6 months versus 12 months of adjuvant
trastuzumab for patients with HER2positive early breast cancer (PHARE): a
randomised phase 3 trial
Speaker: 陳鴻明
Supervisor: 趙大中老師
台北榮民總醫院血液腫瘤科
July 30, 2013
Introduction
• 12-month duration of trastuzumab as adjuvant treatment
versus observation showed a benefit for patients with
HER2-overexpressed early breast cancer in four clinical
trial. N Engl J Med 2005; 353: 1659–72, 353: 1673–84, N Engl J Med 2005; 365: 1273–83.
• In the FinHer trial: trastuzumab for 9 weeks and the
magnitude of benefit seemed similar to the results
observed in the pivotal clinical trials.
• In the HERA trial: potential better efficacy of 2 years of
trastuzumab
N Engl J Med 2006;354:809-820
FinHer study
Docetaxel (100mg/m2) q3w x3 -> F
(600mg/m2) E (60mg/m2) C (600mg/m2)
x3
1010 patients, axillary-node–
positive or N(-) with size >
2cm and PR (-), undergone
breast surgery
Vinorelbine (25mg/m2 on D1, 8, 15 q3w)
x3 -> FEC x 3
N Engl J Med 2006;354:809-820
FinHer study
N Engl J Med 2006;354:809-820
FinHer study
A: Recurrence-free survival : 3
years docetaxel vs.vinorelbine
(91%vs. 86 %t; HR for recurrence
or death, 0.58; 95% CI, 0.40 to
0.85; P = 0.005)
B: OS did not differ between
the groups (P = 0.15).
C: Trastuzumab had better threeyear RFS than without use (89 %
vs. 78%; HR for recurrence or
death, 0.42; 95% CI, 0.21 to 0.83;
P = 0.01).
D: OS (6 vs. 14 patients died;
HR, 0.41; 95% CI, 0.16 to 1.08; P
= 0.07)
N Engl J Med 2006;354:809-820
FinHer study
• Adjuvant treatment with docetaxel, as compared with vinorelbine,
improves recurrence-free survival in women with early breast
cancer.
• A short course (9 weeks) of trastuzumab administered
concomitantly with docetaxel or vinorelbine is effective in women
with breast cancer who have an amplified HER2/neu gene.
N Engl J Med 2006;354:809-820
Final Results of the FinHer Trial
J Clin Oncol 2009;27:5685-5692
Final Results of the FinHer Trial
J Clin Oncol 2009;27:5685-5692
Final Results of the FinHer Trial
• Adjuvant treatment with docetaxel improves DDFS compared with
vinorelbine.
• A brief course of trastuzumab administered concomitantly with
docetaxel is effective
J Clin Oncol 2009;27:5685-5692
HERA Study
One year of trastuzumab (8mg/kg
loading, 6mg/kg q3w)
1694
5081, N(+) or N (-) if tumor >
1 cm, HER2 (+) , completed
locoregional therapy and ≧ 4
cycles of neoadjuvant or
adjuvant chemotherapy
1694
Two years of trastuzumab
1693
Observation
N Engl J Med 2005;353:1659-1672
HERA Study
Unadjusted hazard ratio for an event in
the trastuzumab group, as compared with
the observation group, was 0.54 (95 percent
confidence interval, 0.43 to 0.67; P<0.0001
Overall survival in the two groups was not
significantly different (29 deaths with
trastuzumab vs. 37 with observation).
N Engl J Med 2005;353:1659-1672
HERA Study
• One year of treatment with trastuzumab after adjuvant
chemotherapy significantly reduces the rate of recurrence
(approximately 50 percent for distant recurrence) and
improves disease-free survival among women with HER2positive breast cancer.
• Trastuzumab is effective regardless of the type of
chemotherapeutic regimens received before treatment with
trastuzumab and the extent of nodal involvement.
N Engl J Med 2005;353:1659-1672
Lancet Oncol 2011;12:236-244
HERA Study — 4 years follow up
Lancet Oncol 2011;12:236-244
HERA Study — 4 years follow up
A: 4-year disease-free survival
78・6% versus 72・2%
unadjusted HR was 0・76 (95% CI
0・66–0・87; p<0・0001
B: Overall survival : 89・3%
versus 87・7%, Unadjusted HR
was 0・85 (95% CI 0・70–1・04;
p=0.11)
C: With censoring,
4-year disease-free survival for the
observation group decreased to 71
・7% unadjusted HR was 0・69
(95% CI 0・59–0・79; p<0・
0001)
D: With censoring, overall survival
for the observation group
decreased to 81・5%
unadjusted HR was 0・53 (95% CI
0・44–0・65; p<0・0001)
Lancet Oncol 2011;12:236-244
HERA Study — 4 years follow up
• Adjuvant trastuzumab given sequentially to chemotherapy is
associated with significant and persisting benefits in patients with
HER2-positive early breast cancer.
• The significant disease-free survival benefit is maintained while
the overall survival benefit is no longer significant in intention-totreat analysis, probably because of the effect of trastuzumab and
lapatinib use post-relapse and trastuzumab use before recurrence
in the observation group.
Lancet Oncol 2011;12:236-244
Final analysis of Phase III HERA trial
Confirmed one year of Herceptin treatment
as standard of care in early-stage HER2positive breast cancer
Introduction
• 12 months of adjuvant trastuzumab has been the standard treatment
for patients with HER2-positive early-stage breast cancer.
• However, the optimum duration of treatment has been debated.
• This was a non-inferiority trial of a shorter exposure of 6 months
versus the standard 12 months of trastuzumab for patients with
early breast cancer.
Methods
• Patients
• Women over 18 years of age with invasive early breast
cancer with HER2 overexpression.
• Patients must have received at least 4 cycles of
chemotherapy, had breast-axillary surgery before
randomisation
.
Methods
• Procedures
• One-to-one ratio to receive either 12 months or 6 months of
trastuzumab
• Trastuzumab was administered by intravenous infusions
over 30–90 min every 3 weeks (initial loading dose
8 mg/kg; 6 mg/kg thereafter) in both groups.
• Chemotherapy, hormone therapy, radiation therapy, and
treatment schedules were based on investigator choice.
.
Methods
• Procedures
• After trastuzumab, patients were followed-up by clinical
examination and LVEF every 3 months during the first 2 years and
then every 6 months afterwards.
• Cardiac toxicities:
-- Symptomatic clinical cardiac adverse events,
-- Decrease of the LVEF under 50% (independent from the
baseline value)
-- Absolute drop of LVEF of more than 15% from baseline above
50%, and 10% from baseline with a LVEF below 50%.
.
Methods
• Procedures
• The primary endpoint: disease-free survival, contralateral breast
cancer; second non-breast malignant disease; or death from any
cause.
• Secondary endpoints: cardiac safety, overall survival, and
metastasis-free survival
• The main analyses were done in the intention-to-treat population.
.
Methods
• Statistical analysis
• The null hypothesis: 6 months of trastuzumab treatment is not
inferior to 12-month treatment in terms of disease-free survival.
• The non-inferiority hazard ratio margin of 1·15 was derived from
an estimated absolute difference in 2-year disease-free survival of
2%, based on an expected disease-free survival in the 12-month
group of 85% (initially reported by HERA trial).
• To conclude non-inferiority (ie, reject the null hypothesis), the
upper bound of the 95% CI resulting from the comparison
between the two arms should be less than this prespecified margin.
.
Results
• 2006/5/30 – 2010/7/9, 3384 patients were randomly assigned.
• Median follow-up was 42·5 months
• The mean duration of 12-month trastuzumab treatment was 11·8
months and 6·3 months in the 6-month group.
• The major reasons for this shorter treatment period was cardiac
toxicities
• 2-year disease-free survival was 93·8% (95% CI 92·6–94·9) in the
12-month group and 91·1% (89·7–92·4) in the 6-month group.
• The estimated hazard ratio was 1·28 (95% CI 1·05–1·56)
• Thus we cannot conclude that the 6-month regimen was noninferior to the 12-month schedule (p for non-inferiority=0·29).
Results
• 159 (4·7%) patients died, 66 (3·9%) in the 12-month group and 93
(5·5%) in the 6-month group
• Fewer patients had distant recurrences in the 12-month group than
in the 6-month group (108 [6·4%] vs 141 [8·3%]), hazard ratio
1·33 (95% CI 1·04–1·71).
• The metastasis-free survival in the 12-month group was 95·9%
(95% CI 94·8–96·7) and in the 6-month group was 93·8% (92·5–
94·9).
• Estrogen-receptor-negative + sequential trastuzumab
chemotherapy had significantly different disease-free survival
(hazard ratio 1·57, 95% CI 1·08–2·28).
•175 (10·4%) events in the 12-month group
and 219 (13·0%) in the 6-month group.
•2-year disease-free survival was 93·8%
(95% CI 92·6–94·9) in the 12-month
group and 91·1% (89·7–92·4) in the 6-month
group.
•The estimated hazard ratio was 1·28 (95%
CI 1·05–1·56) in the univariate Cox model
Results
• Serious adverse events were rare (20 [1·2%] in each group).
• Early stopping due to toxicities: 139 (8·2%) vs 38 (2·2%), related
to cardiac events or decreased LVEF:103 (6·1%) vs 32 (1·9%)
• More patients had a cardiac event in the 12-month group (96
[5·7%] vs 32 [1·9%]; p<0·0001).
• More LVEF under 50% in the 12-month group than in the 6-month
group: 106 (6·3%) versus 79 (4·7%) (p=0·04).
• Most events were seen while patients were receiving trastuzumab.
Discussion
• The main characteristics of PHARE patients were similar
to the other reported large prospective
clinical trials, except for a higher proportion of nodenegative disease and small tumour size.
• In PHARE, the overall efficacy results for both groups
combined were favourable.
After a median follow-up of 3·5 years, distant relapses accounted for just under
two-thirds of the events in both groups These rates seem lower than the
proportion found in other randomised trials.
Discussion
• In PHARE, inclusion of patients with a medical history of primary
cancers or other potentially life-threatening diseases--the slightly
greater number of events related to second primary cancers (51
[12·9%] of events) and death from any cause (14 [3·6%] of
events)
• Only 5% of patients had less than 18 months of follow-up;
however, median follow-up is still short, small number of deaths,
the analysis needs longer follow-up.
Discussion
• Randomisation was done while patients were already receiving
trastuzumab---might be one explanation for the low rate of serious
adverse events.
• Rate of cardiac events and decrease under 50% of LVEF were
significantly higher with longer durations of trastuzumab
• 626 patients of oestrogen-receptor-negative tumours with
sequential treatment had the lowest disease-free survival: 89·8%
(95% CI 85·8–92·7) vs 84·5% (80·0–88·1) – The difference
between the 2 groups perhaps contributed to our failure of noninferior result.
Conslusion
• 12 months of adjuvant trastuzumab should remain
the standard of care for women with HER2positive early breast cancer.
Thanks for your attention