From Biology to Bedside: Challenges and Strategies in Developing Combination Cancer Therapies in Early-Phase Trials.

Abstract

Recent advances in next-generation sequencing technology and molecular profiling have significantly expanded our understanding of the tumor mutational landscape, leading to a substantial increase in novel targeted agents. Small molecules have transformed the standard of care for many patients with oncogene-driven cancers. However, single-agent therapies have several limitations, including the development of primary (intrinsic) or secondary (acquired) resistance, which often results in nondurable antitumor responses. Additionally, targeting a single alteration can lead to the upregulation of additional alterations, thereby minimizing activity. The development of novel rational combination strategies is essential to overcome compensatory escape mechanisms and intrinsic and acquired resistance mechanisms, as well as other challenges, such as intratumoral heterogeneity and clonal evolution. In this article, we summarize key aspects of early-phase clinical trials of combination therapy, including regulatory, biological, and logistical considerations-such as biomarker integration, real-time molecular profiling, and adaptive trial infrastructure-that shape the future of combination strategies in early-phase oncology trials. We discuss recent successes with combination therapy in the clinic and some current challenges in developing combination trials. Finally, we expand upon previously published guidance and, in the context of Project Optimus, propose recommendations for designing and conducting early-phase clinical trials of combination therapies.