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:

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:

FinHer study N Engl J Med 2006;354:

FinHer study N Engl J Med 2006;354: 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)

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:

Final Results of the FinHer Trial J Clin Oncol 2009;27:

Final Results of the FinHer Trial J Clin Oncol 2009;27:

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:

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: Two years of trastuzumab

HERA Study N Engl J Med 2005;353: 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< 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:

Lancet Oncol 2011;12:

HERA Study — 4 years follow up Lancet Oncol 2011;12:

HERA Study — 4 years follow up Lancet Oncol 2011;12: 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:

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.

Conslusion 12 months of adjuvant trastuzumab should remain the standard of care for women with HER2- positive early breast cancer.

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