Background: For pts with R/M SCCHN, new standard of care (SoC) has been recently established with pembrolizumab either alone or combined with platin-5FU (KN 048 – median Overall Survival (OS): 13 months when combined). For pts who need chemotherapy, platinum-5FU-pembrolizumab as first-line treatment appears associated with substantial toxicity that precludes its use in fragile patients. In this context, we investigated the efficacy and tolerance of PDL-1 inhibition with durvalumab combined with weekly carboplatin-paclitaxel as first-line treatment in frail R/M SCCHN pts. Methods: This single-arm phase II study enrolled pts in first-line of their R/M SCCHN and not eligible to standard cisplatin-based CT with an ECOG PS of 0 or 1. Pts received 4 cycles of CT (carboplatin AUC2; paclitaxel 80mg/m² both at D1, D8, D15) and durvalumab (D) 1500mg repeated every 4 weeks for a maximum of 12 months. The primary endpoint was OS Rate at 12 months (m). The study used a Fleming A’Hern design (inefficacy boundary: 47% and target efficacy: 65%), requiring 38 successes among 64 pts. Secondary endpoints were Progression-Free Survival (PFS), Time to Treatment Failure (TTF), objective response rate (ORR) and tolerance. Results: 64 pts (median age 69.5y; 90.6% males, 62.5% PS1) were included, regardless of their PDL-L1 status. Primary tumors were mainly located in oropharynx (37.5%) and larynx (28.1%) with 37.3% PD-L1 CPS≥20. 54.9% were metastatic. The efficacy rule for OS was met with 40 pts (62.5%, unilateral 95%CI: [51.5% - ]) alive at 12m. With a median follow-up of 27.1 m, median OS was 18.0 m (95% CI [11.9-NR]) and the 24m-OS rate was 45% [32%-57%]. Median PFS was 7.0 m (95% CI [5.4-9.9]) and median TTF was 6.0 m (95% CI [4.7-9]). 44/62 pts (71%) achieved an OR (11.3% complete response and 59.7% partial response). Median duration of response was 5.9 m (95% CI [3.4-9.6]). 20.3% of pts experienced G≥3 adverse events related to D, Toxicity led to permanent discontinuation of D in 3.1% of pts. No D-related death was reported. Conclusions: This study performed in fragile patients not amenable to cisplatin-based CT met its primary endpoint on OS and showed a 18 months median OS rate. This combination of durvalumab with weekly carboplatin/paclitaxel was associated with a favorable toxicity profile. Clinical trial information: NCT0372967.