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FDA approves
pembrolizumab for ;rst-
line treatment of head
and neck squamous cell
carcinoma
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On June 10, 2019, the Food and

Drug Administration approved
pembrolizumab (KEYTRUDA,
Merck) for the first-line treatment of
patients with metastatic or
unresectable recurrent head and
neck squamous cell carcinoma
(HNSCC).

Pembrolizumab was approved for

use in combination with platinum
and fluorouracil (FU) for all patients
and as a single agent for patients
whose tumors express PD‑L1
(Combined Positive Score [CPS] ≥1)
as determined by an FDA‑approved
test. The FDA also expanded the
intended use for the PD-L1 IHC
22C3 pharmDx kit to include use as
a companion diagnostic device for
selecting patients with HNSCC for
treatment with pembrolizumab as a
single agent.
Approval was based on KEYNOTE-
048 (NCT02358031), a randomized,
multicenter, three-arm, open‑label,
active‑controlled trial conducted in
882 patients with metastatic
HNSCC who had not previously
received systemic therapy for
metastatic disease or with recurrent
disease who were considered
incurable by local therapies.

Patients were randomized (1:1:1) to

receive one of the following
treatments: pembrolizumab as a
single agent; pembrolizumab,
carboplatin or cisplatin, and FU; or
cetuximab, carboplatin or cisplatin,
and FU. Randomization was
stratified by tumor PD-L1
expression (Tumor Proportion Score
[TPS] ≥50% or <50%), HPV status
according to p16 IHC (positive or
negative), and ECOG PS (0 vs 1).
PD-L1 expression (TPS and CPS)
was determined using the PD-L1
IHC 22C3 pharmDx kit.

Overall survival (OS), sequentially

tested in the subgroup of patients
with CPS ≥20 HNSCC, the subgroup
of patients with CPS ≥1 HNSCC and
the overall population, was the
major efficacy measure.

The trial demonstrated a statistically

significant improvement in OS in
the overall population for patients
randomized to pembrolizumab plus
chemotherapy compared with
cetuximab plus chemotherapy at a
pre-specified interim analysis. The
median OS was 13.0 months for the
pembrolizumab plus chemotherapy
arm and 10.7 months for the
cetuximab plus chemotherapy arm
(HR 0.77; 95% CI: 0.63, 0.93;
p=0.0067). Results were similar in
the CPS ≥20 subgroup (HR 0.69;
95% CI: 0.51, 0.94) and CPS ≥1
subgroup (HR 0.71; 95% CI: 0.57,
0.88).

The trial also demonstrated

statistically significant
improvements in OS for the
subgroups of patients with PD‑L1
CPS ≥1 HNSCC and PD-L1 CPS ≥20
HNSCC randomized to
pembrolizumab as a single agent
compared with cetuximab plus
chemotherapy. In the CPS ≥1
subgroup, the median OS was 12.3
months for the pembrolizumab arm
and 10.3 months for the cetuximab
plus chemotherapy arm (HR 0.78;
95% CI: 0.64, 0.96; p=0.0171). For
the CPS ≥20 subgroup, the median
OS was 14.9 months for the
pembrolizumab arm and 10.7
months for the cetuximab plus
chemotherapy arm (HR 0.61; 95%
CI: 0.45, 0.83; p=0.0015). At the
time of the interim analysis, there
was no significant difference in OS
between the pembrolizumab as a
single agent arm and the cetuximab
plus chemotherapy arm for the
overall population.

There were no significant

differences in progression-free
survival for either pembrolizumab-
containing arm compared to the
cetuximab plus chemotherapy arm
in any population.

The most common adverse reactions

reported in ≥20% of patients who
received pembrolizumab as a single
agent in KEYNOTE-048 were
fatigue, constipation, and rash. The
most common adverse reactions
reported in ≥20% of patients who
received pembrolizumab in
combination with chemotherapy in
KEYNOTE-048 were nausea,
fatigue, constipation, vomiting,
mucosal inflammation, diarrhea,
decreased appetite, stomatitis, and
cough.

The recommended pembrolizumab

dose for HNSCC is 200 mg
administered as an intravenous
infusion over 30 minutes every
3 weeks until disease progression,
unacceptable toxicity, or up to
24 months in patients without
disease progression.

View full prescribing information for

KEYTRUDA.

FDA granted this application

priority review. A description of
FDA expedited programs is in
the Guidance for Industry:
Expedited Programs for Serious
Conditions-Drugs and Biologics.

Project Facilitate: The

Oncology Center of Excellence
program for Expanded Access
—For assistance with single-patient
INDs for investigational oncology
products, healthcare professionals
may contact OCE’s Project
Facilitate at 240-402-0004 ( or
email
OncProjectFacilitate@fda.hhs.gov.

Healthcare professionals should

report all serious adverse events
suspected to be associated with the
use of any medicine and device to
FDA’s MedWatch Reporting System
or by calling 1-800-FDA-1088 (.

Follow the Oncology Center of

Excellence on
Twitter @FDAOncology (.

Check out recent approvals at the

OCE’s podcast, Drug Information
Soundcast in Clinical Oncology
(D.I.S.C.O.).

Content current as of:

06/11/2019

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