Abstract
BACKGROUND: The wide use of high-throughput technologies has facilitated the rise of precision medicine. The European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT) guides treatment decisions, and for ESCAT I alterations, the role of specific targeted therapy is unquestionable. Nevertheless, the impact of inhibiting ESCAT II and III alterations needs to be further elucidated. This study aims to evaluate the potential benefit of an experimental molecular-matched approach for patients diagnosed with advanced solid tumors harboring ESCAT tier II-III alterations. MATERIALS AND METHODS: We analyzed the next-generation sequencing data from 1230 advanced cancer patients between January 2020 and December 2023 in our institutional molecular tumor board (MTB). Patients presenting with ESCAT tier I-III alterations were selected to receive either standard molecular-matched therapy or an experimental treatment in early-phase clinical trials. RESULTS: A total of 1091 of 1230 consecutive advanced cancer patients (88.7%) harbored at least one molecular alteration, which was classified as ESCAT tier I (n = 415, 33.8%), ESCAT tier II-III (n = 391, 31.8%), and ESCAT tier IV-X (n = 285, 13.6%). Two hundred and four (49.2%) patients presenting ESCAT tier I alterations were treated with targeted therapies, whereas 31 patients (7.9%) harboring ESCAT tier II-III alterations were enrolled in early-phase clinical trials. Among patients with an ESCAT tier II-III alteration, a molecular-matched therapy was associated with better overall survival (OS) (univariable Cox hazard ratio 0.46, P = 0.002), with a median OS of 31 versus 11 months. In addition, patients with ESCAT II-III alterations who received experimental therapies as second line demonstrated a median progression-free survival of 4.0 months, higher than those receiving a new agent afterward (2.0 months). CONCLUSIONS: Our study underscores the critical role of MTBs in optimizing clinical outcomes for patients with advanced cancer through precise identification of actionable molecular alterations. Our findings highlight the necessity of incorporating ESCAT II and III alterations into precision medicine frameworks to expand therapeutic opportunities and the importance of earlier targeting of driver alterations.