More is Better or Less is More: Isolating the Contribution of Effect in Treatment Sequences

Combination therapy is a critical treatment approach across many disease settings, including cancer, cardiovascular diseases, and infectious diseases. For instance, in solid tumors, perioperative regimens often include a combination of neoadjuvant therapy, surgery, and adjuvant therapy. Similarly, in hematological malignancies, maintenance therapy is frequently administered following induction or consolidation therapies. However, the question remains: is more always better, or could less be more? Patients may face overtreatment, increased toxicity, and unnecessary burdens if the contribution of each therapy component is not well understood. This uncertainty raises the issue of whether every patient truly needs each component of a combination therapy. At a recent FDA Oncologic Drugs Advisory Committee meeting on July 25, 2024, regarding the durvalumab perioperative regimen, the agency voiced concerns about the necessity of both treatment phases. The committee unanimously recommended that new trial designs for perioperative regimens in resectable NSCLC should adequately assess the contribution of each treatment phase. This raises a critical question: how should we design trials to isolate the contribution of each component effectively? Possible approaches include re-randomizing treatment arms, adding additional arms, utilizing external data sources, or other innovative methodologies. In time to event analyses, the evaluation of the treatment effect in such designs with treatment sequence is also quite challenging when intercurrent events are present. Our session will explore and discuss the latest developments in evaluating the effects of individual components within combination regimens.