Authors
Harold Nathan Tan, Bettzy Stephen, Oriol Mirallas, Mohamed H Derbala, Israa Salih, Lilibeth Castillo, Yali Yang, Hung Le, Lei Kang, Heather Lin, Joann Lim, Ecaterina E Dumbrava, Timothy A Yap, Jordi Rodón, Sarina A Piha-Paul, Siqing Fu, Stéphane Champiat, Neal Akhave, Renata Ferrarotto, David S Hong, Funda Meric-Bernstam, Faye Johnson, Aung Naing
Published in
JAMA network open. Volume 9. Issue 7. Pages e2623522. Jul 01, 2026. Epub Jul 01, 2026.
Abstract
Immune checkpoint inhibitors (ICIs) have transformed the management of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), yet most patients eventually develop resistance. Investigational immunotherapy strategies beyond checkpoint blockade are being explored, but their clinical activity and associated biomarkers remain poorly defined.
To evaluate the safety, antitumor activity, and biomarkers associated with novel immunotherapy agents in patients with recurrent or metastatic HNSCC treated in early-phase clinical trials.
This retrospective cohort study was conducted at The University of Texas MD Anderson Cancer Center Department of Investigational Cancer Therapeutics and included adult patients (aged ≥18 years) with advanced HNSCC treated with novel immunotherapy agents in early-phase clinical trials between January 1, 2015, and May 31, 2025. Patients were followed up from treatment initiation until disease progression, death, or last clinical contact.
Treatment with investigational immunotherapy agents administered in early-phase clinical trials.
The primary outcomes included treatment-related adverse events, objective response rate (complete or partial response), clinical benefit rate (complete or partial response or stable disease lasting ≥6 months), progression-free survival, and overall survival. Logistic regression was used to evaluate biomarkers associated with the clinical benefit rate, including clinical, genomic, and treatment-related variables, while survival outcomes were estimated using the Kaplan-Meier method.
The sample included 158 patients (median [range] age, 60.7 [25.7-84.6] years; 136 male [86.1%]). The oropharynx was the most common primary site (94 patients [59.6%]). Patients had received a median of 3 prior lines (range, 0-8 prior lines) of systemic therapies, and 126 patients (79.7%) had prior ICI exposure. A total of 91 of 153 patients (59.5%) had human papillomavirus-positive tumors, and PD-L1 combined positive score of at least 1 was observed in 67 of 87 patients (77.0%). Most patients received combination immunotherapy (106 [67.1%]), with a median treatment duration of 2.3 months (range, 0.1-19.7 months). Treatment-related adverse effects occurred in 85 patients (53.8%), including grade 3 or higher events in 23 patients (14.6%). The overall response rate was 7.7% (12 patients), and the clinical benefit rate was 16.1% (25 patients). Bispecific antibodies were associated with improved clinical benefit (odds ratio, 1.95; 95% CI, 1.23-4.15), whereas PIK3CA alterations were associated with reduced benefit (odds ratio, 0.03; 95% CI, 0.00-0.51). Median progression-free survival was 2.3 months (95% CI, 2.0-2.9 months) and median overall survival was 8.3 months (95% CI, 7.2-11.0 months).
This retrospective cohort study of heavily pretreated patients with HNSCC treated in early-phase clinical trials found that novel immunotherapy agents may have manageable toxic effects but modest antitumor activity. Bispecific antibodies may have encouraging activity while genomic alterations may help inform treatment stratification.
PMID:
42461627
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.
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