Sintilimab in Patients with Previously Treated Metastatic Neuroendocrine Neoplasms

Abstract

Background: Neuroendocrine neoplasms (NENs) are a group of diseases that show high heterogeneity but have limited treatment options. This phase I study evaluated the safety and efficacy of sintilimab, anti-PD-1 monoclonal antibody, in treating advanced NENs.

Methods: We prospectively enrolled patients pathologically diagnosed with NENs after standard treatment failure. Neuroendocrine neoplasms were classified into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine cancers (NECs). Every patient received sintilimab, and response was assessed every 9 weeks.

Results: Twenty-four patients with a median age of 57.0 years were enrolled from November 2016 to 2017. The median Ki-67 index was 60%. Five patients had NET, 1 had NET G3, 17 had NEC, and 1 had mixed adenocarcinoma-neuroendocrine carcinoma. The most common primary tumor sites were the pancreas and gastrointestinal tract in 7 and 10 patients, respectively. In phase Ia trial, 2 patients received sintilimab 1 mg/kg every 2 weeks, one received 3 mg/kg every 2 weeks, and 21 patients enrolled in the phase Ib trial received 200 mg every 3 weeks. The objective response rate was 20.8% in all enrolled patients and 27.8% in NEC patients. The median progression-free survival was 2.2 and 2.1 months in patients with NET and NEC, respectively. The median OS was not applicable (NA) and 10.8 months (95% CI, 4.3, NA) with NET and NEC, respectively. The duration of response (DOR) was not reached, with a median follow-up time of 20.7 months. Treatment-related adverse events (TRAE) occurred in 17 (70.8%) patients. The most frequent TRAE was thyroid dysfunction (41.7%), and a grade 3 pulmonary infection occurred in 1 patient. The programmed cell death 1-ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) rate was 18.8% (3 out of 16) and the expression of PD-L1 did not correlate with response.

Conclusion: Sintilimab was well-tolerated and showed encouraging response in NECs.

Clinicaltrials.gov identifier: NCT02937116.

Keywords: anti-PD-1 antibody; checkpoint blockade; immunotherapy; neuroendocrine cancers; neuroendocrine neoplasms.

© The Author(s) 2022. Published by Oxford University Press.

Figures

Figure 1.

Maximum change from baseline in target lesion size assessed per RECIST v1.1 by investigator view with at least one postbaseline radiographic evaluation (n = 19). *Changes of more than 100% were truncated at 100%. Abbreviations: NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; RECIST, Response Evaluation Criteria in Solid Tumors.

Figure 2.

Antitumor activity of sintilimab in the total population. (A) Change from baseline of individual tumor burden in target lesion size (n = 19). *Changes of more than 100% were truncated at 100%. (B) Treatment exposure and duration of response assessed per RECIST v1.1 by investigator review (n = 24). Three patients were not assessed postbaseline as a result of clinical progression (n = 2) and death (n = 1). Two patients had new lesions without assessable RECIST changes and were assessed PD. The 2 black arrows indicate patients who were continuing treatment at the data cutoff date. Abbreviations: NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; RECIST, Response Evaluation Criteria in Solid Tumors; PR, partial response; PD, progressive disease.