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. 2021 Oct 17;13(20):5206. doi: 10.3390/cancers13205206

Table 4.

Selected treatment intensification trials.

Trial Design (No. of Patients) Patient Population Intensification Strategy and Regimens (* Intensification Arm) Primary Outcome Measure Status Summary of Findings (if Completed)
RTOG 0129 [176] Randomized Phase III (n = 721) AJCC 6th ed. Stage III-IVB OC, OP, HP, Larynx; any HPV risk group Accelerated fraction (AFX) RT

  • * AFX: 72 Gy in 42 fx over 6 weeks + Cisplatin 100 mg/m2 Q3W × 2

  • SFX RT 70 Gy in 35 fx over 7 weeks + Cisplatin 100 mg/m2 Q3W × 3

 OS Completed No difference in OS (HR, 0.96; 95% CI, 0.79 to 1.18; p = 0.37).
RTOG 0522 [177] Randomized Phase III (n = 891) AJCC 6th ed. stage III-IVB OC, OP, HP, Larynx; any HPV risk group Combination chemotherapy

  • Arm 1: AFX RT + Cisplatin 100 mg/m2 Q3W × 2

  • * Arm 2: AFX RT + Cisplatin 100 mg/m2 Q3W × 2 + Cetuximab 400 mg/m2 then 250 mg/m2 q1w × 7

 PFS Completed No difference in PFS, OS, LRF. Higher acute toxicities with the addition of cetuximab
PARADIGM [178] Randomized Phase III (n = 145) AJCC 6th ed. Stage IVA-IVB (T3/T4 or N2/N3, but not T1/N2) OC, OP, Larynx; any HPV risk group Induction chemotherapy

  • * Arm 1: Docetaxel 75 mg/m2, Cisplatin 80 mg/m2, 5-FU 800 mg/m2/d days 1–4 Q3w × 3 followed by CRT with carboplatin or docetaxel

  • Arm 2: AFX RT + cisplatin 100 mg/m2 Q4W × 2

 OS Completed No difference in OS (HR, 1.09; 95% CI 0.59–2.03). poor accrual (145 of 300 planned)
JAVELIN-Head and Neck 100 [179] Randomized Phase III (n = 697) AJCC 7th ed. HPV- Stage III, IVA, IVb disease; non-OP HPV+Stage III, IVA, IVB disease; HPV+ OP T4 or N2c or N3 disease Combination PD-1 blockade + CRT

  • * Avelumab SFX RT 70 Gy over 7 weeks

  • SFX RT 70 Gy in 35 fx over 7 weeks + Cisplatin 100 mg/m2 Q3W × 3

 PFS Completed Median PFS was not reached in either group, however stratified hazard ratio (1.21 [95% CI 0.93–1.57]) favored the placebo group (one-sided p = 0.92)
KEYNOTE-412 [NCT03040999] Randomized Phase III (n = 780 planned) AJCC 7th ed OP HPV+ (any T4 or N3), OP HPV− (any T3-T4 or N2a-N3), or larynx/HP/OC (any T3-T4 or N2a-N3) Combination PD-1 blockade + CRT

  • * Pembrolizumab + CRT (AFX or SFX 70 Gy) + Cisplatin 100 mg/m2 Q3W × 2–3

  • CRT (AFX or SFX 70 Gy) + Cisplatin 100 mg/m2 Q3W × 2–3

 Event Free Survival (EFS) Ongoing NA
KEYNOTE-689 [NCT03765918] Randomized Phase III (n = 704 planned) AJCC 8th ed. resectable, stage III/IVA HPV− or T4N0-2 HPV+ Neoadjuvant PD-1 blockade

  • * Pembrolizumab Q3W × 2 doses pre-operatively followed by risk-adapted PORT or POCRT (cisplatin) + pembrolizumab

  • Surgery followed by adjuvant risk adapted PORT or POCRT (cisplatin)

 Major Pathological Response (mPR) and EFS Ongoing NA
RTOG 1216 [NCT01810913] Randomized phase II/III (n = 480 planned) Resected AJCC 7th ed Stage III-IVB HPV+ or HPV− disease with high-risk features (ENE or positive margins) Adjuvant POCRT + PD-L1 blockade

  • POCRT 60 Gy + cisplatin 40 mg/m2 Q1W × 6

  • POCRT 60 Gy + docetaxel 15 mg/m2 Q1w × 6 + cetuximab + Cetuximab 400 mg/m2 then 250 mg/m2 q1w × 7

  • POCRT 60 Gy + cisplatin 40 mg/m2 Q1W × 6 + Atezolizumab 1200 mg Q3W × 8

 Phase II-DFSPhase III-OS Ongoing NA

* Intensification Arm