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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

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.

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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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  1. 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

  2. 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

  3. N Engl J Med 2006;354:809-820

  4. FinHer study Docetaxel (100mg/m2) q3w x3 -> F (600mg/m2) E (60mg/m2) C (600mg/m2) x 3 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

  5. FinHer study N Engl J Med 2006;354:809-820

  6. 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

  7. 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

  8. Final Results of the FinHer Trial J Clin Oncol 2009;27:5685-5692

  9. Final Results of the FinHer Trial J Clin Oncol 2009;27:5685-5692

  10. Final Results of the FinHer Trial • Adjuvant treatment with docetaxel improves DDFS compared with vinorelbine. • A brief course oftrastuzumab administered concomitantly with docetaxel is effective J Clin Oncol 2009;27:5685-5692

  11. 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 cyclesof neoadjuvant or adjuvant chemotherapy 1694 Two years of trastuzumab 1693 Observation N Engl J Med 2005;353:1659-1672

  12. 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

  13. 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

  14. Lancet Oncol 2011;12:236-244

  15. HERA Study — 4 years follow up Lancet Oncol 2011;12:236-244

  16. 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

  17. 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

  18. Final analysis of Phase III HERA trial Confirmed one year of Herceptin treatment as standard of care in early-stage HER2-positive breast cancer

  19. Introduction • 12 months of adjuvant trastuzumab has been the standard treatment for patients withHER2-positive early-stage breast cancer. • However, the optimum duration of treatment has been debated. • This was anon-inferiority trial of a shorter exposure of 6 months versus the standard 12 months of trastuzumab for patients with early breast cancer.

  20. 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 .

  21. Methods • Procedures • One-to-one ratio to receive either12 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. .

  22. 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%. .

  23. 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. .

  24. 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. .

  25. 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).

  26. Results • 159 (4·7%) patients died, 66 (3·9%) in the 12-monthgroup and 93 (5·5%) in the 6-month group • Fewer patients had distant recurrences inthe 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). • Themetastasis-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 significantlydifferent disease-free survival (hazard ratio 1·57, 95% CI 1·08–2·28).

  27. 175 (10·4%) events in the 12-month group and219 (13·0%) in the 6-month group. • 2-year disease-freesurvival 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

  28. 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.

  29. 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.

  30. 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.

  31. 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.

  32. 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.

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

  34. Thanks for your attention

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