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

Abstract

Purpose: Patients with recurrent or metastatic neuroendocrine neoplasms (NENs) had a poor prognosis and few treatment options. Toripalimab, a humanized IgG4 antibody specific for human PD-1 receptor, was first approved to treat 2nd line metastatic melanoma in China in 2018. Experimental Design: The multiple-center phase Ib trial enrolled patients with NENs (Ki-67≥10%) after failures of 1st line therapy to received 3 mg/kg toripalimab once every two weeks. The primary objective was objective response rate (ORR) and safety. PD-L1 expression and whole exome sequencing were performed on tumor biopsies. Secondary objectives included duration of response (DOR), disease control rate (DCR), progression free survival and overall survival. Results: Of 40 patients included from April 2017 to December 2018, 8 partial responses and 6 stable diseases were observed, for a 20% ORR and a 35% DCR. The median DOR was 15.2 months. Patients with PD-L1 expression (≥10%) or high tumor mutational burden (TMB) had better ORR than PD-L1 <10% (50.0% vs 10.7%, p=0.019) and TMB low patients (75.0% vs 16.1%, p=0.03). 3/8 (37.5%) responders harbored ARID1A mutations while only 1/27 non-responder was mutated (p=0.03). Of note, 1 exceptional responder with TMB-L, MSS and PD-L1 negative had multiple genomic arrangements with high prediction score for neoantigens. Conclusions: Toripalimab had antitumor activity and safety in treating recurrent or metastatic NENs. Patients with positive PD-L1 expression, TMB-H (top 10%) and/or MSI-H might preferentially benefit from the treatment. The genomic mutation of ARID1A and high genomic rearrangements might be correlated with clinical benefit.