-up

What is the duration of treatment after reaching complete response?

What is the preferred 2nd line regimen?

EMILIA Study Design

Study endpoints:

• Primary endpoints: PFS (IRC), OS and safety

• Secondary endpoints: included PFS (investigator-assessed), ORR (IRF), DoR and PRO (time to symptom progression)

• DoR, duration of response; IRC, independent review committee; ORR, objective response rate; OS, overall survival;PD, progressive disease; PFS, progression-free survival; po, orally; PRO, patient-reported outcomes;

• q3w: once every 3 weeks; qd, once daily; bid, twice dailyVerma S, et al. N Engl J Med 2012; 367:1783–1791 and Erratum N Engl J Med 2013; 368:2442.

• Verma S, et al. ESMO 2012; Abstract LBA12: oral presentation.

Patients with HER2-positive LABC or mBC

(N = 991) • Prior treatment with trastuzumab and

taxane

• Progression on metastatic treatment during or within 6 months of adjuvant treatment

T-DM1 (3.6 mg/kg) q3w ivn = 495

PD

Lapatinib (1250 mg/day, qd po)

+ capecitabine(1000 mg/m2 bid po,

Days 1–14) q3wn = 496

PD

R1:1

TDM1 extended median OS

• * Efficacy stopping boundary p = 0.0037 or HR = 0.73

• Verma S, et al. N Engl J Med 2012; 367:1783–1791 (supplementary material available with the publication online).

• Erratum, N Engl J Med 2013; 368:2442.

OS (confirmatory analysis)

78.4%

85.2%

64.7%

51.8%

Pro

po

rtio

n s

urv

ivin

g

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

0.0

0.2

0.4

0.6

0.8

1.0

Time (months)

Median (mo) No. events

Lapatinib + capecitabine

25.1 182

T-DM1 30.9 149Stratified HR = 0.68*

(95% CI = 0.55, 0.85); p ≤ 0.001

No. at risk:Lapatinib +

capecitabine 496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4

T-DM1 495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5

Δ~= 6.0 months

Pro

po

rtio

n p

rogr

ess

ion

-fre

e

Median, months (95% CI)

Lapatinib + capecitabine

6.5 (5.5, 7.2)

T-DM1 12.6 (8.4, 20.8)

Difference: 12.7% (95% CI = 6.0, 19.4)p < 0.001

0.0

0.2

0.4

0.6

0.8

1.0

Time (months)

Pat

ien

ts, %

30.8%

43.6%

0

10

20

30

40

50

T-DM1

173/397120/389

Lapatinib + capecitabine

TDM1 led to higher ORR and longer DoR

• * By independent reviewVerma S, et al. N Engl J Med 2012; 367:1783–1791 and Erratum, N Engl J Med 2013; 368:2442.

• Verma S, et al. ESMO 2012; Abstract LBA12: oral presentation.

DoR in the EMILIA studyORR* in the EMILIA study

No. at risk

Lapatinib + capecitabine 120 105 77 48 32 14 9 8 3 3 1 1 0 0 0 0 0 0 0T-DM1 173 159 126 84 65 47 42 33 27 19 12 8 2 0 0 0 0 0 0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

ESO–ESMO International Consensus Guidelines, Annals of Oncology 29: 1634–1657, 2018

The standard first-line therapy for patients previously untreated with anti-HER2 therapy is the combination of ChT + trastuzumab and pertuzumab (Level of Evidence – 1A)

After 1st line trastuzumab-based therapy, T-DM1 provides superior efficacy relative to other HER-2-based therapies in the 2nd line (versus lapatinib+capecitabine) and beyond (versus treatment of physician’s choice). T-DM1 should be preferred in patients who have progressed through at least 1 line of trastuzumab-based therapy, because it provides an OS benefit (Level of Evidence – 1A)

Regarding duration of treatment after reaching complete response

Two Tikvah(s)…

After 4 months of TDM1 2 brain metastases, new bone lesions

Patient refused to treatment (after completing 24 months of TP). Complete response on imaging every 4-6 months.

TDM1 efficacy in brain metastases

EMILIA- OS for Patients with CNS mets at baseline

How would you proceed with patient ?

1. Lapatinib + Capecitabine

2. SRS and switch to Lapatinib + Capecitabine

3. SRS and chemotherapy + Trastuzumab + Pertuzumab

4. Neratinib + Capecitabine

5. Clinical trial

6. NGS test

Tikvah

What is the preferred next line of treatment?

Lapatinib

Neratinib

Phase II trial of Neratinib and Capecitabine for Patients with Human Epidermal Growth Factor Receptor 2-Positive (HER2+) Breast Cancer Brain Metastases

Presented By Rachel Freedman at 2017 ASCO Annual Meeting

Slide 25

Presented By Rachel Freedman at 2017 ASCO Annual Meeting

Tucatinib

Margetuximab

Conclusions

• Variable course

• Rise of oral inhibitors

• Critical lack of biomarkers

– Genes

– Microenvironment

– Microbiome

Thanks!