QuoteReplyTopic: Keytruda (Pembrolizumab) + Chemo Boosts Response Posted: Oct 07 2019 at 8:51pm
Pembrolizumab Plus Chemo Boosts Response in Triple-Negative Breast Cancer
Adding the immunotherapy pembrolizumab (Keytruda) to neoadjuvant
chemotherapy improved the pathological complete response rate in
patients with early triple-negative breast cancer, according to interim results of the KEYNOTE-522 study presented at the European Society for Medical Oncology Congress 2019, held Sept. 27 to Oct. 1 in Barcelona.
Data also indicated improvement in event-free survival, an important
outcome in patients with triple-negative disease, which often recurs
early on, experts said.
The study included 1,174 patients with triple-negative disease and
randomly assigned them 2:1 to pembrolizumab 200 mg three times a week or
placebo, both in combination with 4 cycles of paclitaxel plus
carboplatin, then 4 cycles of doxorubicin or epirubicin plus
cyclophosphamide. After surgery, patients received pembrolizumab or
placebo for 9 cycles or until disease recurrence or unacceptable
toxicity, according to the results.
Median follow-up was 15.5 months. Pathological complete response was
evaluable in 602 patients. The combination of pembrolizumab plus
chemotherapy significantly improved pathologic complete response from
51.2% with placebo to 64.8% with the combination (P=.00055).
“We found a 13.6% difference which is a clinically meaningful
benefit,” study author Peter Schmid, MD, PhD, of Barts Cancer Institute,
Queen Mary University of London, UK, said in a press release.
Patients assigned to the combination also saw a trend toward improved event-free survival (HR=0.63; 95% CI, 0.43-0.93).
“These are preliminary data, but they provide a strong sign that the
addition of immune therapy to neoadjuvant chemotherapy prevents breast
cancer recurrence,” Schmid said in the release. “If we prevent
recurrence, we cure more patients, but we need longer-term data for
confirmation.”
Looking at results by PD-L1 status, the immunotherapy combination
resulted in a pathologic complete response rate of 68.9% compared with
54.9% for placebo in the PD-L1-positive population, and 45.3% compared
with 30.3% in the PD-L1-negative population.
Commenting on the results for ESMO, Prof Fabrice André, Institut
Gustave Roussy, Villejuif, France, said, “This is a good situation to
test whether the FDA will approve a drug for triple negative breast
cancer based on pathological complete response. The combination of the
anti-PD-1 monoclonal antibody pembrolizumab plus chemotherapy could
become a standard of care if approved.”
I'd like to see a trial with the standard ac, then t - the carb & Taxol then A.C. + Keytruda Is brutal, lots of treatment delays doing it with carb, plus going into A.C. After that is just mean. More women make it thru the standard without delay and far less sick.
IDC, 2.2 cm, Stage IIb,lumpectomy 1/30/09 ACx4,Tx4 36 rads 6/1/16 Local recurrence same breast, same spot 1.8cm Carb.4x every 3 wks, Taxol 12x once wk. Dbl Mast. PCR!! Reconstruction fail, NED!
Dr. Dent Discusses Immunotherapy in Early-Stage Breast Cancer
We spoke with Dr. Rebecca Dent, MD, at the European Society for Medical
Oncology Congress 2019, held in Barcelona, Spain from September 27, 2019
to October 1, 2019. Dr. Dent shared her the use of immunotherapy in
early-stage breast cancer in relation to the KEYNOTE-522 study.
Transcript:
"The bigger question is ‘what should be the chemotherapy backbone?’
We know that certain chemotherapies can actually act like
immunomodulators. If you look at specifically platinum-based
chemotherapy, what we know is that actually can suppress some of the
immunosuppressive elements of breast cancer, specifically looking at
suppression of myeloid stem cells and tumor-associated macrophages. We
have the biology to explain why it would work earlier and now we
actually have a study that actually looked at that.
The KEYNOTE-522 study was looking at early, triple-negative breast
cancer in the neoadjuvant setting…a really representative population
with almost half the patients being node-positive. It included PD-L1
positive and PD-L1 negative, but about 80% of those patients were PD-L1
positive. The backbone of this particular study was looking at an
anthracycline/taxane-platinum which is the most robust control arm you
can have with the highest pathological complete response rates reported
in literature and this is plus or minus pembrolizumab in the early
breast cancer setting. Then the patients proceeded with surgery and then
they continued on pembrolizumab (Keytruda) or a placebo.
This is the first read of the results that were presented at this
meeting which showed an impressive improvement in pathological complete
response rate, regardless of the definition used. The most stringent
definition showed an almost 14% improvement. What was actually most
interesting though was you saw an even larger benefit in the PDL-1
negative population. In those patients, again, you see greater than 15,
almost 20% improvement in pathological complete response in the PD-L1
negative which we’re actually seeing hints of in some of the smaller
phase II studies. Independent of PD-L1 status, immune checkpoint
inhibitors seem to work."
Neoadjuvant Pembrolizumab Combo Prolongs pCR in Phase III TNBC Study
Neoadjuvant treatment with the combination of pembrolizumab (Keytruda)
and chemotherapy extended pathological complete response (pCR) rates by
13.6 percentage points (CI, 5.4-21.8) compared with chemotherapy alone
for patients with early triple-negative breast cancer (TNBC), according
to findings from the phase III KEYNOTE-522 study presented at the ESMO
Congress 2019.
Additionally, following neoadjuvant therapy and surgery, patients in the
pembrolizumab arm went on to receive adjuvant pembrolizumab, which was
compared with a matched placebo arm. After a median of 15.2 months of
follow-up, the event-free survival (EFS) rate with pembrolizumab was
91.3% compared with 85.3% for placebo; however, this benefit was not yet
statistically significant (HR, 0.63; 95% CI, 0.43-0.93).
"The addition of pembrolizumab to platinum-containing chemotherapy
resulted in a statistically significant and, in my opinion, also
clinically meaningful improvement in pathological complete response
rates," Peter Schmid, MD, PhD, from the Barts Cancer Institute, Queen
Mary University. "Neoadjuvant pembrolizumab plus chemotherapy followed
by adjuvant pembrolizumab showed a favorable trend for EFS compared with
chemotherapy alone, at this very early time with only 15 months of
follow up."
The KEYNOTE-522 trial randomized patients with TNBC in a 2:1 ratio to
receive pembrolizumab at 200 mg every 3 weeks (n = 784) or placebo (n =
390). All patients received 4 cycles of carboplatin plus paclitaxel
followed by 4 cycles of doxorubicin or epirubicin plus cyclophosphamide.
Following surgery, adjuvant pembrolizumab was continued for 9 cycles or
until disease recurrence or unacceptable toxicity. EFS and pCR were
dual primary endpoints for the study, which defined pCR as ypT0/Tis or
ypN0.
Patients with both node-negative and node-positive TNBC were included in
the study. Of those enrolled, tumor stage ranged from T1c N1/N2 to T2
to T4 and N0 to N2, per AJCC criteria. All patients had an ECOG
performance status of 0 or 1. Patients were evenly stratified between
groups based on nodal status, tumor size, and carboplatin schedule
(weekly versus every 3 weeks).
The pCR rate was 64.8% with pembrolizumab plus chemotherapy compared
with 51.2% for chemotherapy alone, showing a statistically significant
improvement with the PD-1 inhibitor (P = .00055). The benefit
remained consistent, regardless of pCR definition. Using the ypT0 ypN0
definition, the pCR rate was 59.9% with pembrolizumab and 45.3% with
placebo. By the ypT0/Tis definition, the pCR rate was 68.6% and 53.7%,
for pembrolizumab and placebo, respectively.
In the PD-L1–positive group (CPS ≥1; n = 498), the pCR rate was 68.9%
compared with 54.9%, for pembrolizumab and placebo, respectively. This
was equivalent to a 14.2 percentage point increase (CI, 5.3-23.1). In
PD-L1–negative patients (n = 97), the pCR rate was 45.3% with
pembrolizumab versus 30.3% for placebo, an 18.3 percentage point
increase (CI, -3.3 to 36.8).
For the early EFS analysis, 7.4% of events had occurred in the
pembrolizumab arm compared with 11.8% in the placebo group. "There's
already a difference between the two curves," said Schmid. "We will have
subsequent event-free survival analyses coming out soon." The data lock
for the current analysis was April 24, 2019.
"Each phase of the study contributed separately to the overall benefit,"
Schmid noted. "Pathological CR rate is obviously driven by the
neoadjuvant part but when we look at recurrence and event-free survival,
that's driven, possibly, by the neoadjuvant and adjuvant path. What we
can't answer in this study is if you have a similar benefit with just
neoadjuvant chemotherapy and pembrolizumab and how much each part of the
treatment contributes."
. . .The FDA has granted a breakthrough therapy designation to pembrolizumab
plus neoadjuvant chemotherapy, based on earlier findings for the
combination in patients with high-risk, early-stage TNBC from the
KEYNOTE-173 and the I-SPY 2 trials. Submission of a supplemental new
drug application for pembrolizumab in TNBC is highly likely, based on
the KEYNOTE-522 data.
"This is a breakthrough because you can increase pCR and by association
you can increase survival. This is an important trial from which we will
have a lot of data from in the future," said ESMO expert discussant
Giuseppe Curigliano, MD, PhD, head of the Division of Early Drug
Development at European Institute of Oncology, Italy. "The combination
of immunotherapy plus chemotherapy for early triple-negative breast
cancer, according to the data presented here, is a new standard of care
for early triple-negative breast cancer."
KEYNOTE-522 Meets EFS End Point in High-Risk, Early TNBC
Pembrolizumab plus chemotherapy as neoadjuvant therapy followed
by adjuvant monotherapy in patients with early triple-negative breast
cancer was superior in terms of event-free survival versus matched
placebo.
The
phase 3 KEYNOTE-522 trial (NCT03036488) of neoadjuvant chemotherapy
plus either pembrolizumab (Keytruda) or placebo followed by single-agent
adjuvant therapy for high-risk, early triple-negative breast cancer
(TNBC) met its dual primary end point of event-free survival (EFS),
according to the company responsible for developing the PD-1 inhibitor,
Merck.1
An interim analysis by the independent Data
Monitoring Committee indicated a statistically significant improvement
in EFS with the experimental versus the control regimen, featuring a
safety profile that was consistent with the known effects of
pembrolizumab.
“Keytruda is the first immunotherapy to show
positive results for event-free survival in patients with high-risk
early-stage TNBC, a particularly aggressive form of breast cancer,” Roy
Baynes, MD, PhD, senior vice president and head of global clinical
development, chief medical officer, Merck Research Laboratories, said in
a press release.
The
investigators enrolled 1174 patients in the study and randomized them
2:1 to either the experimental or control arms. Pembrolizumab was
administered every 3 weeks plus paclitaxel weekly and carboplatin
(weekly or every 3 weeks) for 4 cycles, followed by pembrolizumab plus
cyclophosphamide every 3 weeks and either doxorubicin or epirubicin for 4
cycles as neoadjuvant therapy prior to surgery, followed by 9 cycles of
pembrolizumab every 3 weeks as adjuvant therapy post-surgery. Those in
the control arm received matching placebo and the same regimen of
chemotherapy.
The proportion of patients achieving pCR with
pembrolizumab was 64.8% (95% CI, 59.9%-69.5%) versus 51.2% (95% CI,
44.1%-58.3%) in the placebo/chemotherapy group (estimated treatment
difference, 13.6 percentage points; 95% CI, 5.4-21.8; P
<.001). These results were generally consistent across subgroups. At
18 months, patients who were alive without disease progression
precluding definitive surgery, without local or distant recurrence, and
with a second primary tumor comprised 91.3% (95% CI, 88.8%-93.3%) of
patients in the pembrolizumab arm versus 85.3% (95% CI, 80.3%-89.1%) of
patients with placebo. The risk of death or disease progression that
would preclude definitive surgery, local or distant recurrence, or a
second or primary tumor was reduced by 37% with pembrolizumab (HR, 0.63;
95% CI, 0.43-0.93).
“The improvement in pathological complete
response rates initially observed following pre-operative treatment was
encouraging, and now that we are seeing the data mature after 4 years to
include a statistically significant improvement in event-free
survival,” Barnes said. “[W]e look forward to working with the FDA and
other global authorities to bring this new option to patients as quickly
as possible.”
In March 2021, a complete response letter was issued by the FDA for the biologics license application
pursuing approval for pembrolizumab as adjuvant/neoadjuvant therapy for
patients with high-risk, early TNBC. The application was based on the
trial’s pCR results and early EFS data, with the FDA Oncologic Drugs
Advisory Committee voting to defer a regulatory decision until more
information was available.
FDA panel: Defer decision on pembrolizumab for early-stage triple-negative breast cancer
An FDA advisory committee voted unanimously to recommend deferral of a
regulatory decision on pembrolizumab for the treatment of patients with
high-risk, early-stage triple-negative breast cancer.
The FDA’s Oncologic Drugs Advisory Committee (ODAC) did not support
accelerated approval of pembrolizumab (Keytruda, Merck), an anti-PD-1
monoclonal antibody, in combination with chemotherapy in the neoadjuvant
setting and as a single agent in the adjuvant setting for this patient
population, due in part to concerns about immature EFS and OS data from
the KEYNOTE-522 trial.
“It is to be expected that [KEYNOTE-522] will turn out to be positive
as the data mature. However, it is of interest that when the first
interim analysis data were published, there was a difference in
pathologic complete response rates between the two arms of about 14% —
which is quite remarkable — but it is now down to 7%,” Philip C. Hoffman, MD,
ODAC chairperson and professor of medicine at University of Chicago,
said after the vote. “It is reasonably likely that this difference in
pathologic complete response will lead to an improvement in EFS and OS,
but data do change as they mature, and the fact that we are seeing
trends toward improvement does not mean that the data cannot change with
time. We should not underestimate the safety concerns, either.”
As previously reported by Healio, the placebo-controlled KEYNOTE-522 trial is the first phase 3 trial to evaluate immunotherapy for early-stage triple-negative breast cancer.
Researchers evaluated the neoadjuvant pembrolizumab-chemotherapy
combination followed by adjuvant pembrolizumab, vs. placebo and
chemotherapy followed by placebo, among 1,174 patients with previously
untreated, nonmetastatic, centrally confirmed triple-negative breast
cancer.
Results of an interim analysis showed the addition of pembrolizumab
to neoadjuvant chemotherapy significantly increased the pathologic
complete response rate (64.8% vs. 51.2%; percentage-point difference,
13.6%; P = .00055). The most recent interim analysis, including
all randomly assigned patients, showed a percentage-point increase of
7.5% (95% CI, 1.6-13.4) with pembrolizumab (63% vs. 55.5%).
However, the FDA expressed concern that the improvement in pathologic
complete response may not be adequate to predict improvement in
long-term outcomes of patients with early-stage disease, and EFS and OS
data remain immature for definitive analysis.
ODAC panelists also expressed concerns about immune-related adverse
events observed with pembrolizumab among this patient population.
Nineteen percent of patients who received pembrolizumab in the
KEYNOTE-522 trial had an unresolved immune-mediated adverse event at
last assessment, including hypothyroidism (11%), adrenal insufficiency
(2%) and hypophysitis (2%). Of note, 16% of patients initiated thyroid
hormone replacement therapy during the study, and 14% remained on
therapy at last study assessment.
Four patient deaths occurred that may have been due to immune-related
adverse events. One patient died of adrenal crisis on day 1 after
surgery and one patient died of autoimmune encephalitis while receiving
adjuvant pembrolizumab.
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