Background: TPExtreme trial comparing EXTREME regimen to the taxane-based TPEx confirmed the encouraging survival results of the TPEx regimen, despite lack of significant overall survival (OS) increase, with a significantly lower toxicity than the EXTREME regimen. Herein, the QoL and exploratory analyses of survival according to 2^nd line treatments focusing on immunotherapy (IO) are presented. Methods: Randomized (1:1), open-label trial. Main inclusion criteria were R/M HNSCC not suitable for loco-regional treatment, age 18-70 years, PS < 2, creatinin clearance > 60ml/min, prior cisplatin < 300 mg/m². 539 pts were enrolled over a period of 37 months (mo). QoL was evaluated with QLQ-C30 questionnaire at baseline, week(W)12, W18, W26 and analyzed by linear mixed model. The primary QoL endpoint was the Global Health Status score. 2^nd line treatments were collected for 501 (93%) patients (pts), 256 in the EXTREME arm and 245 in the TPEx arm. Results: The percentage of QLQ-C30 questionnaires filled at baseline, W12, W18 and W26 were similar in the 2 arms, 89%, 52%, 43%, and 39% in the EXTREME arm and 91%, 59%, 40%, and 37% in the TPEx arm, respectively.. Higher scores of Global Health Status (p = 0.02), physical functioning (p = 0.009) and role functioning (p = 0.013) and lower scores of appetite loss (p = 0.041) were observed in the TPEx arm than in the EXTREME arm. No significant difference was observed for the other scores. In 2^nd line treatment, 120 (47%) pts in the EXTREME arm and 109 (44%) in the TPEx arm received chemotherapy +/- cetuximab (CT); 41 (16%) pts in the EXTREME arm and 41 (17%) in the TPEx arm received IO, mainly anti-PD-1/PD-L1. 79% and 85% of these 2^nd line treatments were given after progression in EXTREME and TPEx arms respectively. Median OS (95%CI) since randomization was 17.6 (15.2 – 19.5) mo with CT and 19.4 (13.4 – 22.3) mo with IO in the EXTREME arm vs 14.9 (13.0 – 16.3) and 21.9 (15.9 – 35.0) mo in the TPEx arm (interaction test p = 0.077) respectively. Median OS since start of 2^nd line was 9.3 mo with CT and 8.3 mo with IO in the EXTREME arm, and 7.1 and 11.6 mo respectively in the TPEx arm. Conclusions: An improvement in the QoL of patients was observed in the TPEx arm compared to that of the EXTREME arm. Exploratory analysis showed that the taxane-based TPEx regimen followed by IO in 2^nd line could provide interesting median OS for pts who need CT in 1^st line, with less toxicity than EXTREME. This sequential treatment deserves to be compared to a strategy that starts with Platinum+5FU+pembrolizumab. Clinical trial information: NCT02268695.