Journal of Clinical Oncology,
Journal Year:
2018,
Volume and Issue:
36(7), P. 633 - 641
Published: Jan. 16, 2018
Purpose
Treatment
of
advanced
non-small-cell
lung
cancer
with
immune
checkpoint
inhibitors
(ICIs)
is
characterized
by
durable
responses
and
improved
survival
in
a
subset
patients.
Clinically
available
tools
to
optimize
use
ICIs
understand
the
molecular
determinants
response
are
needed.
Targeted
next-generation
sequencing
(NGS)
increasingly
routine,
but
its
role
identifying
predictors
not
known.
Methods
Detailed
clinical
annotation
data
were
collected
for
patients
treated
anti-programmed
death-1
or
death-ligand
1
[anti-programmed
cell
death
(PD)-1]
therapy
profiled
targeted
NGS
(MSK-IMPACT;
n
=
240).
Efficacy
was
assessed
Response
Evaluation
Criteria
Solid
Tumors
(RECIST)
version
1.1,
benefit
(DCB)
defined
as
partial
response/stable
disease
that
lasted
>
6
months.
Tumor
mutation
burden
(TMB),
fraction
copy
number-altered
genome,
gene
alterations
compared
among
DCB
no
(NDB).
Whole-exome
(WES)
performed
49
compare
quantification
TMB
versus
WES.
Results
Estimates
correlated
well
WES
(ρ
0.86;
P
<
.001).
greater
than
NDB
(
.006).
more
common,
progression-free
longer
at
increasing
thresholds
above
below
50th
percentile
(38.6%
v
25.1%;
.001;
hazard
ratio,
1.38;
.024).
The
genome
highest
those
NDB.
Variants
EGFR
STK11
associated
lack
benefit.
PD-L1
expression
independent
variables,
composite
plus
further
enriched
ICIs.
Conclusion
accurately
estimates
elevated
likelihood
did
correlate
expression;
both
variables
had
similar
predictive
capacity.
incorporation
into
multivariable
models
should
result
power.
Science,
Journal Year:
2018,
Volume and Issue:
359(6382), P. 1350 - 1355
Published: March 22, 2018
The
release
of
negative
regulators
immune
activation
(immune
checkpoints)
that
limit
antitumor
responses
has
resulted
in
unprecedented
rates
long-lasting
tumor
patients
with
a
variety
cancers.
This
can
be
achieved
by
antibodies
blocking
the
cytotoxic
T
lymphocyte–associated
protein
4
(CTLA-4)
or
programmed
cell
death
1
(PD-1)
pathway,
either
alone
combination.
main
premise
for
inducing
an
response
is
preexistence
cells
were
limited
specific
checkpoints.
Most
who
have
maintain
disease
control,
yet
one-third
relapse.
Mechanisms
acquired
resistance
are
currently
poorly
understood,
but
evidence
points
to
alterations
converge
on
antigen
presentation
and
interferon-γ
signaling
pathways.
New-generation
combinatorial
therapies
may
overcome
mechanisms
checkpoint
therapy.
New England Journal of Medicine,
Journal Year:
2017,
Volume and Issue:
377(25), P. 2500 - 2501
Published: Dec. 20, 2017
In
a
survey
of
the
spectrum
mutational
burdens
in
27
types
cancers,
there
was
correlation
between
an
increased
burden
and
response
to
checkpoint
inhibition
PD-1
PD-L1.
New England Journal of Medicine,
Journal Year:
2018,
Volume and Issue:
378(22), P. 2093 - 2104
Published: April 16, 2018
Nivolumab
plus
ipilimumab
showed
promising
efficacy
for
the
treatment
of
non–small-cell
lung
cancer
(NSCLC)
in
a
phase
1
trial,
and
tumor
mutational
burden
has
emerged
as
potential
biomarker
benefit.
In
this
part
an
open-label,
multipart,
3
we
examined
progression-free
survival
with
nivolumab
versus
chemotherapy
among
patients
high
(≥10
mutations
per
megabase).
Journal of Clinical Oncology,
Journal Year:
2019,
Volume and Issue:
38(1), P. 1 - 10
Published: Nov. 4, 2019
Genomes
of
tumors
that
are
deficient
in
DNA
mismatch
repair
(dMMR)
have
high
microsatellite
instability
(MSI-H)
and
harbor
hundreds
to
thousands
somatic
mutations
encode
potential
neoantigens.
Such
therefore
likely
be
immunogenic,
triggering
upregulation
immune
checkpoint
proteins.
Pembrolizumab,
an
anti‒programmed
death-1
monoclonal
antibody,
has
antitumor
activity
against
MSI-H/dMMR
cancer.
We
report
data
from
the
phase
II
KEYNOTE-158
study
pembrolizumab
patients
with
previously
treated,
advanced
noncolorectal
cancer.Eligible
histologically/cytologically
confirmed
cancer
who
experienced
failure
prior
therapy
received
200
mg
once
every
3
weeks
for
2
years
or
until
disease
progression,
unacceptable
toxicity,
patient
withdrawal.
Radiologic
imaging
was
performed
9
first
year
12
thereafter.
The
primary
end
point
objective
response
rate
per
Response
Evaluation
Criteria
Solid
Tumors
(RECIST)
version
1.1,
as
assessed
by
independent
central
radiologic
review.Among
233
enrolled
patients,
27
tumor
types
were
represented,
endometrial,
gastric,
cholangiocarcinoma,
pancreatic
cancers
being
most
common.
Median
follow
up
13.4
months.
Objective
34.3%
(95%
CI,
28.3%
40.8%).
progression-free
survival
4.1
months
2.4
4.9
months)
median
overall
23.5
13.5
not
reached).
Treatment-related
adverse
events
occurred
151
(64.8%).
Thirty-four
(14.6%)
had
grade
5
treatment-related
events.
Grade
pneumonia
one
patient;
there
no
other
fatal
events.Our
demonstrates
clinical
benefit
anti-programmed
among
treated
unresectable
metastatic
Toxicity
consistent
previous
experience
monotherapy.
Annals of Oncology,
Journal Year:
2018,
Volume and Issue:
30(1), P. 44 - 56
Published: Nov. 1, 2018
Treatment
with
immune
checkpoint
blockade
(ICB)
agents
such
as
anti-programmed
cell
death
protein
1
(PD-1),
death-ligand
(PD-L1),
and/or
anti-cytotoxic
T-lymphocyte-associated
4
(CTLA-4)
can
result
in
impressive
response
rates
and
durable
disease
remission
but
only
a
subset
of
patients
cancer.
Expression
PD-L1
has
demonstrated
utility
selecting
for
to
ICB
proven
be
an
important
biomarker
patient
selection.
Tumor
mutation
burden
(TMB)
is
emerging
potential
biomarker.
However,
refinement
interpretation
contextualization
required.
New England Journal of Medicine,
Journal Year:
2020,
Volume and Issue:
383(23), P. 2207 - 2218
Published: Dec. 2, 2020
Programmed
death
1
(PD-1)
blockade
has
clinical
benefit
in
microsatellite-instability–high
(MSI-H)
or
mismatch-repair–deficient
(dMMR)
tumors
after
previous
therapy.
The
efficacy
of
PD-1
as
compared
with
chemotherapy
first-line
therapy
for
MSI-H–dMMR
advanced
metastatic
colorectal
cancer
is
unknown.
