Nanoliposomal Irinotecan in Combination With 5‐Fluorouracil and Leucovorin for Advanced Head and Neck and Esophageal Squamous Cell Carcinoma After Prior Platinum‐Based Chemotherapy or Chemoradiotherapy: A Multicenter Phase II Trial

Purpose To evaluate the efficacy and safety of nanoliposomal irinotecan (nal‐IRI) plus 5‐fluorouracil (5‐FU) and leucovorin (LV) in patients with platinum‐refractory or intolerant head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC). Methods In this multicenter, phase 2 study (NCT03712397), patients with advanced HNSCC ( n = 43) or ESCC ( n = 16) who had failed or were intolerant to platinum‐based chemotherapy received biweekly nal‐IRI 80 mg/m 2 (equivalent to 70 mg/m 2 of irinotecan base), LV 400 mg/m 2 , and 5‐FU 2400 mg/m 2 until progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR). Results In the intent‐to‐treat analysis, the ORR and disease control rate were 8.5% and 59.3% for the entire group. In the HNSCC subgroup, ORR and disease control rate were 11.6% and 65.1%, with a median progression‐free survival (PFS) of 2.7 months and an overall survival (OS) of 8.1 months. By contrast, no objective responses were observed in ESCC (ORR 0%, disease control rate 43.8%, median OS 4.2 months). The most common grade 3/4 toxicities were lymphopenia (50.8%), neutropenia (42.4%), leukopenia (33.9%), anemia (28.8%), and anorexia (8.5%). Conclusions Nal‐IRI/5‐FU/LV demonstrates modest activity with acceptable safety profiles in patients with platinum‐refractory or intolerable advanced HNSCC. The exploratory findings warrant confirmation in larger, randomized studies. Trial Registration ClinicalTrials.gov : NCT03712397