This is the text extract for Appendix Three: Trastuzumab (Herceptin) Clinical Trial Summaries, browse documents here.

---

Appendix Three: Trastuzumab (Herceptin) Clinical Trial Summaries

Sequential treatment trials, long duration (12 month)1 regimens HERA Trial N9831 (Arm B)

Patient Numbers Observation: 1,693 Trastuzumab (1 yr): 1,694 1 Trastuzumab (2 yr): 1,694 1 loading dose (8mg/kg) trastuzumab, then 6mg/kg every 3 weeks for one year or two years (17 or 35 infusions, respectively). Observation: 979 Trastuzumab: 985

Concurrent treatment trials, long duration (12 month) regimens N9831 (Arm BCIRG0062 B31 C)

Observation: 979 Trastuzumab: 840 Observation: 1,073 Trastuzumab: 1,074 Observation: 1,024 Trastuzumab: 1,019

Concurrent treatment trials with short duration regimens FinHer Trial

Observation: (116) vinorelbine – 58 docetaxel – 58 Trastuzumab: (116) docetaxel - 54 vinorelbine - 62 9 trastuzumab infusions at 1 week intervals. First dose 4mg/kg (90min infusion), remaining doses 2mg/kg (30 min infusion) Short duration : 115 patients Long duration: 112 patients

E21983

Intervention

1 loading dose (4mg/kg) trastuzumab, then 2mg/kg every week for 52 weeks

1 loading dose (4mg/kg) trastuzumab, then 2mg/kg every week for 52 weeks

1 loading dose (4mg/kg) trastuzumab, then 2mg/kg every week for 52 weeks

1 loading dose (4mg/kg) trastuzumab, then 2mg/kg every week for 52 weeks

Short duration: 10 trastuzumab infusions at 1 week intervals. Trastuzumab given in combination with paclitaxel– Loading dose 4mg/kg followed by 9 weeks 2mg/kg Long duration: As above but with further 52 weeks of trastuzumab at 2mg/kg per week.

Timing of treatment

Sequential (after completion of all chemotherapy – anthracycline 4 5 chemotherapy and taxane treatment )

Concurrent with taxane (paclitaxel), after completion of anthracycline chemotherapy

Concurrent with taxane (docetaxel) treatment, before 2 anthracycline chemotherapy

Short duration: Concurrent with taxane treatment, before anthracycline 2 chemotherapy Long duration: concurrent and sequential DFS at 5 yrs: 76% short duration 75% long duration Note that a pilot study, not designed to 3 report efficacy

Disease free survival Hazard Ratio (95% confidence interval)

12-mth median f/up: 0.54 (0.43-0.67) 23-mth median f/up: 0.64 (0.54-0.76)

0.87 (0.67-1.13)

0.55 (CI not 6 reported )

23-mth median f/up: 0.49 (0.37-0.79) 36-mth median f/up: 0.61 (0.48-0.76)

0.45 (CI not 3 reported )

36-mth median f/up: 0.42 (0.21-0.83)

Overall DFS HR Overall survival (95% CI)

0.70 (0.61-0.81) (2-yr HERA f/u) 12-mth median f/up: 0.85 (0.55-1.33) 0.76 (0.47-1.23) 23-mth median f/up: 0.66 (0.47-0.91)

0.53 (0.46-0.62) (3-yr BCIRG006 f/u) 36-mth median f/up: Not reported 0.59 (0.42-0.85) (joint analysis (joint analysis with with B31 = 0.67 N9831 arm C = (0.48-0.93)) 0.67 (0.48-0.93)) Not reported 0.63 (0.50-0.80)

0.42 (0.21.0.83) 36-mth median f/up: 0.41 (0.16-1.08)

N/A – placebo group data not reported OS at 5 yrs: 89% short duration 83% long duration Note that E2198 is a pilot study, not 3 designed to report efficacy N/A – placebo group data not reported

Overall OS HR (95% CI)

0.72 (0.55-0.94)

0.41 (0.16-1.08)

1 2

No evidence is available on the outcomes of the 2 year trastuzumab treatment arm in the HERA trial. Note that there was also an arm to BCIRG006 (‘arm TCH’) that consisted of 6 cycles of docetaxel and carboplatin with concurrent trastuzumab (i.e. no anthracycline chemotherapy). However, because this regimen is not comparable to the other regimens, these results are not presented in this table. For further information regarding BCIRG006 see Appendix One: Minutes of the relevant clinical advisory committee meetings. 3 The E2198 study (Sledge et al, poster presentation at ASCO 2006) was not designed to test efficacy, and was not powered to determine equivalence, and results comparing the treatment arms to the control arm have yet to be reported. However, the results supported the efficacy of short duration concurrent trastuzumab therapy when administered before anthracycline containing chemotherapy, as demonstrated in the FinHer study (Appendix One: Minutes of the relevant clinical advisory committee meetings). 4 Anthracycline containing chemotherapy regimens (FEC or FAC). 5 The HERA trial allowed several different chemotherapy regimens. 6 Note that N9831 Arm C and trial B31 data were only published as a joint analysis (Romond, 2005) without stating the hazard ratios’ confidence intervals for the individual trials. Confidence limits for the disease recurrence HR for N9831 Arm B were stated in the 2005 conference presentation on the ASCO website.