Trastuzumab Adjuvant Survival Benefit
Gianni L, Dafni U, Gelber RD, et al
Lancet Oncol. 2011;12:236-244
The HERA (Herceptin® Adjuvant) trial, an international, multicenter, randomized, open-label, phase 3 trial, compares treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant or adjuvant chemotherapy in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival (DFS). After a positive first-interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab.
Gianni and coworkers reported the outcomes for the trastuzumab and observation groups at a median follow-up of 48.4 months and assessed the effect of the extensive crossover from the observation group to trastuzumab treatment. The HERA trial involved 1698 patients randomly assigned to an observation group and 1703 patients to the 1-year treatment with trastuzumab group. Of the1698 patients in the observation group, 885 (65%) crossed over to trastuzumab, corresponding to 52%. These patients tended to be younger; to have received anthracyclines and taxanes; and, to a lesser extent, to be premenopausal with hormone-positive breast cancer that was node positive. Intention-to-treat analysis of DFS showed a significant benefit in favor of patients in the 1-year trastuzumab group compared with the observation group. Intention-to-treat analysis of overall survival showed no difference. Patients from the observation group who crossed over to receive trastuzumab began treatment at a median of 22.8 months from randomization. Patients in the selective crossover cohort had fewer DFS events than patients in the observation group. Higher incidences of grade 3-4 and fatal adverse events were noted in the 1-year trastuzumab group compared with the observation group. The most common adverse events (each < 1%) were congestive heart failure, hypertension, arthralgia, back pain, infection, vasomotor symptoms, headache, and diarrhea. As reported previously, 1 cardiac death occurred in the observation group. More patients on 1-year trastuzumab had congestive heart failure with a confirmed drop in left ventricular ejection fraction.
The investigators concluded that treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover from the observation group to trastuzumab treatment was associated with improved outcomes for this cohort.
Early outcomes for treatment with trastuzumab have been reported at a median follow-up of 1 and 2 years. On the basis of significant observed benefit, a protocol amendment allowed patients in the observation group who were alive and disease free as of May 16, 2005 to cross over to treatment with trastuzumab regardless of the time elapsed from the time of random assignment. The data monitoring committee for this trial decided to continue the trial as planned, without release of the data for the 2-year trastuzumab group until the final event-driven analysis. Data updates for the 1-year trastuzumab vs observation group comparison were planned for every 2 years. This is the report from a median follow-up of 4 years.
After all statistical considerations used for this analysis, the conclusion is that the censored analysis for overall survival is strongly biased in favor of 1-year trastuzumab treatment. The unadjusted hazard ratio for risk for a DFS event in the selective crossover cohort compared with the cohort remaining on observation at similar follow-up duration following randomization was 0.69, and this is statistically significant.
This study confirms that the significant DFS benefit originally reported at 1-year median follow-up is sustained at 4-year median follow-up, despite the substantial crossover of patients from the observation group to treatment with trastuzumab. However, the overall survival benefit is no longer statistically significant, and this is because a significant proportion of patients originally assigned to observation eventually crossed over to the treatment arm. The other large trials assessing 1-year adjuvant trastuzumab and reporting sustained efficacy had a much lower degree of crossover. The Breast Cancer International Research Group 006 trial did not permit or facilitate crossover, and only 1.6% of patients in the control group crossed over to treatment with trastuzumab. In the North Central Cancer Treatment Group trial N9831 and the National Surgical Adjuvant Breast and Bowel Project B-31, about 21% of patients in the control groups crossed over to trastuzumab. A recent update at a 5.5-year median follow-up reported the superiority of its sequential group over control, thus confirming the clinical benefit of a sequential approach used in the HERA trial.
The investigators commented that, although exploratory, their findings suggest a difference for the risk for a DFS event in the cohort receiving trastuzumab starting 23 months after randomization. This study confirms that adjuvant trastuzumab given sequentially to chemotherapy is associated with significant and persisting benefits that are maintained at 4 years. The extensive selective crossover attenuated the efficacy findings.
The use of a late anti-HER2 strategy is being prospectively tested in the Tykerb Evaluation After Chemotherapy (TEACH) trial, with lapatinib as the anti-HER2 drug. The data are consistent with the hypothesis that risk for relapse persists over time and that patients may derive further benefit from treatment that extends beyond 1 year. We will learn much more in the near future about the timing of anti-HER2 therapy and the possible uses of combined or sequential anti-HER2 therapies. This study also reminds us that we need to keep study design in mind when analyzing long-term results.
Abstract
Treatment With Trastuzumab for 1 Year After Adjuvant Chemotherapy in Patients With HER2-Positive Early Breast Cancer: A 4 Year Follow-up of a Randomised Controlled Trial
Gianni L, Dafni U, Gelber RD, et al
Lancet Oncol. 2011;12:236-244
Study Summary
The HERA (Herceptin® Adjuvant) trial, an international, multicenter, randomized, open-label, phase 3 trial, compares treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant or adjuvant chemotherapy in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival (DFS). After a positive first-interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab.
Gianni and coworkers reported the outcomes for the trastuzumab and observation groups at a median follow-up of 48.4 months and assessed the effect of the extensive crossover from the observation group to trastuzumab treatment. The HERA trial involved 1698 patients randomly assigned to an observation group and 1703 patients to the 1-year treatment with trastuzumab group. Of the1698 patients in the observation group, 885 (65%) crossed over to trastuzumab, corresponding to 52%. These patients tended to be younger; to have received anthracyclines and taxanes; and, to a lesser extent, to be premenopausal with hormone-positive breast cancer that was node positive. Intention-to-treat analysis of DFS showed a significant benefit in favor of patients in the 1-year trastuzumab group compared with the observation group. Intention-to-treat analysis of overall survival showed no difference. Patients from the observation group who crossed over to receive trastuzumab began treatment at a median of 22.8 months from randomization. Patients in the selective crossover cohort had fewer DFS events than patients in the observation group. Higher incidences of grade 3-4 and fatal adverse events were noted in the 1-year trastuzumab group compared with the observation group. The most common adverse events (each < 1%) were congestive heart failure, hypertension, arthralgia, back pain, infection, vasomotor symptoms, headache, and diarrhea. As reported previously, 1 cardiac death occurred in the observation group. More patients on 1-year trastuzumab had congestive heart failure with a confirmed drop in left ventricular ejection fraction.
The investigators concluded that treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover from the observation group to trastuzumab treatment was associated with improved outcomes for this cohort.
Viewpoint
Early outcomes for treatment with trastuzumab have been reported at a median follow-up of 1 and 2 years. On the basis of significant observed benefit, a protocol amendment allowed patients in the observation group who were alive and disease free as of May 16, 2005 to cross over to treatment with trastuzumab regardless of the time elapsed from the time of random assignment. The data monitoring committee for this trial decided to continue the trial as planned, without release of the data for the 2-year trastuzumab group until the final event-driven analysis. Data updates for the 1-year trastuzumab vs observation group comparison were planned for every 2 years. This is the report from a median follow-up of 4 years.
After all statistical considerations used for this analysis, the conclusion is that the censored analysis for overall survival is strongly biased in favor of 1-year trastuzumab treatment. The unadjusted hazard ratio for risk for a DFS event in the selective crossover cohort compared with the cohort remaining on observation at similar follow-up duration following randomization was 0.69, and this is statistically significant.
This study confirms that the significant DFS benefit originally reported at 1-year median follow-up is sustained at 4-year median follow-up, despite the substantial crossover of patients from the observation group to treatment with trastuzumab. However, the overall survival benefit is no longer statistically significant, and this is because a significant proportion of patients originally assigned to observation eventually crossed over to the treatment arm. The other large trials assessing 1-year adjuvant trastuzumab and reporting sustained efficacy had a much lower degree of crossover. The Breast Cancer International Research Group 006 trial did not permit or facilitate crossover, and only 1.6% of patients in the control group crossed over to treatment with trastuzumab. In the North Central Cancer Treatment Group trial N9831 and the National Surgical Adjuvant Breast and Bowel Project B-31, about 21% of patients in the control groups crossed over to trastuzumab. A recent update at a 5.5-year median follow-up reported the superiority of its sequential group over control, thus confirming the clinical benefit of a sequential approach used in the HERA trial.
The investigators commented that, although exploratory, their findings suggest a difference for the risk for a DFS event in the cohort receiving trastuzumab starting 23 months after randomization. This study confirms that adjuvant trastuzumab given sequentially to chemotherapy is associated with significant and persisting benefits that are maintained at 4 years. The extensive selective crossover attenuated the efficacy findings.
The use of a late anti-HER2 strategy is being prospectively tested in the Tykerb Evaluation After Chemotherapy (TEACH) trial, with lapatinib as the anti-HER2 drug. The data are consistent with the hypothesis that risk for relapse persists over time and that patients may derive further benefit from treatment that extends beyond 1 year. We will learn much more in the near future about the timing of anti-HER2 therapy and the possible uses of combined or sequential anti-HER2 therapies. This study also reminds us that we need to keep study design in mind when analyzing long-term results.
Abstract
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