A phase Ib study of SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC).
Authors: Yunpeng Yang, Yuangyuan Zhao, Ting Zhou, Gang Chen, Yan Huang, Feng Liu, Zhigang Liu, Song Qu, Yu Lei, Xiaozhong Chen, Lizhu Lin, Zhichao Fu, Xiaojing Zhang, Zeyu Yang, Chuanpei Huang, Li Zhang
Journal: Journal of Clinical Oncology (2022)

6024 Background: Immune checkpoint inhibitors (ICIs) demonstrated favorable antitumor activity in RM-NPC. However, only a subset of patients derived benefits. Combining ICIs with agents blocking immunosuppressive pathway may expand the clinical benefit of ICIs to more patients. Transforming growth factor β (TGF-β) participates in tumor immune escape. SHR-1701 is a bifunctional fusion protein composed of a mAb against PD-L1 fused to the extracellular domain of TGF-β receptor II. Here, we report the safety and efficacy of SHR-1701 in RM-NPC patients. Methods: This is an ongoing, multicenter, open-label, phase Ib study (NCT04282070). Patients with confirmed RM-NPC who failed prior platinum-based chemotherapy (Arm 1) or both platinum-based chemotherapy and anti-PD-1/PD-L1 antibody treatment (Arm 2) were enrolled to receive SHR-1701 30 mg/kg intravenously once every three weeks until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was safety. The secondary endpoints were objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: 54 patients with RM-NPC were enrolled (Arm 1, n = 30; Arm 2, n = 24). All patients had stage IVb disease and 34 (63%) had received ≥2 lines prior therapies. At data cutoff on Nov 19, 2021, the median SHR-1701 exposure was 6.7 cycles (range 2-23) in Arm 1 and 2.1 cycles (range 1-17) in Arm 2. Grade ≥3 treatment-related adverse events (TRAEs) were observed in 10 patients (18.5%), with the most common being anemia (7.4%) and hemoptysis (3.7%). Two patients (3.7%) discontinued study treatment due to AEs (peripheral nerve injury and epistaxis, n = 1 each), and 10 patients (18.5%) had dose delay caused by AEs. Investigator reported immune related AEs (irAEs) of grade ≥3 occurred in five patients (9.3%). One death (1.9%) from unknown cause was observed, and the causality was deemed as not assessable. At data cutoff, the ORR was 33.3% (95% CI 17.3-52.8) in Arm 1 and 4.2% (95% CI 0.1-21.1) in Arm 2. Responses were ongoing in nine (90.0%) and no patients, respectively, and the median DoR was not reached in Arm 1 and 4.1 months in Arm 2. The DCR was 53.3% (95% CI 34.3-71.7) and 25.0% (95% CI 9.8-46.7), respectively. The median PFS was 5.3 months (95% CI 1.3-not reached) in Arm 1 and 1.4 months (95% CI 1.3-2.7) in Arm 2. At data cutoff, five patients (16.7%) in Arm 1 and eight patients (33.3%) in Arm 2 had died, and the median OS was not reached in both Arms. The 12-month OS rate was 79.9% (95% CI 53.2-92.3) and 71.9% (95% CI 47.6-86.4), respectively. Conclusions: SHR-1701 showed tolerable toxicity profile and promising antitumor activity in patients with RM-NPC who failed prior platinum-based chemotherapy. Clinical trial information: NCT04282070.