On June 16, 2018 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, reported one oral and three poster presentations at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) being held June 14-17, 2018 in Stockholm, Sweden (Press release, Verastem, JUN 16, 2018, View Source;p=RssLanding&cat=news&id=2354840 [SID1234527361]).

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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 (Free EHA Whitepaper) 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-δ and PI3K-γ 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-γ inhibition impairs function of cancer-supportive macrophages and T cells."

Details for the EHA (Free EHA Whitepaper) 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. Matthew Davids, Dana-Farber Cancer Institute
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. Peter Hillman, St. James University Hospital, Leeds, UK
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 (Free ASH Whitepaper) 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. Carla Casulo, University of Rochester, Wilmot Cancer Center
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. David Weaver, Verastem Oncology
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 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.

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.

On June 16, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that positive results from the pivotal QuANTUM-R phase 3 study of single agent quizartinib were presented today as a late-breaking oral presentation in the plenary program at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Stockholm, Sweden (Press release, Daiichi Sankyo, JUN 16, 2018, View Source [SID1234527368]).

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QuANTUM-R study results showed that patients with relapsed/refractory acute myeloid leukemia (AML) with FLT3-ITD mutations who received single agent quizartinib had a 24 percent reduction in the risk of death compared to patients who received salvage chemotherapy (hazard ratio [HR] = 0.76, P=0.0177, 95 percent CI 0.58-0.98). The median overall survival was 6.2 months (two-sided 95 percent CI 5.3-7.2) for patients treated with quizartinib and 4.7 months (two-sided 95 percent CI 4.0-5.5) for patients treated with salvage chemotherapy. The estimated survival probability at 1 year was 27 percent for patients who received quizartinib and 20 percent for patients who received salvage chemotherapy.

"FLT3-ITD mutated AML represents a high unmet need entity as patients with this aggressive form of the disease have an overall dismal prognosis as evidenced by low response rates to current available therapies, high risk of relapse and a shorter overall survival than those without this mutation," said Jorge E. Cortes, MD, Deputy Chair of the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "In relapsed/refractory AML with FLT3-ITD mutations, these findings represent the first reported clinical data demonstrating that a single agent can significantly improve overall survival, suggesting that quizartinib could potentially help these patients live longer. Additionally, in the study, a higher proportion of patients received a stem cell transplant in the quizartinib arm compared to the chemotherapy arm."

Secondary and key exploratory analyses including composite complete remission (CRc) are consistent and supportive of the primary analysis.

"Results of this study are consistent with previous phase 2 studies of quizartinib and demonstrate the value of targeting the FLT3-ITD driver mutation. We are encouraged by these data, which will form the basis of regulatory submissions to health authorities. If approved, quizartinib has the potential to redefine the treatment of patients with relapsed/refractory AML with FLT3-ITD mutations," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "These results also build on our understanding of this difficult-to-treat type of AML as we continue to explore the potential role of quizartinib in combination with chemotherapy and other novel mechanisms to further advance the treatment of patients with relapsed/refractory and newly-diagnosed AML with FLT3-ITD mutations."

The safety profile observed in QuANTUM-R appears consistent with that observed at similar doses in the quizartinib clinical development program. The median treatment duration with quizartinib was 4 cycles of 28 days (97 days; range: 1-1,182 days) versus 1 cycle (range: 1-2) in the salvage chemotherapy arm. The median relative dose intensity for quizartinib was 89 percent. Incidence of treatment-emergent adverse events were comparable between patients who received single agent quizartinib (n=241) and those who received salvage chemotherapy (n=94). The most common adverse events (>30 percent, any Grade) in patients treated with quizartinib versus chemotherapy, respectively, included nausea (48 vs 42 percent), thrombocytopenia (39 vs 34 percent), fatigue (39 vs 29 percent), musculoskeletal pain (37 vs 28 percent), pyrexia (38 vs 45 percent), anemia (37 vs 32 percent), neutropenia (34 vs 26 percent), febrile neutropenia (34 vs 28 percent), vomiting (33 vs 21 percent) and hypokalemia (32 vs 28 percent). The most common adverse events Grade ≥3 (>10 percent of patients) were thrombocytopenia (35 vs 34 percent), anemia (30 vs 29 percent), neutropenia (32 vs 25 percent), febrile neutropenia (31 vs 21 percent), leukopenia (17 vs 16 percent), sepsis/septic shock (16 vs 18 percent), hypokalemia (12 vs 9 percent) and pneumonia (12 vs 9 percent). QTcF >500 msec occurred in 8 patients (3.3 percent) and 2 out of 241 patients discontinued quizartinib due to QTcF prolongation. There were no reported events of Grade 4 QTcF prolongation (Torsade de Pointe, sudden death or cardiac arrest) in the quizartinib arm.

About the QuANTUM-R Study

QuANTUM-R is a pivotal, global, phase 3, open-label randomized study that enrolled 367 patients with FLT3-ITD-mutated AML who were refractory to or in relapse following (with duration of remission of six months or less) standard first-line AML therapy with or without hematopoietic stem cell transplantation (HSCT). Patients were randomized in a 2:1 ratio to receive either single agent oral quizartinib (60 mg, with 30 mg lead-in) or salvage chemotherapy. The primary objective of the study was to determine whether single agent quizartinib prolonged overall survival compared to salvage chemotherapy.

About Quizartinib

Quizartinib, the lead investigational agent in the AML Franchise of the Daiichi Sankyo Cancer Enterprise, is an oral selective FLT3 inhibitor currently in global phase 3 development for relapsed/refractory (QuANTUM-R) and newly-diagnosed (QuANTUM-First) AML with FLT3-ITD mutations, and phase 2 development for relapsed/refractory AML with FLT3-ITD mutations in Japan.

Quizartinib has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed/refractory AML. Quizartinib also has been granted Orphan Drug designation by the FDA and European Medicines Agency (EMA) for the treatment of AML. Quizartinib is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

About Acute Myeloid Leukemia with FLT3-ITD Mutations

AML is an aggressive blood and bone marrow cancer that causes uncontrolled growth and accumulation of malignant white blood cells that fail to function normally and interfere with the production of normal blood cells.1 The five-year survival rate of AML reported from 2005 to 2011 was approximately 26 percent, which was the lowest of all leukemias.1

FLT3 gene mutations are one of the most common genetic abnormalities in AML.2 The FLT3-ITD mutation is the most common FLT3 mutation, affecting approximately one in four patients with AML.3,4,5,6 Patients with FLT3-ITD-mutated AML have a worse overall prognosis, including an increased incidence of relapse, an increased risk of death following relapseand a higher likelihood of relapse following HSCT as compared to those without this mutation.7,8

On June 15, 2018 BeiGene, Ltd. (NASDAQ:BGNE), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported that results on its investigational BTK inhibitor zanubrutinib, from two poster presentations at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) (Press release, BeiGene, JUN 15, 2018, View Source;p=RssLanding&cat=news&id=2354713 [SID1234527334]). The EHA (Free EHA Whitepaper) meeting is taking place in Stockholm, Sweden from June 14-17, 2018.

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"We continue to be encouraged by the quality and durability of response with zanubrutinib in the treatment of patients with Waldenström macroglobulinemia (WM), particularly with the observation that 43 percent of the evaluable patients achieved a very good partial response (VGPR). Additionally, the safety results from the combined experience in four ongoing monotherapy trials demonstrate that zanubrutinib was generally well-tolerated," commented Jane Huang, M.D., Chief Medical Officer, Hematology, at BeiGene. "As these results mature, and as we near completion of enrollment in our Phase 3 trial comparing zanubrutinib with ibrutinib in patients with WM, we are hopeful that zanubrutinib, if approved, may represent a valuable treatment option for patients with this disease."

In addition to zanubrutinib data presentations, BeiGene is providing the following updates to its planned development program for zanubrutinib:

BeiGene has received results from the independent review of response data from the 86-patient single-arm pivotal Phase 2 study of zanubrutinib in Chinese patients with relapsed or refractory mantle cell lymphoma (MCL). The overall response rate (ORR) of 84 percent (59% complete response rate) met the pre-specified criteria for a positive trial, and the median duration of response has not been reached with 8.3 months median follow-up. The safety profile was consistent with previously reported clinical data for zanubrutinib. BeiGene plans to submit its first new drug application (NDA) for zanubrutinib in China for the treatment of patients with relapsed or refractory MCL later this year. Full results of the study are planned to be presented at an upcoming major medical conference.

The global Phase 3 study comparing zanubrutinib to ibrutinib in patients with WM has met its enrollment target. The trial has closed new patient screening and is expected to complete enrollment in July. The Company plans to submit its first NDA in the United States for zanubrutinib in patients with WM in 2019.
Zanubrutinib in WM from Phase 1 Trial (EHA #PS1186)

A Phase 1 trial of zanubrutinib as a monotherapy in patients with different subtypes of B-cell malignancies, including WM, is being conducted in Australia, New Zealand, the United States, Italy, and South Korea. As of November 3, 2017, 67 patients with WM have been enrolled in the trial and were evaluable for safety. Fifty-one patients were evaluable for efficacy, excluding those with less than 12 weeks of follow-up (n=13) and those with IgM less than 5 g/L at baseline (n=3). Of the 51 patients evaluable for efficacy, 12 were treatment naïve and 39 patients were relapsed or refractory to prior treatment. At the time of the data cutoff, 59 patients remained on study treatment. Results included:

For the 51 patients with WM evaluable for response, the ORR was 92 percent (47/51), and major response rate was 80 percent, with 43 percent of patients achieving a VGPR (defined as a >90% reduction in baseline IgM levels and improvement of extramedullary disease by CT scan).

The 12-month progression-free survival (PFS) was estimated at 91 percent. The median PFS had not yet been reached.

Median time to response (partial response or higher) was 88 days (range, 77-279).

The median IgM decreased from 32.5 g/L (range, 5.3-88.5) at baseline to 4.9 g/L (range, 0.1-57).

Of 22 patients with hemoglobin <10 g/dL at baseline, the median increased from 8.7 g/dL (range, 6.3-9.8) to 13.8 g/dL (range, 7.7-15.8).

While the presence of MYD88L265P appears to be associated with response and depth of response with zanubrutinib treatment, significant activity was also observed in patients with MYD88WT (ORR 83%, major response rate 50%, VGPR rate 17%).

The most frequent adverse events (AEs) (>15%, all Grade 1-2 but one) of any attribution were petechia/purpura/contusion (37%), upper respiratory tract infection (34%), constipation (18%) and diarrhea (18%). Grade 3-4 AEs of any attribution reported in two or more patients included anemia (7%), neutropenia (6%), basal cell carcinoma (3%), hypertension (3%), squamous cell carcinoma (3%), pyrexia (3%), pneumonia (3%), major hemorrhage (3%), and actinic keratosis (3%).

Serious AEs (SAEs) were seen in 22 patients (33%), with events in five patients (7%) considered possibly related to zanubrutinib treatment: febrile neutropenia, colitis, atrial fibrillation, hemothorax (spontaneous), and headache.

Atrial fibrillation/flutter was experienced by four patients (6%), all Grade 1-2. Major hemorrhage was seen in two patients (3%).

Four patients (6%) discontinued due to AEs: fatal worsening bronchiectasis, prostate cancer, gastric adenocarcinoma, and acute myeloid leukemia.

Two patients (3%) discontinued study treatment due to disease progression as assessed by investigator and one patient remains on treatment post disease progression.
"Zanubrutinib continues to demonstrate robust activity in patients with WM. Deeper response rates have been maintained with longer follow-up in the Phase 1 trial and we are optimistic that zanubrutinib will demonstrate both high rates of activity and tolerability for patients, based on its potency and high-degree of selectivity," said Judith Trotman, M.D., Director, Clinical Research Unit in Haematology, Concord Hospital, and Professor at the University of Sydney, Australia.

Pooled Analysis of Safety Data from Zanubrutinib Monotherapy Trials (EHA #PF445)

Pooled safety data from patients with various B-cell lymphomas in four ongoing zanubrutinib monotherapy studies, totaling 476 patients with a median exposure of seven months, will be presented at the EHA (Free EHA Whitepaper) meeting. Overall, the data suggest that exposure levels of zanubrutinib resulting in complete and sustained BTK inhibition can be achieved and that zanubrutinib was generally well-tolerated. Results included:

Events of interest with BTK inhibitor therapy, such as atrial fibrillation/flutter (2%), major hemorrhage (2%), and Grade 3 and above diarrhea (1%) have been infrequent.

Treatment discontinuation due to zanubrutinib-related AEs was uncommon (3%).

The majority of patients (94%) experienced one or more AE of any attribution, primarily Grades 1 or 2. The most common Grade 3 or higher AEs of any attribution were neutropenia/neutrophil count decreased/febrile neutropenia (14%), anemia (7%) and thrombocytopenia/platelet count decreased (7%).

SAEs were reported in 116 patients (24%), with 38 patients (8%) assessed by the investigator as related to zanubrutinib. The most common SAEs were pneumonia/lung infection (6%), pleural effusion (1%), and febrile neutropenia (1%). The only treatment-related SAE reported in greater than one percent of patients was pneumonia/lung infection (2%). No cases of pneumocystis jiroveci pneumonia (PJP) or cytomegalovirus (CMV) reactivation were reported.

The most common bleeding events observed included petechiae/purpura/contusion (26%) and hematuria (11%). Major hemorrhage (2%) included gastrointestinal hemorrhage/melena (n=3), intraparenchymal CNS hemorrhage Grade 5, hematuria, purpura, hemorrhagic cystitis, renal hematoma, and hemothorax (1 each). The median time to first major hemorrhage was 1.2 months.

Amongst patients with emergent atrial fibrillation/flutter (n=8), a majority had known risk factors including hypertension (n=2), pre-existing cardiovascular disease (n=2), and concurrent infection (n=1).

The cumulative rates of Grade 3 or higher infections were 14 percent at six months, 19 percent at 12 months and 21 percent at 18 months. The exposure-adjusted incidence rate was 1.82 per 100 person-months.

The most common second primary malignancies included basal cell carcinoma (3%) and squamous cell carcinoma of the skin (1%).
"While BTK inhibitor therapy has historically been shown to be highly effective in the treatment of certain chronic B cell malignancies, such as chronic lymphocytic leukemia (CLL), WM, and MCL, specific events such as atrial fibrillation, serious diarrhea, and CNS bleeding, as well as appreciable overall rates of discontinuation of treatment due to tolerability or toxicity, remain concerns. With this pooled safety analysis of zanubrutinib monotherapy, we wanted to further assess whether its selectivity profile would translate into tolerability. We are encouraged that the low rates of BTK inhibitor-associated events, as well as low rates of toxicity-related treatment discontinuation, may allow for continuous disease control. We are hopeful that, if approved, patients with these hematologic malignancies could potentially lessen drug safety concerns, to focus on their lives rather than their disease," said Constantine Tam, M.D., Director of Haematology, St. Vincent’s Hospital and Consultant Haematologist, Peter MacCallum Cancer Center, in Australia.

Today’s Investor Conference Call & Webcast Information

Date and Time: Friday, June 15, 2018, 8:00 am EDT (Friday, June 15, 2018, 8:00 pm China Standard Time)

Dial-In Numbers: 1-844-461-9930 or 1-478-219-0535 (U.S.), 400-682-8609 or 800-870-0169 (China), 852-30114522 (Hong Kong), 65-66221010 (Singapore), 61-282239773 (Australia), 0856619361 (Sweden), or 1-478-219-0535 (International).

Conference ID Number: 7756029

Webcast and Replay: A live webcast and replay of the event will be available on BeiGene’s investor website, View Source The dial-in replay will be available approximately two hours after the conference and will be available for two days following the event. It can be accessed by dialing 1-855-859-2056 (U.S.) or 1-404-537-3406 (International), or 400-683-7185 (China).
About Zanubrutinib
Zanubrutinib (BGB-3111) is an investigational small molecule inhibitor of Bruton’s tyrosine kinase (BTK) that is currently being evaluated in a broad pivotal clinical program globally and in China as a monotherapy and in combination with other therapies to treat various lymphomas.

On June 15, 2018 Oncopeptides AB (Nasdaq Stockholm: ONCO) reported that they are presenting updated interim data with Ygalo (melflufen) from the ongoing HORIZON trial at the 23rd EHA (Free EHA Whitepaper) congress in Stockholm (Press release, Oncopeptides, JUN 15, 2018, View Source [SID1234527353]).

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The updated phase II-data show a clinical data set with an Overall Response Rate (ORR) of 32.1% and a Clinical Benefit Rate (CBR) of 39.3% with Ygalo in relapsed/refractory multiple myeloma patients refractory to pomalidomide and/or daratumumab after failing on immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs).

The data are presented in a poster that can be found at: www.oncopeptides.se/presentations/EHA

CEO comments

"In HORIZON, we are studying the activity of Ygalo in myeloma patients that have failed on all, or the majority of, treatments that are currently in use. In addition, half the patients in HORIZON are ISS stage III and half the patients have high-risk cytogenetics. This means that the patients are very ill, since both parameters are strong predictors of poor treatment outcome. To our knowledge this is the highest combined number in any study in myeloma to date. Despite all this, we see a tumor response in 32% of patients, disease stabilization in 84% of patients, positive initial indication of the duration of the treatment effect as well as a manageable safety profile for Ygalo. We have made the decision to expand the HORIZON trial to further understand the efficacy of Ygalo in this very difficult to treat patient population", said Jakob Lindberg, CEO of Oncopeptides.

Professor Paul G. Richardson comments

"With an increasing number of patients with highly resistant myeloma there is a real need for additional treatment options based on new mechanisms of action. Ygalo, a peptidase-enhanced compound, with its potent activity, manageable tolerability and lack of shared resistance mechanisms with other modalities, is a promising molecule that is making encouraging progress in clinical development" said Professor Paul Richardson, Harvard Medical School at the Dana-Farber Cancer Institute, Boston, USA.

About the HORIZON study

The study recruitment is ongoing. The interim data presented at the EHA (Free EHA Whitepaper) congress are based on a data cut-off dated May 10th 2018 with 62 patients treated. The patients in the study should be refractory to pomalidomide and/or daratumumab after failing on IMiDs and PIs.

Conclusions regarding HORIZON

The study continues to develop positively in this heavily pretreated patient group that is refractory to pomalidomide and/or daratumumab after failing on IMiDs and PIs with few remaining treatment options.

54% of patients in the study had high-risk cytogenetics, 46% of patients were ISS stage III, the median number of prior lines of therapy was 5.5 and the median time since initial diagnosis was 6.1 years.
100% of patients were refractory to pomalidomide or daratumumab, 98% had disease progression on or within 60 days of completion of the last therapy, 89% were double-refractory to IMiD:s and PI:s and 56% were refractory to both pomalidomide and daratumumab.
Analysis of the preliminary efficacy results showed an ORR of 32.1%, a CBR of 39.3% and that 84% of the patients achieved disease stabilization (SD or better).

Subgroup analysis suggests that response does not vary across refractory subsets but rather with the underlying disease and health status of the patient (in line with the observation made in Oncopeptides phase II study O-12-M1).
Time-to-next-treatment was maintained compared to the previous line of therapy without the deterioration normally seen in myeloma patients.
In the previous line of therapy, 75% of the patients were treated with antibody-based therapies or 2nd/3rd generation PI:s and IMiD:s, and 46% received triple combination therapies.
This study confirms earlier results from the O-12-M1 study in a more resistant patient population. The efficacy results in this interim analysis are encouraging with an ORR of 32,1% and a CBR of 39,3%.

Ygalo showed a manageable safety and tolerability profile. Treatment-related grade 3/4 AEs were reported in 48 (77%) patients with the majority being hematologic. Treatment-related non-hematologic grade 3/4 AEs were rare with infections in only 6% of patients.

About Ygalo

Ygalo is an alkylating peptide, belonging to the novel class of Peptidase Enhanced Compounds (PEnCs), targeting the multiple myeloma (MM) transformation process with a unique mechanism of action.

Aminopeptidases are heavily over-expressed in MM cells and are key to the transformational process of the disease. Ygalo selectively targets MM cells through aminopeptidase-driven accumulation, where in vitro experiments show a 50-fold enrichment of alkylating metabolites in MM cells. The enrichment results in selective cytotoxicity (increased on-target potency and decreased off-target toxicity), overcomes resistance pathways of existing myeloma treatments (including alkylators) and demonstrates strong anti-angiogenic properties.

Ygalo in clinical development

Ygalo has been used to treat late-stage RRMM patients in both phase I and phase II clinical studies (O-12-M1) with favorable results. Currently, Ygalo is being studied in three clinical trials for the treatment of multiple myeloma. The current studies are HORIZON, OCEAN and ANCHOR. A fourth study, BRIDGE in RRMM patients with impaired renal function will be initiated during Q3 this year to further investigate Ygalo in multiple myeloma.

The current clinical study program is intended to demonstrate better results from treatment with Ygalo compared to established alternative drugs for patients with late-stage multiple myeloma. Ygalo could potentially provide physicians with a new treatment option for patients suffering from this serious disease.

Ygalo has been investigated in the treatment of late-stage relapsed refractory multiple myeloma (RRMM) patients. This was done in the clinical study O-12-M1 where strong final results were reported in December 2017. Currently, three clinical studies are ongoing with Ygalo.

HORIZON is a Phase II study that studies the effect of Ygalo in late-stage RRMM patients with few or no remaining established treatment options. Updated interim data from this study are presented at EHA (Free EHA Whitepaper) in June 2018.

OCEAN is Oncopeptides´ pivotal Phase III study where Ygalo is compared directly with current standard of care, pomalidomide, in late-stage RRMM patients.

In the ANCHOR study, Ygalo will be administered in combination with either bortezomib or daratumumab in RRMM patients. The results of this study aim to create understanding and knowledge among treating physicians for how Ygalo can be used in combination with these drugs. In addition, the results could open up for the use of Ygalo in earlier lines of treatment.

On June 15, 2018 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported data from the final analysis of the CLL11 study evaluating Gazyva/Gazyvaro (obinutuzumab)-based treatment in previously untreated chronic lymphocytic leukaemia (CLL) which will be presented during the Presidential Symposium at the 23rd European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress, 14 – 17 June, in Stockholm (Press release, Hoffmann-La Roche, JUN 15, 2018, View Source [SID1234527335]). After a follow-up of nearly five years, final results showed clinically meaningful improvements with Gazyva/Gazyvaro plus chlorambucil across multiple endpoints, including progression-free survival (PFS) and overall survival (OS), when compared head-to-head with MabThera/Rituxan (rituximab) plus chlorambucil. Gazyva/Gazyvaro-based treatment reduced the risk of death by 24% compared to MabThera/Rituxan-based treatment (median OS not reached vs. 73.1 months, HR= 0.76; 95% CI 0.60-0.97; p<0.0245). These new data add to the growing body of evidence for the OS benefit with Gazyva/Gazyvaro in first-line CLL after the previously reported OS benefit with Gazyva/Gazyvaro combined with chlorambucil versus chlorambucil alone.

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"We are very pleased that the majority of patients treated with Gazyva/Gazyvaro are still alive after nearly five years of follow-up in the CLL11 study," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "This meaningful survival benefit compared to MabThera/Rituxan-based therapy reinforces that Gazyva/Gazyvaro-based therapy is an important option for people with previously untreated CLL."

After a median observation time of nearly five years (59.4 months) this final analysis of the CLL11 study demonstrated:

A reduction in the risk of disease progression or death of 51% for patients treated with Gazyva/Gazyvaro plus chlorambucil versus those treated with MabThera/Rituxan plus chlorambucil (median PFS 28.9 vs. 15.7 months, HR= 0.49; 95% CI 0.41-0.58; p<0.0001).
A clinically meaningful improvement in OS for patients receiving Gazyva/Gazyvaro plus chlorambucil compared to MabThera/Rituxan plus chlorambucil. At the time of final analysis the median OS in the Gazyva/Gazyvaro plus chlorambucil arm was not yet reached which means that more than half of these patients were still alive after nearly five years. A 24% reduction in the risk of death was observed with Gazyva/Gazyvaro plus chlorambucil treatment (median OS not reached vs. 73.1 months, HR= 0.76; 95% CI 0.60-0.97; p<0.0245).
A prolonged time to initiation of the next therapy (time to new treatment; TTNT) with Gazyva/Gazyvaro plus chlorambucil (median 56.4 vs. 34.9 months, Gazyva/Gazyvaro plus chlorambucil vs. MabThera/Rituxan plus chlorambucil, HR= 0.58; 95% CI 0.46-0.73; p<0.0001).
Patients treated with Gazyva/Gazyvaro plus chlorambucil achieved a higher rate of minimal residual disease (MRD) negativity versus those treated with MabThera/Rituxan plus chlorambucil (24% vs. 2% of patients MRD-negative, Gazyva/Gazyvaro plus chlorambucil vs. MabThera/Rituxan plus chlorambucil). Being MRD negative means no cancer can be detected in the blood and or bone marrow using a sensitive test.
No new or unexpected safety concerns for the combination of Gazyva/Gazyvaro plus chlorambucil.

Gazyva/Gazyvaro is currently approved in more than 90 countries in combination with chlorambucil, for people with previously untreated CLL, based on previously reported data from the CLL11 study.1

About the CLL11 study
CLL11 is a phase III, multicenter, open-label, randomised three-arm study to investigate the safety and efficacy profile of Gazyva/Gazyvaro plus chlorambucil compared to MabThera/Rituxan plus chlorambucil or chlorambucil alone in nearly 800 people with previously untreated CLL and comorbidities. The primary endpoint of the study is PFS with secondary endpoints including response rate, molecular remission rate, OS, TTNT and safety profile. In terms of analysis, the study was divided into three stages:

Stage 1a compared the addition of Gazyva/Gazyvaro to chlorambucil vs. chlorambucil alone
Stage 1b compared the addition of MabThera/Rituxan to chlorambucil vs. chlorambucil alone
Stage 2 compared Gazyva/Gazyvaro plus chlorambucil to MabThera/Rituxan plus chlorambucil
About Gazyva/Gazyvaro (obinutuzumab)
Gazyva/Gazyvaro is an engineered monoclonal antibody designed to attach to CD20, a protein expressed on certain B cells, but not on stem cells or plasma cells. Gazyva/Gazyvaro is designed to attack and destroy targeted B-cells both directly and together with the body’s immune system. Gazyva is marketed as Gazyvaro in the EU and Switzerland.

Gazyva/Gazyvaro is currently approved in more than 90 countries in combination with chlorambucil for people with previously untreated chronic lymphocytic leukaemia (CLL), in more than 80 countries in combination with bendamustine for people with certain types of previously treated follicular lymphoma and in more than 60 countries in combination with chemotherapy for previously untreated, follicular lymphoma.

Additional combination studies investigating Gazyva/Gazyvaro with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are underway across a range of blood cancers.

About Chronic Lymphocytic Leukaemia
Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in the Western world. 2 CLL mainly affects men and the median age at diagnosis is about 70 years.3 Worldwide, the incidence of all leukaemias is estimated to be over 350,000 and CLL is estimated to affect around one-third of all people newly diagnosed with leukaemia.4

About Roche in haematology