Evolving landscape of targeted therapies in early phase clinical trials

Background Early phase clinical trials assessing targeted therapies have historically been associated with a wide range of efficacy rates and toxicities. Recently, the implementation of molecular prescreening programs and the development of more selective and potent targeted agents may associate with improved outcomes. Patients and methods We analyzed patient-level data from the 360 RESISTANCE (360R), a prospective study evaluating the outcomes of patients treated with targeted therapies in early phase clinical trials at Vall d´Hebron University Hospital. Objective response rate (ORR) was the primary endpoint. We also aimed to evaluate trends in efficacy and toxicity of targeted therapies over time by analyzing the ratio of progression-free survival (PFS) in early phase clinical trial (PFS2) over PFS on prior therapy (PFS1). Results Between 2015 and 2023, 261 patients were enrolled in the 360R encompassing 74 different clinical trials, of which, 156 patients (59.8%) were treated with molecularly matched targeted therapies and 105 (40.2%) treated with non-matched targeted therapies. The most frequent targets were FGFR signaling pathway (14.2%), epigenetic pathways (13.8%), Ras/Raf/MAPK pathway (12.3%), SHP2 (7.7%) and ErbB family pathway (6.5%). ORR increased over time: 6.4% (in 2015–2016), 14.3% (in 2017–2018), 18.2% (in 2019–2020) and 25.4% (in 2021–2023). PFS2/PFS1 ratio was ≥ 1.3 in 36.2% for all targeted therapies (40.6% in matched vs 29.4% in non-matched). The rate of grade 3–4 treatment-related adverse events remained stable. No treatment-related deaths were observed. Conclusions Encouraging trends for improved efficacy were observed for targeted therapies in early phase clinical trials, especially for molecularly matched agents. These findings highlight the potential value of molecular prescreening programs matching patients to clinical trials assessing targeted therapies.