Merck’s KEYTRUDA® (pembrolizumab) Demonstrates Improved Overall Survival as First-Line Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma at Final Analysis of Pivotal Phase 3 KEYNOTE-048 Trial
May 31, 2019
Survival Benefit Now Observed with KEYTRUDA in Combination with
Chemotherapy in All Patient Populations (Regardless of PD-L1 Expression)
and with KEYTRUDA Monotherapy in Patients Whose Tumors Expressed PD-L1
at CPS ≥1
Data Presented Today at 2019 ASCO Annual Meeting
KENILWORTH, N.J.–(BUSINESS WIRE)–lt;a href="https://twitter.com/search?q=%24MRK&src=ctag" target="_blank"gt;$MRKlt;/agt; lt;a href="https://twitter.com/hashtag/ASCO19?src=hash" target="_blank"gt;#ASCO19lt;/agt;–Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced the presentation of the final analysis of the pivotal
Phase 3 KEYNOTE-048 trial investigating KEYTRUDA, Merck’s anti-PD-1
therapy, as monotherapy and in combination with chemotherapy, for the
first-line treatment of patients with recurrent or metastatic head and
neck squamous cell carcinoma (HNSCC) at the 2019 American Society of
Clinical Oncology (ASCO) Annual Meeting (Abstract #6000). Data include
the first-time presentation of certain overall survival (OS) hypotheses
from the KEYTRUDA in combination with chemotherapy study arm based on
PD-L1 expression and the KEYTRUDA monotherapy study arm in the total
patient population. Results of an interim analysis were presented at the
European Society for Medical Oncology (ESMO) 2018 Congress and
demonstrated superior OS outcomes for KEYTRUDA in combination with
chemotherapy in the total population and KEYTRUDA monotherapy in
patients whose tumors expressed PD-L1 with Combined Positive Score (CPS)
≥20 and CPS ≥1 compared with the EXTREME regimen, the current standard
of care.
“It is exciting to see the full results from this trial, which is the
first study to show superior overall survival over the current standard
of care known as the EXTREME regimen,” said Dr. Danny Rischin, director
of the department of medical oncology, Peter MacCallum Cancer Centre,
Melbourne, Australia. “Patients with recurrent or metastatic head and
neck cancer have a poor prognosis with limited treatment options. These
findings underscore the potential of KEYTRUDA monotherapy and in
combination with platinum-based chemotherapy to become important new
treatment options.”
The new findings presented today from the final analysis showed that
KEYTRUDA in combination with chemotherapy (carboplatin or cisplatin plus
5-FU) reduced the risk of death by 40% in patients whose tumors
expressed PD-L1 with CPS≥20, demonstrating significantly longer OS (14.7
months [95% CI, 10.3-19.3]) compared with the EXTREME regimen (cetuximab
with carboplatin or cisplatin plus 5-fluorouracil [5-FU]), the current
standard of care (11.0 months [95% CI, 9.2-13.0]) (HR=0.60 [95% CI,
0.45-0.82]; p=0.0004). For the dual primary endpoint of progression-free
survival (PFS), statistical significance was not achieved for KEYTRUDA
in combination with chemotherapy in the CPS≥20 population compared with
the EXTREME regimen (HR=0.73 [95% CI, 0.55-.97]; p=0.0162). New findings
for the CPS ≥1 population showed KEYTRUDA in combination with
chemotherapy reduced the risk of death by 35% in these patients, with
significantly longer OS (13.6 months [95% CI, 10.7-15.5]) compared with
the EXTREME regimen (10.4 months [95% CI, 9.1-11.7]) (HR=0.65 [95% CI,
0.53-0.80]; p<0.0001). Per the sequential testing strategy, superiority
for PFS was not tested in this population (HR=0.82 [95% CI, 0.67-1.00]).
Results for OS with KEYTRUDA monotherapy in the total population were
consistent with the previously presented interim analysis, where
non-inferiority was demonstrated (HR=0.83 [95% CI, 0.70-0.99];
p=0.0199), with a median OS of 11.5 months (95% CI, 10.3-13.4) for
KEYTRUDA monotherapy in the total population compared with 10.7 months
(95% CI, 9.3-11.7) for the EXTREME regimen. There was no difference in
PFS between KEYTRUDA monotherapy in the total population and the EXTREME
regimen (HR=1.34 [95% CI, 1.13-1.59]).
“As a company, Merck is committed to advancing research in this
challenging treatment setting through our expansive head and neck cancer
clinical research program,” said Dr. Jonathan Cheng, vice president,
clinical research, Merck Research Laboratories. “The full data from
KEYNOTE-048 illustrate the impact of KEYTRUDA as monotherapy and in
combination with chemotherapy as potential new first-line treatment
options for patients with recurrent or metastatic head and neck squamous
cell carcinoma. We would like to sincerely thank the patients and
investigators for their involvement in KEYNOTE-048.”
As previously announced, the U.S. Food and Drug Administration (FDA) has
granted priority review for a new supplemental Biologics License
Application (sBLA) seeking approval for KEYTRUDA as monotherapy or in
combination with platinum and 5-FU chemotherapy for the first-line
treatment of patients with recurrent or metastatic HNSCC based in part
on data from the second interim analysis of KEYNOTE-048. The FDA has set
a Prescription Drug User Fee Act (PDUFA), or target action, date of June
10, 2019.
Study Design and Additional Data from KEYNOTE-048 (Abstract #6000)
KEYNOTE-048, a randomized, open-label Phase 3 trial (ClinicalTrials.gov,
NCT02358031), evaluated KEYTRUDA in combination with chemotherapy or
KEYTRUDA monotherapy, compared with the EXTREME regimen, as first-line
treatment in patients with recurrent or metastatic HNSCC. The dual
primary endpoints were OS and PFS. The secondary endpoints were PFS (at
six months and 12 months), objective response rate (ORR) and time to
deterioration in the Quality of Life Global Health Status/Quality of
Life Scales of the European Organization for Research and Treatment of
Cancer (EORTC) Quality of Life Questionnaire and Safety. Duration of
response (DOR) was evaluated as part of a pre-specified exploratory
analysis. The primary and secondary endpoints, as well as exploratory
DOR analysis, were evaluated in patients whose tumors expressed PD-L1
(CPS ≥20 and CPS ≥1) and in the total population, based on a fixed
sequential testing strategy. Data cutoff for the final analysis was Feb.
25, 2019; data cutoff for the previously presented second interim
analysis was June 13, 2018. Details of the OS benefit observed at the
final analysis are below:
|
Summary of Overall Survival |
||||
| Population (number of patients with event) | Final Analysis Hazard Ratio (95% CI) | |||
| KEYTRUDA Monotherapy | ||||
| PD-L1 CPS ≥20 (n=133) vs. EXTREME (n=122) | 0.58 (0.44-0.78)b | |||
| PD-L1 CPS ≥1 (n=257) vs. EXTREME (n=255) | 0.74 (0.61-0.90)b | |||
| Total Population (n=301) vs. EXTREME (n=300) | 0.83 (0.70-0.99); p=0.0199c | |||
|
KEYTRUDA in Combination with |
||||
| PD-L1 CPS ≥20 (n=126) vs. EXTREME (n=110) | 0.60 (0.45–0.82); p=0.0004a | |||
| PD-L1 CPS ≥1 (n=242) vs. EXTREME (n=235) | 0.65 (0.53–0.80); p<0.0001a | |||
| Total Population (n=281) vs. EXTREME (n=278) | 0.72 (0.60-0.87)b | |||
| a | Superiority demonstrated. | |
| b |
No new statistical testing performed because population previously demonstrated superiority at interim analysis. |
|
| c | Superiority not demonstrated. | |
The secondary endpoint of ORR was 42.9% for KEYTRUDA in combination with
chemotherapy in patients whose tumors expressed PD-L1 with CPS ≥20
compared with 38.2% for the EXTREME regimen. The ORR was 36.4% in
patients whose tumors expressed PD-L1 with CPS ≥1 for KEYTRUDA in
combination with chemotherapy compared with 35.7% for the EXTREME
regimen. The median DOR was 7.1 months (range, 2.1+ to 39.0+) for
KEYTRUDA in combination with chemotherapy in patients whose tumors
expressed PD-L1 with CPS ≥20 compared with 4.2 months (range, 1.2+ to
31.5+) for the EXTREME regimen. The median DOR was 6.7 months (range,
1.6+ to 39.0+) for KEYTRUDA in combination with chemotherapy in patients
whose tumors expressed PD-L1 with CPS ≥1 compared with 4.3 months
(range, 1.2+ to 31.5+) for the EXTREME regimen.
In the KEYTRUDA monotherapy arm, an analysis of the total patient
population showed an ORR of 16.9% compared with 36.0% for the EXTREME
regimen; the median DOR was 22.6 months (range, 1.5+ to 43.0+) compared
with 4.5 months (range, 1.2+ to 38.7+) for the EXTREME regimen.
As previously reported, there were no new safety concerns identified
with the use of KEYTRUDA in KEYNOTE-048. Grade 3-5 all-cause adverse
events occurred in 54.7%, 85.1% and 83.3% of patients in the KEYTRUDA
monotherapy, KEYTRUDA in combination with chemotherapy and EXTREME
regimen arms, respectively. Adverse events resulting in discontinuation
occurred in 12.0%, 32.6% and 27.5% of patients in the KEYTRUDA
monotherapy, KEYTRUDA in combination with chemotherapy and EXTREME
regimen arms, respectively. Treatment-related deaths occurred in 1.0%,
4.0% and 2.8% of patients in the KEYTRUDA monotherapy, KEYTRUDA in
combination with chemotherapy and EXTREME regimen arms, respectively.
Grade 3-5 immune-mediated or infusion reactions occurred in 7.0%, 5.4%
and 10.5% of patients in the KEYTRUDA monotherapy, KEYTRUDA in
combination with chemotherapy and EXTREME regimen arms, respectively.
Additional Information About KEYNOTE-048
KEYNOTE-048 enrolled 882 patients with recurrent or metastatic HNSCC who
were randomized to one of three regimens as first-line therapy, as
follows:
-
KEYTRUDA monotherapy (200 mg fixed dosed every three weeks [Q3W]) for
up to 24 months (n=301); or -
KEYTRUDA (200 mg fixed dose Q3W) in combination with cisplatin (100
mg/m2 IV Q3W) or carboplatin (AUC 5 IV Q3W) plus 5-FU (1000
mg/m2/day IV continuous from Day 1-4 Q3W (maximum six
cycles), followed by additional KEYTRUDA monotherapy maintenance
therapy until progression of disease, toxicity or until the patient
had received a maximum of 24 months total treatment (n=281); or -
EXTREME regimen including cetuximab at a loading dose (400 mg/m2
IV) followed by weekly doses (250 mg/m2 IV) in combination
with cisplatin (100 mg/m2 IV Q3W) or carboplatin (AUC 5 IV
Q3W) plus 5-FU (1000 mg/m2/day IV) continuous from Day 1-4
Q3W (maximum six cycles), followed by additional cetuximab monotherapy
maintenance therapy until progression of disease or toxicity (n=300).
About Head and Neck Cancer
Head and neck cancer describes a number of different tumors that develop
in or around the throat, larynx, nose, sinuses and mouth. Most head and
neck cancers are squamous cell carcinomas that begin in the flat,
squamous cells that make up the thin surface layer of the structures in
the head and neck. Two substances that greatly increase the risk of
developing head and neck cancer are tobacco and alcohol. It is estimated
that there were more than 887,000 new cases of head and neck cancer
diagnosed and over 453,000 deaths from the disease worldwide in 2018. In
the U.S. alone, it is estimated that there will be more than 65,000 new
cases of head and neck cancer diagnosed and over 14,000 deaths from the
disease in 2019.
About KEYTRUDA® (pembrolizumab) Injection,
100mg
KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of
the body’s immune system to help detect and fight tumor cells. KEYTRUDA
is a humanized monoclonal antibody that blocks the interaction between
PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes
which may affect both tumor cells and healthy cells.
Merck has the industry’s largest immuno-oncology clinical research
program. There are currently more than 1,000 trials studying KEYTRUDA
across a wide variety of cancers and treatment settings. The KEYTRUDA
clinical program seeks to understand the role of KEYTRUDA across cancers
and the factors that may predict a patient’s likelihood of benefitting
from treatment with KEYTRUDA, including exploring several different
biomarkers.
KEYTRUDA® (pembrolizumab) Indications and
Dosing
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or
metastatic melanoma. The recommended dose of KEYTRUDA in patients with
unresectable or metastatic melanoma is 200 mg administered as an
intravenous infusion over 30 minutes every three weeks until disease
progression or unacceptable toxicity.
KEYTRUDA is indicated for the adjuvant treatment of patients with
melanoma with involvement of lymph node(s) following complete resection.
The recommended dose of KEYTRUDA for the adjuvant treatment of adult
patients with melanoma is 200 mg administered as an intravenous infusion
over 30 minutes every three weeks until disease recurrence, unacceptable
toxicity, or for up to 12 months in patients without disease recurrence.
Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is
indicated for the first-line treatment of patients with metastatic
nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK
genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel or
paclitaxel protein-bound, is indicated for the first-line treatment of
patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line treatment
of patients with stage III NSCLC who are not candidates for surgical
resection or definitive chemoradiation, or metastatic NSCLC, and whose
tumors express PD-L1 [tumor proportion score (TPS) ≥1%] as determined by
an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, as a single agent, is indicated for the treatment of patients
with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined
by an FDA-approved test, with disease progression on or after
platinum-containing chemotherapy. Patients with EGFR or ALK genomic
tumor aberrations should have disease progression on FDA-approved
therapy for these aberrations prior to receiving KEYTRUDA.
In NSCLC, the recommended dose of KEYTRUDA is 200 mg administered as an
intravenous infusion over 30 minutes every three weeks until disease
progression, unacceptable toxicity, or up to 24 months in patients
without disease progression.
When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA
should be administered prior to chemotherapy when given on the same day.
See also the Prescribing Information for the chemotherapy agents
administered in combination with KEYTRUDA, as appropriate.
Head and Neck Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent or
metastatic head and neck squamous cell carcinoma (HNSCC) with disease
progression on or after platinum-containing chemotherapy. This
indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA 200 mg
is administered as an intravenous infusion over 30 minutes every three
weeks until disease progression, unacceptable toxicity, or up to 24
months in patients without disease progression.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients
with refractory classical Hodgkin lymphoma (cHL), or who have relapsed
after 3 or more prior lines of therapy. This indication is approved
under accelerated approval based on tumor response rate and durability
of response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in the
confirmatory trials. In adults with cHL, KEYTRUDA 200 mg is administered
as an intravenous infusion over 30 minutes every three weeks until
disease progression or unacceptable toxicity, or up to 24 months in
patients without disease progression. In pediatric patients with cHL,
KEYTRUDA is administered as an intravenous infusion over 30 minutes at a
dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until
disease progression or unacceptable toxicity, or up to 24 months in
patients without disease progression.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients
with refractory primary mediastinal large B-cell lymphoma (PMBCL), or
who have relapsed after 2 or more prior lines of therapy. This
indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in confirmatory trials. KEYTRUDA is not recommended for
the treatment of patients with PMBCL who require urgent cytoreductive
therapy.
In adults with PMBCL, KEYTRUDA 200 mg is administered as an intravenous
infusion over 30 minutes every three weeks until disease progression,
unacceptable toxicity, or up to 24 months in patients without disease
progression. In pediatric patients with PMBCL, KEYTRUDA is administered
as an intravenous infusion over 30 minutes at a dose of 2 mg/kg (up to a
maximum of 200 mg) every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without disease
progression.
Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma (mUC) who are not eligible
for cisplatin-containing chemotherapy and whose tumors express PD-L1
[combined positive score (CPS) ≥10] as determined by an FDA-approved
test, or in patients who are not eligible for any platinum-containing
chemotherapy regardless of PD-L1 status. This indication is approved
under accelerated approval based on tumor response rate and duration of
response. Continued approval for this indication may be contingent upon
verification and description of clinical benefit in the confirmatory
trials.
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma (mUC) who have disease
progression during or following platinum-containing chemotherapy or
within 12 months of neoadjuvant or adjuvant treatment with
platinum-containing chemotherapy.
In locally advanced or metastatic urothelial carcinoma, KEYTRUDA 200 mg
is administered as an intravenous infusion over 30 minutes every three
weeks until disease progression or unacceptable toxicity, or up to 24
months in patients without disease progression.
Microsatellite Instability-High (MSI-H) Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients
with unresectable or metastatic microsatellite instability-high (MSI-H)
or mismatch repair deficient (dMMR)
-
solid tumors that have progressed following prior treatment and who
have no satisfactory alternative treatment options, or -
colorectal cancer that has progressed following treatment with
fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials. The safety and
effectiveness of KEYTRUDA in pediatric patients with MSI-H central
nervous system cancers have not been established.
In adult patients with MSI-H cancer, KEYTRUDA 200 mg is administered as
an intravenous infusion over 30 minutes every three weeks until disease
progression, unacceptable toxicity, or up to 24 months in patients
without disease progression. In pediatric patients with MSI-H cancer,
KEYTRUDA is administered as an intravenous infusion over 30 minutes at a
dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until
disease progression or unacceptable toxicity, or up to 24 months in
patients without disease progression.
Gastric Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent
locally advanced or metastatic gastric or gastroesophageal junction
(GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined
by an FDA-approved test, with disease progression on or after two or
more prior lines of therapy including fluoropyrimidine- and
platinum-containing chemotherapy and if appropriate, HER2/neu-targeted
therapy. This indication is approved under accelerated approval based on
tumor response rate and durability of response. Continued approval for
this indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials. The recommended dose of
KEYTRUDA is 200 mg as an intravenous infusion over 30 minutes every
three weeks until disease progression, unacceptable toxicity, or up to
24 months in patients without disease progression.
Cervical Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent or
metastatic cervical cancer with disease progression on or after
chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an
FDA-approved test. This indication is approved under accelerated
approval based on tumor response rate and durability of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in the confirmatory
trials. The recommended dose of KEYTRUDA is 200 mg as an intravenous
infusion over 30 minutes every three weeks until disease progression,
unacceptable toxicity or up to 24 months in patients without disease
progression.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with hepatocellular
carcinoma (HCC) who have been previously treated with sorafenib. This
indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials. The recommended dose of
KEYTRUDA is 200 mg as an intravenous infusion over 30 minutes every
three weeks until disease progression, unacceptable toxicity, or up to
24 months in patients without disease progression.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients
with recurrent locally advanced or metastatic Merkel cell carcinoma.
This indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials. The recommended dose of
KEYTRUDA in adults is 200 mg administered as an intravenous infusion
over 30 minutes every three weeks until disease progression,
unacceptable toxicity, or up to 24 months in patients without disease
progression. The recommended dose of KEYTRUDA in pediatric patients is 2
mg/kg (up to a maximum of 200 mg), administered as an intravenous
infusion over 30 minutes every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without disease
progression.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the first-line
treatment of patients with advanced renal cell carcinoma. In renal cell
carcinoma, KEYTRUDA 200 mg is administered as an intravenous infusion
over 30 minutes every 3 weeks in combination with 5 mg axitinib orally
twice daily until disease progression, unacceptable toxicity, or for
KEYTRUDA, up to 24 months in patients without disease progression. When
axitinib is used in combination with KEYTRUDA, dose escalation of
axitinib above the initial 5 mg dose may be considered at intervals of
six weeks or longer. See also the Prescribing Information for
recommended axitinib dosing information.
Selected Important Safety Information for KEYTRUDA (pembrolizumab)
Injection, 100mg
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases.
Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers
receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4
(0.
Contacts
Media:
Pamela Eisele
(267) 305-3558
or
Ayn Wisler
(908)
740-5590
Investors:
Teri Loxam
(908) 740-1986
or
Peter
Dannenbaum
(908) 740-1037