Pembro showed antitumor activity and manageable toxicity in R/M HNSCC in an extended phase 1b study. KEYNOTE-040 (NCT02252042) was a global, open-label, phase 3 study of pembro vs SOC for R/M HNSCC.
Eligible pts with SCC of the oral cavity, oropharynx, hypopharynx, or larynx who had recurrence or PD after a platinum-containing regimen were randomized 1:1 to pembro 200 mg Q3W for 24 mo or investigator choice of standard doses of methotrexate (M), docetaxel (D), or cetuximab (C). Randomization was stratified by ECOG PS (0 vs 1), HPV status (p16 positive vs negative), and PD-L1 tumor proportion score (TPS) (≥50% vs
495 pts enrolled: 247 were assigned to pembro, 248 to SOC (65 M, 110 D, 73 C). After median follow-up of 7.3 mo, 8.9% of pts remained on pembro, 0.9% on SOC. Pembro prolonged OS in the ITT population, but the difference did not achieve statistical significance (HR 0.81, one-sided P = .0204; Table). There was no difference in PFS (Table). ORR was higher with pembro (Table). Pembro outcomes were improved in pts with PD-L1–expressing tumors (Table). 12.5% of pts in the SOC arm received subsequent immunotherapy, potentially impacting OS. Grade 3-5 drug-related AE incidence was 13.4% with pembro and 36.3% with SOC; 1.6% and 0.9%, respectively, died of drug-related AEs.
LBA45_PR OS, PFS, and ORR in KEYNOTE-040
|Total||PD-L1 CPS ≥1%||PD-L1 TPS ≥50%|
|N = 247||N = 248||n = 196||n = 191||n = 64||n = 65|
|Median (95% CI), mo||8.4||7.1||8.7||7.1||11.6||7.9|
|HRa (95% CI)||0.81 (0.66-0.99)||0.75 (0.59-0.95)||0.54 (0.35-0.82)|
|Median (95% CI), mo||2.1||2.3||2.2||2.3||3.5||2.2|
|HRa (95% CI)||0.95 (0.79-1.16)||0.89 (0.72-1.11)||0.58 (0.39-0.87)|
One-sided P value stratified by the randomization stratification factors.b
Assessed per RECIST v1.1 by blinded, independent central review.
Pembro provided an 19% reduction in the risk of death over SOC in pts with R/M HNSCC, although the prespecified efficacy boundary was not reached; subsequent immunotherapy in the SOC arm may have confounded OS analysis. Greater differences in OS, PFS, and ORR favoring pembro were seen in patients with PD-L1 expressing tumors.
Clinical trial identification
ClinicalTrials.gov number NCT02252042, originally posted Sep 25, 2014; EudraCT number 2014-001749-26, originally issued 1-Aug-2014
Legal entity responsible for the study
Merck & Co., Inc.
Merck & Co., Inc.
E.E. Cohen: Advisory board member for Human Longevity Inc., Merck, and CARsgen Therapeutics. Receiving honoraria from Merck, Pfizer, Celgene, AstraZeneca, Bristol-Myers Squibb, Merck Serono, Amgen, Apexigen, and Vigilant Biosciences. K.J. Harrington: Advisory board member, speakers\' bureau, and honoraria: MSD, AstraZeneca, Bristol-Myers Squibb, Merck, and Pfizer Research funding: MSD, AstraZeneca. C. Le Tourneau: Advisory board: MSD, AstraZeneca, Bristol-Myers Squibb, Amgen. Honoraria: Merck Serono, AstraZeneca, Bristol-Myers Squibb. Travel expenses: Bristol-Myers Squibb, MSD, Merck Serono. J. Dinis: Advisory board: Roche, PharmaMar, Bristol-Myers Squibb, Merck Serono. Research funding: Boehringer Ingelheim. Honoraria: Bristol-Myers Squibb, Merck Serono. Travel expenses: Bristol-Myers Squibb, PharmaMar. L. Licitra: Consulting or advisory role: Eisai, Bristol-Myers Squibb, MSD, Merck-Serono, Boehringer Ingelheim, Debiopharm, Jobi, Novartis, AstraZeneca, Bayer, Roche, Amgen, DOBI. Travel: Merck-Serono, Debiopharm, DOBI, Bayer, Amgen. M-J. Ahn: Advisory board member and honoraria: AstraZeneca, Merck, Lilly, Bristol-Myers Squibb, Roche A. Soria: Advisory board: Bristol-Myers Squibb, Roche, Novartis, Incyte. Speakers\' bureau: Roche, Novartis, MSD, Bristol-Myers Squibb. Travel: Roche, MSD, Bristol-Myers Squibb. J-P. Machiels: Advisory board: MSD (uncompensated), AstraZeneca, Debio, Nonbiotix, Innate. Research funding: Novartis, Bayer, Janssen. N. Mach: Advisory board: MSD, Bristol-Myers Squibb, Amgen. Honoraria: Bristol-Myers Squibb R. Mehra: Consulting: Genentech. B. Burtness: Advisory board member: Merck, Boehringer Ingelheim, AstraZeneca, Amgen Research funding (to institution): Merck, Advaxis, Bristol-Myers Squibb. Travel expenses: Boehringer Ingelheim. Y. Wang, A.J. Tuozzo, R. Swaby: Employment and stock ownership: Merck & Co., Inc. D. Soulieres: Advisory board member and research funding: Merck & Co.