Abstract C070: Evolving Paradigms and shifting priorities in the landscape of Phase 1 Oncology Trials: 2021–2024

Abstract Background: The phase 1 clinical trial landscape has evolved significantly with the advancement of oncology therapeutics. While targeted therapies and immunotherapies have dominated early-phase development, their relative distribution and design strategies continue to shift. This study analyzed trends in investigational agent classes in contemporary phase 1 oncology trials. Methods: We conducted a comprehensive review of 367 industry-sponsored phase 1 solid tumor clinical trial protocols initiated at a network of Sarah Cannon Research Institute drug development units between 2021 and 2024. Data extraction focused on investigational agent classification and mechanism of action. Temporal trends were analyzed using chi-square tests, with statistical significance set at p < 0.05. Results: Of the 367 protocols, targeted therapies accounted for 44% (n=162), immunotherapies for 39% (n=142), and antibody-drug conjugates (ADCs) for 13% (n=49). Targeted therapy trials represented 51% of trials in 2021, down to 36% in 2023, and up to 48% in 2024. Most targeted agents were small molecule inhibitors (n=137, 85%), with a smaller subset being protein degraders (n=15, 9%). The most common targets were RAS/MAPK (n=38, 23%) and receptor tyrosine kinases/cell surface receptors (n=34, 21%). Direct (K)RAS inhibitors represented a significantly higher proportion of targeted therapy trials in 2024 (n=10, 20%) compared to 2021–2023 (n=7, 6%) (p=0.01). Among immunotherapy trials, monoclonal and bispecific antibodies were the most common modalities (n=51, 36%), followed by CD3-targeting T-cell engagers (n=23, 16%), small molecule inhibitors (n=21, 15%), and immune effector cell therapies (n=18, 13%). Modified cytokines, oncolytic viruses, vaccines, and fusion proteins each comprised a smaller share. The proportion of immunotherapy trials remained stable across the years. ADCs represented 4% of trials in 2021, increasing to 16%, 11%, and 20% in 2022, 2023, and 2024, respectively. The most common ADC targets were HER2 (n=5), FRα (n=4), B7-H4 (n=4), and B7-H3 (n=3). The predominant payloads were topoisomerase I inhibitors (TOP1) (n=23, 48%) and tubulin inhibitors (n=17, 35%). There was a significant increase in ADCs using TOP1 payloads in 2023–2024 (68%) compared to 2021–2022 (20%) (p=0.003). Chemotherapy trials comprised only 1% (n=4) of all studies, with none initiated in 2024. Conclusion: The phase 1 oncology trial landscape reflects a dynamic and evolving therapeutic environment. Targeted therapies and immunotherapies remain prominent, while ADCs—particularly those with TOP1 inhibitor payloads—are experiencing notable growth. These trends highlight a shift in early-phase development priorities, with increasing focus on KRAS-targeted agents and ADC platforms, and a marked decline in traditional chemotherapy trials. However, with many ADCs entering phase 1 trials that share similar targets and payloads, particularly TOP1 inhibitors, there is a growing need for diversification in payload strategies to enhance therapeutic differentiation and address resistance mechanisms. Citation Format: Deepak Bhamidipati, Suzanne Jones, Anusha Khawaja, David Spigel, Gerald Falchook, Manish Patel, Howard Burris, Vivek Subbiah. Evolving Paradigms and shifting priorities in the landscape of Phase 1 Oncology Trials: 2021–2024 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C070.