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
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6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive 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. - PowerPoint PPT PresentationTRANSCRIPT
6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive 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
1010 patients, axillary-node–positive or N(-) with size > 2cm and PR (-), undergonebreast surgery
Docetaxel (100mg/m2) q3w x3 -> F (600mg/m2) E (60mg/m2) C (600mg/m2) x 3
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
N Engl J Med 2006;354:809-820
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 betweenthe groups (P = 0.15). C: Trastuzumab had better three-year 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)
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
5081, N(+) or N (-) if tumor > 1 cm, HER2 (+) , completed locoregional therapy and ≧ 4 cycles of neoadjuvant or adjuvant chemotherapy
One year of trastuzumab (8mg/kg loading, 6mg/kg q3w)
Observation
N Engl J Med 2005;353:1659-1672
Two years of trastuzumab
1694
1694
1693
HERA Study
N Engl J Med 2005;353:1659-1672
Unadjusted hazard ratio for an event inthe trastuzumab group, as compared with the observation group, was 0.54 (95 percentconfidence 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).
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 HER2-
positive 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
Lancet Oncol 2011;12:236-244
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)
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-to-
treat 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 HER2-positive 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 non-
inferior 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-monthgroup 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 node-
negative 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 non-
inferior result.
Conslusion
• 12 months of adjuvant trastuzumab should remain the standard of care for women with HER2-positive early breast cancer.
Thanks for your attention