NP-101 in Combination with Nivolumab and Ipilimumab in Metastatic Extra-pulmonary Neuroendocrine Carcinomas (EP-NECs): A Pilot Study.

Extrapulmonary Neuroendocrine Carcinomas (EP-NECs) are a heterogeneous group of rare tumors with poor clinical outcomes. These patients have limited treatment options after progressing on first-line platinum-based chemotherapy. Although dual immune checkpoint inhibitors (ICIs) with anti-CTLA-4 and anti-PD-1 blockade have significantly improved outcomes for several solid tumors, they demonstrated modest activity for EP-NECs with 9-26% response rates and low survival rates. Preliminary data demonstrated that NP-101 (Nigella Sativa formulation) enhances T-cell infiltration and is synergistic with dual ICPIs in NECs' cellular models. This pilot study evaluated the tolerability and efficacy of NP-101 plus nivolumab and ipilimumab in patients with metastatic EP-NECs refractory to first-line platinum-based chemotherapy. This is a single-arm pilot study (NCTNCT05262556) in which patients with metastatic EP-NECs received NP-101 (oral capsules), 3000 mg daily, plus ICPIs (intravenous nivolumab 3 mg/kg and Ipilimumab 1 mg/kg) every 3 weeks for 4 cycles. Non-progressors received NP-101 (3000 mg daily), plus biweekly maintenance of nivolumab (240 mg), and then completed 24 weeks of treatment. Treatment-related adverse events (TR-AEs) were characterized according to CTCAE v4.03. The response rate was estimated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The Kaplan Meir method was used to estimate median PFS and OS. Twelve patients received ≥1 dose of NP-101 and nivolumab plus ipilimumab. There were no dose limiting toxicities (DLTs). Grade 1/2 TR-AEs occurred in 100% (12/12) of patients. The most common G1/2 TR-AEs included: fatigue (75%), nausea (41.7%), pruritus (41.7%), muscle weakness (33.3%), vomiting (25%), rash (25%) and abdominal pain (25%). Eight patients (66%) experienced grade 3/4 TR-AEs including: rash (33.3%), nausea (16.7%), vomiting (16.7%), and transaminitis (16.7%). No treatment-related Grade 5 toxicities or deaths were recorded. The objective response rate was 41.7% [2/12 (16%) complete response (CR) + 3/12 (25%) partial response (PR); 95% CI:15.2-72.3%] for all patients and 50% (2/8 CR + 2/8 PR, 95% CI: 0.16 - 0.84) for patients with NEC of gastrointestinal origin. The median duration of response was 7.5 months. As for the median progression-free survival, it was 5.7 months, and median overall survival (OS) was 10.5 months with a median follow up of 10.4 months. The combination of NP-101 plus dual ICPIs (nivolumab and ipilimumab) was safe and well-tolerated with preliminary evidence of anti-neoplastic activity. Currently, a randomized phase II clinical trial evaluating the combination is under development.