The Evolution of Clinical Trials in Metastatic Breast Cancer: Design Features and Endpoints That Matter

Abstract

The evolution of thought in assessing benefit in clinical trials of systemic therapy for metastatic breast cancer (MBC) is well documented, with most agents garnering regulatory approval based either on an advantage in overall survival (OS), time to progression (TTP), or progression-free survival (PFS) over an existing standard of care or objective response rate (ORR). Previous guidance for industry on clinical trial endpoints for the approval of cancer drugs and biologics was provided by the U.S. Food and Drug Administration (FDA) in 2007 and recently updated in 2018. The more recent FDA guidance recognizes that advances in science are facilitating the development of oncology products, which “may also result in the identification of additional endpoints that may be used to support approval of oncology products.” This article critically addressed the evolution of thought on the advancement of clinical trials in MBC, from various stakeholder perspectives. Despite the term “stakeholder,” the objective of all co-authors and parties concerned is to promote and inform the optimal design, conduct, and reporting of clinical trials for women with advanced breast cancer toward improving and extending lives. This article provides an overview of the evolving perspectives on this issue from the physician, regulatory agency, and patient and/or advocate points of view.

Biases in study design, implementation, and data analysis that distort the appraisal of clinical benefit and ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scoring

“… 61 Although some degree of attrition is expected with each subsequent line of therapy, nearly one-third of patients not getting any subsequent therapy post first-line is an astoundingly aberrant figure given that most women with estrogen receptor-positive HER2-negative breast cancer routinely survive for >2 years after first progression and generally receive four subsequent lines of therapy or more. 59 This major divergence from SOC for a substantial proportion of patients renders the OS data from this study non-generalisable. Indeed, it is plausible that the failure to provide subsequent standard therapy to more than a quarter of the patients who progressed on the study may have exaggerated the OS gain from ribociclib compared with placebo.…”

“… 58 In some settings, such as hormone-responsive breast cancer, it is not uncommon for patients to receive more than five subsequent therapy lines. 59 …”

“…58 In some settings, such as hormone-responsive breast cancer, it is not uncommon for patients to receive more than five subsequent therapy lines. 59 When patients receive optimal post-progression therapy, any advantage gained by the experimental treatment may be impacted by subsequent therapies. 58 When the PFS gain is maintained or even improved after optimal postprogression therapies and reflected in an OS gain, the benefit is recognised as being important.…”

Human Factors Engineering: Designing for Diversity and Accessibility

“…Human factors methods toolbox provides us with approaches to identify barriers to inclusion and can thus inform solutions for overcoming them. Examples may include partnering/collaborating with community organizations, representatives, and patients -including the 'patient voice' (Seidman, et al, 2020) to inform the design, recruitment, and retention of clinical trials and other research; providing childcare, transportation, compensation, parking and food vouchers, to research participants and budgeting for them in grants and contracts. Without this inclusion, we cannot inform tailored and effective solutions that are critically needed.…”

A view on the landscape of breast cancer brain metastases

“…The treatment landscape is changing with newer modalities and therapeutics being introduced; one key barrier is the exclusion of patients of BCBM from clinical trials [ 7 , 12 , 38 ]. The design of clinical trials needs to not only incorporate untreated BCBM but also there is a need to encourage diversity as well as patient advocacy through the use of patient reported outcomes [ 39 ].…”