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Nanoparticle Albumin-Bound Paclitaxel and Nivolumab for PD-1 Inhibitor-Refractory Recurrent or Metastatic Head and
Douglas Adkins1,2,3, Jessica C Ley2, Christine Auberle1,2,3
1Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA.
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: H1 ≥ 50 vs. H0 ≤ 30%, type I error 0.05; power 0.80). H0 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: H1 6.0 vs. H0 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. H0, 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.
Insights
This study found that nanoparticle albumin-bound paclitaxel combined with nivolumab showed promising results for patients with recurrent or metastatic head and neck squamous-cell carcinoma (RM-HNSCC) that did not respond to PD-1 inhibitors. The combination therapy demonstrated a significant objective response rate and improved progression-free survival compared to standard treatments.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Standard therapies for PD-1 inhibitor-refractory recurrent or metastatic head and neck squamous-cell carcinoma (RM-HNSCC) have limited efficacy.
- Nanoparticle albumin-bound (nab)-paclitaxel targets cancer cells via macropinocytosis, a pathway common in HNSCC due to hyperactivated EGFR/RAS/PIK3CA signaling.
- Nab-paclitaxel may reverse resistance to PD-1 inhibitors by altering immune cells and priming tumor response.
Purpose of the Study:
- To evaluate the efficacy of combining nab-paclitaxel with nivolumab in patients with PD-1 inhibitor-refractory RM-HNSCC.
- To determine the objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS) of this combination therapy.
Main Methods:
- A single-arm, phase 2 clinical trial was conducted.
- 46 patients with PD-1 inhibitor-refractory RM-HNSCC received nab-paclitaxel and nivolumab in 28-day cycles.
- The primary endpoint was ORR (RECIST1.1); secondary endpoints included DoR, PFS, and OS. A Simon optimal two-stage design was used for sample size calculation.
Main Results:
- The objective response rate (ORR) was 46.7% (21/45 evaluable patients), exceeding the primary hypothesis threshold (p=0.0073).
- Median duration of response (DoR) was 6.1 months.
- Median progression-free survival (PFS) was 5.5 months, and median overall survival (OS) was 13.9 months, with no treatment-related deaths.
Conclusions:
- The combination of nab-paclitaxel and nivolumab demonstrated superior objective response rate and median progression-free survival compared to historical standard therapies for PD-1 inhibitor-refractory RM-HNSCC.
- This combination represents a promising therapeutic option for patients with advanced HNSCC who have progressed on PD-1 inhibitors.
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