Safety, Efficacy and Biomarkers of Toripalimab in Patients with Recurrent or Metastatic Neuroendocrine Neoplasms: A Multiple-Center Phase Ib Trial

Background: Patients with recurrent or metastatic neuroendocrine neoplasms (NENs) after failure of 1st line therapy have a poor prognosis and few treatment options. Tumor infiltrating lymphocytes were often found within NENs. PD-1 checkpoint blockade thus provides a potential therapeutic opportunity for NEN patients refractory to somatostatin analog therapy, target therapy or chemotherapy. Toripalimab, a humanized IgG4 monoclonal antibody against PD-1 has shown clinical activities in several phase I/II trials of solid tumors. Methods: We conducted a multiple-center phase Ib trial evaluating the safety and efficacy of toripalimab in recurrent or metastatic NENs (Ki-67≥10%) after failures of 1st line therapy. Patients received 3 mg/kg toripalimab through intravenous infusion once every two weeks until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The primary objective was objective response rate (ORR) and safety. Secondary objectives included duration of response (DOR), disease control rate (DCR), progression free survival (PFS) and overall survival. PD-L1 expression and whole exome sequencing were performed on tumor biopsies for biomarker analysis. Findings: From April 2017 to December 2018, forty patients were enrolled in the study. As of Aug 30, 2019, eight partial responses and six stable diseases were observed as assessed by investigator per RECIST v1.1, for a 20% ORR and a 35% DCR. The median DOR was 15.2 months with 4 out of 8 responses still ongoing. Notably, patients with high PD-L1 expression (≥10%) in tumor biopsies or high tumor mutational burden (TMB) had significant better ORR than PD-L1 expression <10% (50.0% versus 10.7%, p=0.019) and TMB low patients (75.0% versus 16.1%, p=0.03). By the cut-off date, 95.0% of patients experienced treatment-related adverse events (TRAE). The most common TRAE included elevated ALT, AST or total bilirubin, fatigue, proteinuria, vomiting and decreased appetite. Grade 3 and above TRAE occurred in 27.5% patients. 55.0% patients experienced immune-related AEs, including elevated AST/ALT/Direct Bilirubin and hypothyroidism. Treatment was terminated in four patients due to TRAE. Interpretation: Toripalimab demonstrated a manageable safety profile and a promising anti-tumor activity in metastatic NEN patients after failure of 1st line therapy. Tumor high PD-L1 expression (≥10%) or TMB high (top 10%) patients might preferentially benefit from the treatment. Funding: Shanghai Junshi Biosciences Co., LTD, Shanghai, China. Declaration of Interest: Weifeng Wang is employed by OrigiMed. Hui Feng, Hai Wu and Sheng Yao are employed by Shanghai Junshi Biosciences. The rest of authors have no disclosures of potential conflicts of interests. Ethical Approval: The study was approved by Peking University Cancer Hospital institutional review board and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Each patient provided written informed consent.