Safety, efficacy, pharmacokinetics of uliledlimab alone or combined with toripalimab in advanced solid tumor: Initial results of a phase I/II study.
Authors: Zhou Qing , Wu Lin , Cui Jiuwei , Jiang Bo , Yao Yu , Zhang Jian , Zhao Mingfang , Dong Xiaorong , Liu Anwen , Ma Rui , Du Yingying , Wang Huijuan , Wang Buhai , Hu Xiaohua , Pan Hongming , Zhang Haibo , Zhao Yiqiang , Meng Yuan , Zhu Andrew X. , Wu Yi-Long 
Published: June 2022

e21123

Background: Upregulation of CD73 results in the adenosine overproduction, which suppresses immune responses in tumoral microenvironment. Uliledlimab (ULI), a differentiated anti-CD73 antibody, inhibits adenosine generation in a non-competitive manner and suppresses tumor growth when combined with a PD-(L)1 inhibitor. Methods: The dose-escalation and dose expansion phase I/II study (NCT04322006) was designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of ULI alone, or combined with toripalimab (TOR) in patients with advanced solid tumor. ULI was administered iv. at 2, 5,10 mg/kg weekly (QW) or at 15, 20, 30 mg/kg every 3 weeks (Q3W) alone, or combined with TOR (240 mg, iv, Q3W) in dose escalation. Preliminary efficacy of ULI (20 mg/kg Q3W) + TOR (240 mg Q3W) was examined in non-small cell lung cancer (NSCLC) in dose expansion cohorts. Serum concentration of ULI and soluble CD73, CD73 receptor occupancy (RO) in circulating CD19+ B cells were detected. Tumor response was assessed by RECIST1.1/iRECIST. Results: As of 12/5/2021, a total of 92 patients were enrolled: 12 in dose escalation of ULI alone, 9 in ULI+TOR dose escalation group, and 71 in ULI+TOR dose expansion cohorts. ULI was well-tolerated with no DLT observed in dose escalation. Most of treatment-related adverse event (TRAE) were grade 1-2 with grade 3-4 TRAE occurring in 2 patients with decreased lymphocyte count and 1 with transient QT prolongation in ULI monotherapy group, and 2 patients each with hypotension and diarrhea as most reported events in ULI+TOR group. Most common TRAE were grade 1-2 chills (47.8%), vomiting (46.7%), pyrexia (40.2%), diarrhea (32.6%), nausea (19.6%), pruritus (14.1%), rash (13%) that occurred after the first dose of ULI and resolved in subsequent infusions, which can be significantly reduced by steroid-based premedication. The PK of ULI was linear at doses ≥ 5 mg/kg and modelling indicated a mean derived effective t1/2 of ̃13.2 days. Soluble CD73 was undetectable and complete RO was maintained after the first dose at ≥ 15 mg/kg Q3W at Ctrough throughout the dosing interval. As of 12/13/2021, among 48 efficacy-evaluable NSCLC patients in dose expansion cohorts, 6 partial responses (PR) (ORR 12.5%, 95%CI: 4.7%-25.2%) and 21 stable diseases (DCR 56.4%, 95%CI, 41.2%-70.5%) were observed. PRs were observed in 3 out of 8 systematic treatment-naïve patients, and 3 out of 39 patients with relapse/refractory disease to previous systematic treatment including 2 patients received no prior PD-(L)1 inhibitor treatment and 1 patient failed pembrolizumab. Conclusions: ULI was safe and tolerated up to 30 mg/kg Q3W. Linear PK observed at doses ≥ 5 mg/kg with t1/2 of 13.2 days. Full saturation of circulating and cell-bound CD73 was maintained at doses ≥ 15 mg/kg Q3W. ULI combined with TOR exhibited evidence of anti-tumor activity in NSCLC patients. Clinical trial information: NCT04322006.