Nivolumab plus platinum-doublet chemotherapy in treatment-naive patients with advanced grade 3 Neuroendocrine Neoplasms of gastroenteropancreatic or unknown origin: The multicenter phase 2 NICE-NEC trial (GETNE-T1913)

Abstract

The prognosis of patients with advanced high-grade (G3) digestive neuroendocrine neoplasms (NENs) is rather poor. The addition of immune checkpoint inhibition to platinum-based chemotherapy may improve survival. NICE-NEC (NCT03980925) is a single-arm, phase II trial that recruited chemotherapy-naive, unresectable advanced or metastatic G3 NENs of gastroenteropancreatic (GEP) or unknown origin. Patients received nivolumab 360 mg intravenously (iv) on day 1, carboplatin AUC 5 iv on day 1, and etoposide 100 mg/m²/d iv on days 1-3, every 3 weeks for up to six cycles, followed by nivolumab 480 mg every 4 weeks for up to 24 months, disease progression, death or unacceptable toxicity. The primary endpoint was the 12-month overall survival (OS) rate (H₀ 50%, H₁ 72%, β 80%, α 5%). Secondary endpoints were objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and safety. From 2019 to 2021, 37 patients were enrolled. The most common primary sites were the pancreas (37.8%), stomach (16.2%) and colon (10.8%). Twenty-five patients (67.6%) were poorly differentiated carcinomas (NECs) and/or had a Ki67 index >55%. The ORR was 56.8%. Median PFS was 5.7 months (95%CI: 5.1-9) and median OS 13.9 months (95%CI: 8.3-Not reached), with a 12-month OS rate of 54.1% (95%CI: 40.2-72.8) that did not meet the primary endpoint. However, 37.6% of patients were long-term survivors (>2 years). The safety profile was consistent with previous reports. There was one treatment-related death. Nivolumab plus platinum-based chemotherapy was associated with prolonged survival in over one-third of chemonaïve patients with G3 GEP-NENs, with a manageable safety profile.

Fig. 1. PFS and OS of patients with high-grade NENs of GEP or UK origin treated with nivolumab, carboplatin, and etoposide.

A Kaplan Meier showing the OS for the full dataset (n = 37). The red line shows the estimated survival proportion and the shadow area the 95% CI. The red dashed lines indicate the 50% survival probability point estimate. B Multivariable analysis to find potential baseline prognostic factors for OS. The forest plot shows the hazard ratio of each subgroup and its 95% CI. C Kaplan-Meier showing the PFS for the full dataset. D Multivariable analysis to find potential baseline prognostic factors for PFS. The forest plot shows the hazard ratio of each subgroup and its 95% CI. Multivariable analyses were performed using the Cox model and are exploratory. Significance tests are two-sided. Source data are provided as a Source Data file. CGA chromogranin A, CI confidence interval, Diff differentiated, ECOG-PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio, OS overall survival, PFS progression-free survival.

Fig. 2. Efficacy of Nivolumab, Carboplatin and Etoposide as first-line treatment of highgrade NENs of GEP or UK origin.

A Waterfall plot showing objective response rate (ORR) and the percentage of maximum change from baseline tumor size for each patient (n = 37). B Spider plot showing the evolution of relative tumor size from the first dose of study treatment until the last tumor evaluation (n = 37). Asterisk sign indicates PD-L1 positivity, lined plotted columns indicate MSI, dotted plotted columns MSS. Maximum change in tumor size, shown as percentage from baseline, and ORR rates analyzed by subgroups clustered according to baseline characteristics such as primary tumor site (C), Ki-67 proliferation index (D), or tumor differentiation (E). Three patients, one MSS and two unknown died due to disease progression before the first tumor assessment were not evaluated for response. Exploratory subgroup analyses were performed using Fisher’s Exact Test (C) and Pearson’s Chi-squared test (D and E). Significance tests are two-sided. Source data are provided as a Source Data file. DCR disease control rate, EG esophageal and gastric, NE not evaluable, NEC neuroendocrine carcinoma, NET neuroendocrine tumor, ORR objective response rate, PD progressive disease, PR partial response, RECIST Response Evaluation Criteria In Solid Tumors, SD stable disease, SI small intestine, UK unknown.

Fig. 3. Safety profile of nivolumab in combination with carboplatin and etoposide.

A Treatment-related adverse events encountered in >5% of patients. The graph represents the worst grade per patient. The percentage of patients experiencing an event is depicted (n = 37). B Distribution of toxicities by study phase (induction versus maintenance phase) from first dose of study treatment until last follow-up (n = 37 for concomitant phase and n = 24 for maintenance phase). Source data are provided as a Source Data file.