Definitive CRT/RT plus immune checkpoint inhibition trials in unresected locally advanced HNSCC.
| Trial (Identifier) | Phase & design | Population/Setting | Regimen & timing (experimental vs. control) | Primary endpoint | Primary endpoint result | Key feasibility/safety notes |
|---|---|---|---|---|---|---|
| JAVELIN Head & Neck 100 [7] (NCT02952586) | Phase III; randomized; double-blind; placebo-controlled | Newly diagnosed, unresected locally advanced HNSCC eligible for cisplatin-based CRT | Avelumab lead-in (single dose 7 days pre-CRT) + concurrent with cisplatin-CRT + maintenance q2w up to 12 months vs. placebo + CRT | PFS (investigator-assessed) | PFS not improved; stratified HR 1.21 (95% CI 0.93–1.57), one-sided P = 0.92 (numerically favored placebo) | Common grade ≥ 3 TRAEs: neutropenia 16% vs. 15%, mucosal inflammation 14% vs. 13%, dysphagia 14% vs. 14%, anemia 12% vs. 13%. OS not reached; OS HR 1.31 (95% CI 0.93–1.85), one-sided P = 0.94 (hierarchical testing limited after primary endpoint not met) (Lee et al., 2021 [7]) |
| KEYNOTE-412 [8] (NCT03040999) | Phase III; randomized; double-blind; placebo-controlled | Newly diagnosed, high-risk, unresected locally advanced HNSCC | Pembrolizumab q3w up to 17 doses (1 pre-CRT, 2 during CRT, then maintenance) + cisplatin-CRT vs. placebo + CRT | EFS | EFS did not meet prespecified significance: HR 0.83 (95% CI 0.68–1.03), P = 0.043 (threshold P < 0.024) | Grade ≥ 3 AEs: 92% vs. 88%. OS at 36 months: 72% vs. 70% (HR 0.90, 95% CI 0.71–1.15). AEs led to discontinuation of any study treatment: 41% vs. 33% (Machiels et al., 2024 [8]) |
| GORTEC 2015-01 [9] (PembroRad) (NCT02707588) | Phase II; randomized | Locally advanced HNSCC unfit for high-dose cisplatin | Pembrolizumab + RT (concurrent) vs. cetuximab + RT (concurrent) | LRC at 15 months | LRC at 15 months: 60% vs. 59%; OR 1.05 (95% CI 0.43–2.59), P = 0.91 | No significant differences in PFS (HR 0.85, 95% CI 0.55–1.32, P = 0.47) or OS (HR 0.83, 95% CI 0.49–1.40, P = 0.49). Grade ≥ 3 AEs: 74% vs. 92% (P = 0.006). Rare but severe vascular toxicity reported in pembrolizumab-RT arm (including arterial thromboses and retinal artery occlusion) (Tao et al., 2023 [9]) |
| Weiss et al., 2020 [24] (RT + pembrolizumab; cisplatin-contraindicated) (NCT02609503) | Phase II; single-arm | Stage III–IV HNSCC cisplatin-ineligible/contraindicated | Definitive RT + pembrolizumab (concurrent × 3 doses, then adjuvant × 3 doses) | Primary: median PFS ≥ 16 months (target) | Primary endpoint met; median PFS not reached at median follow-up 21 months; estimated 24-mo PFS 71% (95% CI 49–84) and 24-month OS 75% (95% CI 51–88) | High grade 3/4 lymphopenia: 58.6% (Weiss et al., 2020 [24]) |
Summary of definitive (non-surgical) trials evaluating PD-1/PD-L1 immune checkpoint inhibitors combined with RT or cisplatin-based CRT in unresected locally advanced HNSCC. Across randomized phase III CRT platforms (JAVELIN Head & Neck 100; KEYNOTE-412) and cisplatin-ineligible phase II RT-based platforms (PembroRad; Weiss et al. [24]), adding immune checkpoint inhibition to definitive RT/CRT did not consistently improve primary survival or locoregional control endpoints in unselected populations. Feasibility and safety interpretation should account for backbone therapy (CRT vs. RT-only), eligibility (cisplatin-eligible vs. ineligible), and protocol-specific definitions of treatment interruption/discontinuation. AEs: adverse events; CI: confidence interval; CRT: chemoradiotherapy; EFS: event-free survival; HNSCC: head and neck squamous cell carcinoma; HR: hazard ratio; OS: overall survival; PD-1: programmed cell death 1; PD-L1: programmed death-ligand 1; PFS: progression-free survival; q2w: every 2 weeks; q3w: every 3 weeks; RT: radiotherapy; TRAEs: treatment-related adverse events.