optimal sequencing in her2- positive mbc · optimal sequencing in her2-positive mbc shlomit strulov...
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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!