Multicenter phase 1/2 study of onatasertib, a dual TORC1/2 inhibitor, combined with the PD-1 antibody toripalimab in advanced solid tumors

Abstract Preclinical studies have indicated that the combination of mTORC1/2 inhibitors with PD-1 antibodies exhibits synergistic effects on solid tumors. However, no clinical data supporting this combination have been reported. Therefore, we conducted a clinical trial (NCT 04337463) to investigate the efficacy and safety of combining onatasertib, an mTORC1/2 inhibitor, with toripalimab, a PD-1 antibody in patients with advanced solid tumors. This open-label, phase 1/2 clinical trial included dose escalation and dose expansion cohorts to evaluate safety, tolerability, objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). A total of 46 patients were enrolled and received onatasertib at doses of 15 mg, 20 mg, or 30 mg once daily (QD), combined with toripalimab 240 mg every 3 weeks (Q3W). No dose-limiting toxicities were observed, and the most common grade 3 or 4 treatment emergent adverse events were lymphopenia (23.9%) and rash (19.6%). The overall ORR was 26.1%, with a DCR of 73.9%, and a median PFS of 4.3 months. In cervical cancer patients, regardless of PD-L1 expression, the ORR was 52.4%, DCR was 90.5% and median PFS was 5.8 months. Notably, the 15 mg combination dose demonstrated a median PFS of 7.8 months. In conclusion, the safety profile of onatasertib in combination with toripalimab was manageable and showed encouraging clinical activity in advanced solid tumors, particularly among cervical cancer patients, irrespective of PD-L1 expression. The recommended phase 2 dose for the combination was determined to be onatasertib 15 mg QD and toripalimab 240 mg Q3W.