scholarly journals Updated Standardized Definitions for Efficacy End Points (STEEP) in Adjuvant Breast Cancer Clinical Trials: STEEP Version 2.0

2021 ◽  
pp. JCO.20.03613
Author(s):  
Sara M. Tolaney ◽  
Elizabeth Garrett-Mayer ◽  
Julia White ◽  
Victoria S. Blinder ◽  
Jared C. Foster ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Disease Free Survival ◽  
Invasive Disease ◽  
Cancer Clinical Trials ◽  
Recurrence Rates ◽  
End Points ◽  
Free Survival ◽  
End Point ◽  
Adjuvant Breast Cancer ◽  
Disease Free

PURPOSE The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007, provide standardized definitions of adjuvant breast cancer clinical trial end points. Given the evolution of breast cancer clinical trials and improvements in outcomes, a panel of experts reviewed the STEEP criteria to determine whether modifications are needed. METHODS We conducted systematic searches of ClinicalTrials.gov for adjuvant systemic and local-regional therapy trials for breast cancer to investigate if the primary end points reported met STEEP criteria. On the basis of common STEEP deviations, we performed a series of simulations to evaluate the effect of excluding non–breast cancer deaths and new nonbreast primary cancers from the invasive disease–free survival end point. RESULTS Among 11 phase III breast cancer trials with primary efficacy end points, three had primary end points that followed STEEP criteria, four used STEEP definitions but not the corresponding end point names, and four used end points that were not included in the original STEEP manuscript. Simulation modeling demonstrated that inclusion of second nonbreast primary cancer can increase the probability of incorrect inferences, can decrease power to detect clinically relevant efficacy effects, and may mask differences in recurrence rates, especially when recurrence rates are low. CONCLUSION We recommend an additional end point, invasive breast cancer–free survival, which includes all invasive disease–free survival events except second nonbreast primary cancers. This end point should be considered for trials in which the toxicities of agents are well-known and where the risk of second primary cancer is small. Additionally, we provide end point recommendations for local therapy trials, low-risk populations, noninferiority trials, and trials incorporating patient-reported outcomes.

scholarly journals Adding pertuzumab to adjuvant therapy for high-risk HER2-positive early breast cancer in APHINITY: a GRADE analysis

2020 ◽  
Vol 9 (6) ◽  
pp. 423-430 ◽  
Author(s):  
Alberto Zambelli ◽  
Giovanni Pappagallo ◽  
Paolo Marchetti
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Adjuvant Therapy ◽  
Early Breast Cancer ◽  
Disease Free Survival ◽  
Invasive Disease ◽  
Her2 Positive ◽  
Free Survival ◽  
Distant Relapse ◽  
Disease Free

Aim: Adding pertuzumab to standard trastuzumab-based adjuvant therapy significantly improved invasive disease-free survival (IDFS) in the APHINITY trial. However, the magnitude of benefit was marginal in the overall population. Methods: We used GRADE (Grading of Recommendations Assessment, Development and Evaluation) analysis on data from APHINITY to build summary-of-findings tables to evaluate the efficacy, safety and quality of evidence of predefined clinical outcomes for the addition of pertuzumab to trastuzumab-based adjuvant therapy in patients with high-risk HER2-positive early breast cancer. Results: Pertuzumab significantly improved 3-year, event-free, absolute benefit in disease-free survival, IDFS and distant relapse-free interval (DFRI) in patients with node-positive or hormone receptor-negative disease. The analysis provides strength of evidence supporting the addition of pertuzumab in this patient population.

Correlation between changes in 2- or 3-year disease-free survival (DFS) and 5-year overall survival (OS) in adjuvant breast cancer trials from 1966–2006

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 581-581
Author(s):  
R. C. Ng ◽  
G. R. Pond ◽  
P. A. Tang ◽  
P. W. MacIntosh ◽  
L. L. Siu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Sample Size ◽  
Prediction Interval ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Free Survival ◽  
Adjuvant Breast Cancer ◽  
Cancer Trials ◽  
Disease Free

581 Background: Although disease-free survival (DFS) is accepted as a valid endpoint in adjuvant breast cancer trials, improvement in 2- or 3-year DFS has never been formally established as an adequate surrogate for 5- or 10-year overall survival (OS). We set out to establish if changes in 2- or 3-year DFS can be used to accurately predict changes in 5- or 10-year OS. Method: We conducted a systematic Medline search for phase III randomized adjuvant breast cancer trials published between 1966–2006 with >100 patients per arm with data for 2- and 3-year DFS as well as 5- or 10-year OS. Only trials of systemic therapies (e.g. chemotherapy, hormonal therapy) were included. We excluded studies investigating the effects of surgery, radiotherapy and neoadjuvant treatment. A univariate regression model weighted by trial sample size was constructed to determine if changes in 2-year DFS between treatment arms within trials were predictive of changes in 5- year OS. Computations of the correlation coefficient, proportion of variation, predicted estimates and 95% prediction interval were undertaken. Results: 126 studies containing 149 treatment arms met the inclusion criteria. Median sample size per trial was 533 and median follow up time was 81 months. Only 26 trials provided 10-year OS data thus association with 10-year OS was not attempted. Results were similar between analyses using either 2- or 3-year DFS, hence only 2-year DFS statistics are reported. 2-year DFS was a significant predictor of 5-year OS regardless of what other covariates were included (p<0.001). For every 1% increase in difference between treatment arms in 2-year DFS, the estimated difference in 5-year OS increased by 0.52%. The proportion of variation explained (R2) ranged from 0.38 to 0.49, with a wide prediction interval. Indeed, if a future trial accrued 1,000 patients and the 2-year DFS in the experimental arm was better than the control by 10%, the 95% prediction interval would still range from -0.2% to 11%. Conclusion: There is a statistically significant correlation, of moderate strength, between changes in 2-year DFS between treatment arms and changes in 5-year OS but the wide prediction intervals mean that the correlation is not strong enough to be used as a surrogate. No significant financial relationships to disclose.

Invasive disease-free survival benefit following neratinib as extended adjuvant therapy in centrally-confirmed HER2+ early-stage breast cancer: The ExteNET phase III randomized placebo-controlled trial.

2015 ◽  
Vol 33 (28_suppl) ◽  
pp. 117-117 ◽  
Author(s):  
Arlene Chan ◽  
Miguel Martin ◽  
Gunter Von Minckwitz ◽  
Bent Ejlertsen ◽  
Stephen K. L. Chia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Therapy ◽  
Ductal Carcinoma ◽  
Early Stage ◽  
Disease Free Survival ◽  
Metastatic Breast ◽  
Invasive Disease ◽  
Phase Iii ◽  
Free Survival ◽  
Disease Free

117 Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor with clinical efficacy in trastuzumab pre-treated HER2-positive (HER2+) metastatic breast cancer (BC). ExteNET is an ongoing multicenter randomized placebo-controlled phase III trial evaluating the efficacy and safety of a 1-year course of neratinib in patients with early-stage HER2+ BC after trastuzumab-based adjuvant therapy (clinicaltrials.gov: NCT00878709). Methods: Women with locally-confirmed early-stage HER2+ BC were randomly assigned to oral neratinib 240mg/day or matching placebo for 1 year. Archived diagnostic tumor samples were submitted for HER2 gene amplification testing at a central laboratory. Primary endpoint: invasive disease-free survival (iDFS). Secondary endpoints: DFS including ductal carcinoma in situ (DFS+DCIS); distant disease-free survival (DDFS); time to distant recurrence (TDR). Stratified Cox proportional-hazards models were used to estimate hazard ratios (HR) for the ITT and amended ITT (aITT) populations; unstratified models were used for the centrally confirmed HER2 population. Treatment groups were compared using 2-sided log-rank tests. Results: The ITT population included 2840 patients (neratinib, N=1420; placebo, N=1420). The higher-risk aITT population (i.e. node-positive disease and randomized ≤1 year of completing prior trastuzumab) included 1873 patients (neratinib, N=938; placebo, N=935). Of the tumor samples analyzed, 1463 (86%) were centrally confirmed (neratinib, N=741; placebo, N=722). Conclusions: Neratinib significantly improves iDFS in trastuzumab-treated early-stage HER2+ BC patients. An enhanced treatment effect is observed with neratinib in women with centrally confirmed HER2+ tumors. Clinical trial information: NCT00878709. [Table: see text]

Randomized, phase II trial to evaluate the efficacy and safety of atezolizumab plus capecitabine adjuvant therapy compared to capecitabine monotherapy for triple receptor-negative breast cancer (TNBC) with residual invasive cancer after neoadjuvant chemotherapy (MIRINAE trial, KCSG-BR18-21).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS597-TPS597
Author(s):  
In Hae Park ◽  
Gun Min Kim ◽  
Jee Hyun Kim ◽  
Hanjo Kim ◽  
Kyong Hwa Park ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Adjuvant Therapy ◽  
Phase Ii ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Disease Free Survival ◽  
Invasive Disease ◽  
Free Survival ◽  
Disease Free

TPS597 Background: Triple negative breast cancer (TNBC), lack of ER, PR and HER2 expression, is known to have aggressive clinical features such as early recurrence, drug resistance, and frequent distant metastasis at the diagnosis. The most effective chemotherapy combinations used for early TNBC include anthracycline, taxanes, and/or platinum agents. Achieving a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) provides important prognostic information and is considered as a surrogate endpoint in many clinical trials especially with TNBC. Patients with residual invasive disease after NAC have a high risk for early relapse and worse prognosis compared to those with pCR. Therefore, patients who did not get pCR could be better candidates for additional adjuvant treatment because their risk of recurrence would be higher than those with pCR. The CREATE-X (capecitabine for residual cancer as adjuvant therapy) trial howed that adjuvant capecitabine treatment improved 5-yr rate of disease free survival in TNBC subtype. A recent study indicated that immunosuppressive microenvironment had developed even in early stage of TNBC with increased T cells with a high exhaustion signature which are targets of immune modulating agents. Therefore, earlier cooperation of immune modulating drugs would be beneficial by generating a long-lasting anti-tumor immune response to micrometastatic disease, thus preventing disease relapse or recurrence. Methods: This study is a phase II, multicenter, randomized open label trial of atezolizumab (anti-PD-L1 antibody) and capecitabine compared with capecitabine in patients with TNBC who had residual disease after NAC. 284 patients will be enrolled from 15 sites in Korea with a primary objective to access the 5-yr invasive disease-free survival (IDFS) rate. Secondary objectives include 5-yr IDFS rate in PD-L1 positive population, distant relapse free survival (DRFS), overall survival (OS), and safety. Major inclusion and exclusion criteria are followings; 1) histologically confirmed TNBC, 2) received anthracycline and taxane based NAC followed by complete breast surgery, 3) residual disease after NAC must be ≥1cm in the greatest dimension, and/or have macroscopically positive lymph nodes. The study is open with 13 patients enrolled at the time of submission. Clinical trial information: NCT03756298 .

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