New Data Evaluating KEYTRUDA® (pembrolizumab) in Combination with Chemotherapy for First-Line Treatment of Non-Small Cell Lung Cancer Demonstrate Response Rates Ranging from 48 to 71 Percent
June 4, 2016 7:00 am ET
Based on Initial Results Presented at 2016 ASCO Annual Meeting, Merck Has Initiated Two Phase 3 Studies
KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced findings from an initial proof-of-concept study of
KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy,
combined with standard treatments, one with bevacizumab and others
without, in non-small cell lung cancer (NSCLC) including chemotherapy in
previously untreated patients with NSCLC; the study showed overall
response rates (ORR) ranging from 48 to 71 percent, depending on the
therapy used. These data, from the phase 1/2 KEYNOTE-021 trial, will be
presented today at the 52nd Annual Meeting of the American
Society of Clinical Oncology (ASCO) by Dr. Shirish Gadgeel of the
Barbara Ann Karmanos Cancer Institute (Abstract #9016) from 8:00 – 11:30
a.m. CDT (Location: Hall A) and in a poster discussion from 3:00 – 4:15
p.m. CDT (Location: E354b).
“Combining KEYTRUDA and chemotherapy in the first-line lung cancer
treatment setting is an important part of our effort to develop more
treatment options for patients with non-small cell lung cancer,” said
Dr. Roger Dansey, senior vice president and therapeutic area head,
oncology late-stage development, Merck Research Laboratories. “This
study has helped us to identify chemotherapy options for combination
with KEYTRUDA regardless of PD-L1 expression to take forward in phase 3
The findings presented at ASCO 2016 were based on 74 patients who were
treated with KEYTRUDA and one of three different chemotherapy regimens
in the phase 1b portion of the study. The data, across all three cohorts
including patients with and without PD-L1 tumor expression, showed an
ORR of 57 percent (n=42/74, 95% CI, 45-68), including one complete
response and 41 partial responses. Median duration of follow-up was 12
months (range <1-21).
“These results are encouraging because they provide initial evidence
that adding chemotherapy to KEYTRUDA may increase response rates and
open new treatment paths for a broader range of patients with advanced
non-small cell lung cancer,” said Dr. Gadgeel, professor, leader of the
multidisciplinary thoracic oncology team, Karmanos Cancer
Institute/Wayne State University in Detroit.
The highest response rates were observed in a group of 24 patients who
received KEYTRUDA (pembrolizumab) in combination with carboplatin plus
pemetrexed (Cohort C), with an ORR of 71 percent (n=17/24, 95% CI,
49-87), including one complete response and 16 partial responses. In
this same group, median progression-free survival (PFS) was 10.2 months
(95% CI, 6.3-15.2), and median overall survival (OS) was not reached
(95% CI, 13.9-NR). Median duration of follow-up was 16 months (range
In the group that received KEYTRUDA plus carboplatin and paclitaxel
(Cohort A), ORR was 52 percent (n=13/25, 95% CI, 31-72) and all
responses were partial responses. Median PFS in this cohort was 10.3
months (95% CI, 3.7-NR), and median OS was not reached (95% CI,
11.0-NR). Median duration of follow-up was 13 months (range 2-21).
In the cohort that received KEYTRUDA in addition to carboplatin,
paclitaxel, and bevacizumab (Cohort B), ORR was 48 percent (n=12/25, 95%
CI, 28-69) and all responses were partial responses. Median PFS was not
reached (95% CI, 4.1-NR), and median OS was not reached (95% CI, NR-NR).
Median duration of follow-up was 9 months (range <1-17).
Overall Response Rates by Cohort
|0||0||4% (1)||1% (1)|
|Partial Response||52% (13)||48% (12)||67% (16)||55% (41)|
Responses were seen across all levels of PD-L1 expression, including in
patients with PD-L1 negative tumors. PD-L1 levels assessed included high
expression (tumor proportion score [TPS] of greater than or equal to 50
percent), any expression (TPS of greater than or equal to 1 percent),
and negative expression (PD-L1 of less than 1 percent).
Overall Response Rates by PD-L1 Tumor Proportion Score
PD-L1 TPS Status
The safety profile of KEYTRUDA (pembrolizumab) in combination with
chemotherapy in this study was consistent with that observed previously.
One dose-limiting toxicity event occurred in Cohort C, which
subsequently led to discontinuation (Grade 3 toxic epidermal
necrolysis). Three patients in Cohort B discontinued due to
treatment-related adverse events (Grade 3 pneumonitis, drug
hypersensitivity, and autoimmune colitis). No patients in Cohort A
discontinued because of treatment-related adverse events. Grade 3-5
adverse events occurred in 56, 71, and 67 percent of patients in Cohorts
A, B, and C, respectively. In Cohort B, the most common Grade 3-4
adverse events were drug hypersensitivity (8%), febrile neutropenia
(8%), neutropenia (8%), white blood cell count decreased (8%), pneumonia
(8%), and pulmonary embolism (8%). Immune-mediated adverse events,
primarily Grades 1-2, were observed across cohorts. The most common
Grade 3 immune-mediated adverse events were colitis (4% Cohort C), rash
papular (4% Cohort A), pancreatitis (4% Cohort B), pneumonitis (4%
Cohort B), and toxic epidermal necrolysis (4% Cohort C). There were no
treatment-related deaths across cohorts; there was one death in Cohort B
(Grade 5 pericardial effusion) which was not treatment-related.
Based on these findings, Merck has initiated two phase 3 trials in
patients with previously untreated NSCLC. KEYNOTE-189 is evaluating the
combination of KEYTRUDA plus a platinum/pemetrexed-based chemotherapy
regimen in patients with non-squamous NSCLC. KEYNOTE-407 will study
KEYTRUDA combined with carboplatin and paclitaxel or nab-paclitaxel in
patients with squamous NSCLC. Merck has a robust clinical development
program for KEYTRUDA in lung cancer, with five registration-enabling
studies currently underway. The KEYTRUDA clinical development program
includes more than 30 tumor types in more than 270 clinical trials,
including more than 100 trials that combine KEYTRUDA with other cancer
About the KEYNOTE-021 Study (Cohorts A-C)
KEYNOTE-021 is a phase 1/2 multicenter, open-label, randomized,
multi-cohort trial with Cohorts A, B, and C evaluating KEYTRUDA
(pembrolizumab) in combination with chemotherapy in patients with
chemotherapy-naïve, EGFR- and ALK-negative unresectable or metastatic
NSCLC. Patients were randomized to receive 2 mg/kg or 10 mg/kg of
KEYTRUDA every three weeks plus one of several chemotherapy regimens for
four cycles – Cohort A (any histology): carboplatin AUC 6 plus
paclitaxel 200 mg/m2 followed by maintenance KEYTRUDA; Cohort
B (non-squamous histology): carboplatin AUC 6 plus paclitaxel 200 mg/m2
plus bevacizumab 15 mg/kg followed by maintenance KEYTRUDA plus
bevacizumab; or Cohort C (non-squamous histology): carboplatin AUC 5
plus pemetrexed 500 mg/m2 followed by maintenance KEYTRUDA
plus pemetrexed. The primary efficacy outcome measures were ORR as
assessed every six weeks for the first 18 weeks, followed by every nine
weeks for the remainder of the first year, using RECIST v1.1 by a
central imaging vendor. Secondary outcome measures included OS, PFS, and
duration of response.
KEYTRUDA is a humanized monoclonal antibody that works by increasing the
ability of the body’s immune system to help detect and fight tumor
cells. KEYTRUDA 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.
KEYTRUDA is indicated for the treatment of patients with unresectable or
KEYTRUDA is also indicated for the treatment of patients with metastatic
non-small cell lung cancer (NSCLC) whose tumors express PD-L1 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. This
indication is approved under accelerated approval based on tumor
response rate and durability of response. An improvement in survival or
disease-related symptoms has not yet been established. Continued
approval for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials.
KEYTRUDA is administered at a dose of 2 mg/kg as an intravenous infusion
over 30 minutes every three weeks for the approved indications.
Selected Important Safety Information for KEYTRUDA
Immune-mediated pneumonitis occurred in 19 (3.5%) of 550 patients,
including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis
and occurred more frequently in patients with a history of
asthma/chronic obstructive pulmonary disease (5.4%) or prior thoracic
radiation (6.0%). Monitor patients for signs and symptoms of
pneumonitis. Evaluate suspected pneumonitis with radiographic imaging.
Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold
KEYTRUDA (pembrolizumab) for Grade 2; permanently discontinue KEYTRUDA
for Grade 3 or 4 or recurrent Grade 2 pneumonitis.
Immune-mediated colitis occurred in 4 (0.7%) of 550 patients, including
Grade 2 (0.2%) or 3 (0.4%) colitis. Monitor patients for signs and
symptoms of colitis. Administer corticosteroids for Grade 2 or greater
colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue
KEYTRUDA for Grade 4 colitis.
Immune-mediated hepatitis occurred in patients receiving KEYTRUDA.
Monitor patients for changes in liver function. Administer
corticosteroids for Grade 2 or greater hepatitis and, based on severity
of liver enzyme elevations, withhold or discontinue KEYTRUDA.
Hypophysitis occurred in 1 (0.2%) of 550 patients, which was Grade 3 in
severity. Monitor patients for signs and symptoms of hypophysitis
(including hypopituitarism and adrenal insufficiency). Administer
corticosteroids and hormone replacement as clinically indicated.
Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4
Hyperthyroidism occurred in 10 (1.8%) of 550 patients, including Grade 2
(0.7%) or 3 (0.3%) hyperthyroidism. Hypothyroidism occurred in 38 (6.9%)
of 550 patients, including Grade 2 (5.5%) or 3 (0.2%) hypothyroidism.
Thyroid disorders can occur at any time during treatment. Monitor
patients for changes in thyroid function (at the start of treatment,
periodically during treatment, and as indicated based on clinical
evaluation) and for clinical signs and symptoms of thyroid disorders.
Administer replacement hormones for hypothyroidism and manage
hyperthyroidism with thionamides and beta-blockers as appropriate.
Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.
Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 3
(0.1%) of 2117 patients. Monitor patients for hyperglycemia or other
signs and symptoms of diabetes. Administer insulin for type 1 diabetes,
and withhold KEYTRUDA and administer anti-hyperglycemics in patients
with severe hyperglycemia.
Immune-mediated nephritis occurred in patients receiving KEYTRUDA.
Monitor patients for changes in renal function. Administer
corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for
Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.
Other clinically important immune-mediated adverse reactions can occur.
For suspected immune-mediated adverse reactions, ensure adequate
evaluation to confirm etiology or exclude other causes. Based on the
severity of the adverse reaction, withhold KEYTRUDA and administer
corticosteroids. Upon improvement to Grade 1 or less, initiate
corticosteroid taper and continue to taper over at least 1 month. Based
on limited data from clinical studies in patients whose immune-related
adverse reactions could not be controlled with corticosteroid use,
administration of other systemic immunosuppressants can be considered.
Resume KEYTRUDA (pembrolizumab) when the adverse reaction remains at
Grade 1 or less following corticosteroid taper. Permanently discontinue
KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs
and for any life-threatening immune-mediated adverse reaction.
The following clinically significant, immune-mediated adverse reactions
occurred in less than 1% of 550 patients: rash, vasculitis, hemolytic
anemia, serum sickness, and myasthenia gravis.
Severe and life-threatening infusion-related reactions have been
reported in 3 (0.1%) of 2117 patients. Monitor patients for signs and
symptoms of infusion-related reactions including rigors, chills,
wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever.
For Grade 3 or 4 reactions, stop infusion and permanently discontinue
Based on its mechanism of action, KEYTRUDA can cause fetal harm when
administered to a pregnant woman. If used during pregnancy, or if the
patient becomes pregnant during treatment, apprise the patient of the
potential hazard to a fetus. Advise females of reproductive potential to
use highly effective contraception during treatment and for 4 months
after the last dose of KEYTRUDA.
KEYTRUDA was discontinued due to adverse reactions in 14% of 550
patients. Serious adverse reactions occurred in 38% of patients. The
most frequent serious adverse reactions reported in at least 2% of
patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism,
and pneumonitis. The most common adverse reactions (reported in at least
20% of patients) were fatigue (44%), cough (29%), decreased appetite
(25%), and dyspnea (23%).
No formal pharmacokinetic drug interaction studies have been conducted
It is not known whether KEYTRUDA is excreted in human milk. Because many
drugs are excreted in human milk, instruct women to discontinue nursing
during treatment with KEYTRUDA and for 4 months after the final dose.
Safety and effectiveness of KEYTRUDA have not been established in
Our Focus on Cancer
Our goal is to translate breakthrough science into innovative oncology
medicines to help people with cancer worldwide. At Merck Oncology,
helping people fight cancer is our passion and supporting accessibility
to our cancer medicines is our commitment. Our focus is on pursuing
research in immuno-oncology and we are accelerating every step in the
journey – from lab to clinic – to potentially bring new hope to people
As part of our focus on cancer, Merck is committed to exploring the
potential of immuno-oncology with one of the fastest-growing development
programs in the industry. We are currently executing an expansive
research program that includes more than 270 clinical trials evaluating
our anti-PD-1 therapy across more than 30 tumor types. We also continue
to strengthen our immuno-oncology portfolio through strategic
acquisitions and are prioritizing the development of several promising
immunotherapeutic candidates with the potential to improve the treatment
of advanced cancers.
For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.
For 125 years, Merck has been a global health care leader working to
help the world be well. Merck is known as MSD outside the United States
and Canada. Through our prescription medicines, vaccines, biologic
therapies, and animal health products, we work with customers and
operate in more than 140 countries to deliver innovative health
solutions. We also demonstrate our commitment to increasing access to
health care through far-reaching policies, programs and partnerships.
For more information, visit www.merck.com
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Patient Information/Medication Guide for KEYTRUDA at
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