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Verastem Oncology Presents Duvelisib Data at EHA 2018 Annual Meeting

Verastem, Inc. (Nasdaq: VSTM), the Company or Verastem Oncology, a
biopharmaceutical company focused on developing and commercializing
medicines to improve the survival and quality of life of cancer
patients, today announced one oral and three poster presentations at the
23rd Congress of the European Hematology Association (EHA) being held
June 14-17, 2018 in Stockholm, Sweden.

Data were presented on the Company’s lead product candidate, duvelisib,
a first-in-class oral dual inhibitor of phosphoinositide 3-kinase
(PI3K)-delta and PI3K-gamma. An oral presentation by Dr. Matthew Davids,
Dana-Farber Cancer Institute, highlighted the latest data from a Phase
Ib/II study evaluating duvelisib in combination with FCR (dFCR) as a
frontline treatment in younger patients with chronic lymphocytic
leukemia (CLL). Three poster presentations highlighted additional
duvelisib data, including crossover extension results from the Phase 3
DUO™ study in patients with relapsed or refractory CLL/small lymphocytic
lymphoma (SLL), and new biomarker analyses on the tumor microenvironment
modulation from the DUOTM study and the Phase 2 DYNAMOTM
study in patients with refractory indolent non-Hodgkin lymphoma (iNHL),
and the dual PI3K-delta and PI3K-gamma activity of duvelisib in the
CONTEMPOTM study in patients with untreated follicular
lymphoma (FL) who are treated with duvelisib in combination with CD20
antibody immunotherapy.

“Dr. Matthew Davids gave an oral presentation of new clinical data from
the ongoing Phase Ib/II study evaluating duvelisib in combination with
FCR (chemo-immunotherapy) in younger, fit CLL patients,” said Diep Le,
MD, PhD, Chief Medical Officer of Verastem Oncology. “The combination
regimen achieved an overall response rate (ORR) of 94%, including 26% of
patients experiencing a complete response or complete response with
incomplete blood count recovery (CR/CRi), and 68% achieving a partial
response. In addition, patients also experienced a high rate of bone
marrow MRD negativity of 76%, which is significantly higher than
historical data with FCR. Importantly, the results from this study
demonstrated that duvelisib can be combined with a triple
chemo-immunotherapy in the front-line setting with an acceptable safety
profile”.

Dr. Le added, “In addition, the DUO crossover extension data presented
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. 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. Collectively, the data presented at EHA this year
continue to provide important insights to guide the future clinical
development of duvelisib across a wide range of hematologic
malignancies, both as a monotherapy and in combination with other
agents.”

Jonathan Pachter, PhD, Chief Scientific Officer of Verastem Oncology,
commented, “The results presented by Drs. Casulo and Weaver continue to
provide important evidence that the dual inhibition of PI3K-? and PI3K-?
by duvelisib potentially yields added clinical benefit for CLL/SLL and
FL patients by targeting both malignant B cells and the supportive tumor
microenvironment. For example, these data indicate that duvelisib
significantly inhibits chemokines from both cancer cells and the tumor
microenvironment, and specifically, PI3K-? inhibition impairs function
of cancer-supportive macrophages and T cells.”

Details for the EHA 2018 presentation and posters are as follows:

Oral Presentation

Title: A Phase IB/II Study of duvelisib in combination with FCR
(dFCR) for Frontline Therapy of Younger CLL PatientsLead author:
Dr. Matthew Davids, Dana-Farber Cancer InstituteFinal Abstract
Code: S807Summary: FCR is a common initial therapy for
younger CLL patients; however, only about 20% will achieve a CR/CRi with
minimum residual disease (MRD) negativity in the bone marrow (BM-MRD-).
Oral duvelisib had previously shown promising efficacy in CLL, and
therefore, the purpose of this study was to investigate the safety and
rate of CR/CRi with BM-MRD- following treatment with dFCR. This Phase
Ib/II study utilized a standard 3 + 3 design and included 2 dose levels
of oral duvelisib (25mg once daily or 25mg twice daily). Duvelisib was
given for 1 week with FCR added on Day 8. Up to 6 cycles of dFCR were
administered, followed by up to 2 years of duvelisib maintenance.

Among the 31 patients evaluable for post-dFCR response, the ORR was 94%,
with 26% achieving a CR (n=4) or CRi (n=4), and 68% achieving a partial
response (PR). The best rate of MRD- in the BM in patients with at least
one evaluation was 81% (25 of 31). All patients who achieved CR/CRi at
primary endpoint were also BM-MRD- (26%). Among survivors, the median
follow-up is 24.5 months (range 6.9-46). Two-year progression-free
survival and overall survival are both 97%. Eight patients have now
completed two years of duvelisib maintenance therapy. The most common
all grade non-hematologic adverse events were nausea (72%, all Grade
1/2), fatigue (69%, 3% Grade 3), fever (53%, all Grade 1/2), diarrhea
(47%, 3% Grade 3), transaminitis (34%, 28% Grade 3/4), anorexia (34%,
all Grade 1/2), vomiting (28%, all Grade 1/2), pruritus (16%, 3% Grade
3), arthritis (9%, all Grade 2) and CMV reactivation (6%, both Grade 2).
The most common all grade hematologic adverse events were
thrombocytopenia (65%; 34% Grade 3-4), neutropenia (59%; 50% Grade 3-4),
and anemia (38%, 16% Grade 3). Serious AEs included transaminitis (n=9,
including 5 Grade 3, 4 Grade 4), febrile neutropenia (n=6, all Grade 3),
pneumonia (n=6, including 3 cases of PJP despite planned prophylaxis),
and colitis (n=2, including 1 Grade 2 and 1 Grade 3). Based on these
results the recommended Phase 2 dose of duvelisib in combination with
FCR was 25mg twice daily. These results support the thesis that dFCR is
an effective regimen for the initial therapy of younger, fit CLL
patients and results in a high 81% rate of BM-MRD negativity,
significantly higher than historical data with FCR; however infectious
and immune-mediated toxicities were observed.

A copy of the oral presentation is available here.

Poster Presentations

Title: The Efficacy of Duvelisib Monotherapy Following Disease
Progression on Ofatumumab Monotherapy in Patients with
Relapsed/Refractory CLL or SLL in a Phase 3 Crossover Extension StudyLead
author: Dr. Peter Hillman, St. James University Hospital, Leeds, UKFinal
Abstract Code: PF354Summary: 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 ofatumumab 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 ofatumumab 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-?,?, on
components of the tumor microenvironment in previously untreated
follicular lymphomaLead author: Dr. Carla Casulo,
University of Rochester, Wilmot Cancer CenterFinal Abstract Code:
PF646Summary: 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-? assays and PI3K-?
assays, with PI3K-?-selective (idelalisib, TGR-1202, IPI-3063) and
PI3K-?-selective (IPI-549) inhibitors were compared.

Duvelisib and idelalisib potently inhibited LPS-induced human monocytes
via PI3K-?, compared with the PI3K-? 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-? dependent
fMLP-stimulated human monocytes compared to idelalisib and TGR-1202. In
FL patients treated with duvelisib, these PI3K-? and PI3K-? selective
assays were inhibited 1-4 hours post treatment. Consistent with a PI3K-?
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-?
inhibitor IPI-3063. Collectively, these results support the thesis that
duvelisib disrupts PI3K- ?,? 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: Duvelisib inhibition of chemokines in patients with CLL
(DUO study) and iNHL (DYNAMO study).Lead author: Dr. David
Weaver, Verastem OncologyFinal Abstract Code: PF649Summary:
PI3K-? inhibition directly targets proliferation and survival of
malignant leukemia and lymphoma cells, while PI3K-? 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 TNF?, IL-10, IL2R?, 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.

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 Verastem Oncology

Verastem, Inc. (Nasdaq:VSTM), operating as Verastem Oncology, is a
biopharmaceutical company focused on developing and commercializing
medicines 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 2019 or at all;
that even if data from clinical trials is positive, regulatory
authorities may require additional studies for approval or may approve
for indications or patient populations that are not as broad as intended
and the product may not prove to be safe and effective or may require
labeling with use or distribution restrictions; 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 DUO 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,
NCT020045225 www.clinicaltrials.gov,
NCT018828036 www.clinicaltrials.gov,
NCT02783625, NCT02158091

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