Background: Based on the hypothesis of a potential synergistic effect of the anti-PD1 pembrolizumab when combined with RT, this new combination was tested in a phase II randomized trial against the SoC cetuximab-RT in LA-SCCHN. Methods: Patients (pts) were randomized between cetuximab (Arm A : 400 mg/m² loading dose and 250 mg/m² weekly) and Pembrolizumab (Arm B : 200 mg Q3W during RT). In both arms, patients received IRMT (69.96 Gy in 33 fractions). Main Inclusion criteria were : pts unfit for high dose cisplatin, non operable stage III-IVa-b SCC of oral cavity, oropharynx, hypopharynx and larynx. Treatment allocation was performed by randomization 1:1, stratified on N stage (N0-1 vs N2-3) , tumor location and p16 status. To detect a difference between arms of 60% to 80% in loco-regional control at 15 months (primary endpoint), inclusion of 66 pts per arm was required to achieve a power of at least 0.85 at 2-sided significance level of 0.20, with less than 15% unevaluable pts. Results: from 05/16 to 10/17, 133 pts were randomized in 27 centers, 66 in Arm A and 67 in Arm B. Median age was 65 years, 92% were smokers, 60% of oropharynx, 28% p16+ and 26%, 56% and 19% of stage III, IVa and IVb respectively. Both arms were well balanced. At the time of the abstract writing, full and cleaned safety and compliance data were available for 77 pts (58%). Data for all the randomized pts will be presented at the meeting. In Arm A and B, 25 and 18 Serious Adverse Events (SAE) occurred and 94% and 78% pts had at least one CTCAE v4 grade 3 AE in arm A and B respectively. The compliance to RT was not different (full total dose received by 86% and 88% pts in Arm A and B respectively). Mucositis >= grade 3 was observed in 57% (Arm A) versus 24% (Arm B) of pts (p = 0.004) (but no difference in dysphagia, 34% versus 39%). In radiation field dermatitis >= grade 3 occurred more frequently in Arm A (49% versus 17%) (p=0.003). Conclusions: Preliminary data indicate that tolerance of pembrolizumab-RT was good when compared to cetuximab-RT in LA-SCCHN. Updated and complete safety results will be presented at the meeting. Clinical trial information: NCT02707588