Spartalizumab in metastatic, well/poorly differentiated neuroendocrine neoplasms

Abstract

Spartalizumab, a humanized anti-programmed death protein 1 (PD-1) monoclonal antibody, was evaluated in patients with well-differentiated metastatic grade 1/2 neuroendocrine tumors (NET) and poorly-differentiated gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC). In this phase II, multicenter, single-arm study, patients received spartalizumab 400 mg every 4 weeks until confirmed disease progression or unacceptable toxicity. The primary endpoint was confirmed overall response rate (ORR) according to blinded independent review committee using response evaluation criteria in solid tumors 1.1. The study enrolled 95 patients in the NET group (30, 32 and 33 in the thoracic, gastrointestinal, and pancreatic cohorts, respectively), and 21 patients in the GEP-NEC group. The ORR was 7.4% (95% confidence interval [CI]: 3.0, 14.6) in the NET group (thoracic, 16.7%; gastrointestinal, 3.1%; pancreatic, 3.0%), which was below the predefined success criterion of ≥10%, and 4.8% (95% CI: 0.1, 23.8) in the GEP-NEC group. In the NET and GEP-NEC groups, the 12-month progression-free survival was 19.5% and 0%, respectively, and the 12-month overall survival was 73.5% and 19.1%, respectively. The ORR was higher in patients with ≥1% PD-L1 expression in immune/tumor cells or ≥1% CD8+ cells at baseline. The most common adverse events considered as spartalizumab-related included fatigue (29.5%) and nausea (10.5%) in the NET group, and increased aspartate and alanine aminotransferases (each 14.3%) in the GEP-NEC group. The efficacy of spartalizumab was limited in this heterogeneous and heavily pre-treated population; however, the results in the thoracic cohort is encouraging and warrants further investigation. Adverse events were manageable and consistent with previous experience.

Systemic Treatment of Gastroenteropancreatic Neuroendocrine Carcinoma

“…Patients with PD-L1 expressions of more than 1% or presenting with more than 1% of CD8+ cells at baseline were observed to have higher ORR. The primary endpoint was not met [81]. Clarifying results from clinical trials are awaited (Table 2) concerning the efficacy of immunotherapy in NEC patients.…”

Genetic Drivers of Ileal Neuroendocrine Tumors

“…Finally, I-NETs are also thought to be poor candidates for immunotherapies. In a phase II trial of PD1-targeting monoclonal antibody spartalizumab, patients with well-differentiated gastrointestinal NETs showed only a 3.1% overall response rate, which was below the trial's pre-defined success criterion of 10% [12]. No partial responses to nivolumab/ipilimumab combination therapy were detected in five patients with low grade small intestinal NETs, while a partial response was detected in one patient with a high grade small intestinal neuroendocrine carcinoma (SI-NEC) [13].…”

Outcomes of small‐cell versus large‐cell gastroenteropancreatic neuroendocrine carcinomas: A population‐based study

“…Whether the SC versus LC histology could affect this chemotherapy choice is unclear. Similarly, immune checkpoint inhibitors (ICIs) have been approved for the treatment of patients with extensive‐stage SCLC, 18,19 and they are being actively investigated among patients with GEP‐NENs 20,21 . Importantly, studies exploring the use of ICIs among those patients should stratify the outcomes according to SC versus LC histology to examine the impact of this finding.…”