Transcript 6 months versus 12 months of adjuvant trastuzumab for patients with
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 (-), undergone breast 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
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 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) 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
1694 One year of trastuzumab (8mg/kg loading, 6mg/kg q3w) 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 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
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-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-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 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.