Disease-free survival as a surrogate for overall survival in patients with HER2-positive, early breast cancer in trials of adjuvant trastuzumab for up to 1 year: a systematic review and meta-analysis

Abstract

Background: Although frequently used as a primary endpoint, disease-free survival has not been validated as a surrogate for overall survival in early breast cancer. We investigated this surrogacy in the adjuvant setting of treatment with anti-HER2 antibodies.

Methods: In a systematic review and meta-analysis, we identified published and non-published randomised controlled trials with completed accrual and available disease-free survival and overall survival results for the intention-to-treat population as of September 2016. Bibliographic databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials), clinical trial registries (Clinicaltrials.gov, EU Clinical Trials Register, WHO International Clinical Trials Registry Platform, and PharmNet.Bund), and trial registries from relevant pharmaceutical companies were searched. Eligibility for treatment of HER2-positive early breast cancer required at least one group to have an anti-HER antibody treatment (ie, trastuzumab, pertuzumab, or trastuzumab emtansine) planned for 12 months, and at least one control arm with chemotherapy without the antibody, a lower total dose or duration of the antibody, or observation alone. Units of analysis were contrasts: two-group trials gave rise to one contrast, whereas trials with more than two groups gave rise to more than one contrast. We excluded trials enrolling patients with recurrent, metastatic, or non-invasive disease, and those testing neoadjuvant therapy exclusively. Our primary objective was to estimate patient-level and trial-level correlations between disease-free survival and overall survival. We measured the association between disease-free survival and overall survival using Spearman's correlation coefficient (r_s), and the association between hazard ratios (HRs) for disease-free survival and overall survival using R². We computed the surrogate threshold effect, the maximum HR for disease-free survival that statistically predicts an HR for overall survival less than 1·00 in a future trial.

Findings: Eight trials (n=21 480 patients) gave rise to a full set (12 contrasts). Patient-level associations between disease-free and overall survival were strong (r_s=0·90 [95% CI 0·89-0·90]). Trial-level associations gave rise to values of R² of 0·75 (95% CI 0·50-1·00) for the full set. Subgroups defined by nodal status and hormone receptor status yielded qualitatively similar results. Depending on the expected number of deaths in a future trial, the surrogate threshold effects ranged from 0·56 to 0·81, based on the full set.

Interpretation: These findings suggest that it is appropriate to continue to use disease-free survival as a surrogate for overall survival in trials in HER-2-positive, early breast cancer. The key limitation of this study is the dependence of its results on the trials included and on the existence of an outlying trial.

Funding: Roche Pharma AG.

Figure 1:. Study selection

Details of inclusion and exclusion criteria are provided in the appendix p 3. Data maturity for disease-free survival and overall survival was arbitrarily defined, with immaturity meaning that results were not yet published at the time the analysis was done. *See the Results for description of how these 8 trials were arrived at.

Figure 2:. Trial-level association between the hazard ratio for disease-free survival and the hazard ratio for overall survival in each contrast of the reduced set

Analysis is weighted by the number of deaths in each contrast. Each circle represents one contrast, with size proportional to the number of deaths. ACT=doxorubicin, cyclophosphamide, and docetaxel. ACTH=doxorubicin, cyclophosphamide, docetaxel, and trastuzumab. HR=hazard ratio. L=lapatinib. T=trastuzumab. TCH=docetaxel, carboplatin, and trastuzumab. T→L=trastuzumab followed by lapatinib. TL=trastuzumab plus lapatinib.

Figure 3:. Trial-level association between the hazard ratio for disease-free survival and the hazard ratio for a proxy to breast cancer-specific survival in each contrast of the reduced set

Analysis is adjusted for the magnitude of the estimation errors in the treatment effect estimates. Each circle represents one contrast, with size proportional to the number of deaths. The curved diagonal lines are the 95% prediction limits for the regression line. ACT=doxorubicin, cyclophosphamide, and docetaxel. ACTH=doxorubicin, cyclophosphamide, docetaxel, and trastuzumab. HR=hazard ratio. L=lapatinib. T=trastuzumab. TCH=docetaxel, carboplatin, and trastuzumab. T→L=trastuzumab followed by lapatinib. TL=trastuzumab plus lapatinib.