National Cancer Institute Breast Cancer Steering Committee Working Group Report on Meaningful and Appropriate End Points for Clinical Trials in Metastatic Breast Cancer

Abstract

Purpose: To provide evidence-based consensus recommendations on choice of end points for clinical trials in metastatic breast cancer, with a focus on biologic subtype and line of therapy.

Methods: The National Cancer Institute Breast Cancer Steering Committee convened a working group of breast medical oncologists, patient advocates, biostatisticians, and liaisons from the Food and Drug Administration to conduct a detailed curated systematic review of the literature, including original reports, reviews, and meta-analyses, to determine the current landscape of therapeutic options, recent clinical trial data, and natural history of four biologic subtypes of breast cancer. Ongoing clinical trials for metastatic breast cancer in each subtype also were reviewed from ClinicalTrials.gov for planned primary end points. External input was obtained from the pharmaceutic/biotechnology industry, real-world clinical data specialists, experts in quality of life and patient-reported outcomes, and combined metrics for assessing magnitude of clinical benefit.

Results: The literature search yielded 146 publications to inform the recommendations from the working group.

Conclusion: Recommendations for appropriate end points for metastatic breast cancer clinical trials focus on biologic subtype and line of therapy and the magnitude of absolute and relative gains that would represent meaningful clinical benefit.

Fig 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram for literature analysis. Flow diagram illustrates the selection of articles for analysis. (*) Not relevant on end point issue for randomized controlled trials.

Fig 2.

(A) Working group consensus on preferred end points by biologic subtype and line of therapy. (B) Hypothetical scenarios for expected postprogression survival (PPS) and choice of preferred end point. In settings such as first-line treatment of triple-negative metastatic breast cancer (TNMBC) where expected PPS is < 12 months, overall survival (OS) is the preferred primary end point. In settings such as hormone receptor–negative (HR–)/human epidermal growth factor receptor 2–positive (HER2+) or HR+/HER2+ MBC where PPS is > 12 months, in both the first- and later-line settings, progression-free survival (PFS) is the end point of choice, and OS could be considered as a coprimary end point. In settings such as HR+/HER2– MBC, given the expected long PPS, PFS is the most appropriate end point. When such patients have disease that is refractory to endocrine therapy and have been exposed to several lines of chemotherapy, where PPS is expected to be much shorter, OS may be the most meaningful and appropriate end point. (*) Line of therapy may be endocrine therapy, chemotherapy, HER2-targeted therapy, combinations, and so forth. (†) Months shown are for illustrative purposes only. 1°, primary end point; 2°, secondary end point; PRO, patient-reported outcome; RR, response rate.