Optimal Sequencing in HER2-Positive mBC

Shlomit Strulov Shachar MD

Rambam Health Care Campus

KM

• 56 Y/O

• Postmenopausal

• Married +4

• Lung metastases on chest x-ray done by PCP

• Presented in the ER

• Right breast mass

Imaging

Biopsy

• Invasive ductal carcinoma

• ER positive

• PR negative

• HER 2 -3+

• Ki 67 -25%

How would you treat ?

1. Pertuzumab + Trastuzumab +paclitaxel

2. TDM-1

3. Pertuzumab + Trastuzumab +Vinorelbine

4. Lapatinib + xeloda

5. Letrozole

6. Pertuzumab + Trastuzumab +Letrozole

How would you treat ?

1. Pertuzumab + Trastuzumab +paclitaxel

2. TDM-1

3. Pertuzumab + Trastuzumab +Vinorelbine

4. Lapatinib + xeloda

5. Letrozole

6. Pertuzumab + Trastuzumab +Letrozole

What is the preferred 1st line regimen?

Updated PFS – PERJETA, Herceptin and Docetaxel significantly extend Progression Free Survival (PFS)

•ITT population. Stratified by geographic region and neo/adjuvant chemotherapy. 8

n at risk

0 6 37 87 121 179 284 402

0 6 21 51 75 110 223 406

Ptz + T + D

Pla + T + D

0

0

0

10

20

30

40

50

60

70

80

90

100

PFS

(%

)

0 10 20 30 40 50 80 60

Time (months)

70

Ptz + T + D: median 18.7 months

Pla + T + D: median 12.4 months

Δ 6.3 months

HR 0.68 95% CI = 0.58, 0.80

p < 0.0001

Swain SM, Baselga J, Kim SB, et al: Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724-34, 2015

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

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

•ITT population. Stratified by geographic region and neo/adjuvant chemotherapy.

•CI, confidence interval; Pla, placebo; Ptz, pertuzumab. 9 9

OS

(%)

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 70 60

Time (months)

HR 0.68 95% CI = 0.56, 0.84

p = 0.0002

Ptz + T + D

Pla + T + D

1 28 104 226 268 318 371

0 23 91 179 230 289 350

n at risk

Ptz + T + D

Pla + T + D

402

406

40.8 months

56.5 months

Δ 15.7 months

Swain SM, Baselga J, Kim SB, et al: Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724-34, 2015

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

PERUSE- Efficacy 1L pertuzumab and trastuzumab with taxane therapy in HER2-positive laBC or mBC

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

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 Censored 0

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)

VELVET Cohort 1 Cohort 2

N 106 107

ORR (%) 74.2 (95% CI 63.8–82.9) 63.7 (95% CI 53.0–73.6)

Median PFS (months) 14.3 (95% CI 11.2–17.5) 11.5 (95% CI 10.3–15.8)

After 6 cycles

After 12 cycles-CR

How would you treat?

1. Continue 8 more cycles pertuzumab+trastuzumab+paclitaxel

2. Replace paclitaxel with endocrine therapy

3. Omit paclitaxel and continue pertuzumab+trastuzumab

4. Replace paclitaxel with gemcitabine

After 12 cycles-CR

How would you treat?

1. Continue 8 more cycles pertuzumab+trastuzumab+paclitaxel

2. Replace paclitaxel with endocrine therapy

3. Omit paclitaxel and continue pertuzumab+trastuzumab

4. Replace paclitaxel with gemcitabine

18 months later...

• Imaging:

• Lung metastases +new lesions in the liver

How would you treat ?

No Clinical trial available for second line

1. Lapatinib + capcetibine

2. Trastuzumab + gemcitabine

3. Trastuzumab Emtansine (TDM-1)

4. Pertuzumab + Trastuzumab + vinorelbine

How would you treat ?

No Clinical trial available for second line

1. Lapatinib + capcetibine

2. Trastuzumab + gemcitabine

3. Trastuzumab Emtansine (TDM-1)

4. Pertuzumab + Trastuzumab + navelbine

What is the preferred 2nd line regimen?

Breast Cancer Treatment Goals

Kadcyla Trastuzumab Emtansine (T-DM1)

• T-DM1 is a novel antibody drug-

conjugate

• Trastuzumab linked to DM1, a

microtubule inhibitor up to 400-fold

more potent than paclitaxel

• Average of 3.5 DM1 per antibody.

• T-DM1 binds to HER2 with affinity

similar to trastuzumab

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 daily

Verma 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 iv n = 495

PD

Lapatinib (1250 mg/day, qd po)

+ capecitabine (1000 mg/m2 bid po,

Days 1–14) q3w n = 496

PD

R 1:1

Pro

po

rtio

n p

rogr

ess

ion

-fre

e

Time (months)

Kadcyla improved PFS by 50%

• IRC, independent review committee

• 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.

Median (months)

Lapatinib + capecitabine

6.4

T-DM1 9.6 Stratified HR = 0.65

(95% CI = 0.55, 0.77), p < 0.001

PFS (IRC)

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

0.0

0.2

0.4

0.6

0.8

1.0

No. at risk by independent review: Lapatinib +

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

T-DM1 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0

50% absolute

improvement

Kadcyla Extended median OS to nearly 31 months Significantly extended OS by nearly 6 months

• * 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 30.9 149 Stratified 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

173/397 120/389

Lapatinib + capecitabine

Kadcyla led to a higher ORR and a longer DoR

• * By independent review Verma 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 study ORR* 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 0 T-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

Overview of Adverse Events

aCap + Lap: CAD, multiorgan failure, coma, hydrocephalus, ARDS; aT-DM1: metabolic encephalopathy. bEvaluable pts: 445 (Cap + Lap); 481 (T-DM1).

Cap + Lap (n=488)

T-DM1 (n=490)

All-grade AE, n (%) 477 (97.7) 470 (95.9)

Grade ≥3 AE, n (%)

278 (57.0) 200 (40.8)

AEs leading to treatment discontinuation (for any study drug), n (%)

52 (10.7)

29 (5.9)

AEs leading to death on treatment, n (%)a

5 (1.0) 1 (0.2)

Cardiac dysfunction AEs,a n (%) All grades Grade 3

15 (3.1)

2 (0.4)

9 (1.8) 1 (0.2)

LVEF <50% and ≥15-point decrease from baseline, %

b

7 (1.6)

8 (1.7)

Verma et al, ESMO 2012 Blackwell et al, ASCO 2012

3 months later..

• Partial response

8 months later..

• Tumor progression in the liver

How would you treat ?

1. Lapatinib + capcetibine

2. Trastuzumab + gemcitabine

3. Trastuzumab + vinorelbine

4. Clinical trial

Margetuximab

TUCATINIB

Summary

Systemic therapies for HER2+ advanced BC Standards of care in 2017

Piccart M. SABCs Dec 8-12, SABCS 2015

THANK YOU!