Application of mTORC1 Inhibitors for Tissue-Agnostic Management of Standard-Therapy-Refractory Solid Tumors

SIMPLE SUMMARY: Hyperactivation of the mTOR pathway is a common occurrence in malignancies. This study investigated the clinical benefit of the tissue-agnostic application of mTOR inhibitors for the therapeutic management of a pan-cancer cohort of patients with mTOR pathway aberrations. Seventy-one patients were offered the targeted therapy and twenty-three eventually received it. Only three patients (4.2%) achieved stable disease, of whom one experienced progressive disease again after 9.1 months. Thus, in selected patients with heavily pretreated solid tumors with activation of the mTOR pathway, the antitumoral activity of mTORC1 inhibition was weak. ABSTRACT: In this analysis, we examined the efficacy, feasibility, and limitations of the application of mTOR inhibitors based on the individual molecular profiles of pretreated cancer patients after the failure of all standard treatments in the palliative setting. In this single-center, real-world analysis of our platform for precision medicine, we analyzed the molecular characteristics of 71 cancer patients. The tumor samples of the patients were analyzed using next-generation sequencing panels of mutation hotspots, microsatellite stability testing, and immunohistochemistry. All profiles were reviewed by a multidisciplinary team to provide a targeted treatment recommendation after a consensus discussion. Seventy-one cancer patients with activation of the mTOR pathway were offered an mTORC1-inhibitor-based targeted therapy, and twenty-three (32.4%) of them eventually received the targeted therapy. Only three patients (4.2%) achieved stable disease, of whom one experienced progressive disease again after 9.1 months. The median time to treatment failure was 2.8 months. In total, 110 mutations were detected in 60 patients (84.5%). The three most frequent mutations were found in TP53, PTEN, and KRAS, which accounted for over 50% (56.4%) of all mutations. In sum, in selected patients with heavily pretreated solid tumors with activation of the mTOR pathway, the antitumoral activity of mTORC1 inhibition was weak.