In CLL/SLL Patients in the DUO Study, Duvelisib
Treatment Rapidly Increased Lymphocytes and Resulted in Shrinkage
of Lymph Nodes, With 86% of Patients Achieving a Lymph Node
Response
Dose Modifications Utilized in the DUO Study
May Be Used to Manage Adverse Events for CLL/SLL Patients Receiving
COPIKTRA
Verastem, Inc. (Nasdaq:VSTM) (Verastem Oncology or the Company),
a biopharmaceutical company focused on developing and
commercializing medicines seeking to improve the survival and
quality of life of cancer patients, today announced that two
posters highlighting clinical data for COPIKTRA™ (duvelisib) in
patients with relapsed or refractory chronic lymphocytic
leukemia/small lymphocytic lymphoma (CLL/SLL) were presented at the
European Hematology Association (EHA) 2019 Annual Meeting which
took place June 13-16, 2019, in Amsterdam. One poster describes
results from a post-hoc analysis evaluating the effect of COPIKTRA
on lymphocytosis in patients with relapsed or refractory CLL/SLL
from the Phase 3 DUO study, including patients with high-risk
factors. The other poster describes dose modification data from
patients with relapsed or refractory CLL/SLL in the DUO study.
COPIKTRA, a targeted oral inhibitor of phosphoinositide 3-kinase
(PI3K), and the first approved dual inhibitor of PI3K-delta and
PI3K-gamma, received approval as monotherapy from the U.S. Food and
Drug Administration (FDA) in September 2018 for the treatment of
patients with relapsed or refractory CLL/SLL after at least two
prior therapies.
“Duvelisib is a potent oral dual inhibitor of PI3K-delta and
-gamma with clinical activity in patients with CLL/SLL after at
least two prior therapies,” said Hagop Youssoufian, MSc, M.D., Head
of Medical Strategy at Verastem Oncology. “In a post-hoc analysis
authored by Dr. Barrientos and colleagues, duvelisib induced rapid
and transient lymphocytosis that was associated with a reduction in
lymphadenopathy, including in high-risk patients. Notably,
duvelisib also resulted in resolution of lymphocytosis at up to 21
weeks, and the majority of patients achieved a lymph node response
and also achieved rapid shrinkage of their lymph nodes.”
Patterns of Duvelisib-Induced Lymphocytosis in Patients with
Relapsed/Refractory CLL/SLL, Including Those with High-Risk
Factors
In this study, researchers aimed to characterize the clinical
profile and kinetics associated with duvelisib-related
lymphocytosis. Lymphocytosis is an increase in the number of
lymphocytes (white blood cells) in the blood and is a recognized
biological marker of treatment with B-cell receptor pathway
inhibitors. Similar to ibrutinib and idelalisib, duvelisib
treatment induces lymphocytosis in patients with CLL. This post hoc
analysis defined response in patients (n=158) with relapsed or
refractory CLL/SLL, including high-risk subgroups, which were
characterized by unmutated IGHV (n=110), 17p deletion/TP53 mutation
(n=48), 11q deletion (n=38), and bulky disease (n=74).
Of 158 patients treated with duvelisib, 78% experienced
lymphocytosis. Median time to onset of lymphocytosis was one week
across all patients, including patients in the high-risk subgroups.
Median time to resolution of lymphocytosis was 14 weeks, with a 50%
reduction from baseline at 21 weeks. Similar results were observed
regardless of high-risk status. Rapid shrinkage of lymph nodes was
noted, with 86% of patients achieving lymph node response. Among
patients who achieved a response with duvelisib at first or second
assessment, 78% and 86%, respectively, experienced lymphocytosis;
median time to resolution of lymphocytosis in these patients was 12
and 18 weeks, respectively. Prolonged lymphocytosis (for >12
months) occurred in 12 patients (8%). The overall response rate in
patients with prolonged lymphocytosis was 83%. Of note, the median
PFS was similar among patients with and without prolonged
lymphocytosis; 22.1 months (95% CI, 12.9-27.6), compared to 24
months (95% CI, 20.5-NE), respectively. Overall, there were low
rates of tumor lysis syndrome (1 patient; 0.6%). These results
showed that duvelisib monotherapy induced rapid and transient
lymphocytosis temporally associated with a reduction in
lymphadenopathy in patients with relapsed or refractory
CLL/SLL.
Effect of Dose Modification on Response to COPIKTRA in
Patients with Relapsed or Refractory CLL/SLL in the Phase 3 DUO
Study
The randomized, multicenter, open-label, Phase 3 DUO study,
compared COPIKTRA versus ofatumumab in 319 adult patients with CLL
(n=312) or SLL (n=7) after at least one prior therapy. The study
randomized patients with a 1:1 ratio to receive either COPIKTRA
25mg twice daily until disease progression or unacceptable
toxicity, or ofatumumab, an approved standard of care treatment for
use in CLL/SLL, for 7 cycles. This analysis examined dose
modification patterns and their impact on response to COPIKTRA.
Dose interruptions or dose reductions to 15mg, 10mg or 5mg twice
daily were permitted per study protocol to manage
treatment-emergent adverse events (TEAEs). Responses were assessed
per an Independent Review Committee.
Among the 158 COPIKTRA-treated patients in the DUO study, the
median duration of exposure was 11.6 months, versus 5.3 months for
patients treated with ofatumumab. The most common cause of dose
interruption was diarrhea (23%), followed by neutropenia (12%) and
pneumonia or colitis (11% each). Among responders (n=118), median
time to first response on COPIKTRA was 1.9 months and the estimated
median duration of response was 11.1 months. Median time to first
dose interruption was 3.9 months and median duration of dose
interruption was 15 days (range 1 to 133 days). Response to
COPIKTRA was improved or maintained in most patients evaluated for
response who had at least one dose interruption for >1 week
(84%) or >2 weeks (82%) followed by at least 3 weeks on
COPIKTRA. In a landmark analysis, median PFS was similar in
patients with dose interruptions and those without dose
interruptions for >1 week (17.8 versus 16.3 months) or >2
weeks (17.8 versus 16.3 months) within the first 3 months. The
median time to dose reduction after a complete response or partial
response was 5.6 months (n=25) and median duration was 3.4 months.
Median time to onset across adverse events of special interest
(AESIs) after starting COPIKTRA ranged from 2.2 to 4.3 months.
Median time to resolution was within 4 weeks across AESIs.
Proportions of patients experiencing AESIs were stable or decreased
over time after 3-6 months: 0-3 months, 64%; >3-6 months, 63%;
>6-9 months, 47%; >9-12 months, 52%, and seldom led to
discontinuation of COPIKTRA (≤10%). These findings support the
thesis that dose interruptions or dose reductions may be useful in
managing TEAEs with COPIKTRA and that dose interruptions of >1-2
weeks or more did not appear to significantly impact response to
COPIKTRA or PFS.
PDF copies of these poster presentations are available here.
Details for the EHA 2019 poster presentations are as
follows:
Title: Effect of dose modifications on response to
duvelisib in patients with relapsed/refractory (R/R) CLL/SLL in the
DUO trialLead author: Paolo Ghia, Università Vita-Salute San
RaffaeleSession: 6. Chronic lymphocytic leukemia and related
disorders - ClinicalAbstract #: PS1157
Title: Patterns of duvelisib-induced lymphocytosis in
patients with relapsed/refractory chronic lymphocytic
leukemia/small lymphocytic leukemia including those with high-risk
factors treated in the DUO trialLead author: Jacqueline
Barrientos, Zucker School of Medicine at
Hofstra/NorthwellSession: 6. Chronic lymphocytic leukemia
and related disorders - ClinicalAbstract #: PS1160
Important Safety Information
WARNING: FATAL AND SERIOUS TOXICITIES:
INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and
PNEUMONITIS
•Fatal and/or serious infections occurred
in 31% of COPIKTRA-treated patients. Monitor for signs and symptoms
of infection. Withhold COPIKTRA if infection is suspected.
•Fatal and/or serious diarrhea or colitis
occurred in 18% of COPIKTRA-treated patients. Monitor for the
development of severe diarrhea or colitis. Withhold COPIKTRA.
•Fatal and/or serious cutaneous reactions
occurred in 5% of COPIKTRA-treated patients. Withhold COPIKTRA.
•Fatal and/or serious pneumonitis occurred
in 5% of COPIKTRA-treated patients. Monitor for pulmonary symptoms
and interstitial infiltrates. Withhold COPIKTRA.
WARNINGS AND PRECAUTIONS
Infections: Serious, including fatal (4%), infections
occurred in 31% of patients receiving COPIKTRA (N=442). The most
common serious infections were pneumonia, sepsis, and lower
respiratory infections. Median time to onset of any grade infection
was 3 months, with 75% of cases occurring within 6 months. Treat
infections prior to initiation of COPIKTRA. Advise patients to
report new or worsening signs and symptoms of infection. Cases of
Pneumocystis jirovecii pneumonia (PJP) (1%) and cytomegalovirus
(CMV) reactivation/infection (1%) occurred in patients taking
COPIKTRA. Provide prophylaxis for PJP during treatment and
following completion of treatment until the absolute CD4+ T cell
count is greater than 200 cells/µL. Consider prophylactic
antivirals during COPIKTRA treatment to prevent CMV infection
including CMV reactivation.
Diarrhea or Colitis: Serious, including fatal (<1%),
diarrhea or colitis occurred in 18% of patients receiving COPIKTRA
(N=442). Median time to onset of any grade diarrhea or colitis was
4 months, with 75% of cases occurring by 8 months. The median event
duration was 0.5 months. Advise patients to report any new or
worsening diarrhea.
Cutaneous Reactions: Serious, including fatal (<1%),
cutaneous reactions occurred in 5% of patients receiving COPIKTRA
(N=442). Fatal cases included drug reaction with eosinophilia and
systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN).
Median time to onset of any grade cutaneous reaction was 3 months
with a median event duration of 1 month. Presenting features for
the serious events were primarily described as pruritic,
erythematous, or maculo-papular. Less common presenting features
include exanthem, desquamation, erythroderma, skin exfoliation,
keratinocyte necrosis, and papular rash. Advise patients to report
new or worsening cutaneous reactions.
Pneumonitis: Serious, including fatal (<1%),
pneumonitis without an apparent infectious cause occurred in 5% of
patients receiving COPIKTRA (N=442). Median time to onset of any
grade pneumonitis was 4 months with 75% of cases occurring within 9
months. The median event duration was 1 month with 75% of cases
resolving by 2 months.
Hepatotoxicity: Grade 3 and 4 ALT and/or AST elevation
developed in 8% and 2%, respectively, of patients receiving
COPIKTRA (N=442). Two percent of patients had both an ALT or AST
> 3 X ULN and total bilirubin > 2 X ULN. Median time to onset
of any grade transaminase elevation was 2 months with a median
event duration of 1 month. Monitor hepatic function during
treatment with COPIKTRA.
Neutropenia: Grade 3 or 4 neutropenia occurred in 42% of
patients receiving COPIKTRA (N=442), with Grade 4 neutropenia
occurring in 24% of all patients. Median time to onset of grade ≥3
neutropenia was 2 months. Monitor neutrophil counts at least every
2 weeks for the first 2 months of COPIKTRA therapy, and at least
weekly in patients with neutrophil counts < 1.0 Gi/L (Grade
3-4).
Embryo-Fetal Toxicity: COPIKTRA can cause fetal harm when
administered to a pregnant woman. Advise pregnant women of the
potential risk to a fetus and conduct pregnancy testing before
initiating COPIKTRA treatment. Advise females of reproductive
potential and males with female partners of reproductive potential
to use effective contraception during treatment and for at least 1
month after the last dose.
ADVERSE REACTIONS
B-cell Malignancies Summary
Fatal adverse reactions within 30 days of the last dose occurred
in 8% (36/442) of patients treated with COPIKTRA 25 mg BID. Serious
adverse reactions were reported in 289 patients (65%). The most
frequent serious adverse reactions that occurred were infection
(31%), diarrhea or colitis (18%), pneumonia (17%), rash (5%), and
pneumonitis (5%). The most common adverse reactions (reported in
≥20% of patients) were diarrhea or colitis, neutropenia, rash,
fatigue, pyrexia, cough, nausea, upper respiratory infection,
pneumonia, musculoskeletal pain and anemia.
CLL/SLL
Fatal adverse reactions within 30 days of the last dose occurred
in 12% (19/158) of patients treated with COPIKTRA and in 4% (7/155)
of patients treated with ofatumumab. Serious adverse reactions were
reported in 73% (115/158) of patients treated with COPIKTRA and
most often involved infection (38%; 60/158) and diarrhea or colitis
(23%; 36/158). The most common adverse reactions with COPIKTRA
(≥20% of patients) were diarrhea or colitis, neutropenia, pyrexia,
upper respiratory tract infection, pneumonia, rash, fatigue,
nausea, anemia and cough.
For specific information on the management of the adverse
reactions above, please review Dose Modifications for Adverse
Reactions within the full Prescribing Information.
DRUG INTERACTIONS
CYP3A Inducers: Coadministration with a strong CYP3A
inducer may reduce COPIKTRA efficacy. Avoid coadministration with
strong CYP3A4 inducers.
CYP3A Inhibitors: Coadministration with a strong CYP3A
inhibitor may increase the risk of COPIKTRA toxicities. Reduce
COPIKTRA dose to 15 mg BID when coadministered with a strong CYP3A4
inhibitor.
CYP3A Substrates: Coadministration of COPIKTRA with
sensitive CYP3A4 substrates may increase the risk of toxicities of
these drugs. Consider reducing the dose of the sensitive CYP3A4
substrate and monitor for signs of toxicities of the coadministered
sensitive CYP3A substrate.
To report Adverse Reactions, contact FDA at 1-800-FDA-1088
(1-800-332-1088) or www.fda.gov/medwatch and Verastem
Oncology at 1-877-7RXVSTM (1-877-779-8786).
Please see accompanying full Prescribing
Information, including Boxed Warning.
About Chronic Lymphocytic Leukemia/Small Lymphocytic
Lymphoma
Chronic lymphocytic leukemia (CLL) and small lymphocytic
lymphoma (SLL) are cancers that affect lymphocytes and are
essentially the same disease, with the only difference being the
location where the cancer primarily occurs. When most of the cancer
cells are located in the bloodstream and the bone marrow, the
disease is referred to as CLL, although the lymph nodes and spleen
are often involved. When the cancer cells are located mostly in the
lymph nodes, the disease is called SLL. The symptoms of CLL/SLL
include a tender, swollen abdomen and feeling full even after
eating only a small amount. Other symptoms can include fatigue,
shortness of breath, anemia, bruising easily, night sweats, weight
loss, and frequent infections. However, many patients with CLL/SLL
will live for years without symptoms. There are approximately
200,000 patients in the US affected by CLL/SLL with nearly 20,000
new diagnoses this year alone. While there are therapies currently
available, real-world data reveals that a significant number of
patients either relapse following treatment, become refractory to
current agents, or are unable to tolerate treatment, representing a
significant medical need. The potential of additional oral agents,
particularly as a monotherapy that can be used in the general
community physician’s armamentarium, may hold significant value in
the treatment of patients with CLL/SLL.
About COPIKTRA™ (duvelisib)
COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase
(PI3K), and the first approved dual inhibitor of PI3K-delta and
PI3K-gamma, two enzymes known to help support the growth and
survival of malignant B-cells. PI3K signaling may lead to the
proliferation of malignant B-cells and is thought to play a role in
the formation and maintenance of the supportive tumor
microenvironment.1,2,3 COPIKTRA is indicated for the treatment of
adult patients with relapsed or refractory chronic lymphocytic
leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two
prior therapies and relapsed or refractory follicular lymphoma (FL)
after at least two prior systemic therapies. COPIKTRA is also being
developed by Verastem Oncology for the treatment of peripheral
T-cell lymphoma (PTCL), for which it has received Fast Track
status, and is being investigated in combination with other agents
through investigator-sponsored studies.4 For more information on
COPIKTRA, please visit www.COPIKTRA.com. Information about
duvelisib clinical trials can be found on
www.clinicaltrials.gov.
About Verastem Oncology
Verastem Oncology (Nasdaq: VSTM) is a commercial
biopharmaceutical company committed to the development and
commercialization of medicines to improve the lives of patients
diagnosed with cancer. We are driven by the strength, tenacity and
courage of those battling cancer – single-minded in our resolve to
deliver new therapies that not only keep cancer at bay, but improve
the lives of patients diagnosed with cancer. Because for us, it’s
personal.
Our first FDA approved product is now available for the
treatment of patients with certain types of indolent non-Hodgkin’s
lymphoma (iNHL). Our pipeline comprises product candidates that
seek to treat cancer by modulating the local tumor
microenvironment. For more information, please visit
www.verastem.com.
Forward looking statements notice
This press release and the commentary in the conference call to
be held today each include forward-looking statements about
Verastem Oncology’s strategy, future plans and prospects, including
statements regarding the development and activity of Verastem
Oncology’s lead product COPIKTRA, and Verastem Oncology’s PI3K
program generally, its commercialization of COPIKTRA, the potential
commercial success of COPIKTRA, including financial guidance and
patient population estimates, the anticipated adoption of COPIKTRA
by patients and physicians, the structure of its planned and
pending clinical trials and the timeline and indications for
clinical development, regulatory submissions and commercialization
activities. The words "anticipate," "believe," "estimate,"
"expect," "intend," "may," "plan," "predict," "project," "target,"
"potential," "will," "would," "could," "should," "continue," and
similar expressions are intended to identify forward-looking
statements, although not all forward-looking statements contain
these identifying words. Each forward-looking statement is subject
to risks and uncertainties that could cause actual results to
differ materially from those expressed or implied in such
statement.
Applicable risks and uncertainties include the risks and
uncertainties, among other things, regarding: the commercial
success of COPIKTRA in the United States; physician and patient
adoption of COPIKTRA, including those related to the safety and
efficacy of COPIKTRA; the uncertainties inherent in research and
development of COPIKTRA, such as negative or unexpected results of
clinical trials; whether and when any applications for COPIKTRA may
be filed with regulatory authorities in any other jurisdictions;
whether and when regulatory authorities in any other jurisdictions
may approve any such other applications that may be filed for
COPIKTRA, which will depend on the assessment by such regulatory
authorities of the benefit-risk profile suggested by the totality
of the efficacy and safety information submitted and, if approved,
whether COPIKTRA will be commercially successful in such
jurisdictions; our ability to obtain, maintain and enforce patent
and other intellectual property protection for COPIKTRA and our
other product candidates; the scope, timing, and outcome of any
legal proceedings; decisions by regulatory authorities regarding
labeling and other matters that could affect the availability or
commercial potential of COPIKTRA; the fact that regulatory
authorities in the U.S. or other jurisdictions, if approved, could
withdraw approval; whether preclinical testing of our product
candidates and preliminary or interim data from clinical trials
will be predictive of the results or success of ongoing or later
clinical trials; that the timing, scope and rate of reimbursement
for our product candidates is uncertain; that third-party payors
(including government agencies) may not reimburse for COPIKTRA;
that there may be competitive developments affecting our product
candidates; that data may not be available when expected; that
enrollment of clinical trials may take longer than expected; that
COPIKTRA or our other product candidates will cause unexpected
safety events, experience manufacturing or supply interruptions or
failures, or result in unmanageable safety profiles as compared to
their levels of efficacy; that COPIKTRA will be ineffective at
treating patients with lymphoid malignancies; that we will be
unable to successfully initiate or complete the clinical
development and eventual commercialization of our product
candidates; that the development and commercialization of our
product candidates will take longer or cost more than planned; that
we may not have sufficient cash to fund our contemplated
operations; that we, CSPC Pharmaceutical Group, Yakult Honsha Co.,
Ltd. or Infinity Pharmaceuticals, Inc. will fail to fully perform
under the duvelisib license agreements; that we may be unable to
make additional draws under our debt facility or obtain adequate
financing in the future through product licensing, co-promotional
arrangements, public or private equity, debt financing or
otherwise; that we will not pursue or submit regulatory filings for
our product candidates, including for duvelisib in patients with
chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
or indolent non-Hodgkin lymphoma (iNHL) in other jurisdictions; and
that our product candidates will not receive regulatory approval,
become commercially successful products, or result in new treatment
options being offered to patients.
Other risks and uncertainties include those identified under the
heading "Risk Factors" in the Company’s Quarterly Report on Form
10-Q for the quarterly period ended March 31, 2019, as filed with
the Securities and Exchange Commission (SEC) on May 9, 2019, its
Annual Report on Form 10-K for the year ended December 31, 2018 as
filed with the SEC on March 12, 2019 and in any subsequent filings
with the SEC. The forward-looking statements contained in this
press release reflect Verastem Oncology’s views as of the date
hereof, and the Company does not assume and specifically disclaims
any obligation to update any forward-looking statements whether as
a result of new information, future events or otherwise, except as
required by law.
References
1 Winkler D.G., Faia K.L., DiNitto J.P. et al. PI3K-delta and
PI3K-gamma inhibition by IPI-145 abrogates immune responses and
suppresses activity in autoimmune and inflammatory disease models.
Chem Biol 2013; 20:1-11.2 Reif K et al. Cutting Edge: Differential
Roles for Phosphoinositide 3 kinases, p110-gamma and p110-delta, in
lymphocyte chemotaxis and homing. J Immunol 2004:173:2236-2240.3
Schmid M et al. Receptor Tyrosine Kinases and TLR/IL1Rs
Unexpectedly activate myeloid cell PI3K, a single convergent point
promoting tumor inflammation and progression. Cancer Cell
2011;19:715-727.4 www.clinicaltrials.gov, NCT03372057.
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Verastem Oncology:John DoyleVice President, Investor Relations
& Finance+1 781-469-1546jdoyle@verastem.com
Investors:Joseph RayneArgot Partners+1
617-340-6075joseph@argotpartners.com
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