Background: KEYNOTE-048 was an open-label, randomized phase 3 study of P or P + chemotherapy (C) vs EXTREME (E) as first-line systemic therapy for R/M HNSCC (NCT02358031).

Methods: Patients (pts) with R/M HNSCC not curable by local therapy and with no prior systemic therapy (R/M setting) who provided a tumor sample for PD-L1 testing were randomized to P 200 mg Q3W, P + C (cisplatin 100 mg/m2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2/d for 4 d Q3W), or E (cetuximab 400 mg/m2 loading/250 mg/m2 QW + C) given until PD, unacceptable toxicity, 6 cycles (C), or 24 mo (P). Primary end points for P vs E and P + C vs E were PFS and OS in the PD-L1 combined positive score (CPS) ≥20 and ≥1 and total populations (pop). Cutoff date for this final PFS/interim OS analysis was Jun 13, 2018 (minimum follow-up, ∼17 mo).

Results: 882 pts were randomized: 301 to P, 281 to P + C, 300 to E. P was superior to E for OS in CPS ≥20 (N = 255; median 14.9 vs 10.7 mo; HR 0.61 [95% CI 0.45-0.83]; P = 0.0007) and ≥1 (N = 512; median 12.3 vs 10.3 mo; HR 0.78 [95% CI 0.64-0.96]; P = 0.0086); OS for P was non-inferior to E in the total pop (N = 601). P did not prolong PFS in CPS ≥20 (P = 0.5); per the analysis plan, no further PFS testing was done for P vs E. Confirmed ORR (P vs E) was 23% vs 36% for CPS ≥20, 19% vs 35% for CPS ≥1, and 17% vs 36% for the total pop; median DOR was 20.9 vs 4.2 mo, 20.9 vs 4.5 mo, and 20.9 vs 4.5 mo. Gr 3-5 drug-related AE rates were 17% (P) vs 69% (E). P + C was non-inferior and superior to E for OS in the total pop (N = 559; median 13.0 vs 10.7 mo; HR 0.77 [95% CI 0.63-0.93]; P = 0.0034); OS for P + C was not significantly superior to E in CPS ≥20 and ≥1 at this interim analysis. PFS was not prolonged with P + C (P = 0.2). For P + C vs E, confirmed ORR was 36% vs 36%, median DOR was 6.7 vs 4.3 mo, and gr 3-5 drug-related AE rates were 71% vs 69%.

Conclusions: For first-line R/M HNSCC, P significantly improved OS over E in the PD-L1 CPS ≥20 and ≥1 populations and was noninferior in the total population with favorable safety. P + C significantly improved OS in the total population with safety comparable to E. P and P + C responses were durable. These data support pembrolizumab and pembrolizumab + platinum + 5-FU as new first-line standards of care for R/M HNSCC. The study continues to the final OS analysis.

Clinical trial identification: NCT0235803; Trial initiation, February 6, 2015.

Editorial acknowledgement: Medical writing and editorial assistance was provided by Melanie Leiby, an employee of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study: Merck & Co., Inc.

Funding: Merck & Co., Inc.

Disclosure: B. Burtness: Advisory board member: Merck, Astra-Zeneca, Bristol-Myers Squibb, Aduro, Amgen, Genentech; Research funding: Merck, Advaxis, Bristol-Myers Squibb; Honoraria: IDDI; Travel expenses, including accommodations: Boehringer Ingelheim. K.J. Harrington: Advisory board member, honoraria, travel expenses: MSD, Merck-Serono, Bristol-Myers Squibb, AstraZeneca, Pfizer; Speakers' bureau: MSD, Merck-Serono, Bristol-Myers Squibb, AstraZeneca; Research funding: MSD, AstraZeneca. R. Greil: Advisory board member: Celgene, Novartis, Roche, Bristol-Myers Squibb, Takeda, Abbvie, AstraZeneca; Honoraria: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol-Myers Squibb, MSD, Sandoz. D. Soulières: Advisory board member: Merck, Bristol-Myers Squibb, Pfizer, AstraZeneca; Research funding: Merck, Bristol-Myers Squibb, Pfizer, Novartis. M. Tahara: Advisory board member: Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Bayer, AstraZeneca, Pfizer, Aspyrian; Honoraria: Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Bayer, AstraZeneca, Eisai. G. De Castro Jr.: Advisory board member: MSD, Bristol-Myers Squibb; Speakers' bureau, honoraria, travel expenses: MSD, Bristol-Myers Squibb, Merck-Serono. N. Baste Rotllan: Advisory board member: Bristol-Myers Squibb, Merck Serono, Nanobiotix T. Fuereder: Advisory board member and research funding: MSD, Merck KGgA; Honoraria: MSD, Merck KGgA, Roche, Pfizer, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb. B.G.M. Hughes: Advisory board member: MSD, Bristol-Myers Squbb, Roche, AstraZeneca, Pfizer, Boehringer Ingelheim, Eisai; Research funding: Amgen; Travel expenses: Boehringer Ingelheim. R. Mesia: Advisory board member: MSD, Bristol-Myers Squibb, Merck KGaA, AstraZeneca, Roche; Speakers bureau: Bristol-Myers Squibb, Merck KGaA; Travel expenses: Merck KGaA, Bristol-Myers Squibb. N. Ngamphaiboon: Advisory board: Roche, MSD, Amgen, Novartis, Taiho; Speakers' bureau: AstraZeneca, Roche, MSD, Eli Lilly; Research funding: Pfizer, MSD, Roche; Honoraria: Roche, MSD, Amgen, Novartis, Taiho; Travel expenses: Merck, Roche, Eisai, Taiho, Amgen. T. Rordorf: Honoraria for advisory boards: MSD, Bristol-Myers Squibb, Amgen. W.Z. Wan Ishak: Advisory board member: MSD, Roche, Eli Lilly; Speakers' bureau: Roche, Pfizer, Eli Lilly, Eisai; Research funding: Roche, MSD, Amgen; Honoraria: Eli Lilly, AstraZeneca, Eisai, Pfizer; Travel: Eisai, Pfizer, Eli Lilly, AstraZeneca, MSD. A. Roy, J. Cheng, F. Jin: Employee and stock owner: Merck & Co., Inc. D. Rischin: Advisory board member (all uncompensated): Merck, Bristol-Myers Squibb, Amgen; Research funding: Merck, Bristol-Myers Squibb, Regeneron, Amgen, Genentech-Roche, GlaxoSmithKline; Travel expenses: Merck. All other authors have declared no conflicts of interest.