Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase II KEYNOTE-158 Study

Abstract

Purpose: KEYNOTE-158 (ClinicalTrials.gov identifier: NCT02628067) investigated the efficacy and safety of pembrolizumab across multiple cancers. We present results from patients with previously treated advanced well-differentiated neuroendocrine tumors (NET).Patients and Methods: Pembrolizumab 200 mg was administered every 3 weeks for 2 years or until progression, intolerable toxicity, or physician/patient decision. Tumor imaging was performed every 9 weeks for the first year and then every 12 weeks. Endpoints included objective response rate (ORR) per RECIST v1.1 by independent central radiologic review (primary) and duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (secondary).Results: A total of 107 patients with NETs of the lung, appendix, small intestine, colon, rectum, or pancreas were treated. Median age was 59.0 years (range, 29-80), 44.9% had ECOG performance status 1, 40.2% had received ≥3 prior therapies for advanced disease, and 15.9% had PD-L1-positive tumors (combined positive score ≥1). Median follow-up was 24.2 months (range, 0.6-33.4). ORR was 3.7% (95% CI, 1.0-9.3), with zero complete responses and four partial responses (three pancreatic and one rectal) all in patients with PD-L1-negative tumors. Median DOR was not reached, with one of four responses ongoing after ≥21 months follow-up. Median PFS was 4.1 months (95% CI, 3.5-5.4); the 6-month PFS rate was 39.3%. Median OS was 24.2 months (95% CI, 15.8-32.5). Treatment-related adverse events (AE) occurred in 75.7% of patients, 21.5% of whom had grade 3-5 AEs.Conclusions: Pembrolizumab monotherapy showed limited antitumor activity and manageable safety in patients with previously treated advanced well-differentiated NETs.

PDX1 DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis

“…This also suggests an important role for immune modulation in GEP-NENs and DNA methylation might be a mechanism to regulate the gene expression of these proteins. Multiple studies evaluating immunotherapy in well-differentiated GEP-NENs are ongoing, but so far, observed response rates have been low [45,46]. Possible explanations are the cold immune microenvironment, i.e., the lack of immune cells, which might be caused by the described immune modulation in GEP-NENs resulting in immune evasion, and the low tumor mutational burden in GEP-NENs, as a high tumor mutational burden has been shown to associate with an increased benefit of immunotherapy [47].…”

Beyond Traditional Morphological Characterization of Lung Neuroendocrine Neoplasms: In Silico Study of Next-Generation Sequencing Mutations Analysis across the Four World Health Organization Defined Groups

“…High rate of mutations could result in the formation of neoantigens, which is hypothesized to enhance the anti-tumor immune response [ 37 ]. In NETs, both the anti-PD1 agents pembrolizumab and spartalizumab have proven to be safe, but the results are unsatisfactory in terms of activity [ 38 , 39 ]. We observed low somatic coding mutation per case for both NETs, but also higher mutation load (≥6 somatic mutations) for two TCs and four ACs.…”

Systemic Treatment Selection for Patients with Advanced Pancreatic Neuroendocrine Tumours (PanNETs)

“…Unfortunately, immunotherapy with checkpoint inhibitors in patients with PanNETs has led to disappointing results (Table S5). Pembrolizumab, an anti-programmed death-1 (PD-1) antibody, has been explored in well-differentiated NEN population first in a phase Ib study (KEYNOTE -028 [49]; 16 patients with PanNETs included) followed by a phase II clinical trial (KEYNOTE-158 [48]; number of patients with PanNETs not specified). Reported median PFS was short (4.5 months in PanNETs) [49] and observed responses were low (6% in PanNETs) [49].…”