A phase 1/2 study of the TORC1/2 inhibitor onatasertib combined with toripalimab in patients with advanced solid tumors.
Authors: Shu Pei , Li Xiaoyu , Yuan Li , Zhou Qi , Li Guiling , Zhang Keqiang , Xie Hui , Wang Yongsheng , Li Qiu , Zheng Li 
Published: June 2023

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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 updated 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. Methods: This study consists of 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 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). Results: As of Oct 21, 2022 cut-off, 46 advanced solid tumor pts were enrolled with 10 pts in the dose escalation phase and 36 pts in the dose expansion phase. Median age was 53 years. Baseline ECOG scores were 0 (13 pts) and 1 (33 pts) with a median of 2 prior lines of therapy (0-7); 27 pts had stage IV disease. Twenty-one cervical cancer (CC) pts were enrolled in total with the similar baseline characteristics. No dose-limiting toxicity was reported in dose escalation phase. The study did not reach MTD. Forty-five pts (97.8%) had ≥ 1 TEAEs; 32 (69.6%) pts had grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAEs included lymphocyte count decreased (23.9%), rash (19.6%) and hyperglycemia (10.9%). The RP2D for onatasertib was determined to be 15 mg in combination with the recommended dose of tori. Among the 46 treated pts, ORR was 26.1% (12/46, all confirmed), and DCR was 73.9%. In 21 pts with CC, ORR was 52.4%, including 1 CR and 10 PR, and DCR was 90.5%. One CC pt with negative PD-L1 expression achieved CR and remains on treatment after 883 days. The ORR was 75% (6/8) and 41.7% (5/12) for CC pts with PD-L1 positive and negative expressions, respectively. One CC pt with prior anti-PD-1 therapy also reached PR. Another PR was achieved in nasopharyngeal carcinoma (NPC) for over 2 years. Median PFS in all treated pts and CC cohort was 4.3 months(m) and 7.2 m, respectively. Pharmacokinetic profiles of ATG-008 in combination with PD-1 antibody were similar to ATG-008 monotherapy, across Asia Pacific and U.S. patient populations. Conclusions: Onatasertib in combination with tori is tolerable with encouraging response rate and disease stabilisation in pts with advanced solid tumors, especially in CC pts. Expansion enrolment for CC and NPC is ongoing. Clinical trial information: NCT04337463 .