Lung cancer is the leading cause of deaths with 1.88 million cases and ranks fifth in the incidence of cancer in human (3.34 million) according to 2017 statistics worldwide and emerges as a global health burden.
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THE ROLE OF IMMUNE CHECKPOINT INHIBITOR
PEMBROLIZUMAB IN TREATMENT OF PATIENTS
WITH NON-SMALL CELL LUNG CANCER: REVIEW
Pham Thi Kim Nhung 1 ; Ta Ba Thang 1 ; Dao Ngoc Bang 1
SUMMARY
Lung cancer is the leading cause of deaths with 1.88 million cases and ranks fifth in the incidence of cancer in human (3.34 million) according to 2017 statistics worldwide and emerges
as a global health burden Immunotherapy, especially using immune checkpoint inhibitors has opened novel therapeutic opportunities that are effective for patients with advanced stage of lung cancer, who poorly responds or does not respond to chemoradiation therapy Pembrolizumab (keytruda) is a monoclonal antibody against PD-1 on surface of T-lymphocytes that have been shown improvement of overall survival, progression-free survival and mortality in non-small cell lung cancer patients based on the results of a series of clinical trials such as Keynote 010, 024, 021, 042, 189, 407 This is also the scientific basis for indication of keytruda that was approved by the United States Food and Drug Administration
* Keywords: Non-small cell lung cancer; PD-1; Pembrolizumab
IMMUNE CHECKPOINT INHIBITOR
DRUGS AND MECHANISM OF
PEMBROLIZUMAB (KEYTRUDA)
Immunotherapy is becoming increasingly
an effective treatment in malignant
diseases It differs from other methods
such as surgery, chemotherapy, radiotherapy,
targeted therapy in enhancing action of
the immune system to fight against
cancer cells by a “natural” way
In the past, immunotherapy in cancer
treatment was mainly non-specific
viaenhancing the function of the general
immune system or reducing the favorable micro-environment for the development and spread of cancer cells, such as vaccination against viruses that can lead to cancer, using cytokines (IL-2, IFN)
as an mediator… Currently, specific immunotherapy is focused on helping the component of the patient’s immune system to identify cancer cell easier and improve the effectiveness of immune response killing cancer cells such as using monoclonal antibodies (mAbs) or using of modified immune cells
1 103 Military Hospital
Corresponding author: Pham Thi Kim Nhung (khanhnhu106@gmail.com)
Date received: 09/09/2019
Date accepted: 15/10/2019
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Monoclonal antibodies are the most
common passive immunotherapy with many
types of antibodies approved by the United
States Food and Drug Administration
These antibodies can attack cancer cells
directly or attach specific protein on cancer
cells that help to transport chemotherapy
or radiotherapy, or flag cancer cells to the
immune system to recognize and destroy
In addition, monoclonal antibodies can
release or “unlock” immune checkpoint
inhibitor so that the immune system
becomes activated and perform the
function of killing cancer cells
Immune checkpoints are surface
receptors which regulate cell signals and
inhibit immune activity of T lymphocytes
In cancerous microenvironment, cancer
cells often express CTLA-4 ligand, PD-L1
ligand, thereby inhibiting T cell activity As
a result, immune checkpoint inhibitor
drugs will be a potential approach for
cancer immunotherapy
PD-1 (programmed cell death receptor 1)
is an immunosuppressant receptor
defined after CTLA-4 This receptor has
2 ligands (PD-L1 or B7-H1 or CD274) and
PD-L2 or B7-DC or CD273) [1] Although
the interaction between PD-L2 and PD-1
is 2 - 6 times higher than PD-L1 and PD-1,
PD-L1 is still the main ligand of PD-1 [2]
PD-1 is a negative regulatory receptor,
expressed only on the surface of
activated T lymphocytes while its ligands
(PD-L1 and PD-L2) can be expressed in
tumor cells under the action of cytokines
and interferons produced by activated
T cells or soluble in serum
The interaction of PD-L1 with the PD-1 receptor transmits an immunosuppressive signal to the T cell, resulting in an inactivated status of T cell or inhibited
T cells PD-1 also inhibits T cell activity by reducing the activating signal of the CD28 receptor, inhibiting the activity of the CD28 receptor PD-1 mainly controls the activity of activated T cell in peripheral tissues In addition, PD-1/PD-L1 pathway
is also thought to play a role in controlling the T cell invasion into the tumor, hence preventing the direct contact of activated
T cells and cancer cells [3] Therefore, monoclonal antibodies against PD-1 or PD-L1 will interact with PD-1 or PD-L1 respectively, helping to reactivate T cell
PD-L1 is a type 1 transmembrane protein (B7-H1); PD-L1 expression in tumor cells promotes regulations and self-tolerance of immune system by eliminating tumor cells by binding to
T lymphocyte Mechanism of “escaping” the control of immune system of the tumor cells: The immune system plays an important dual role in cancer through the process of immune repair Both the innate and adaptive immune system inhibit tumor growth and kill cancer cells during the elimination phage or immuno-surveillance However, tumor cells are able to escape this elimination phase by a variety of mechanisms such as creating a local immunosuppressive state, producing cytokines that have an immunosuppressive function, creating defects in the presentation
of tumor antigens to T cell or expression
of molecules that regulate immune check point like CTLA-4, PD-1 and PD-L1 Hence, tumor cells disrupt normal
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immune function to create favorable
conditions for tumor cells to grow For
example, the heterozygous loss of HLA
(human leukocyte antigen) appearing in
approximately 40% of patients with early
stage non-small cell lung cancer (NSCLC)
is a special manifestation of “escaping”
One of the cancer therapeutic strategies
to combat “escaping” is to reactivate T
cell mediated antitumor activity by
modulating the interaction between the
receptor and the ligand of immune
checkpoint In normal conditions, the
receptor of immune check point has the
function of limiting the activity of T cell,
preventing the destruction of normal cells,
creating balance
Mechanism of pembrolizumab (keytruda):
pembrolizumab is a monoclonal antibody
against the PD-1 receptor on the surface
of T cell Until now, there have been many
applications of immune checkpoint inhibitor
drugs in cancer treatment such as NSCLC,
colorectal cancer, stomach cancer, cervical
cancer, kidney cancer, melanoma…
However, for NSCLC, pembrolizumab
(keytruda) and nivolumab (opdivo),
atezolizumab (tecentriq) are the main
choice
CLINICAL STUDIES/TRIALS ON THE
EFFECTIVENESS OF
PEMBROLIZUMAB (KEYTRUDA) ON
NSCLC
1 General information
Pembrolizumab (keytruda) is a product
of MSD company This drug has been
applied in a series of clinical trials such as
Keynote 010, 024, 021, 042, 189, 407
and has shown positive results, opening
up new opportunities for patients with
NSCLC It is also the scientific basis for keytruda’s indications for this group of patients
2 Clinical trials
KEYNOTE 010 is a randomized,
open-label, phase 2/3 study that evaluate the efficacy of keytruda compared with standard chemotherapy in 1,034 advanced stage NSCLC patients, progression after platinum regimen with PD-L1 expression
on at least 1% Patients were randomly assigned (1:1:1) in 3 groups: 345 patients received pembrolizumab 2 mg/kg every
3 weeks; 346 patients received pembrolizumab 10 mg/kg every 3 weeks and 343 patients received docetaxel
75 mg/m2 every 3 weeks In addition, the number of patients with high PD-L1 expression (TPS ≥ 50%) were 139, 151 and 152 in 3 groups, respectively The endpoints were overall survival and progression free survival, rate of complete response and time of response [4] In this trial, treatment was discontinued for adverse reactions in 8% of the 682 patients receiving keytruda across both doses The most common adverse events resulting in permanent discontinuation of keytruda occurred in 23% of patients, the most common were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decrease appetite (1.3%) and pneumonitis (1%) Grade 3 - 5 treatment - related adverse events were less common with pembrolizumab than with docetaxel (43 of 339 patients (13%) received 2 mg/kg, 55 of 343 patients (16%) received 10 mg/kg, and 109 of 309 patients (35%) received docetaxel In the total population, median overall survival was
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10.4 months with pembrolizumab 2 mg/kg,
12.7 months with pembrolizumab
10 mg/kg, and 8.5 months with docetaxel
Overall survival was significantly longer
for pembrolizumab 2 mg/kg versus
docetaxel (hazard ratio [HR] 0.71, 95%CI:
0.58 - 0.88; p = 0.0008) and for
pembrolizumab 10 mg/kg versus docetaxel
(0.61, 0.49 - 0.75; p < 0.0001) Median
progression-free survival was 3.9 months
with pembrolizumab 2 mg/kg, 4.0
months with pembrolizumab 10 mg/kg, and
4.0 months with docetaxel, with no
significant difference in pembrolizumab
2 mg/kg versus docetaxel (0.88, 0.74 -
1.05; p = 0.07) or for pembrolizumab 10
mg/kg versus docetaxel (HR 0.79, 95%CI:
0.66 - 0.94; p = 0.004) Among patients
with at least 50% of tumor cells
expressing PD-L1, overall survival was
significantly longer with pembrolizumab
2 mg/kg than with docetaxel (median 14.9
months vs 8.2 months; HR 0.54, 95%CI:
0.38 - 0.77; p = 0.0002) and with
pembrolizumab 10 mg/kg than with
docetaxel (17.3 months vs 8.2 months;
0.50, 0.36 - 0.70; p < 0.0001) Likewise,
for this patient population,
progression-free survival was significantly longer with
pembrolizumab 2 mg/kg than with
docetaxel (median 5.0 months vs 4.1
months; HR 0.59, 95%CI: 0.44 - 0.78; p =
0.0001) and with pembrolizumab
mg/kg than with docetaxel (5.2 months vs
4.1 months; 0.59, 0.45 - 0.78; p <
0.0001) Keytruda was approved for
treatment of advanced stage NSCLC with
the fix dose of 200 mg every 3 weeks until
disease progression or unacceptable
toxicity or up to 24 months in patients
without disease progression [5]
KEYNOTE 042 is a randomized,
multi-center, open-label, active-controlled trial conducted in large scale of 32 countries,
in 21 centers in 1,274 patients with stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC and whose tumors expressed PD-L1 (TPS ≥ 1%) and who had not received prior systemic treatment for metastatic NSCLC, no EGFR or ALK genomic tumor aberration Patients were randomized (1:1) to receive keytruda 200 mg intravenously every three weeks up to 35 cycles (n = 637) or investigator’s choice of either of the following chemotherapy regimens (n = 637): pemetrexed 500 mg/m2 or paclitaxel
200 mg/m2 and carboplatin AUC 5 to
6 mg/mL/min every three weeks on day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every three weeks for patients with nonsquamous histologies PD-L1 expression detected by IHC: 599/1,274 patients (47%) with PD-L1 expression TPS ≥ 50%; 818/1,274 patients (64%) with PD-L1 TPS ≥ 20%
Overall survival was significantly longer in the pembrolizumab group than
in the chemotherapy group in all three TPS populations (≥ 50% HR 0.69, 95%CI: 0.56 - 0.85, p = 0.0003; ≥ 20% 0.77, 0.64 - 0.92, p = 0.0020, and ≥ 1% 0.81, 0.71 - 0.93, p = 0.0018) The median survival values by TPS population were 20.0 months (95%CI: 15.4 - 24.9) for pembrolizumab versus 12.2 months (10.4 - 14.2) for chemotherapy, 17.7 months (15.3 - 22.1) versus 13.0 months (11.6 - 15.3), and 16.7 months (13.9 - 19.7) versus 12.1 months (11.3 - 13.3),
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respectively Treatment-related adverse
events of grade 3 or worse occurred in
113 of 636 patients (18%) treated in the
pembrolizumab group and in 252 of
615 patients (41%) in the chemotherapy
group and led to death in 13 patients (2%)
and 14 patients (2%), respectively The
benefit-to-risk profile suggests that
pembrolizumab monotherapy can be
extended as first-line therapy to patients
with locally advanced or metastatic
non-small-cell lung cancer without sensitizing
EGFR or ALK alterations and with low
PD-L1 TPS [6]
KEYNOTE 024 is a randomized,
open-label, phase 3 study evaluating keytruda
monotherapy compared to standard
of care (SOC) platinum-containing
chemotherapy for the treatment of
patients with both squamous (18%) and
non-squamous (82%) metastatic NSCLC
The study enrolled patients who had not
received prior systemic chemotherapy
treatment and whose tumors had high
PD-L1 expression (TPS ≥ 50%) and with
no EGFR or ALK aberrations 305 patients
randomized receive keytruda 200 mg
every 3 weeks or investigator-choice
SOC platinum-based chemotherapy
(pemetrexed + carboplatin, pemetrexed +
cisplatin, gemcitabin + cisplatin,
gemcitabin + carboplatin or paclitaxel +
carboplatin) Pemetrexed maintenance
therapy was permitted for patients with
non squamous histologies The primary
endpoint was progression free survival
(PFS), overall survival (OS) and objective
response rate (ORR) [7] At May 2016,
the trial was followed 11.2 months There
were 189 patients progressive or died
Median PFS was 10.3 months (95%CI:
6.7 to not reached) in the pembrolizumab group versus 6.0 months (95%CI: 4.2 - 6.2)
in the chemotherapy group The estimated percentage of patients who were alive and had no disease progression at 6 months was 62.1% (95%CI: 53.8 - 69.4)
in the pembrolizumab group and 50.3 (95%CI: 41.9 - 58.2) in the chemotherapy group Progression free survival was significantly longer in the pembrolizumab group than in the chemotherapy group (HR for disease progression or death, 0.5;
95%CI: 0.37 - 0.68, p < 0.001) At this time, 108 deaths were reported The estimated percentage of patients who were alive at 6 months was 80.2%
(95%CI: 72.9 - 85.7) in the pembrolizumab group and 72.4% (95%CI: 64.5 - 78.9) in the chemotherapy group; median overall survival was not reached in either group
Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group (hazard ratio for death, 0.60; 95%CI: 0.41 - 0.89; p = 0.005)
The objective response rate, assessed according to RECIST, was 44.8% (95%CI:
36.8 - 53.0) in the pembrolizumab group and 27.8% (95%CI: 20.8 - 35.7) in the chemotherapy group The median time to response was 2.2 months in both groups
Keytruda combined pemetrexed and platinum using for patients with advanced stage nonsquamous NSCLC without EGFR/ALK aberrations had been demonstrated improvement in OS (HR 0.49, 95%CI: 0.38 - 0.64, p < 0.00001);
PFS (HR 0.52, 95%CI: 0.43 - 0.64,
p < 0.00001) and a half decreasing risk of death compared to chemotherapy group
This results were observed in KEYNOTE
189 clinical trial [8]
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KEYNOTE 407 is a randomized,
double-blind, multicenter, placebo-controlled
study The criteria for this study were
metastatic squamous NSCLC, regardless
of tumor PD-L1 expression status and no
prior systemic treatment for metastatic
disease Keytruda in combination with
chemotherapy (carboplatin and either
paclitaxel or nab-paclitaxel) significantly
improved overall survival, reducing the
risk of death by 36% compared to
chemotherapy alone (HR = 0.64; 95%CI:
0.49 - 0.85; p = 0.0017) This results are
the basis for FDA approval of keytruda in
first step treatment in combination with
carboplatin and paclitaxel/nab-paclitaxel
for patients with advanced squamous
NSCLC regardless of tumor PD-L1
expression status [9]
KEYNOTE 021 was conducted on 123
previously untreated patients with metastatic
nonsquamous NSCLC with no EGFR or
ALK genomic tumor aberrations and
irrespective of PD-L1 expression In this
trial, keytruda + pem/carbo demonstrated
an objective response rate (ORR) that
was nearly double the ORR of pem/carbo
alone (55% [95%CI: 42 - 68] compared to
29% [95%CI: 18 - 41], respectively; all
responses were partial responses) In
addition, median PFS in patient treated
with keytruda + pem/carbo is 13 months
compared to 8.9 months in patients with
pem/carbo alone Patients in the keytruda
combination arm received keytruda 200 mg,
pemetrexed 500 mg/m2 and carboplatin
AUC 5 mg/mL/min every three weeks for
four cycles followed by keytruda every
three weeks [10]
INDICATIONS OF PEMBROLIZUMAB (KEYTRUDA) FOR NSCLC
From the first approval on October
2nd 2015, FDA has updated 6 times of keytruda indications for NSCLC patients, including:
- To treat patients with advanced (metastatic) NSCLC whose disease has progressed after other treatment and with tumors that express a protein called PD-L1
- To treat patients with metastatic NSCLC (as the first line treatment) whose tumors have high PD-L1 expression (tumor proportion score-TPS-of 50% or more) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberration
- To treat patients with stage III NSCLC (as monotherapy for the first step treatment) who are not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC and whose tumors express PD-L1 ≥ 1% with
no EGFR or ALK genomic tumor aberration
- To treat as monotherapy for the second step or greater treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥ 1%) with disease progression on or after platinum-containing chemotherapy Patients with EGFR or ALK genomic tumor aberration should have disease progression on FDA-approved therapy for these aberration prior to receiving keytruda
- To treat in combination with pemetrexed and platinum chemotherapy for the first line treatment of patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberration, irrespective
of PD-L1 expression
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- To treat in combination with carboplatin
and either paclitaxel or nab-paclitaxel for
the first line treatment of patients with
metastatic squamous NSCLC regardless
of tumor PD-L1 expression status
CONCLUSION
Pembrolizumab (keytruda) is a
monoclonal antibody against PD-L1 and a
potential immuno-therapy for NSCLC
patients It has been demonstrated
effectively with improvement of OS, PFS
and mortality
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2003, 307 (3), pp.672-677
3 Teixido et al PD-L1 expression testing
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4 Herbst R.S et al Pembrolizumab versus
docetaxel for previously treated,
PD-L1-positive, advanced non-small cell lung cancer
(KEYNOTE-010): A randomised controlled trial Lancet 2016, 387(10027), pp.1540-1550
5
https://www.fda.gov/drugs/resources- information-approved-drugs/pembrolizumab-keytruda-checkpoint-inhibitor Pembrolizumab (KEYTRUDA) Checkpoint Inhibitor 2016
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versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small cell lung cancer (KEYNOTE-042): A randomized, open-label, controlled, phase 3 trial Lancet, 2019
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8 Gandhi L et al Pembrolizumab plus
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9
https://www.fda.gov/drugs/fda-approves- pembrolizumab-combination-chemotherapy-first-line-treatment-metastatic-squamous-nsclc FDA approves pembrolizumab in combination with chemotherapy for first-line treatment of metastatic squamous NSCLC 2018
10
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2017, 5,10