Elsevier

The Lancet Oncology

Volume 20, Issue 3, March 2019, Pages 361-370
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(18)30750-2Get rights and content

Summary

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 (rs), 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 (rs=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.

Introduction

Breast cancer is divided into molecular subtypes with relevant prognostic and predictive implications for clinical practice.1 In HER2-positive breast cancer, adjuvant therapy with trastuzumab improves outcomes.2, 3, 4 Although shorter and longer durations of trastuzumab therapy,2, 5, 6, 7, 8 as well as other anti-HER2 agents,9, 10, 11 have been investigated in the adjuvant setting, 1 year of trastuzumab remains the most common option for treatment.1, 12 The development of novel adjuvant regimens is a lengthy process, and the analysis of overall survival requires a long follow-up. One possibility to expedite drug development and patient access to improved regimens is to test new drugs as neoadjuvant therapies, because drugs that perform well in this context are more promising in the adjuvant setting than regimens that add no improvements in clinical or pathological responses when used as neoadjuvant treatment. However, doubts remain about the predictive ability of the neoadjuvant platform,13, 14 and another possibility to expedite the development of adjuvant therapy is to use surrogates for overall survival.15 Although disease-free survival has often been used as the primary endpoint in adjuvant trials of breast cancer, to our knowledge it has not been formally validated in this setting, as it has in others—for example, colon, stomach, and lung cancer.16, 17, 18 Meta-analyses of individual-patient data from randomised trials provide two measures of association between the potential surrogate and the final endpoint of interest: the patient-level associations, and the trial-level associations.19 Patient-level associations denote the prognostic role of the surrogate (eg, whether patients with prolonged disease-free survival are also more likely to have prolonged overall survival), whereas trial-level associations provide predictive information (ie, whether treatment-induced changes in the surrogate endpoint are accompanied by proportional changes in the final endpoint). These two associations are independent, as shown by a strong patient-level association but weak trial-level association between pathological complete response and overall survival in a pooled analysis of neoadjuvant therapy trials in breast cancer.14 Our study was done to evaluate the role of disease-free survival as a surrogate for overall survival in the adjuvant treatment of HER2-positive breast cancer.

Research in context

Evidence before this study

Although disease-free survival has often been used as a primary endpoint in adjuvant trials of breast cancer, it has not been formally validated as a surrogate for overall survival. This systematic review and meta-analysis was done to evaluate the role of disease-free survival as a surrogate for overall survival in the adjuvant treatment of HER2-positive early breast cancer. In October, 2015, and October, 2016, bibliography 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 for published or unpublished randomised clinical trials in HER2-positive early breast cancer on anti-HER2 monoclonal antibodies. Search terms were “breast cancer” and synonyms; “trastuzumab”, “pertuzumab”, or “trastuzumab emtansine”, and synonyms; and “phase 2” or “phase 3” or “phase 4”. Data were provided by investigators for all but one of the nine eligible trials.

Added value of this study

A two-level modelling approach was used to estimate the association between disease-free survival and overall survival (patient-level association) and between the treatment effects on these endpoints (trial-level association). Patient-level associations were strong (rs=0·90 [95% CI 0·89–0·90]). Trial-level associations were moderate or strong, depending on the set analysed (R2 0·75 [95% CI 0·50–1·00] in the full analysis set, 0·84 [0·67–1·00] in the reduced set). These results suggest that disease-free survival has good overall statistical validity as a surrogate for overall survival in the adjuvant treatment of HER2-positive, early breast cancer. These results apply mainly to the adjuvant use of trastuzumab for 12 months and cannot be readily extrapolated to other types of adjuvant anti-HER2 therapy, whether changing the agent (trastuzumab) or the duration of treatment.

Implications of all the available evidence

The levels of association could be sufficient for the purpose of replacing a final endpoint such as overall survival. This surrogacy has implications for trial design as well as for the approval of novel agents. Further studies should assess disease-free survival as a surrogate for overall survival in other breast cancer phenotypes.

Section snippets

Search strategy and selection criteria

In this systematic review and meta-analysis, eligible studies were randomised clinical trials of adjuvant therapy for patients with stage I–III breast cancer, with randomisation done after surgery and accrual completed as of September, 2016; patients had to have HER2-positive disease, either exclusively or with stratification for HER2 positivity ascertained by the accepted methods of immunohistochemistry and fluorescent in-situ hybridisation (of note, patients with HER2-negative disease were

Results

Of 3075 trials identified from clinical trial registries and 1320 publications identified from bibliographic databases, eight trials with available and mature data met eligibility criteria, and were included in analyses (figure 1, table 1). There was no concern about data duplication, because each trial was independent. The trial E219826 did not fulfil all selection criteria, because in the experimental group (as defined in this analysis) trastuzumab was planned for 12 weeks more than the usual

Discussion

The results of this systematic review and meta-analysis suggest a strong association between disease-free survival and overall survival, and between the treatment effects on these two endpoints, when assessing adjuvant trastuzumab in patients with early HER2-positive breast cancer. The measure of treatment-level association (R2) was equal to or above 0·75 in both the full and the post-hoc reduced sets analysed herein; this value is a commonly used threshold for accepting the validity of a

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