Safety and Efficacy of Allogeneic Natural Killer Cells in Combination with Pembrolizumab in Patients with Chemotherapy-Refractory Biliary Tract Cancer: A Multicenter Open-Label Phase 1/2a Trial

SIMPLE SUMMARY: Since there is no effective subsequent-line therapy for patients with cisplatin/gemcitabine-refractory advanced biliary tract cancer, there is an urgent need for new treatment options. This phase 1 and 2a study is the first clinical trial reporting the safety and the efficacy of allogeneic NK cells (“SMT-NK”) in combination with pembrolizumab in patients with chemotherapy-refractory advanced biliary tract cancer. We found that the SMT-NK can be safely administered with pembrolizumab to patients with the chemotherapy-refractory advanced biliary tract cancer, and the combinational therapy of SMT-NK and pembrolizumab showed improved efficacy outcome compared to recent trials using pembrolizumab alone. This study provides evidence for a new possible treatment option for advanced biliary tract cancer patients. ABSTRACT: Background and Aim: This study investigated the administration of combination therapy, allogeneic natural killer (NK) cells and pembrolizumab in the treatment of advanced biliary tract cancer to determine the safety and tolerability (phase 1) and the efficacy and safety (phase 2a). Methods: Forty patients (phase 1, n = 6; phase 2a, n = 34) were enrolled between December 2019 and June 2021. The patients received highly activated allogeneic NK cells (“SMT-NK”) on weeks 1 and 2 and pembrolizumab on week 1. This 3-week schedule (one cycle) was repeated until confirmed disease progression, intolerable adverse events (AEs), patient withdrawal, or finishing the maximum treatment schedule. The tumor response was evaluated after every three cycles. Results: In phase 1, four patients (66.7%) experienced seven AEs, but no severe AE was observed. In phase 2a, 126 AEs occurred in 29 patients (85.3%). Severe AEs (≥grade 3) were reported in 16 patients (47.1%). The overall response rate (ORR) was 17.4% in the full analysis set and 50.0% in the per-protocol set. Conclusions: SMT-NKs plus pembrolizumab resulted in no severe AEs directly related to the drug combination. The combination therapy also exerted antitumor activity with improved efficacy compared to the recent monotherapy with pembrolizumab in patients with advanced biliary tract cancer.