A phase 1/2 study of onatasertib, a dual TORC1/2 inhibitor, combined with the PD-1 antibody toripalimab in patients with advanced solid tumors (TORCH-2).
Authors: Shu Pei , Li Xiaoyu , Yuan Li , Xie Hui , Zhou Qi , Wang Yongsheng , Li Qiu , Zheng Li 
Published: June 2022

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Background: Pre-clinical studies suggest synergistic activity of the combination of inhibitors of mTOR with a PD-1 antibody in solid tumors. Here we report initial results of a phase 1/2 open-label, dose escalation and expansion trial of the oral TORC1/2 inhibitor, onatasertib (ATG-008) in combination with toripalimab (tori), a PD-1 monoclonal antibody, in patients (pts) with advanced solid tumors (NCT04337463). Methods: This study consists of two phases: dose escalation and dose expansion. The primary objective in the dose escalation phase was to evaluate safety and tolerability of onatasertib combined with tori, followed by a dose expansion phase to assess antitumor efficacy and verify the safety and tolerability profile of the combination therapy. Primary endpoints included maximum tolerated dose (MTD), recommended phase II dose (RP2D) and efficacy of the combination. Other endpoints included pharmacokinetics, and exploratory biomarkers of drug activity. Prior check point (anti-PD-1, anti-PD-L1, CTLA-4), mTOR and/or PI3K/AKT/mTOR inhibitor therapy was excluded, regardless of PD-L1 expression. Onatasertib was administered orally once a day (QD) at three dose levels (15, 20 and 30mg) in combination with tori at the approved dose of 240 mg, once every 21 days (Q3W). Efficacy assessments are reported based on RECIST1.1 criteria. Results: As of Dec 20, 2021 cut-off, 28 advanced solid tumor pts were enrolled in the study with 10 pts in the dose escalation phase and 18 pts in the dose expansion phase. Median age was 52 years. Baseline ECOG scores were 0 (4 pts) and 1 (24 pts) with a median of 2 prior lines therapy (0-7), 21 pts had stage IV disease. No dose-limiting toxicities were reported in dose escalation phase. The study did not reach MTD. All pts had ≥ 1 TEAEs; 19 (67.9%) pts had grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAEs included lymphocyte count decreased (21.4%), rash (14.3%) and hyperglycemia (10.7%). AEs lead to discontinuation in 2 pts (7.1%). The RP2D for onatasertib was determined to be 15-20 mg in combination with the recommended dose of tori. Among the 21 efficacy evaluable (EE) pts, the ORR was 28.6% (6 pts, 5 confirmed) and DCR was 71.4% (15 pts). In 5 EE pts with cervical cancer, 1 complete response (CR) and 3 partial responses (PR) were observed (all confirmed). One cervical cancer pt with negative PD-L1 expression achieved CR and remains on treatment after 580 days. Two other PRs were seen (one nasopharyngeal carcinoma, one ovarian carcinoma). Median progression free survival (PFS) in the whole cohort was 3.52 months and 18-month PFS rate was 31.2%. Conclusions: Onatasertib in combination with tori is tolerable with encouraging response rates and disease stabilisation in subjects with advanced solid tumors, especially in cervical cancer. Expansion enrolment for cervical cancer is ongoing and updated information will be presented. Clinical trial information: NCT04337463.