1. TRAIN-2 (BOOG ): Phase III Trial of Neoadjuvant Chemotherapy ± Anthracyclines With Dual HER2 Blockade in HER2+ EBC
CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois
*Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals
EBC, early breast cancer.
This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

2. Neoadjuvant CT ± Anthracyclines With Dual HER2 Blockade in HER2+ EBC: Background
For pts with HER2+ breast cancer:
Neoadjuvant treatment with dual HER2 blockade increases pCR rates[1,2]
TCH, an anthracycline-free option with a single HER2 inhibitor,[3] is available though treatment duration (18 wks) is shorter than standard sequential therapy (24 wks)
Substitution of weekly paclitaxel and an extended treatment duration may be beneficial[4-6]
Lack of comparative data on dual HER2 blockade ± anthracyclines in neoadjuvant setting
Current analysis designed to compare safety, efficacy of anthracycline- containing vs anthracycline-free regimens of the same duration with dual HER2 blockade in pts with stage II-III HER2+ breast cancer[7]
EBC, early breast cancer; pCR, pathologic CR; TCH, docetaxel/carboplatin/trastuzumab.
References:
1. Gianni L, et al. Lancet Oncol. 2012;13:25-32.
2. Baselga J, et al. Lancet. 2012;379:
3. Slamon D, et al. N Engl J Med. 2011;365:
4. Sparano JA, et al. N Engl J Med. 2008;358:
5. van Ramshorst MS, et al. Eur J Cancer. 2017;74:47-54.
6. von Minckwitz G, et al. Breast Cancer Res Treat. 2011;125:
7. van Ramshorst MS, et al. ASCO Abstract 507.
Slide credit: clinicaloptions.com
References in slidenotes.

3. Surgery + adjuvant therapy‡
TRAIN-2: Study Design
Multicenter, randomized phase III study in the Netherlands
Primary endpoint: pCR (ypT0/is, ypN0) by local assessment
Secondary endpoints: RFS, BCSS, OS, toxicity
Stratified by cT (0-2 vs 3-4), cN (neg vs pos), ER (neg vs pos), and age (< 50 vs ≥ 50 yrs)
PTC* + Pertuzumab Q3W
(n = 219)
Treatment-naive pts with HER2-positive, stage II-III breast cancer and LVEF ≥ 50%
(N = 438)
9 cycles
Surgery + adjuvant therapy‡
FEC-T † +
Pertuzumab Q3W (n = 219)
PTC* +
Pertuzumab Q3W
(n = 219)
3 cycles
6 cycles
AUC, area under the concentration curve; BCSS, breast cancer-specific survival; ER, estrogen receptor; FEC-T, 5-fluorouracil/epirubicin/cyclophosphamide/trastuzumab; LVEF, left ventricular ejection fraction; pCR, pathologic CR; PTC, paclitaxel/trastuzumab/carboplatin; RFS, recurrence-free survival.
*21-day cycles: PTC + pertuzumab Day 1, P Day 8; paclitaxel 80 mg/m2, carboplatin AUC 6 mg.min/mL.
†21-day cycles. 5-fluorouracil 500 mg/m2, epirubicin 90 mg/m2, cyclophosphamide 500 mg/m2.
Trastuzumab 6 mg/kg with 8-mg/kg loading dose, pertuzumab 420 mg with 840-mg loading dose.
‡To complete 1 yr of adjuvant trastuzumab; endocrine therapy for ER+ and/or PgR+ tumors.
Slide credit: clinicaloptions.com
van Ramshorst MS, et al. ASCO Abstract 507.

4. TRAIN-2: Baseline Characteristics
FEC-T +
Pertuzumab
(n = 219)
PTC +
Median age,
yrs (range)
49 (25-73)
48 (22-75)
Clinical T-stage, n (%)
cT0-2
cT3-4
148 (68)
71 (32)
154 (70)
65 (30)
Clinical N-stage, n (%)
cN negative
cN positive
83 (38)
136 (62)
76 (35)
143 (65)
Disease stage, n (%) II
III
141 (64)*
78 (36)
151 (69)†
68 (31)
Characteristic,
n (%)
FEC-T +
Pertuzumab
(n = 219)
PTC +
HR status
ER- and PgR-
ER+ and/or PgR+
90 (41)
129 (59)
93 (42)
126 (58)
Tumor grade 1 2 3
Unknown
7 (3)
102 (46)
17 (8)
12 (5)
99 (45)
94 (42)
14 (6)
FEC-T, 5-fluorouracil/epirubicin/cyclophosphamide + trastuzumab; PTC, paclitaxel/trastuzumab/carboplatin.
*Includes 1 pt with stage IV disease.
†Includes 1 pt with stage I disease.
Slide credit: clinicaloptions.com
van Ramshorst MS, et al. ASCO Abstract 507.

5. TRAIN-2: Treatment Exposure
FEC-T + Pertuzumab (n = 219)
PTC + Pertuzumab (n = 219)
Median number of cycles (range)
9 (3-9)
9 (1-9)
Reason for treatment d/c, n (%)
AEs
Patient decision
Other
31 (14)
5 (2)
4 (2)*
26 (12)
7 (3)
4 (2)
*Death due to pulmonary embolism, n = 1.
AE, adverse event; FEC-T, 5-fluorouracil/epirubicin/cyclophosphamide + trastuzumab; PTC, paclitaxel/trastuzumab/carboplatin.
Slide credit: clinicaloptions.com
van Ramshorst MS, et al. ASCO Abstract 507.

6. P value for interaction .32
TRAIN-2: pCR
100
P = .51
FEC-T + Pertuzumab
P = .75
PTC + Pertuzumab
89%
84% 80
67%
68%
P = .61
55% 60
51%
pCR rate (ypT0/is, ypN0), % 40 20
FEC-T, 5-fluorouracil/epirubicin/cyclophosphamide + trastuzumab; pCR, pathologic CR; PTC, paclitaxel/trastuzumab/carboplatin
All Pts
ER- and PgR-
ER+ and/or PgR+
P value for interaction .32
Slide credit: clinicaloptions.com
van Ramshorst MS, et al. ASCO Abstract 507. Reproduced with permission.

7. TRAIN-2: pCR Subgroup Analysis
FEC-T+Ptz
PTC+Ptz
Characteristic
FEC-T + Pertuzumab
PTC + Pertuzumab n
pCR, %
All pts
212 67
206 68
ER+ and/or PgR+
ER- and PgR-
125 87 51 89
116 90 55 84
< 50 yrs
≥ 50 yrs 96 65
110 71
cT0-2
cT3-4
142 70 64
145 61
cN negative
cN positive 80
132 75
131 72 66 II
III
135 77 69
1-2 3 99 62
101 91
Favors FEC-T+Ptz
Favors PTC+Ptz
OR (95%CI)
1.07 ( )
1.17 ( )
0.71 ( )
1.14 ( )
1.00 ( )
1.03 ( )
1.14 ( )
0.86 ( )
1.20 ( )
1.08 ( )
1.03 ( )
1.13 ( )
1.03 ( )
ER, estrogen receptor; FEC-T, 5-fluorouracil/epirubicin/cyclophosphamide + trastuzumab; pCR, pathologic CR; PTC, paclitaxel/trastuzumab/carboplatin; Ptz, pertuzumab.
0.2 1 5
Slide credit: clinicaloptions.com
van Ramshorst MS, et al. ASCO Abstract 507. Reproduced with permission.

8. TRAIN-2: Adverse Events
Grade ≥ 3 AEs, %
FEC-T + Pertuzumab (n = 220)*
PTC + Pertuzumab (n = 218)
P Value
Grade 3
Grade 4
Hematologic
Neutropenia
Anemia
Thrombocytopenia
Febrile neutropenia 41 20 14 10 18
< 1 3 47 21 16 1 6
.34
.91
.71
< .0001
Nonhematologic AEs occurring in ≥ 5% of pts in either arm
Diarrhea
Peripheral neuropathy†
Hypokalemia
Fatigue
Increased ALT 12 5 8 17 7 4
.14
.56
.02
.67
.49
AEs, adverse events; ALT, alanine aminotransferase; FEC-T, 5-fluorouracil/epirubicin/cyclophosphamide + trastuzumab; PTC, paclitaxel/trastuzumab/carboplatin.
*Developed acute myeloid leukemia, n = 1.
†Grade 2 neuropathy occurred in 25% of pts in FEC-T + pertuzumab arm vs 24% of pts in PTC + pertuzumab arm (P = .92).
Slide credit: clinicaloptions.com
van Ramshorst MS, et al. ASCO Abstract 507.

9. TRAIN-2: Cardiac Safety
Cardiac Outcome
FEC-T + Pertuzumab (n = 220)
PTC + Pertuzumab (n = 218)
P Value
Ejection fraction decrease, %
LVEF decrease ≥ 10% or LVEF < 50%
LVEF decrease ≥ 10% and LVEF < 50% 29 5 17 3
.003
.32
Other grade ≥ 2 cardiac AEs, n
Symptomatic LV systolic dysfunction
Myocardial infarction
Acute coronary syndrome
Arrhythmias 2 1
FEC-T, 5-fluorouracil/epirubicin/cyclophosphamide + trastuzumab; LV, left ventricular; LVEF, left ventricular ejection fraction; PTC, paclitaxel/trastuzumab/carboplatin
Slide credit: clinicaloptions.com
van Ramshorst MS, et al. ASCO Abstract 507.

10. TRAIN-2: Conclusions
In treatment-naive pts with stage II-III HER2+ EBC, efficacy of neoadjuvant anthracycline-containing vs anthracycline-free regimens with dual HER2 blockade comparable
Study did not meet primary endpoint, but pCR rates high (67% to 68%) regardless of treatment arm
Long-term follow-up needed to assess survival
Febrile neutropenia, LVEF decline significantly reduced with anthracycline-free PTC regimen
Study investigators conclude that anthracycline-free regimens may offer treatment alternatives for HER2+ EBC in neoadjuvant setting
EBC, early breast cancer; LVEF, left ventricular ejection fraction; pCR, pathologic CR; PTC, paclitaxel/trastuzumab/carboplatin
Slide credit: clinicaloptions.com
van Ramshorst MS, et al. ASCO Abstract 507.

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