Journal of Clinical Oncology,
Journal Year:
2020,
Volume and Issue:
38(22), P. 2476 - 2487
Published: April 23, 2020
PURPOSE
Merkel
cell
carcinoma
(MCC)
is
a
rare,
aggressive
skin
cancer
commonly
driven
by
the
polyomavirus
(MCPyV).
The
programmed
death-1
(PD-1)/programmed
death-ligand
1
(PD-L1)
immunosuppressive
pathway
often
upregulated
in
MCC,
and
advanced
metastatic
MCC
frequently
responds
to
PD-1
blockade.
We
report
what
we
believe
be
first
trial
of
anti–PD-1
neoadjuvant
setting
for
resectable
MCC.
METHODS
In
phase
I/II
CheckMate
358
study
virus-associated
types,
patients
with
received
nivolumab
240
mg
intravenously
on
days
15.
Surgery
was
planned
day
29.
Tumor
regression
assessed
radiographically
microscopically.
MCPyV
status,
PD-L1
expression,
tumor
mutational
burden
(TMB)
were
pretreatment
biopsies.
RESULTS
Thirty-nine
American
Joint
Committee
Cancer
stage
IIA-IV
≥
dose.
Three
(7.7%)
did
not
undergo
surgery
because
progression
(n
=
1)
or
adverse
events
2).
Any-grade
treatment-related
occurred
18
(46.2%),
grade
3-4
3
(7.7%),
no
unexpected
toxicities.
Among
36
who
underwent
surgery,
17
(47.2%)
achieved
pathologic
complete
response
(pCR).
33
evaluable
(54.5%)
had
reductions
30%.
Responses
observed
regardless
MCPyV,
PD-L1,
TMB
status.
At
median
follow-up
20.3
months,
recurrence-free
survival
(RFS)
overall
reached.
RFS
significantly
correlated
pCR
radiographic
at
time
surgery.
No
patient
relapse
during
observation.
CONCLUSION
Nivolumab
administered
approximately
4
weeks
before
generally
tolerable
induced
pCRs
regressions
one
half
treated
patients.
These
early
markers
predicted
improved
RFS.
Additional
investigation
these
promising
findings
warranted.
Science,
Journal Year:
2020,
Volume and Issue:
367(6477)
Published: Jan. 31, 2020
Presurgical
immune
checkpoint
blockade
Checkpoint
immunotherapy
using
antibodies
that
inhibit
the
programmed
cell
death
1
(PD-1)
or
cytotoxic
T
lymphocyte–associated
protein
4
(CTLA-4)
pathways
has
resulted
in
unprecedented
clinical
outcomes
for
certain
cancers
such
as
melanoma.
Topalian
et
al.
review
advances
neoadjuvant
(presurgical)
an
important
next
step
enhancing
response
of
early-stage
tumors
to
blockade.
They
highlight
mechanistic
rationale
and
recent
trials
based
on
anti–PD-1
ligand
(anti–PD-L1)
therapy.
Pathological
assessment
criteria
may
provide
early
on-treatment
biomarkers
predict
patient
are
also
discussed.
Science
,
this
issue
p.
eaax0182
Nature Medicine,
Journal Year:
2019,
Volume and Issue:
25(12), P. 1916 - 1927
Published: Dec. 1, 2019
Abstract
Immune-checkpoint
blockade
(ICB)
has
demonstrated
efficacy
in
many
tumor
types,
but
predictors
of
responsiveness
to
anti-PD1
ICB
are
incompletely
characterized.
In
this
study,
we
analyzed
a
clinically
annotated
cohort
patients
with
melanoma
(
n
=
144)
treated
ICB,
whole-exome
and
whole-transcriptome
sequencing
pre-treatment
tumors.
We
found
that
mutational
burden
as
predictor
response
was
confounded
by
subtype,
whereas
multiple
novel
genomic
transcriptomic
features
predicted
selective
response,
including
associated
MHC-I
MHC-II
antigen
presentation.
Furthermore,
previous
anti-CTLA4
exposure
different
compared
tumors
were
naive
suggesting
immune
effects
ICB.
Finally,
developed
parsimonious
models
integrating
clinical,
predict
intrinsic
resistance
individual
tumors,
validation
smaller
independent
cohorts
limited
the
availability
comprehensive
data.
Broadly,
present
framework
discover
predictive
build
therapeutic
response.
New England Journal of Medicine,
Journal Year:
2023,
Volume and Issue:
388(9), P. 813 - 823
Published: March 1, 2023
Whether
pembrolizumab
given
both
before
surgery
(neoadjuvant
therapy)
and
after
(adjuvant
therapy),
as
compared
with
adjuvant
therapy
alone,
would
increase
event-free
survival
among
patients
resectable
stage
III
or
IV
melanoma
is
unknown.In
a
phase
2
trial,
we
randomly
assigned
clinically
detectable,
measurable
IIIB
to
IVC
that
was
amenable
surgical
resection
three
doses
of
neoadjuvant
pembrolizumab,
surgery,
15
(neoadjuvant-adjuvant
group)
followed
by
(200
mg
intravenously
every
3
weeks
for
total
18
doses)
approximately
1
year
until
disease
recurred
unacceptable
toxic
effects
developed
(adjuvant-only
group).
The
primary
end
point
in
the
intention-to-treat
population.
Events
were
defined
progression
precluded
surgery;
inability
resect
all
gross
disease;
progression,
complications,
treatment
initiation
within
84
days
recurrence
death
from
any
cause.
Safety
also
evaluated.At
median
follow-up
14.7
months,
neoadjuvant-adjuvant
group
(154
patients)
had
significantly
longer
than
adjuvant-only
(159
(P
=
0.004
log-rank
test).
In
landmark
analysis,
at
years
72%
(95%
confidence
interval
[CI],
64
80)
49%
CI,
41
59)
group.
percentage
treatment-related
adverse
events
grades
higher
during
12%
14%
group.Among
melanoma,
those
who
received
alone.
No
new
identified.
(Funded
National
Cancer
Institute
Merck
Sharp
Dohme;
S1801
ClinicalTrials.gov
number,
NCT03698019.).
