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Verastem Presents Preclinical Data at ASCO-SITC Highlighting the Synergistic Effects of Duvelisib in Combination with Immune Checkpoint or Co-Stimulatory Antibodies in B Cell Lymphoma Model
Data Support Further Exploration of Duvelisib in Combination with Anti-PD-1/PD-L1 or Co-Stimulatory Antibodies in Patients with B Cell Malignancies
“In patients with relapsed or refractory chronic lymphocytic
leukemia/small lymphocytic lymphoma and follicular lymphoma, oral
duvelisib monotherapy has demonstrated efficacy, along with a consistent
and manageable safety profile. However, emerging data suggest that some
aggressive lymphomas will likely require combination therapy to improve
clinical outcomes,” said
Oral duvelisib is the first PI3K inhibitor to show efficacy as an oral
monotherapy in a randomized Phase 3 study in patients with relapsed or
refractory CLL/SLL (the DUO™ study). In the Phase 2 DYNAMO study,
duvelisib achieved meaningful clinical activity in patients diagnosed
with follicular lymphoma (FL), small lymphocytic lymphoma (SLL), or
marginal zone lymphoma (MZL) whose disease is refractory to rituximab
and to a chemotherapy regimen or radioimmunotherapy.
Details for the poster presentation at ASCO-SITC 2018 are:
Title: Dual PI3K-δ,γ inhibitor duvelisib reduces
immunosuppressive Tregs and myeloid cells enhancing efficacy of
checkpoint and co-stimulatory antibodies in a B cell lymphoma model
Session:
Developmental Therapeutics – Poster Session B
Abstract #: 33
Location:
Golden Gate Hall – B2 Level – Poster Board D1
Date and time:
Summary:
Prior published research has shown that PI3K-delta inhibition reduces
immunosuppressive Tregs and PI3K-gamma inhibition reduces
immunosuppressive myeloid cells. As a result, it was hypothesized that
duvelisib may augment the efficacy of immune checkpoint or
co-stimulatory antibodies. For this study,
Duvelisib alone, anti-PD-1 alone and anti-OX40 alone each induced tumor growth delay. When duvelisib and anti-PD-1 were combined, strong anti-tumor synergy was observed. When duvelisib and anti-OX40 were combined, tumor regression was observed which correlated with strong reduction of tumor Tregs, M2 macrophages and myeloid-derived suppressor cells. Immune memory was also assessed by injecting mice that had become tumor free with A20 cells following anti-OX40 alone or duvelisib + anti-OX40 with no further treatment. The mice that had received anti-OX40 alone grew new tumors upon A20 re-challenge, however, all mice that had received duvelisib + anti-OX40 did not grow tumors upon re-challenge and showed elevated memory T cells in blood and spleen. These findings indicate that treatment with duvelisib + anti-OX40 established immune memory. The dual inhibition of PI3K-δ and PI3K-γ appears to make duvelisib effective in reducing both lymphoid and myeloid immuno-suppressive populations, consistent with prior data suggesting that PI3K-δ inhibition reduces immunosuppressive Tregs, whereas PI3K-γ inhibition reduces immunosuppressive myeloid cells. We believe these results showing that dual PI3K-δ and PI3K-γ inhibition can enhance the anti-tumor efficacy of immune checkpoint and co-stimulatory antibodies which potentially support the clinical exploration of duvelisib in combination with these agents.
A copy of the poster presentation will be available here following the conclusion of the poster sessions.
About the Tumor Microenvironment
The tumor microenvironment encompasses various cellular populations and extracellular matrices within the tumor or cancer niche that support cancer cell survival. This includes immunosuppressive cell populations such as regulatory T-cells, myeloid-derived suppressor cells, M2 TAMS, as well as tumor-associated fibroblasts and extracellular matrix proteins which can hamper the entry and therapeutic benefit of cytotoxic immune cells and anti-cancer drugs. In addition to targeting the proliferative and survival signaling of cancer cells, Verastem’s compounds duvelisib and defactinib target the tumor microenvironment as a mechanism of action to potentially improve a patient’s response to therapy.
About Duvelisib
Duvelisib is a first-in-class investigational, 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 is currently being 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 (CLL)/small lymphocytic lymphoma (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 and Verastem intends to submit a 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). Duvelisib is also being developed by Verastem 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
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References
1 Winkler 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 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 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
View source version on businesswire.com: http://www.businesswire.com/news/home/20180126005567/en/
Source:
Verastem, Inc.
Marianne Lambertson, 781-292-4273
Vice
President, Corporate Communications
Investor Relations/Public
Relations
mlambertson@verastem.com