xRead - An Update on Immunotherapy in Head and Neck Cancer (November 2025)
Clinical Review & Education Review
Immunotherapy in Head and Neck Squamous Cell Carcinoma
Table 2. Negative Phase 3 Trials Trial and treatment group
Key inclusion criteria
HPV status Primary outcome (95% CI) Hazard ratio
EAGLE 27 Durvalumab
OS, 7.6 (6.1-9.8) mo OS, 6.5 (5.5-8.2) mo OS, 8.3 (7.3-9.2) mo
0.88 (95% CI, 0.72-1.08); P = .20 a ; 1.04 (95% CI, 0.85-1.26); P = .76 b
R/M disease that progressed after/during platinum therapy
Durvalumab + tremelimumab
Both
SOC
KESTREL 28 Total population
Durvalumab
OS, 9.9 (8.9-11.9) mo OS, 10.7 (9.6-12.2) mo OS, 10.3 (9.0-12.1) mo OS, 10.9 (9.0-14.2) mo OS, 11.2 (9.5-13.9) mo OS, 10.9 (8.3-13.4) mo
1.03 (95% CI, 0.83-1.27) c ; 1.04 (95% CI, 0.87-1.25) d
Durvalumab + tremelimumab
EXTREME
Previously untreated R/M
Both
PD-L1high e
Durvalumab
0.96 (95% CI, 0.69-1.32); P = .79 c ; 1.05 (95% CI, 0.80-1.39) d
Durvalumab + tremelimumab
EXTREME
CheckMate-651 29 Total population
Nivolumab + ipilimumab
OS, 13.9 (12.1-15.8) mo OS, 13.5 (12.6-15.2) mo
0.95 (97.9% CI, 0.80-1.13); P = .50
EXTREME
Previously untreated R/M
Both
CPS ≥ 20
Nivolumab + ipilimumab
OS, 17.6 (13.8-22.0) mo OS, 14.6 (12.3-16.0) mo
0.78 (97.51% CI, 0.59-1.03); P = .047
EXTREME
JAVELIN Head and Neck 100 30 Avelumab + CT + RT
PFS (median not reached) PFS (median not reached)
Previously untreated, locally advanced
Both
1.21 (95% CI, 0.93-1.57); P = .92
Placebo + CT + RT
KEYNOTE-412 31 Pembrolizumab + CT + RT
EFS (median not reached) EFS (median not reached)
High-risk, unresected, locally advanced
0.83 (95% CI, 0.68-1.03); P = .04 f
Both
Placebo + CT + RT GORTEC-REACH 32 Cisplatin fit
Avelumab + cisplatin + RT
1-y PFS, 64% (54%-72%) 1-y PFS, 73% (65%-81%)
1.27 (95% CI, 0.83-1.93)
Cisplatin + RT
Previously untreated, locally advanced
Not stratified
Cisplatin unfit Avelumab + cetuximab + RT
2-y PFS, 44% (35%-53%) 2-y PFS, 31% (23%-40%)
0.84 (95% CI, 0.62-1.15); P = .15
Cetuximab + RT
IMvoke010 33
Atezolizumab
Locally advanced; completed multimodal definitive treatment (surgery + CT + RT, CT + RT, induction CT + surgery + CT + RT)
EFS, 59.5 (46.8-NE) mo EFS, 52.7 (41.4-NE) mo
Both
0.94 (95% CI 0.70-1.26); P = .68
Placebo
b Durvalumab + tremelimumab vs SOC. c Durvalumab vs EXTREME. d Durvalumab + tremelimumab vs EXTREME. e PD-L1 high, at least 25% tumor cell expression of PD-L1. f Significance was set to P .024.
Abbreviations: CPS, combined positive score; CT, chemotherapy; EFS, event-free survival;HPV,humanpapillomavirus;EXTREME,platinum + 5-fluorouracil + cetuximab; NE, not evaluable; OS, median overall survival; PD-L1, programmed cell death 1 ligand 1; PFS, progression-free survival; R/M, recurrent or metastatic; RT, radiation therapy;
SOC, standard of care. a Durvalumab vs SOC.
To our knowledge, the first and only completed phase 3 trial assessing sequential ICI administration is IMvoke010, 33 which evaluated PD-L1–targeting atezolizumab following multimodal definitive treatment. This study was prompted by encouraging results from a phase 1 study of atezolizumab. 41 IMvoke010 found that atezolizumab treatment after com pletion of multimodal definitive treatment did not show a statis tically significant improvement in survival compared with placebo. 42
Ongoing Trials Despite the disappointing results of IMvoke010, there are addi tional ongoing large trials 43-48 assessing ICI efficacy in the postde finitive treatment setting ( Table3 ). eVOLVE-HNSCC is a phase 3 trial assessing the efficacy and safety of volrustromig, an anti–PD-1/ CTLA-4 bispecific humanized immunoglobin G1 monoclonal anti body in patients who completed definitive concurrent chemoradia
524 JAMA Otolaryngology–Head & Neck Surgery May 2025 Volume 151, Number 5 (Reprinted)
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