Introduction: In the phase 3 KEYNOTE-048 trial (NCT02358031) in R/M HNSCC, first-line pembrolizumab (P) monotherapy vs EXTREME (E; chemotherapy [C] + cetuximab) improved overall survival (OS) in PD-L1 combined positive score (CPS) ≥20 and CPS ≥1 populations and led to noninferior OS in the total population with favorable safety; first-line P+C vs E had superior OS in CPS ≥20, CPS ≥1, and total populations with comparable safety. Outcomes in CPS <1 and CPS 1-19 subgroups were not prospectively defined end points; we present a post hoc analysis in these subgroups. Methods: Patients with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to P, P+C, or E. Progression-free survival (PFS), objective response rate (ORR), and duration of response were assessed by RECIST v1.1 per blinded independent central review. OS and PFS were estimated by the Kaplan-Meier method. Hazard ratios and 95% CIs were based on a Cox regression model with Efron's method of tie handling, with treatment as a covariate. Data cutoff was Feb 25, 2019. Results: Baseline characteristics of the CPS <1, CPS 1-19, and CPS ≥20 subgroups were similar to those of the total population. In the CPS <1 subgroup, the HR (95% CI) for OS was 1.51 (0.96-2.37) for P (n = 44) vs E (n = 45) and 1.21 (0.76-1.94) for P+C (n = 39) vs E (n = 43) (Table). In the CPS 1-19 subgroup, HR (95% CI) for OS showed a slight advantage of P (n = 124) vs E (n =133) (0.86 [0.66-1.12]) and favored P+C (n = 116) vs E (n = 125) (0.71 [0.54-0.94]). Conclusions: There was overall evidence of increased efficacy with increasing PD-L1 expression. In the CPS 1-19 subgroup, P+C vs E results were consistent with treatment benefit. Analysis of the CPS <1 subgroup was limited by small patient numbers. Future exploratory analyses of tumor mutational burden and inflamed signatures could further evaluate predictors of benefit in patients with low PD-L1-expressing HNSCC.

Table.

Efficacy in subgroups of patients with PD-L1 CPS <1, CPS 1-19, and CPS ≥20

CPS subgroupTreatmentMedian OS, moOS HR12-mo OS rate, %Median PFS, moPFS HRORR, nMedian DOR, mo
(95% CI)(95% CI)(95% CI)(95% CI)(95% CI)(%)(range)
<1 Pembrolizumab 7.9 1.51 38.6 2.1 4.31 2.6 
 n = 44 (4.7-13.6) (0.96-2.37) (24.5-52.6) (1.9-2.3) (2.63-7.08) (4.5) (2.2-3.0) 
<1 EXTREME 11.3 48.9 6.2 19 7.8 
 n = 45 (9.1-15.9)  (33.7-62.4) (5.1-7.6)  (42.2) (2.0-38.6+) 
<1 Pembrolizumab + Chemotherapy 11.3 1.21 41.0 4.7 1.46 12 5.7 
 n = 39 (9.5-14.0) (0.76-1.94) (25.7-55.8) (3.4-6.2) (0.93-2.30) (30.8) (2.6-20.6+) 
<1 EXTREME 10.7 46.5 6.2 17 4.3 
 n = 43 (8.5-15.9)  (31.2-60.4) (5.0-7.3)  (39.5) (2.0-31.2+) 
1-19 Pembrolizumab 10.8 0.86 44.0 2.2 1.25 18 NR 
 n = 124 (9.0-12.6) (0.66-1.12) (35.1-52.5) (2.1-2.9) (0.96-1.61) (14.5) (1.5+-38.9+) 
1-19 EXTREME 10.1 42.4 4.9 45 5.0 
 n = 133 (8.7-12.1)  (33.9-50.7) (3.8-6.0)  (33.8) (1.4+-38.7+) 
1-19 Pembrolizumab + Chemotherapy 12.7 0.71 52.6 4.9 0.93 34 5.6 
 n = 116 (9.4-15.3) (0.54-0.94) (43.1-61.2) (4.2-5.3) (0.71-1.21) (29.3) (1.6+-25.6+) 
1-19 EXTREME 9.9 41.1 4.9 42 4.6 
 n = 125 (8.6-11.5)  (32.4-49.6) (3.7-6.0)  (33.6) (1.4+-31.4+) 
≥20 Pembrolizumab 14.8 0.58 56.4 3.4 0.99 31 22.6 
 n = 133 (11.5-20.6) (0.44-0.78) (47.5-64.3) (3.2-3.8) (0.76-1.29) (23.3) (2.7-43.0+) 
≥20 EXTREME 10.7 44.9 5.3 44 4.2 
 n = 122 (8.8-12.8)  (35.9-53.4) (4.8-6.3)  (36.1) (1.2+-31.5+) 
≥20 Pembrolizumab + Chemotherapy 14.7 0.60 57.1 5.8 0.76 54 7.1 
 n = 126 (10.3-19.3) (0.45-0.82) (48.0-65.2) (4.7-7.6) (0.58-1.01) (42.9) (2.1+-39.0+) 
≥20 EXTREME 11.0 46.1 5.3 42 4.2 
 n = 110 (9.2-13.0)  (36.6-55.1) (4.9-6.3)  (38.2) (1.2+-31.5+) 
CPS subgroupTreatmentMedian OS, moOS HR12-mo OS rate, %Median PFS, moPFS HRORR, nMedian DOR, mo
(95% CI)(95% CI)(95% CI)(95% CI)(95% CI)(%)(range)
<1 Pembrolizumab 7.9 1.51 38.6 2.1 4.31 2.6 
 n = 44 (4.7-13.6) (0.96-2.37) (24.5-52.6) (1.9-2.3) (2.63-7.08) (4.5) (2.2-3.0) 
<1 EXTREME 11.3 48.9 6.2 19 7.8 
 n = 45 (9.1-15.9)  (33.7-62.4) (5.1-7.6)  (42.2) (2.0-38.6+) 
<1 Pembrolizumab + Chemotherapy 11.3 1.21 41.0 4.7 1.46 12 5.7 
 n = 39 (9.5-14.0) (0.76-1.94) (25.7-55.8) (3.4-6.2) (0.93-2.30) (30.8) (2.6-20.6+) 
<1 EXTREME 10.7 46.5 6.2 17 4.3 
 n = 43 (8.5-15.9)  (31.2-60.4) (5.0-7.3)  (39.5) (2.0-31.2+) 
1-19 Pembrolizumab 10.8 0.86 44.0 2.2 1.25 18 NR 
 n = 124 (9.0-12.6) (0.66-1.12) (35.1-52.5) (2.1-2.9) (0.96-1.61) (14.5) (1.5+-38.9+) 
1-19 EXTREME 10.1 42.4 4.9 45 5.0 
 n = 133 (8.7-12.1)  (33.9-50.7) (3.8-6.0)  (33.8) (1.4+-38.7+) 
1-19 Pembrolizumab + Chemotherapy 12.7 0.71 52.6 4.9 0.93 34 5.6 
 n = 116 (9.4-15.3) (0.54-0.94) (43.1-61.2) (4.2-5.3) (0.71-1.21) (29.3) (1.6+-25.6+) 
1-19 EXTREME 9.9 41.1 4.9 42 4.6 
 n = 125 (8.6-11.5)  (32.4-49.6) (3.7-6.0)  (33.6) (1.4+-31.4+) 
≥20 Pembrolizumab 14.8 0.58 56.4 3.4 0.99 31 22.6 
 n = 133 (11.5-20.6) (0.44-0.78) (47.5-64.3) (3.2-3.8) (0.76-1.29) (23.3) (2.7-43.0+) 
≥20 EXTREME 10.7 44.9 5.3 44 4.2 
 n = 122 (8.8-12.8)  (35.9-53.4) (4.8-6.3)  (36.1) (1.2+-31.5+) 
≥20 Pembrolizumab + Chemotherapy 14.7 0.60 57.1 5.8 0.76 54 7.1 
 n = 126 (10.3-19.3) (0.45-0.82) (48.0-65.2) (4.7-7.6) (0.58-1.01) (42.9) (2.1+-39.0+) 
≥20 EXTREME 11.0 46.1 5.3 42 4.2 
 n = 110 (9.2-13.0)  (36.6-55.1) (4.9-6.3)  (38.2) (1.2+-31.5+) 

Citation Format: Barbara Burtness, Danny Rischin, Richard Greil, Denis Soulières, Makoto Tahara, Gilberto de Castro, Amanda Psyrri, Neus Basté, Prakash Neupane, Åse Bratland, Thorsten Fuereder, Brett G. Hughes, Ricard Mesia, Nuttapong Ngamphaiboon, Tamara Rordorf, Wan Zamaniah Wan Ishak, Joy Ge, Ramona Swaby, Burak Gumuscu, Kevin Harrington. Efficacy of first-line (1L) pembrolizumab by PD-L1 combined positive score <1, 1-19, and ≥20 in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): KEYNOTE-048 subgroup analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-258.