帕博利珠单抗联合兰瑞肽长效制剂治疗晚期进展性胃肠胰神经内分泌肿瘤的 Ib/II 期研究（PLANET）

While performing a study of immune checkpoint blockade with the anti-PD-1 antibody pembrolizumab combined with the somatostatin analogue (SSA) lanreotide in patients with low- and intermediate-grade gastroenteropancreatic neuroendocrine tumors (GEP-NETs), we studied whether there were any immune correlates of response to the anti-PD-1 therapy that could guide future attempts to integrate immunotherapy into the treatment of NETs. Patients with grade 1 and 2 GEP-NETs who had progressed on a prior SSA received lanreotide 90 mg subcutaneously and pembrolizumab 200 mg intravenously every 3 weeks until progression or intolerable toxicity. Objective response rate (ORR) at any time in the study, clinical benefit rate (CBR, defined as stable disease or better), progression-free survival (PFS), and overall survival (OS) were measured.

Changes in T cell subsets in peripheral blood before and during therapy were analyzed by multiparameter mass cytometry (CyTOF). Archived tissue samples were analyzed for PD-L1 expression and TIL infiltration. Twenty-two (22) patients (GI/pancreatic 14/8, median Ki67 7% [IQR 4, 10%], median 1. 5 prior systemic therapies [range 1-4]) were enrolled.

Among the GI-NETs, there was one partial response, the CBR was 50%, the median PFS was 8. 5 months, and the median OS was 32. 7 months. No responses were seen in pancreatic NETs, which had 0% CBR, a PFS of 2. 7 months, and an OS of 23. 9 months. Of the 16 analyzable tumors, 6 had detectable PD-L1 expression and 15 had detectable TILs. Neither TILs nor PD-L1 expression correlated with ORR or CBR.

However, clinical benefit (SD or better) was associated with peripheral blood on-treatment effector memory T cell activation and progressive disease was associated with baseline peripheral blood regulatory T cell (Treg) activation.

We conclude that immune checkpoint blockade had low activity in unselected patients with grade 1 and 2 GEP-NETs.

Further study of strategies to reduce Treg activation or enhance effector memory activation during immunotherapy is warranted.