482 Biomarker analysis from KESTREL identifies tumor cytotoxicity and immunogenic cell death as predictors of benefit with durvalumab plus tremelimumab in HNSCC
Year: 2026
Type: conference-abstract
Abstract: Background The phase III KESTREL trial in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) compared EXTREME, durvalumab, and durvalumab plus tremelimumab, but neither experimental regimen improved overall survival (OS) versus EXTREME in the overall population. 1 Given the heterogeneity of HNSCC and variable benefit from immune checkpoint inhibitor (ICI) therapy, we focused on durvalumab plus tremelimumab and explored whether baseline tumor cytotoxicity, immunogenic cell death (ICD) related signaling, and selected molecular features could help identify subgroups with improved outcomes.Methods Exploratory biomarker analyses were performed in biomarker evaluable patients from KESTREL with baseline tumor RNA-seq and OS data from the EXTREME and durvalumab plus tremelimumab arms (n = 121; n = 42 and n = 79, respectively). Cytotoxicity was quantified using a predefined gene expression signature and dichotomized as high (upper quintile) versus non-high (remaining patients). ICD signaling was assessed using a predefined transcriptomic score comprising JAK2, HMGB1, MT-ATP5, and Hallmark IFN-α response genes and similarly dichotomized. OS was analyzed using Kaplan-Meier estimates and univariable and multivariable Cox proportional hazards models adjustment for HPV status and PD-L1 expression. Additional analyses assessed associations with primary tumor site and ctDNA-defined alterations including EGFR.Results In the durvalumab plus tremelimumab arm, high anti-tumor cytotoxicity was associated with longer OS than non-high group (median 19.7 vs. 7.9 months; HR 0.53, 95% CI 0.29-0.95; p = 0.032). High cytotoxicity tumors showed increased CD8, NK-cell and IFN-γ related effector signatures and were enriched in oropharyngeal and oral cavity versus laryngeal and hypopharyngeal primaries. High cytotoxicity was also correlated with HPV-positive status (36.4% vs. 17.4%; p = 0.011) and higher PD-L1 expression (median TC, 5% vs. 2%; p = 0.0014). High ICD signaling was associated with longer OS in this arm (median 11.0 vs. 8.2 months; HR 0.55, 95% CI 0.31-0.92; p = 0.020). Both cytotoxicity and ICD biomarkers remained significantly associated with OS in the multivariable models. Among exploratory molecular features, EGFR-mutant tumors were associated with reduced clinical benefit from ICI (median 6.5 vs. 13.0 months; HR 1.75, 95% CI 1.15-2.70; p = 0.0089).Conclusions Although the experimental arms in KESTREL did not significantly improve OS in the overall population, these exploratory analyses suggest that benefit with durvalumab plus tremelimumab may be enriched in biomarker defined subsets of HNSCC, characterized by high baseline cytotoxic immune activity and ICD signaling. These findings are consistent with an inflamed (immune-hot) tumor microenvironment and support validation in larger cohorts to assess whether these biomarkers may refine patient selection and inform strategies to convert immune-cold tumors to immune-hot tumors.Acknowledgements We thank the patients, their families, investigators, and study teams who participated in the KESTREL clinical trial. We also thank the AstraZeneca genomics team for their support of this exploratory analysis.Trial Registration ClinicalTrials.gov ID: NCT02551159.Reference Psyrri A, Fayette J, Harrington K, Gillison M, Ahn MJ, Takahashi S, Weiss J, Machiels JP, Baxi S, Vasilyev A, Karpenko A, Dvorkin M, Hsieh CY, Thungappa SC, Segura PP, Vynnychenko I, Haddad R, Kasper S, Mauz PS, Baker V, He P, Evans B, Wildsmith S, Olsson RF, Yovine A, Kurland JF, Morsli N, Seiwert TY. KESTREL investigators. durvalumab with or without tremelimumab versus the EXTREME regimen as first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck: KESTREL, a randomized, open-label, phase III study. Ann Oncol. 2023;34:262–274.Ethics Approval The studies were approved by institutional review boards at participating centers according to local regulations.
Institutions: AstraZeneca (United States), AstraZeneca (Spain)
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225297874