Background
Phase II randomized trial (NRG-HN002). N=306, p16-positive low-to-intermediate risk oropharyngeal SCC (T1–T2 N1–N2b or T3 N0–N2b; AJCC 8th — non-smokers or ≤10 pack-years). Enrolled 2015–2017, 46 NRG Oncology institutions. Two-arm randomization: reduced-dose CRT vs reduced-dose RT alone, to select arm for phase III. Success criterion: 2-year PFS ≥85% (lower bound of exact 95% CI >77%).
Interventions and follow up
Arm A: IMRT 60 Gy/30 fx + weekly cisplatin 40 mg/m²
Arm B: IMRT 60 Gy/30 fx alone (no systemic therapy)
Primary endpoint: 2-year PFS in each arm (go/no-go threshold ≥85%)
mFollow up: 2.6 year
Arm B: IMRT 60 Gy/30 fx alone (no systemic therapy)
Primary endpoint: 2-year PFS in each arm (go/no-go threshold ≥85%)
mFollow up: 2.6 year
Results
2-year PFS (Arm A, CRT 60 Gy): 90.5% (95% CI 84.9–94.4%) — met success criterion
2-year PFS (Arm B, RT 60 Gy alone): 87.6% (95% CI 81.3–92.1%) — CI lower bound 81.3% did not exceed 77% threshold; technically met, less decisively
2-year OS: Arm A 96.7%, Arm B 97.4%
2-year PFS (Arm B, RT 60 Gy alone): 87.6% (95% CI 81.3–92.1%) — CI lower bound 81.3% did not exceed 77% threshold; technically met, less decisively
2-year OS: Arm A 96.7%, Arm B 97.4%
Adverse events
Grade ≥3 acute AEs: 67% (Arm A, CRT) vs 28% (Arm B, RT alone)
Arm A: more dysphagia, mucositis, leukopenia
Arm B: substantially fewer acute toxicities, slightly lower PFS
Late ≥grade 3 dysphagia: 10% vs 3%
Arm A: more dysphagia, mucositis, leukopenia
Arm B: substantially fewer acute toxicities, slightly lower PFS
Late ≥grade 3 dysphagia: 10% vs 3%
Conclusions
Both reduced-dose arms (60 Gy) yielded outstanding 2-year PFS (>87%) and OS (>96%) in low-risk HPV+ OPC. NRG-HN002 recommended Arm A (chemoRT 60 Gy) for phase III advancement based on superior PFS point estimate, establishing the design basis for NRG-HN009. RT alone (60 Gy) remains under investigation for further risk-stratified de-escalation.
Key Limitations
Phase II; not yet validated with a phase III efficacy endpoint; 2-year PFS is a surrogate — late recurrences in HPV+ OPC may emerge beyond this window. Go/no-go threshold design limits direct between-arm comparison. Arm B (RT alone) met threshold but borderline; underpowered to detect a between-arm difference. No biomarker (e.g., ctDNA) stratification.
Clinical Context
Largest randomized trial of de-escalated chemoRT in HPV+ OPC; supports 60 Gy + weekly cisplatin as the de-escalated standard to test in phase III. Standard of care remains 70 Gy + cisplatin until phase III data mature. NRG-HN009 (phase III, 70 Gy vs 60 Gy with cisplatin) ongoing. De-escalation trials now stratified by risk (smoking, T/N stage, ctDNA clearance).
References