Nanoparticle Albumin‐Bound Paclitaxel and Nivolumab for PD ‐1 Inhibitor‐Refractory Recurrent or Metastatic Head and Neck Squamous‐Cell Carcinoma

ABSTRACT Introduction Standard therapy for PD‐1 inhibitor‐refractory recurrent or metastatic head and neck squamous‐cell carcinoma (RM‐HNSCC) has limited activity. Drugs bound to albumin selectively target cancer cells with upregulated macropinocytosis, a process driven by constitutively hyper‐activated EGFR/RAS/PIK3CA signaling, which is common in HNSCC. Nanoparticle albumin‐bound ( nab )‐paclitaxel is active in PD‐1 inhibitor‐naïve RM‐HNSCC and alters immune cells to potentially prime tumor response and reverse resistance to PD‐1 inhibitors. Methods In a single‐arm phase 2 trial, patients with PD‐1 inhibitor‐refractory RM‐HNSCC received nab‐ paclitaxel and nivolumab given in 28‐day cycles. The primary endpoint was objective response rate (ORR), using RECIST1.1. Key secondary endpoints were duration of response (DoR), progression‐free survival (PFS), and overall survival (OS). At least one tumor response assessment was required to be evaluable for ORR and PFS. A Simon optimal two‐stage design tested the primary hypothesis (ORR: H 1 ≥ 50 vs. H 0 ≤ 30%, type I error 0.05; power 0.80). H 0 was rejected if ≥ 19 responses were observed in 46 patients. This sample size had a power of 80% to detect the difference in the key secondary hypothesis (median PFS: H 1 6.0 vs. H 0 3.6 months, two‐sided, one‐sample log rank test; type I error 0.05). Results From 9/28/2021–1/4/2024, 46 patients enrolled into the trial. One patient was not evaluable for ORR and PFS. Tumor response occurred in 21 of 45 evaluable patients (ORR 46.7%, 95% CI: 33.8–59.9; vs. H 0 , p = 0.0073) and included confirmed response in 20 and unconfirmed response in 1. The best tumor response was complete (4), partial (17), stable (18), and progression (6). The median DoR was 6.1 months (95% CI: 2.8–9.4). With a median follow‐up of 14.1 months (IQR: 7.6–20.1), the median PFS was 5.5 months (95% CI: 3.9–7.8) and the median OS was 13.9 months (95% CI: 9.0–18.9). Treatment‐related deaths did not occur. Conclusion Among patients with PD‐1 inhibitor‐refractory RM‐HNSCC, nab ‐paclitaxel and nivolumab resulted in an ORR and median PFS that were better than historically reported with standard therapy. Trial Registration Trial registered on www.clinicaltrials.gov, National Clinical Trial (NCT) 04831320