Duvelisib demonstrates robust clinical activity with 73% ORR and a
median of 15 month PFS in the DUO crossover study of patients who became
relapsed/refractory to ofatumumab in DUO™
Duvelisib’s dual inhibition of PI3K-delta and PI3K-gamma results in
beneficial changes in both the cancer cells and the supportive tumor
microenvironment
Phase I results show defactinib in combination with pembrolizumab and
gemcitabine is well tolerated and shows early signs of clinical activity
in pancreatic cancer including confirmed partial response and long-term
stable disease
BOSTON--(BUSINESS WIRE)--Jun. 4, 2018--
Verastem, Inc. (NASDAQ:VSTM) (Verastem Oncology or the Company), a
biopharmaceutical company focused on developing and commercializing
medicines to improve the survival and quality of life of cancer
patients, today announced the presentation of five posters highlighting
data for its two lead drug candidates, duvelisib and defactinib, at the
54th Annual Meeting of the American Society of Clinical
Oncology (ASCO) being held June 1-5, 2018 in Chicago.
Duvelisib is a first-in-class oral dual inhibitor of phosphoinositide
3-kinase (PI3K)-delta and PI3K-gamma that is currently being developed
for the treatment of relapsed or refractory chronic lymphocytic
leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma
(FL). In addition, duvelisib is being studied in other hematologic
malignancies including peripheral T cell lymphoma (PTCL). In April, the
U.S. Food and Drug Administration (FDA) accepted with Priority Review
Verastem Oncology’s New Drug Application for duvelisib, which has an FDA
target action date of October 5, 2018. Defactinib is an oral small
molecule inhibitor of focal adhesion kinase (FAK) and is currently being
evaluated in combination with immunotherapeutic agents for the treatment
of various cancers including pancreatic, ovarian and non-small cell lung
cancer, and mesothelioma.
“The DUO crossover extension data reported at ASCO this year build upon
the previously reported positive Phase 3 DUO study results and further
support duvelisib’s potential as an oral treatment option for patients
with relapsed or refractory CLL/SLL,” said Diep Le, MD, PhD, Chief
Medical Officer of Verastem Oncology. “Post-crossover, oral duvelisib
monotherapy demonstrated robust clinical activity with a 73% overall
response rate (ORR) and a 15-month median PFS in the 89 patients that
had previously received ofatumumab on DUO and subsequently progressed .
Duvelisib monotherapy also demonstrated a manageable safety profile,
with results from this study consistent with the well-characterized
safety profile of duvelisib monotherapy in previous studies. It is
encouraging to see such a robust response to duvelisib monotherapy,
similar to response observed in the parent DUO study, in patients that
had failed an additional line of therapy and needed a new treatment
option.”
Jonathan Pachter, PhD, Chief Scientific Officer of Verastem Oncology,
commented, “The presented research by Drs. Casulo and Weaver continues
to provide important evidence that the dual PI3K-delta/PI3K-gamma
inhibitory activity of duvelisib results in beneficial anti-tumor
effects on both the cancer cells and their supportive tumor
microenvironment (TME) which has the potential to enhance clinical
efficacy and improve outcomes for patients battling CLL/SLL and FL.”
Dr. Le added, “Dr. Andrea Wang-Gillam presented initial results from an
ongoing Phase 1 study evaluating our lead FAK inhibitor defactinib in
combination with pembrolizumab and gemcitabine in patients with advanced
pancreatic cancer. The triplet appears to be well tolerated, the
recommended Phase 2 dose has been established, and the expansion phase
of the study is ongoing. In addition, promising signs of clinical
activity have been observed with 3 pancreatic cancer patients treated
beyond 250 days, including a confirmed partial response and the other 2
patients with stable disease. All 3 of these patients have also shown
meaningful reductions (57-96%) in the pancreatic cancer marker CA19-9.
Analysis of paired biopsies have also shown that this treatment induced
desirable biomarker changes including increased proliferating CD8+ T
cells and reduced immunosuppressive Tregs and macrophages. Treatment of
pancreatic cancer represents a very important unmet need for patients,
and these initial results are certainly encouraging.”
Details for the ASCO 2018 presentations are as follows:
Duvelisib
Title: The efficacy of duvelisib monotherapy following disease
progression on ofatumumab monotherapy in patients with
relapsed/refractory CLL or SLL in the DUO crossover extension study
Lead
author: Dr. Bryone Kuss, Flinders Medical Centre
Abstract #:
7533
Summary: In the previously reported Phase 3 DUO™ study
oral duvelisib monotherapy achieved a statistically significant
improvement in median progression-free survival (mPFS) compared to
ofatumumab in patients with relapsed or refractory CLL/ SLL (13.3 months
versus 9.9 months, respectively; HR=0.52; p<0.0001), along with a
manageable safety profile (Flinn, ASH 2017). The results reported here
are from the open-label, DUO crossover extension study where patients
with confirmed progressive disease (PD) following treatment with
ofatumumab in DUO were given the option to receive treatment with
duvelisib. Duvelisib 25mg BID was administered until PD, intolerance,
death, or study withdrawal and responses were determined by
investigators using modified IWCLL/IWG criteria.
Among the 89 evaluable patients (median three prior therapies (range
2-8), oral duvelisib monotherapy achieved a 73% overall response rate
(ORR; 95% CI: 64, 82; 5% complete response with incomplete marrow
recovery (CRis), 68% partial responses [PRs]) in the extension study.
While on ofatumamab in the DUO study, these 89 patients had a 28% ORR
(95% CI: 19, 37; 1% complete response (CR), 27% PRs). The mPFS for
duvelisib in the extension study was 15 months (95% CI: 10, 17). While
on ofatumamab in the DUO study, these 89 patients had a mPFS of 9 months
(95% CI: 9, 11), per investigator’s assessment. Notably, 83% of patients
in the duvelisib arm post-crossover had >50% reductions in the size of
their target nodal lesions. These same 89 patients had 27% reductions in
the size of their target nodal lesions in the DUO ofatumumab arm. Median
exposure to duvelisib in the extension study was 32 weeks. The safety
profile of duvelisib monotherapy was manageable and consistent with what
was observed in the Phase 3 DUO study. The most common Grade ≥3
treatment-emergent adverse events were neutropenia (22%), diarrhea
(17%), colitis (9%), pneumonia (9%), rash (5%) and pyrexia (4%). These
data build upon the previously reported positive DUO results and further
support oral duvelisib monotherapy as an effective oral treatment option
for patients with relapsed or refractory CLL/SLL.
A copy of the poster presentation will be available here.
Title: The effect of duvelisib, a dual inhibitor of PI3K-δ,γ, on
components of the tumor microenvironment in previously untreated
follicular lymphoma
Lead author: Dr. Carla Casulo,
University of Rochester, Wilmot Cancer Center
Abstract #:
7579
Summary: In previously reported data from the CONTEMPO
trial, treatment-naive FL patients treated with duvelisib in combination
with rituxumab had an ORR of 93% (36% CRR), and an ORR of 89% (41% CRR)
was observed for patients treated with duvelisib in combination with
obinutuzumab. In this study, blood samples from healthy volunteers and
FL patients treated in the CONTEMPO study, both pre- and post-duvelisib
treatment, were analyzed. Ex vivo and in vitro PI3K-γ
assays and PI3K-δ assays, with PI3K-δ-selective (idelalisib, TGR-1202,
IPI-3063) and PI3K-γ-selective (IPI-549) inhibitors were compared.
Duvelisib and idelalisib potently inhibited LPS-induced human monocytes
via PI3K-δ, compared with the PI3K-γ selective IPI-549. For TGR-1202,
the IC50 was below the recommended Phase 2 dose (RP2D) clinical
exposure. Duvelisib and IPI-549 potently inhibited PI3K-γ dependent
fMLP-stimulated human monocytes compared to idelalisib and TGR-1202. In
FL patients treated with duvelisib, these PI3K-γ and PI3K-δ selective
assays were inhibited 1-4 hours post treatment. Consistent with a PI3K-γ
mechanism, both duvelisib and IPI-549 inhibited macrophage polarization
to M2, reduced CXCL12-induced macrophage migration, and blocked
CXCL12-induced T cell migration, which was not observed with PI3K-δ
inhibitor IPI-3063. Collectively, these results support the thesis that
duvelisib disrupts PI3K- δ,γ function in FL patients inhibiting the TME
through cancer-supportive macrophages and T cells.
A copy of the poster presentation will be available here.
Title: The PRIMO study: A phase 2 study of duvelisib efficacy and
safety in patients with relapsed or refractory peripheral t-cell
lymphoma (PTCL)
Lead author: Dr. Steven Horwitz, Memorial
Sloan Kettering Cancer Center
Abstract #: TPS7590
Summary:
This poster describes the PRIMO study, a Phase 2 open-label clinical
trial evaluating duvelisib monotherapy in adult patients with PTCL, one
of the most aggressive forms of non-Hodgkin lymphoma (NHL). The study
employs a dose optimization phase (DOP) and an Expansion Phase (EP). The
primary objectives are to identify the optimal dose of duvelisib in PTCL
and examine the efficacy, safety, and tolerability of duvelisib at the
optimal dose. The study is expected to enroll up to 120 patients with
histologically confirmed PTCL subtypes of PTCL-NOS, angioimmunoblastic
TCL, anaplastic large cell lymphoma, and natural-killer TCL. Disease
responses will be measured by PET-CT scanning as assessed by an
independent review committee per IWG criteria. The primary endpoint is
ORR (CR + PR) in all patients receiving the optimal dose for at least 1
cycle in either phase. Secondary endpoints include safety, duration of
response, and PFS. This study is open for enrollment. Duvelisib has been
granted Fast Track designation by the U.S. Food and Drug Administration
(FDA) for the treatment of patients with PTCL who have received at least
one prior therapy.
A copy of the poster presentation will be available here.
Title: Duvelisib inhibition of chemokines in patients with CLL
(DUO study) and iNHL (DYNAMO study)
Lead author: Dr. David
Weaver, Verastem Oncology
Abstract #: 12048
Summary:
PI3K-δ inhibition directly targets proliferation and survival of
malignant leukemia and lymphoma cells, while PI3K-γ inhibition modulates
the TME through key support cells, including tumor-associated
macrophages, nurse-like stroma and T cells, and via soluble factors
stimulating tumor growth, survival and migration. Serum samples from
patients in the Phase 3 DUO study in relapsed/refractory CLL/SLL and the
Phase 2 DYNAMO study in relapsed/refractory indolent NHL were collected
at baseline and at C2D1 and used for correlative studies of 24
chemokines, cytokines and serum factors.
In serum samples from the DUO study, CCL1, CCL17, CXCL9, CXCL10, CXCL11,
and IL-10 were reduced in patients treated with duvelisib (median 43.8%)
but not in those treated with ofatumumab (p≤0.0009). Eight chemokines
were reduced in both treatment arms, but the level of reduction was
significantly greater for duvelisib-treated patients (median 64.6% for
duvelisib versus 26.8% for ofatumumab [p≤0.001]). Many of the chemokines
inhibited following duvelisib treatment are associated with the TME,
including TNFα, IL-10, IL2Rα, IL12P40, CCL1, CCL17, CCL19, CXCL9,
CXCL10, CXCL11, and CXCL13. In serum samples from the DYNAMO study, 13
corresponding chemokines were also inhibited (p≤0.008), including TME
factors. Reductions occurred rapidly (by C2D1) in both studies. In DUO,
there was a correlation between duration of response and reduction of
the following chemokines: CCL17, CXCL11, IL-6, TRAIL, VEGF-D and TPO.
These data support the hypothesis that treatment with duvelisib results
in significant reduction of chemokines potentially derived from the
tumor cells and TME and that further investigation of the effects of
duvelisib on TME pharmacodynamic markers is warranted.
A copy of the poster presentation will be available here.
Defactinib
Title: Phase I study of defactinib combined with pembrolizumab
and gemcitabine in patients with advanced cancer
Lead author: Dr.
Andrea Wang-Gillam, Washington University in St. Louis
Abstract
#: 2561
Summary: FAK is consistently hyperactivated in
multiple tumor types including pancreatic ductal adenocarcinoma (PDAC).
Previously reported preclinical research showed that FAK and PD-1
inhibitors elicit significant tumor regression, and a maximal response
is achieved by combining FAK and PD-1 inhibitors with gemcitabine,
suggesting the need for a cytotoxic agent to bolster antigen
presentation. In this ongoing Phase 1, dose-escalation study, defactinib
is being evaluated in combination with Merck’s PD-1 inhibitor
pembrolizumab and gemcitabine in patients with PDAC.
The dose escalation cohort has been completed with a total of 20
patients with refractory solid tumors. Of the 15 patients evaluable for
treatment response, 1 (7%) achieved a confirmed PR and 8 (53%) achieved
stable disease (SD). Of the 8 PDAC patients, 1 (13%) achieved a
confirmed PR and 3 (38%) achieved SD. The median time on treatment was
132 days for all evaluable patients and 158 days for patients with PDAC.
Paired biopsies from PDAC patients showed increased proliferating CD8+ T
cells and decreased T regs in patients with controlled disease compared
to patients with progressive disease. The combination regimen was well
tolerated with no dose limiting toxicities, and therefore the RP2D dose
was established as defactinib (400mg BID, Days 1-21), pembrolizumab
(200mg, Day 1) and gemcitabine (1,000mg/m2, Day 1 and 8). The
common treatment-emergent adverse events were anorexia (50%), fatigue
(40%), diarrhea (40%), fever (40%) and vomiting (35%), but nearly all
were Grade 1/2. There was 1 case of Grade ≥3 diarrhea. An expansion
cohort in patients with PDAC is currently ongoing.
A copy of the poster presentation will be available here.
About Duvelisib
Duvelisib is a first-in-class investigational oral, dual inhibitor of
phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma, two enzymes known
to help support the growth and survival of malignant B-cells and
T-cells. PI3K signaling may lead to the proliferation of malignant B-
and T-cells and is thought to play a role in the formation and
maintenance of the supportive tumor microenvironment.1,2,3
Duvelisib was evaluated in late- and mid-stage extension trials,
including DUO™, a randomized, Phase 3 monotherapy study in patients with
relapsed or refractory chronic lymphocytic leukemia/small lymphocytic
lymphoma (CLL/SLL),4 and DYNAMO™, a single-arm, Phase 2
monotherapy study in patients with refractory indolent non-Hodgkin
lymphoma (iNHL).5 Both DUO and DYNAMO achieved their primary
endpoints. Verastem Oncology’s New Drug Application (NDA) requesting the
full approval of duvelisib for the treatment of patients with relapsed
or refractory CLL/SLL, and accelerated approval for the treatment of
patients with relapsed or refractory follicular lymphoma (FL) was
accepted for filing by the U.S. Food and Drug Administration (FDA),
granted Priority Review and assigned a target action date of October 5,
2018. Duvelisib is also being developed by Verastem Oncology for the
treatment of peripheral T-cell lymphoma (PTCL), and is being
investigated in combination with other agents through
investigator-sponsored studies.6 Information about duvelisib
clinical trials can be found on www.clinicaltrials.gov.
About Defactinib
Defactinib is an investigational inhibitor of focal adhesion kinase
(FAK), a non-receptor tyrosine kinase that mediates oncogenic signaling
in response to cellular adhesion and growth factors.7 Based
on the multi-faceted roles of FAK, defactinib is used to treat cancer
through modulation of the tumor microenvironment and enhancement of
anti-tumor immunity.8,9 Defactinib is currently being
evaluated in three separate clinical collaborations in combination with
immunotherapeutic agents for the treatment of several different cancer
types including pancreatic cancer, ovarian cancer, non-small cell lung
cancer (NSCLC), and mesothelioma. These studies are combination clinical
trials with pembrolizumab and avelumab from Merck & Co. and Pfizer/Merck
KGaA, respectively.10,11,12 Information about these and
additional clinical trials evaluating the safety and efficacy of
defactinib can be found on www.clinicaltrials.gov.
About Verastem Oncology, Inc.
Verastem, (NASDAQ:VSTM), operating as Verastem Oncology, is a
biopharmaceutical company focused on developing and commercializing
drugs to improve the survival and quality of life of cancer patients.
Verastem Oncology is currently developing duvelisib, a dual inhibitor of
PI3K-delta and PI3K-gamma, which has successfully met its primary
endpoint in a Phase 2 study in indolent Non-Hodgkin Lymphoma (iNHL) and
a Phase 3 clinical trial in patients with chronic lymphocytic
leukemia/small lymphocytic lymphoma (CLL/SLL). Verastem Oncology’s New
Drug Application (NDA) requesting the full approval of duvelisib for the
treatment of patients with relapsed or refractory CLL/SLL, and
accelerated approval for the treatment of patients with relapsed or
refractory follicular lymphoma (FL) was accepted for filing by the U.S.
Food and Drug Administration (FDA), granted Priority Review and assigned
a target action date of October 5, 2018. In addition, Verastem Oncology
is developing the FAK inhibitor defactinib, which is currently being
evaluated in three separate clinical collaborations in combination with
immunotherapeutic agents for the treatment of several different cancer
types, including pancreatic cancer, ovarian cancer, non-small-cell lung
cancer (NSCLC), and mesothelioma. Verastem Oncology’s product candidates
seek to treat cancer by modulating the local tumor microenvironment and
enhancing anti-tumor immunity. For more information, please visit www.verastem.com.
Forward-looking statements notice:
This press release includes forward-looking statements about Verastem
Oncology’s strategy, future plans and prospects, including statements
regarding the development and activity of Verastem Oncology’s
investigational product candidates, including duvelisib and defactinib,
and Verastem Oncology’s PI3K and FAK programs generally, the structure
of our planned and pending clinical trials, Verastem Oncology’s
financial guidance and the timeline and indications for clinical
development and regulatory submissions. 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 that approval of
Verastem Oncology’s New Drug Application for duvelisib will not occur on
the expected timeframe or at all, including by the U.S. Food and Drug
Administration’s target action date; that a filing of a European
Marketing Application may not be achieved in fiscal year 2018 or at all;
that even if data from clinical trials is positive, regulatory
authorities may require additional studies for approval and the product
may not prove to be safe and effective; that the preclinical testing of
Verastem Oncology’s product candidates and preliminary or interim data
from clinical trials may not be predictive of the results or success of
ongoing or later clinical trials; that the full data from the DUOTM
study will not be consistent with the previously presented results of
the study; that data may not be available when expected, including for
the Phase 3 DUO study; that the degree of market acceptance of product
candidates, if approved, may be lower than expected; that the timing,
scope and rate of reimbursement for our product candidates is uncertain;
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 our
product candidates will cause unexpected safety events or result in an
unmanageable safety profile as compared to their level of efficacy; that
duvelisib will be ineffective at treating patients with lymphoid
malignancies; that Verastem Oncology will be unable to successfully
initiate or complete the clinical development and eventual
commercialization of its product candidates; that the development and
commercialization of Verastem Oncology’s product candidates will take
longer or cost more than planned; that Verastem Oncology may not have
sufficient cash to fund its contemplated operations; that Verastem
Oncology or Infinity Pharmaceuticals, Inc. will fail to fully perform
under the duvelisib license agreement; that Verastem Oncology may be
unable to make additional draws under its debt facility or obtain
adequate financing in the future through product licensing,
co-promotional arrangements, public or private equity, debt financing or
otherwise; that Verastem Oncology will not pursue or submit regulatory
filings for its product candidates, including for duvelisib in patients
with CLL/SLL or iNHL; and that Verastem Oncology’s 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 Annual Report on Form 10-K for the year
ended December 31, 2017 as filed with the Securities and Exchange
Commission (SEC) on March 13, 2018 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,
NCT02004522
5 www.clinicaltrials.gov,
NCT01882803
6 www.clinicaltrials.gov,
NCT02783625, NCT02158091
7 Schaller M.D. and Parsons J.T. Focal adhesion kinase: an
integrin-linked protein tyrosine kinase. Trends Cell Biol. 1993 3:
258-62.
8 Jiang H et al. Targeting focal adhesion kinase renders
pancreatic cancers responsive to checkpoint immunotherapy. Nat Med 2016:
Aug 22(8) 851-60.
9 Sulzmaier F.J. et al. FAK in cancer: mechanistic findings
and clinical applications. Nature Rev Cancer. 2014 14: 598-610.
10 www.clinicaltrials.gov,
NCT02546531
11 www.clinicaltrials.gov,
NCT02943317
12 www.clinicaltrials.gov,
NCT02758587
View source version on businesswire.com: https://www.businesswire.com/news/home/20180604005874/en/
Source: Verastem, Inc.
Verastem Oncology, Inc.
Marianne M. Lambertson
Vice
President, Corporate Communications
Investor Relations/Public
Relations
+1 781-292-4273
mlambertson@verastem.com
