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Verastem Oncology Presents Data on Two Lead Drug Candidates at ASCO 2018 Annual Meeting
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
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
“The DUO crossover extension data reported at
Dr. Le added, “Dr.
Details for the
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,
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.
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.
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 (
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.
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
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.
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
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
About Verastem Oncology, Inc.
Forward-looking statements notice:
This press release includes forward-looking statements about
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.
4www.clinicaltrials.gov, NCT02004522
5www.clinicaltrials.gov, NCT01882803
6www.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:
9 Sulzmaier F.J. et al. FAK in cancer: mechanistic findings and clinical applications. Nature Rev Cancer. 2014 14: 598-610.
10www.clinicaltrials.gov, NCT02546531
11www.clinicaltrials.gov, NCT02943317
12www.clinicaltrials.gov, NCT02758587
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Source:
Verastem Oncology, Inc.
Marianne M. Lambertson
Vice
President, Corporate Communications
Investor Relations/Public
Relations
+1 781-292-4273
mlambertson@verastem.com