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New long-term data confirm Roche’s Gazyva/Gazyvaro extends the lives of people with chronic lymphocytic leukaemia compared to MabThera/Rituxan

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

BeiGene Provides Development Update and Presents Clinical Data on Zanubrutinib at the 23rd Congress of the European Hematology Association

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.

"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.

ArQule Presents Results from Ongoing Phase 1 Dose Escalation Study of its Reversible BTK Inhibitor, ARQ 531

On June 15, 2018 ArQule, Inc. (Nasdaq:ARQL) today is presenting preliminary results from the Company’s Phase 1 dose escalation study for ARQ 531, an orally bioavailable, potent and reversible inhibitor of both wild type and C481S-mutant Bruton’s tyrosine kinase (BTK) in patients with relapsed or refractory hematologic malignancies at the 23rd Congress of European Hematological Association (EHA) (Free EHA Whitepaper) in Stockholm, Sweden (Press release, ArQule, JUN 15, 2018, View Source [SID1234527333]).

"Preliminary data from our Phase 1 dose escalation trial highlights the potential of ARQ 531 to become a new therapeutic option for patients with B-cell malignancies," commented ArQule Chief Medical Officer and Head of Research and Development, Brian Schwartz, M.D. "There is a significant unmet need for patients with relapsed or refractory B-cell malignancies, in particular those with C481S-mediated resistance to irreversible BTK inhibitors such as ibrutinib. We are especially encouraged by the early signs of anti-tumor activity observed in the first three cohorts."

The reported data from the ongoing Phase 1, open label, single arm dose escalation 3+3 study are from the first three cohorts at dose levels of 5 (n=3), 10 (n=4) and 15 mg (n=4) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), Waldenstrom’s macroglobinemia and B-cell Non-Hodgkin lymphoma.

ARQ 531 demonstrated preliminary anti-tumor activity at all dose levels, resulting in an observed tumor reduction of 35% at 5mg, 33% at 10mg, and 29% at 15mg doses. The 29% tumor reduction in the 15mg cohort was achieved after 8 weeks of treatment in a patient with the BTK C481S-mutation, after 5 prior systemic regimens including ibrutinib and venetoclax, with treatment still ongoing. Overall treatment duration ranged from 1 to 46 weeks with 4 of 11 patients treated still ongoing.

ARQ 531 was well tolerated at all three dose levels, supporting continued dose escalation. No dose limiting toxicities or ARQ 531-related Grade 3 or greater adverse events were observed, and the maximum tolerated dose has not been reached.

The half-life of ARQ 531 was between 22-27 hours suggesting the potential for sustained target inhibition and supporting a once daily dosing regimen with preliminary pharmacokinetics showing increases in exposure that are approximately dose proportional.

The poster, A Phase 1 Dose Escalation Study of ARQ 531 in Selected Patients with Relapsed or Refractory Hematologic Malignancies, is available on ArQule’s website, www.arqule.com, under "Publications and Presentations": View Source

About BTK and ARQ 531

Bruton’s tyrosine kinase, BTK, is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers. ARQ 531 is an orally bioavailable, potent and reversible BTK inhibitor. Biochemical and cellular studies have shown that ARQ 531 inhibits both the wild type and C481S-mutant forms of BTK. The C481S-mutation is a known resistance mechanism for first generation irreversible BTK inhibitors. In preclinical studies, ARQ 531 has demonstrated good oral bioavailability as well as favorable pharmacokinetic, pharmacodynamic and metabolic properties.

Apexigen and Yale Cancer Center Announce Clinical Collaboration to Evaluate APX005M, Cabiralizumab, and Opdivo (Nivolumab) in Patients whose Disease has Progressed on Anti-PD-1/PD-L1 Therapy

On June 14, 2018 Apexigen, Inc., and Yale Cancer Center reported a clinical trial collaboration to evaluate Apexigen’s APX005M in combination with cabiralizumab and Opdivo in patients with advanced solid tumors (Press release, Apexigen, JUN 14, 2018, View Source [SID1234591001]). The Phase 1/2 clinical trial will evaluate the safety, tolerability, and preliminary activity of APX005M in combination with cabiralizumab and Opdivo in metastatic NSCLC, metastatic melanoma and RCC patients whose disease has progressed on prior anti-PD-1/PD-L1 therapy (www.clinicaltrials.gov: NCT03502330). In addition to providing funding, Bristol-Myers Squibb will supply Opdivo and cabiralizumab, an investigational antibody being developed in partnership with Five Prime Therapeutics.

APX005M is an investigational compound that is designed to activate CD40, a key immune co-stimulatory receptor essential to regulating the activation of both innate and adaptive immune responses against cancer. Cabiralizumab (FPA008) is an antibody that inhibits colony stimulating factor-1 receptor (CSF1R) and depletes immunosuppressive tumor associated macrophages (TAMs). Preclinical data from Yale researchers and others have demonstrated that treatment with a combination of CD40 activation and inhibition of CSF-1R modifies tumor-associated macrophages and activates T cells in tumors. This results in converting a "cold" into an "inflamed" tumor microenvironment capable of eliciting protective T cell responses in tumors that are either unresponsive or insensitive to immune checkpoint blockade.

"There is an urgent need to find effective therapies for the growing number of patients who have not responded to checkpoint inhibitors," said Xiaodong Yang, M.D., Ph.D., President and Chief Executive Officer of Apexigen. "CD40 has a fundamental role in the activation of both innate and adaptive immunity, and we believe that CD40 activation by APX005M will become a key component of a number of promising new I-O therapeutic regimens for treating cancer patients."

"This most exciting collaboration between Apexigen and Yale is a result of studies with tumor bearing mice that are poorly responsive to inhibitors of PD-1/PD-L1. Based on these studies, we believe that activation of the innate immune system by APX005M in combination with cabiralizumab will enhance the activity of nivolumab, leading to a novel therapeutic approach for the increasing population of cancer patients who progress on currently approved immune checkpoint inhibitors. This is the first time this combination of drugs has been given to patients and we are eager to initiate this new clinical trial," said Harriet Kluger, M.D., Professor of Medicine at Yale Cancer Center and Principal Investigator of the trial.

AIVITA Biomedical Randomizes First Patient in Phase II Ovarian Cancer Trial

On June 14, 2018 AIVITA Biomedical reported the randomization of its first patient in the Company’s Phase II clinical trial for newly diagnosed advanced ovarian cancer (Press release, AIVITA Biomedical, JUN 14, 2018, View Source [SID1234527445]). The double-blind study will enroll approximately 99 patients who will receive AIVITA’s patient-specific ovarian cancer vaccine, or a control agent. This milestone achievement is the first application of AIVITA’s new ROOT OF CANCER technology, a revolutionary immunotherapy that targets cancer-initiating cells.

AIVITA has received seven patient tumor specimens from a single clinical site, and has successfully generated a treatment for each patient, yielding a 100% manufacturing success rate. Given the success of patient recruitment and manufacturing, AIVITA will now expand the clinical study to multiple centers.

"I’m very proud that our AIVITA team has so clearly demonstrated feasibility and reproducibility in manufacturing these patient-specific treatments," said Dr. Robert Dillman, AIVITA’s Chief Medical Officer. "Quick, reliable and cost-effective production is critical for the viability of both patient and company."

AIVITA’s ROOT OF CANCER technology may soon be applied to both melanoma and glioblastoma multiforme patients. The Company is seeking approval to commercialize the treatment of melanoma patients in Japan and was recently approved to conduct a Phase 2 clinical study in glioblastoma multiforme by the US FDA.

About Ovarian Cancer

Ovarian cancer is the fifth most common cause of female cancer deaths, with an estimated 22,240 new diagnoses in 2018 and 14,070 deaths. The median age at diagnosis is 63, with a 5-year survival rate of less than 50% for all, and about 35% for the two thirds who have advanced disease (stage III or IV) at the time of initial diagnosis. Current standard of care includes surgical debulking and several courses of chemotherapy.

About ROOT OF CANCER

AIVITA’s treatment is a platform technology applicable to most solid tumor types and consists of autologous dendritic cells loaded with autologous tumor antigens from autologous self-renewing tumor-initiating cells.

The ovarian Phase II double-blind study will enroll approximately 99 patients who will be randomized in a 2:1 ratio to receive either the autologous dendritic cell vaccine or autologous monocytes as a comparator.

Patients eligible for randomization and treatment will be those (1) who have undergone debulking surgery, (2) for whom a cell line has been established, (3) who have undergone leukapheresis from which sufficient monocytes were obtained, and (4) have an ECOG performance grade of 0 or 1 (Karnofsky score of 70-100%).

For additional information about AIVITA’s AVOVA-1 trial patients can visit www.clinicaltrials.gov/ct2/show/NCT02033616