Pembro monotherapy is a SOC for R/M HNSCC that has progressed following platinum-containing chemo. In the phase 3 KEYNOTE-040 trial (NCT02252042), pembro had clinically meaningful prolonged OS and a favorable safety profile compared with SOC at the time (HR, 0.80; 95% CI, 0.65-0.98) in platinum-refractory R/M HNSCC. OS benefit was greater in patients (pts) with higher PD-L1 expression. Results of KEYNOTE-040 are presented after 6 years of follow-up. Pts with incurable R/M HNSCC that progressed on or after platinum-containing chemo or ≤6 mo of prior platinum-containing multimodal therapy were randomized 1:1 to receive pembro 200 mg Q3W or investigator’s choice of methotrexate, docetaxel, or cetuximab. Primary end point was OS. Secondary end points were OS (PD-L1 CPS ≥1), ORR, DOR, PFS, and safety. Efficacy end points were evaluated in the ITT, PD-L1 TPS ≥50%, and PD-L1 CPS ≥1 populations. Of 495 pts, 15 (6.1%) and 5 (2.0%) were still being followed up in the pembro and SOC arms, respectively, as of the February 3, 2022, data cutoff date. Median follow-up was 74.8 mo (range, 68.8-85.4). Efficacy data are shown in the table. The 6-year OS rate for pembro vs SOC was 6.5% vs 2.4% for ITT, 8.9% vs 6.3% for TPS ≥50%, and 7.1% vs 2.1% for CPS ≥1 populations. Median OS for pembro vs SOC was 8.4 mo vs 7.1 mo (HR, 0.79; 95% CI, 0.66-0.94) for ITT, 11.6 mo vs 7.9 mo (HR, 0.62; 95% CI, 0.43-0.90) for TPS ≥50%, and 8.7 mo vs 7.1 mo (HR, 0.72; 95% CI, 0.59-0.89) for CPS ≥1 populations. Any-grade treatment-related AEs (TRAEs) occurred in 64.2% of pts in the pembro arm and 83.3% of pts in the SOC arm. Grade 3-5 TRAEs occurred in 13.4% of pts in the pembro arm and 36.8% in the SOC arm.Table: 658MOPembroSOCITT, n247248OS, median, mo8.47.1HR (95% CI)0.79 (0.66-0.94)–6-y OS rate, %6.52.46-y PFS rate, %3.30.4ORR, %15.48.9DOR, median (range), mo18.4 (0.0+ to 65.8+)3.6 (0.0+ to 18.8)PD-L1 TPS ≥50%, n6465OS, median, mo11.67.9HR (95% CI)0.62 (0.43-0.90)–6-y OS rate, %8.96.36-y PFS rate, %4.71.6ORR, %28.19.2DOR, median (range), mo15.1 (0.0+ to 65.1+)4.2 (0.8-18.8)PD-L1 CPS ≥1, n196191OS, median, mo8.77.1HR (95% CI)0.72 (0.59-0.89)–6-y OS rate, %7.12.16-y PFS rate, %3.70.5ORR, %18.48.9DOR, median (range), mo18.4 (0.0+ to 65.8+)4.2 (0.7-18.8)“+” indicates response is ongoing Open table in a new tab “+” indicates response is ongoing Pembro continued to show OS benefit compared with SOC in R/M HNSCC, regardless of PD-L1 expression, after long-term follow-up. OS hazard ratios were similar over time. These results further support the use of pembro as second-line treatment in R/M HNSCC.