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Verastem Oncology Presents Duvelisib Data at EHA 2018 Annual Meeting
Phase Ib/II study of duvelisib in combination with FCR (dFCR) achieves ORR of 94% and 76% bone marrow MRD negativity in frontline therapy in younger CLL patients
Duvelisib demonstrates robust clinical activity in CLL 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™
Additional data support the hypothesis that duvelisib, a first-in-class dual inhibitor of PI3K delta/gamma, targets malignant B-cells directly and modulates the tumor microenvironment
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.
“Dr.
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.”
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 Patients
Lead author:
Dr.
Final Abstract
Code: S807
Summary: 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 Study
Lead
author: Dr.
Final
Abstract Code: PF354
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 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-δ,γ, on
components of the tumor microenvironment in previously untreated
follicular lymphoma
Lead author: Dr.
Final Abstract Code:
PF646
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: Duvelisib inhibition of chemokines in patients with CLL
(DUO study) and iNHL (DYNAMO study).
Lead author: Dr.
Final Abstract Code: PF649
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.
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 Verastem Oncology
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
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Source:
Verastem Oncology
Marianne M. Lambertson, +1 781-292-4273
Vice
President, Corporate Communications
Investor Relations/Public
Relations
mlambertson@verastem.com