On December 8, 2019 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported clinical data from three trials of its BTK inhibitor BRUKINSA (zanubrutinib) were presented at the 61stAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, FL (Press release, BeiGene, DEC 8, 2019, View Source [SID1234552052]). In two oral presentations of BRUKINSA in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), the drug candidate demonstrated consistent safety and a high overall response rate (ORR); in the poster presentation of BRUKINSA combined with BeiGene’s investigational anti-PD-1 antibody tislelizumab in patients with previously treated B-cell malignancies, the combination treatment showed preliminary efficacy and was generally well tolerated.

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"The data presented today showing clinical activity and tolerability of BRUKINSA in patients with CLL or SLL are promising for its potential use in patients living with these cancers," said Constantine S. Tam, M.D., Disease Group Lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at the Peter MacCallum Cancer Center and Director of Hematology at St. Vincent’s Hospital, Australia. "BTK inhibitors have become an important standard of care for B-cell malignancies, offering the potential for durable responses with manageable safety profiles. It’s encouraging to have more evidence that zanubrutinib can be effective in treating CLL or SLL, including in patients with del(17p) who typically have a worse prognosis and few treatment options."

"The results presented today on BRUKINSA, a BTK inhibitor designed to maximize target occupancy and minimize off-target binding, demonstrated robust clinical activity and a safety profile consistent with what we’ve observed to date in our clinical trials, including safety data that supported the recent U.S. FDA accelerated approval in patients with previously treated mantle cell lymphoma," said Jane Huang, M.D., Chief Medical Officer, hematology at BeiGene. "CLL or SLL is the most common type of leukemia in adults, and despite the advancements of BTK inhibitor therapy for these cancers, there remains a need for highly selective BTK inhibitors capable of promoting long-term responses, and with a safety profile that is tolerable over time. The results presented here today further demonstrate the potential for BRUKINSA to help people living with these persistent, life-threatening cancers."

Initial Results from SEQUOIA Trial Arm C in Treatment-Naïve (TN) CLL or SLL Patients with Del(17p)

Presentation 499

Initial results from Arm C in the open-label, Phase 3 SEQUOIA trial (NCT03336333) of BRUKINSA as a monotherapy demonstrated a high ORR in patients with TN CLL or SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)]. The safety profile was consistent with that observed in previous clinical trials of BRUKINSA in B-cell malignancies. At the data cutoff of August 7, 2019, with a median follow-up of 10 months, initial results included:

The ORR was 92.7% (101/109); the partial response (PR) rate was 78.9% (86/109); the PR rate with lymphocytosis was 11.9% (13/109); and the complete response (CR) rate was 1.9% (2/109); only four cases of disease progression occurred;

36.7% of patients (40/109) experienced at least one grade ≥3 adverse event (AE) and only one patient discontinued treatment due to AEs;

The most common grade ≥3 AEs, occurring in more than two patients, were neutropenia (10.1%), pneumonia (3.7%) and hypertension (2.8%);

23.9% of patients (26/109) experienced at least one serious AE; and

One patient experienced a fatal AE, pneumonia leading to sepsis and death, which was considered related to treatment drug by the study investigator.
Updated Results from a Phase 1/2 Trial in Patients with CLL or SLL

Presentation 500

Updated results from the open-label, dose-escalation, single-arm, global Phase 1/2 trial (NCT02343120) showed that BRUKINSA was generally well-tolerated and active in patients with relapsed/refractory (R/R) or TN CLL/SLL, irrespective of del(17p) status (n=123; 101 R/R, 22 TN). At the data cutoff of May 8, 2019, with a median follow-up of 29.5 months, results included:

The ORR was 95.9% (118/123); the PR rate was 73.2% (90/123); the PR rate with lymphocytosis was 6.5% (8/123); the CR rate was 16.3% (20/123), including one patient who achieved a CR with incomplete bone marrow recovery;

The median duration of treatment was 25.8 months and 80% of patients (98/123) remained on study treatment; two-year progression-free survival (PFS) was 91% in R/R patients and 95% in TN patients;

61.8% of patients (76/123) experienced at least one grade ≥3 AE and only five patients discontinued treatment due to AEs;

The most common AEs (≥ 20%) were contusion (47.2%), upper respiratory tract infection (42.3%), diarrhea (31.7%), cough (29.3%), headache (23.6%), and fatigue (20.3%);

47.2% of patients (58/123) experienced at least one serious AE; and

One patient experienced a fatal AE, neoplasm-malignant recurrent squamous cell carcinoma, considered unrelated to treatment drug by the study investigator.
BRUKINSA in Combination with PD-1 Inhibitor Tislelizumab in Patients with Previously Treated B-Cell Lymphoid Malignancies

Presentation 1594

Preliminary findings from the open-label, multicenter, Phase 1b trial (NCT02795182) showed that BRUKINSA in combination with the investigational anti-PD-1 antibody tislelizumab demonstrated a generally manageable toxicity profile in patients with R/R B-cell malignancies. A total of 70 patients enrolled in the trial, including 54 patients with aggressive non-Hodgkin’s lymphomas (NHLs) which consist of diffuse large B-cell lymphoma, transformed follicular lymphoma, Richter’s transformation, and central nervous system (CNS) lymphoma. At the data cutoff of August 31, 2019, with a median follow-up of 8.1 months, preliminary findings included:

Of the 54 patients with aggressive NHLs, the ORR was 37.0% (20/54); the PR rate was 20.4% (11/54); the CR rate was 16.7% (9/54); stable disease (SD) rate was 9.3% (5/54);

71.4% of patients (50/70) experienced at least one grade ≥3 AE and 14.3% of patients (10/70) discontinued BRUKINSA and/or tislelizumab treatment due to AEs;

The most common grade ≥3 AEs were neutropenia (12.9%), anemia (10.0%), thrombocytopenia (7.1%), pneumonia (5.7%), neutrophil count decreased (5.7%), tumor lysis syndrome (4.3%), sepsis (4.3%), immune-mediated enterocolitis (4.3%), hypertension (4.3%), lymphocyte count decreased (2.9%), hemolytic transfusion reaction (2.9%), febrile neutropenia (2.9%), back pain (2.9%), acute kidney injury (2.9%), abscess limb (2.9%), and abdominal pain (2.9%);

Grade ≥3 immune-related AEs (irAEs) were reported in 15.7% of patients (11/70) with immune-mediated enterocolitis (4.3%), and pneumonitis (2.9%) occurring in more than one patient; and

Five patients experienced fatal AEs, four of which in the setting of progressive disease were considered unrelated to treatment including multi-organ dysfunction, septic shock and pneumonia, respiratory failure, and aspiration pneumonia, and one of toxic epidermal necrolysis which was considered related to treatment by the study investigator.
About BRUKINSA (zanubrutinib)

BRUKINSA (zanubrutinib) is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by BeiGene scientists that is currently being evaluated globally in a broad pivotal clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. BRUKINSA was granted accelerated approval by the U.S. FDA to treat adult patients with MCL who have received at least one prior therapy in November 2019. This accelerated approval is based on overall response rate (ORR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

New Drug Applications (NDAs) in China for relapsed refractory (R/R) MCL and R/R chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have been accepted by the China National Medical Products Administration (NMPA) and granted priority review and are pending approval.

BRUKINSA is not approved for use outside the United States. BRUKINSA is not approved for the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma.

IMPORTANT SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher bleeding events including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 2% of patients treated with BRUKINSA monotherapy. Bleeding events of any grade, including purpura and petechiae, occurred in 50% of patients treated with BRUKINSA monotherapy.

Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 23% of patients treated with BRUKINSA monotherapy. The most common Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (27%), thrombocytopenia (10%) and anemia (8%) based on laboratory measurements, were reported in patients treated with BRUKINSA monotherapy.

Monitor complete blood counts during treatment and treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 9% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin), reported in 6% of patients. Advise patients to use sun protection.

Cardiac Arrhythmias

Atrial fibrillation and atrial flutter have occurred in 2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events were reported in 0.6% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for at least 1 week after the last dose. Advise men to avoid fathering a child during treatment and for at least 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse Reactions

The most common adverse reactions in > 10% of patients who received BRUKINSA were neutrophil count decreased (53%), platelet count decreased (39%), upper respiratory tract infection (38%), white blood cell count decreased (30%), hemoglobin decreased (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), musculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuria (12%), fatigue (11%), constipation (11%), and hemorrhage (10%). The most frequent serious adverse reactions were pneumonia (11%) and hemorrhage (5%).

Drug Interactions

CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For coadministration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers: Avoid coadministration with moderate or strong CYP3A inducers.

Specific Populations

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

INDICATION

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Please see full Prescribing Information at beigene.com/PDF/BRUKINSAUSPI.pdf and Patient Information at beigene.com/PDF/BRUKINSAUSPPI.pdf

About the Zanubrutinib Clinical Trial Program

Clinical trials of zanubrutinib include:

Fully-enrolled Phase 3 ASPEN clinical trial in patients with Waldenström macroglobulinemia (WM) comparing zanubrutinib to ibrutinib (NCT03053440), currently the only approved BTK inhibitor for WM;

Phase 3 SEQUOIA trial comparing zanubrutinib with bendamustine plus rituximab in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (NCT03336333);

Phase 3 ALPINE trial comparing zanubrutinib to ibrutinib in patients with relapsed/refractory (R/R) CLL/SLL (NCT03734016);

Phase 2 trial in combination with GAZYVA (obinutuzumab) in patients with R/R follicular lymphoma (FL) (NCT03332017);

Phase 3 trial comparing zanubrutinib and rituximab to bendamustine and rituximab in patients with untreated MCL (NCT04002297);

Phase 2 MAGNOLIA trial in patients with R/R marginal zone lymphoma (MZL) (NCT03846427);

Phase 2 ROSEWOOD trial (NCT03332017) in China comparing obinutuzumab and zanubrutinib vs obinutuzumab alone in treating patients with R/R FL;

Completed Phase 2 trials in patients with R/R MCL (NCT03206970) and R/R CLL/SLL (NCT03206918); and

Completed enrollment in Phase 2 clinical trial in patients with WM (NCT03332173).
About Tislelizumab

Tislelizumab (BGB-A317) is an investigational humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells. Tislelizumab is the first drug candidate produced from BeiGene’s immuno-oncology biologics program and is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers.

Select ongoing clinical trials of tislelizumab include a Phase 3 clinical trial in patients with second-line or third-line non-small cell lung cancer (NSCLC); a Phase 3 clinical trial in first-line patients with hepatocellular carcinoma (HCC); a Phase 3 clinical trial in second-line patients with esophageal squamous carcinoma (ESCC); a Phase 3 clinical trial in first-line patients with gastric cancer (GC); a Phase 3 clinical trial in first-line patients with ESCC; and a Phase 2 clinical trial in second- or third-line patients with HCC. The aforementioned trials are enrolling patients in multiple countries, including the United States, Europe, and China.

In addition to a pivotal Phase 2 clinical trial in patients with relapsed or refractory (R/R) classical Hodgkin’s lymphoma (cHL) and a pivotal Phase 2 clinical trial in patients with locally advanced or metastatic urothelial cancer, BeiGene is conducting a Phase 3 clinical trial in first-line patients with non-squamous NSCLC; a Phase 3 clinical trial in first-line patients with squamous NSCLC; a Phase 3 clinical trial in patients with first-line nasopharyngeal cancer (NPC); a Phase 3 clinical trial in first-line patients with urothelial carcinoma (UC); a Phase 3 clinical trial in patients with localized ESCC; and a Phase 2 trial in patients with MSI-H or dMMR solid tumors. These studies have been enrolling patients primarily in China.

New drug applications (NDA) for tislelizumab in patients with R/R cHL and in patients with previously treated locally advanced or metastatic UC have been accepted and granted priority review by the China National Medical Products Administration (NMPA, formerly known as CFDA). BeiGene has full development and commercial rights to tislelizumab worldwide.

On December 8, 2019 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported updated data from two pivotal phase III Venclexta/Venclyxto (venetoclax) studies (MURANO and CLL14) that highlight Venclexta/Venclyxto combination treatments as chemotherapy-free, fixed-duration options that achieve minimal residual disease (MRD)-negativity, in people with chronic lymphocytic leukaemia (CLL) (Press release, Hoffmann-La Roche, DEC 8, 2019, View Source [SID1234552046]). These data and others from the Venclexta/Venclyxto clinical development programme will be featured in more than 50 abstracts at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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"Venclexta/Venclyxto plus anti-CD20 monoclonal antibody-based regimens continue to demonstrate improved long-term outcomes for people with chronic lymphocytic leukaemia," said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. "These results reinforce the sustained clinical benefits observed in patients with this common type of blood cancer, after completing this fixed-duration, chemotherapy-free treatment."

The pivotal phase III CLL14 study evaluated the combination of Venclexta/Venclyxto plus Gazyva/Gazyvaro (obinutuzumab) in people with previously untreated CLL, who had co-existing medical conditions. At a median follow-up of more than three years (39.57 months), when all patients had been off therapy for a minimum of two years, Venclexta/Venclyxto plus Gazyva/Gazyvaro showed high response rates, including MRD-negativity. Specifically:

Higher rates of MRD-negativity in peripheral blood (76% vs. 35%; p<0.001) and bone marrow (57% vs. 17; p<0.001%) were observed at the end of treatment in people treated with Venclexta/Venclyxto plus Gazyva/Gazyvaro versus Gazyva/Gazyvaro plus chlorambucil, respectively. MRD-negativity indicates that no cancer can be detected using a specific, highly sensitive test, and was defined as less than one CLL cell in 10,000 white blood cells.
MRD-negativity was observed in 42 % of people treated with Venclexta/Venclyxto plus Gazyva/Gazyvaro who achieved a complete response (CR) in the peripheral blood, and 14% of people treated with Gazyva/Gazyvaro plus chlorambucil (p<0.001). In bone marrow, MRD-negativity was observed in 34% of people who achieved a complete response with Venclexta/Venclyxto plus Gazyva/Gazyvaro and 11% of people treated with Gazyva/Gazyvaro plus chlorambucil (p<0.001).
At this updated analysis, the fixed-duration, chemotherapy-free combination of Venclexta/Venclyxto plus Gazyva/Gazyvaro reduced the risk of disease worsening or death by 69% compared to Gazyva/Gazyvaro plus chlorambucil (PFS, as assessed by investigator; HR=0.31; 95% CI 0.22-0.44; p<0.0001).
The most common Grade 3-4 adverse events (AEs) in people treated with Venclexta/Venclyxto plus Gazyva/Gazyvaro were blood and lymphatic system disorders, and infections.
These data were presented on Saturday, December 7, 2019 at 08:45 ET in an oral session (Abstract #36).
The pivotal phase III MURANO study evaluated the combination of Venclexta/Venclyxto plus MabThera/Rituxan (rituximab) in relapsed or refractory (R/R) CLL. Four-year, follow-up data from the study showed sustained OS and PFS benefits with Venclexta/Venclyxto plus MabThera/Rituxan compared to bendamustine plus MabThera/Rituxan (BR). No new safety events were reported in the study. Specifically:

Results showed that Venclexta/Venclyxto plus MabThera/Rituxan significantly reduced the risk of disease progression or death by 81% (HR=0.19; 95% CI: 0.14, 0.25; p<0.0001) compared to BR, with four-year PFS estimates of 57.3% (95 % CI: 49.4, 65.3) vs. 4.6% (95% CI: 0.1, 9.2), respectively.
Venclexta/Venclyxto plus MabThera/Rituxan also reduced the risk of death by 59% (HR=0.41; 95% CI: 0.26, 0.65; p<0.0001), compared to BR, with the Venclexta/Venclyxto plus MabThera/Rituxan treatment arm demonstrating greater sustained OS compared to the BR arm, with four-year OS rates of 85.3% vs. 66.8%, respectively.
Venclexta/Venclyxto plus MabThera/Rituxan showed that people who achieved MRD-negativity showed an improvement in PFS at the end of treatment.
No new safety signals were identified with the combination in this extended follow-up. Common grade 3-4 adverse events with Venclexta/Venclyxto plus MabThera/Rituxan compared to BR, respectively, were low white blood cell count (58.8% vs. 39.9%), anaemia (11.3% vs 13.8%) and low platelet count (5.7% vs 10.1%).
Results from the MURANO study were the basis of regulatory approvals for Venclexta/Venclyxto plus MabThera/Rituxan as a treatment option for people with R/R CLL around the world.
These data will be presented in an oral session on Sunday, December 8, 2019 at 07:30 ET (Abstract #355).
Venclexta/Venclyxto is being developed by AbbVie and Roche. It is jointly commercialised by AbbVie and Genentech, a member of the Roche Group, in the US and commercialised by AbbVie outside of the US.

About the CLL14 study
CLL14 (NCT02242942) is a randomised phase III study evaluating the combination of fixed-duration Venclexta/Venclyxto (venetoclax) plus Gazyva/Gazyvaro (obinutuzumab) compared to Gazyva/Gazyvaro plus chlorambucil in patients with previously untreated chronic lymphocytic leukaemia (CLL) and co-existing medical conditions. 432 patients with previously untreated CLL were randomly assigned to receive either a 12-month duration of Venclexta/Venclyxto alongside six-month duration of Gazyva/Gazyvaro (Arm A) or six-month duration of Gazyva/Gazyvaro alongside 12-month duration of chlorambucil (Arm B). Arm A started with an initial dosing of Gazyva/Gazyvaro followed by a five-week Venclexta/Venclyxto dose ramp-up to help reduce the risk of tumour burden. The primary endpoint of the study is investigator-assessed progression-free survival (PFS). Secondary endpoints include PFS assessed by independent review committee, minimal residual disease status, overall response rate, complete response (with or without complete blood count recovery), overall survival, duration of response, event-free survival, time to next CLL treatment, and safety. The CLL14 study is being conducted in cooperation with the German CLL Study Group, headed by Michael Hallek, MD, University of Cologne.

About the MURANO study
MURANO (NCT02005471) is a phase III open-label, international, multicentre, randomised study evaluating the efficacy and safety of fixed duration Venclexta/Venclyxto (venetoclax) in combination with MabThera/Rituxan (rituximab) compared to bendamustine in combination with MabThera/Rituxan (BR). All treatments were of fixed duration. Following a five-week dose ramp-up schedule for Venclexta/Venclyxto, patients on the Venclexta/Venclyxto plus MabThera/Rituxan arm received six cycles of Venclexta/Venclyxto plus MabThera/Rituxan followed by Venclexta/Venclyxto monotherapy for up to two years total. Patients on the BR arm received six cycles of BR. The study included 389 patients with chronic lymphocytic leukaemia, with or without 17p deletion, who had been previously treated with at least one line of therapy. Patients were randomly assigned in a 1:1 ratio to receive either Venclexta/Venclyxto plus MabThera/Rituxan or BR. The primary endpoint of the study was progression-free survival. Secondary endpoints included overall survival, overall response rate and complete response rate (with or without complete blood count recovery).

About chronic lymphocytic leukaemia
Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in the Western world.1 CLL mainly affects men and the median age at diagnosis is about 70 years.2 Worldwide, the incidence of all leukaemias is estimated to be over 400,0003 and CLL is estimated to affect around one-third of all people newly diagnosed with leukaemia.1

About Venclexta/Venclyxto (venetoclax)
Venclexta/Venclyxto is a first-in-class targeted medicine designed to selectively bind and inhibit the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other tumours, BCL-2 builds up and prevents cancer cells from dying or self-destructing, a process called apoptosis. Venclexta/Venclyxto blocks the BCL-2 protein and works to restore the process of apoptosis.

Venclexta/Venclyxto is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialised by the companies in the United States and commercialised by AbbVie outside of the United States. Together, the companies are committed to research with Venclexta/Venclyxto, which is currently being studied in clinical trials across several types of blood and other cancers.

In the United States, Venclexta has been granted five Breakthrough Therapy Designations by the US Food and Drug Administration: one for previously untreated CLL, two for relapsed or refractory CLL and two for previously untreated acute myeloid leukaemia.

About Roche in haematology
Roche has been developing medicines for people with malignant and non-malignant blood diseases for over 20 years; our experience and knowledge in this therapeutic area runs deep. Today, we are investing more than ever in our effort to bring innovative treatment options to patients across a wide range of haematologic diseases. Our approved medicines include MabThera/Rituxan (rituximab), Gazyva/Gazyvaro (obinutuzumab), Polivy (polatuzumab vedotin), Venclexta/Venclyxto (venetoclax) in collaboration with AbbVie, and Hemlibra (emicizumab). Our pipeline of investigational haematology medicines includes idasanutlin, a small molecule which inhibits the interaction of MDM2 with p53; T-cell engaging bispecific antibodies targeting both CD20 and CD3; Tecentriq (atezolizumab), a monoclonal antibody designed to bind with PD-L1; and crovalimab, an anti-C5 antibody engineered to optimise complement inhibition. Our scientific expertise, combined with the breadth of our portfolio and pipeline, also provides a unique opportunity to develop combination regimens that aim to improve the lives of patients even further.

On December 8, 2019 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported long-term data from a post-hoc analysis, further supporting the sustained clinical benefit of fixed duration treatment with VENCLEXTA/VENCLYXTO (venetoclax) in combination with rituximab (VenR) in patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL) (Press release, AbbVie, DEC 8, 2019, View Source [SID1234552045]). The updated data from the Phase 3 MURANO trial four-year analysis (median follow-up of 48 months with all patients off VENCLEXTA/VENCLYXTO treatment for a median of 22 months) showed that patients with R/R CLL who completed the chemotherapy-free, two-year fixed duration course of VENCLEXTA/VENCLYXTO treatment combination maintained progression-free survival (PFS) and overall survival (OS). Patients who completed treatment with the VENCLEXTA/VENCLYXTO combination also achieved higher rates of minimal residual disease (MRD)-negativity and complete remissions compared to those treated with a standard of care, bendamustine plus rituximab (BR).1 The full results were presented today at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (abstract #355).

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"These results support the benefits of a fixed duration of treatment with venetoclax to reduce the risk of disease progression or death in patients with chronic lymphocytic leukemia," said Mohammed Zaki, M.D., Ph.D., vice president, global head of hematology development at AbbVie. "We remain committed to understanding the full utility of venetoclax combinations and to advancing other clinical development programs with the potential to transform the standards of care for patients with blood cancers."

"In the four-year analysis from the MURANO trial, treatment with the venetoclax combination resulted in an 81 percent reduction in the risk of progression or death compared to the standard of care," said Professor John Seymour, MBBS, Ph.D., lead investigator of the MURANO trial and director of the Department of Hematology at the Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Australia. "The sustained efficacy and manageable safety profile observed in the study further support the clinical benefits of fixed treatment in patients with relapsed or refractory chronic lymphocytic leukemia."

In the post-hoc analysis, median follow-up for patients who completed two years of treatment with the venetoclax combination without progressive disease (n=130) was 22 months (range: 1 to 35 months). PFS (HR, 0.19, 95% CI: 0.14, 0.25, descriptive p<0.0001) and OS (HR 0.41, 95% CI: 0.26,0.65, descriptive p<0.0001) remained durable for patients taking VenR compared to those taking BR. Twenty-four months after patients were off therapy, the investigator (INV)-assessed estimated PFS was 57.3% (95% CI 49.4, 65.3) versus estimated PFS of 4.6% (95% CI, 0.1, 9.2) in patients taking BR. Additionally, the OS analysis showed a four-year event-free rate of 85.3% (95% CI: 89.2, 99.0) in the venetoclax arm compared to 66.8% for BR (medians not reached). The improvements in both PFS and OS were observed despite 79% of patients in the control arm receiving an additional targeted CLL treatment after disease progression.1

By the end of treatment, 64% of patients had achieved MRD-negativity, and 87% of those patients remained free of disease progression two years post-treatment.1 MRD-negativity is defined as the presence of less than one CLL cell in 10,000 white blood cells remaining in the blood or bone marrow following treatment. Achieving MRD-negativity was assessed as a secondary endpoint because it is associated with improved clinical outcomes.2 Higher rates of MRD-negativity were observed off treatment in patients taking VenR than in those taking standard of care BR.1

The safety profile of the combination is consistent with the known safety profile of each individual therapy alone. There were no new serious safety issues observed in the MURANO study since the last update. Excluding non-melanoma skin cancer, there was one report of melanoma in the standard of care cohort, and one report of melanoma and one report of breast cancer in the venetoclax combination cohort.1

Venetoclax, a first-in-class oral B-cell lymphoma-2 (BCL-2) inhibitor, is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of Roche Group, in the U.S. and by AbbVie outside the U.S.

Design and Results of the Phase 3 MURANO Trial
A total of 389 patients with R/R CLL who had received at least one prior therapy were enrolled in the international, multicenter, open-label, randomized Phase 3 MURANO trial. The trial was designed to evaluate the efficacy and safety of venetoclax in combination with rituximab (n=194) compared with bendamustine in combination with rituximab (n=195). The median age of patients in the trial was 65 years (range: 22 to 85).3

The primary efficacy endpoint was INV-assessed PFS. At the time of the primary analysis, median PFS with venetoclax in combination with rituximab was not reached compared with 17.0 months for bendamustine in combination with rituximab (HR: 0.17; 95% CI: 0.11, 0.25; p<0.0001). In the primary efficacy analysis, the median follow-up for PFS was 23.8 months (range: 0 to 37.4). Additional efficacy endpoints included independent review committee (IRC)-assessed PFS, INV- and IRC-assessed overall response rate (defined as complete response + complete response with incomplete marrow recovery + partial response + nodular partial response), OS and rates of MRD-negativity.3

About VENCLEXTA/VENCLYXTO (venetoclax)
VENCLEXTA/VENCLYXTO (venetoclax) is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. VENCLEXTA/VENCLYXTO targets the BCL-2 protein and works to help restore the process of apoptosis.

VENCLEXTA/VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers.

VENCLEXTA/VENCLYXTO is approved in more than 50 countries, including the U.S. AbbVie, in collaboration with Roche, is currently working with regulatory agencies around the world to bring this medicine to additional eligible patients in need.

Uses and Important VENCLEXTA (venetoclax) U.S. Safety Information [4]

Uses
VENCLEXTA is a prescription medicine used:

to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) who:
are 75 years of age or older, or
have other medical conditions that prevent the use of standard chemotherapy.
VENCLEXTA was approved based on response rates. Continued approval for this use may depend on the results of an ongoing study to find out how VENCLEXTA works over a longer period of time.

It is not known if VENCLEXTA is safe and effective in children.

Important Safety Information

What is the most important information I should know about VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your healthcare provider will do tests to check your risk of getting TLS before you start taking VENCLEXTA. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with VENCLEXTA.

It is important to keep your appointments for blood tests. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water when taking VENCLEXTA to help reduce your risk of getting TLS. Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Your healthcare provider may delay, decrease your dose, or stop treatment with VENCLEXTA if you have side effects.

Who should not take VENCLEXTA?

Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased TLS.

Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other, causing serious side effects.
Do not start new medicines during treatment with VENCLEXTA without first talking with your health care provider.
Before taking VENCLEXTA, tell your healthcare provider about all of your medical conditions, including if you:

have kidney problems.
have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium.
have a history of high uric acid levels in your blood or gout.
are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during, or after treatment with VENCLEXTA, until your healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your healthcare provider right away.
are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA.
What should I avoid while taking VENCLEXTA?
You should not drink grapefruit juice, or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Low white blood cell counts (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with VENCLEXTA.
Infections. Death and serious infections such as pneumonia and blood infection (sepsis) have happened during treatment with VENCLEXTA. Your healthcare provider will closely monitor and treat you right away if you have a fever or any signs of infection during treatment with VENCLEXTA.
Tell your healthcare provider right away if you have a fever or any signs of an infection during treatment with VENCLEXTA.

The most common side effects of VENCLEXTA when used in combination with obinutuzumab or rituximab or alone in people with CLL or SLL include low white blood cell counts; low platelet counts; low red blood cell counts; diarrhea; nausea; upper respiratory tract infection; cough; muscle and join pain; tiredness; and swelling of your arms, legs, hands, and feet.

The most common side effects of VENCLEXTA in combination with azacitidine, or decitabine, or low-dose cytarabine in people with AML include low white blood cell counts; nausea; diarrhea; low platelet counts; constipation; fever with low white blood cell counts; low red blood cell counts, infection in blood; rash; dizziness; low blood pressure; fever; swelling of your arms, legs, hands, and feet; vomiting; tiredness; shortness of breath; bleeding; infection in lung; stomach (abdominal) pain; pain in muscles or back; cough; and sore throat.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. For more information, ask your healthcare provider or pharmacist.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit View Source or call 1-800-FDA-1088.

If you cannot afford your medication, contact www.medicineassistancetool.org for assistance.

The full U.S. prescribing information, including Medication Guide, for VENCLEXTA can be found here.

Indication and Important VENCLYXTO (venetoclax) EU Safety Information5

Indication
Venclyxto in combination with rituximab is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy.

Venclyxto monotherapy is indicated for the treatment of CLL:

in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor, or
in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.
Contraindications
Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumor lysis syndrome (TLS). Concomitant use of preparations containing St. John’s wort as VENCLYXTO efficacy may be reduced.

Special Warnings & Precautions for Use
Tumor lysis syndrome (TLS), including fatal events, has occurred in patients with previously treated CLL with high tumor burden when treated with VENCLYXTO. VENCLYXTO poses a risk for TLS in the initial 5-week dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLYXTO and at each dose increase. Patients should be assessed for risk and should receive appropriate prophylaxis, monitoring, and management for TLS.

Neutropenia (grade 3 or 4) has been reported and complete blood counts should be monitored throughout the treatment period. Serious infections including events of sepsis with fatal outcome have been reported. Supportive measures including antimicrobials for any signs of infection should be considered.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions
CYP3A inhibitors may increase VENCLYXTO plasma concentrations. At initiation and dose-titration phase: Strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations. At steady daily dose: If moderate or strong CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may decrease VENCLYXTO plasma concentrations. Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions
The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in the combination study with rituximab were neutropenia, diarrhea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhea, nausea, anemia, fatigue, and upper respiratory tract infection.

The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with rituximab or as monotherapy were pneumonia, febrile neutropenia and TLS.

Discontinuation due to adverse reactions occurred in 16% of patients receiving venetoclax plus rituximab and 9% receiving venetoclax monotherapy. Dosage adjustments due to adverse reactions occurred in 15% of patients receiving venetoclax plus rituximab and 2% receiving venetoclax monotherapy. Dose interruptions occurred in 71% of patients treated with the combination of venetoclax and rituximab.

Specific Populations
Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS. Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined. For patients with severe (Child-Pugh C) hepatic impairment, a dose reduction of at least 50% throughout treatment is recommended.

VENCLYXTO may cause embryo-fetal harm when administered to a pregnant woman. Advise nursing women to discontinue breastfeeding during treatment.

This is not a complete summary of all safety information. See VENCLYXTO full summary of product characteristics (SmPC) at www.ema.europa.eu. Globally, prescribing information varies; refer to the individual country product label for complete information.

About AbbVie in Oncology

At AbbVie, we strive to discover and develop medicines that deliver transformational improvements in cancer treatment by uniquely combining our deep knowledge in core areas of biology with cutting-edge technologies, and by working together with our partners – scientists, clinical experts, industry peers, advocates, and patients. We remain focused on delivering these transformative advances in treatment across some of the most debilitating and widespread cancers. We are also committed to exploring solutions to help patients obtain access to our cancer medicines. AbbVie’s oncology portfolio now consists of marketed medicines and a pipeline containing multiple new molecules being evaluated worldwide in more than 300 clinical trials and more than 20 different tumor types. For more information, please visit View Source

On December 8, 2019 Bristol-Myers Squibb Company (NYSE: BMY) reported data from multiple studies evaluating lisocabtagene maraleucel (liso-cel), an investigational CD19-directed CAR T-cell therapy with a defined composition of purified CD8+ and CD4+ CAR T cells, were presented during the 2019 ASH (Free ASH Whitepaper) Annual Meeting in Orlando, Fla (Press release, Bristol-Myers Squibb, DEC 8, 2019, View Source [SID1234552044]). These studies included an evaluation of liso-cel in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) (TRANSCEND CLL 004); a study in second-line patients with relapsed or refractory large B-cell non-Hodgkin’s lymphoma (NHL) patients who were ineligible for high-dose chemotherapy and hematopoietic stem cell transplant (HSCT) (PILOT); and a separate analysis of patients with relapsed/refractory large B-cell non-Hodgkin lymphoma who received liso-cel in the outpatient setting across three studies.

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"As we continue to evaluate liso-cel in important new disease settings and areas of unmet medical need, we are encouraged to see the early results from these studies," said Stanley Frankel, M.D., Senior Vice President, Cellular Therapy Development for Bristol-Myers Squibb. "The results in relapsed or refractory CLL and SLL demonstrated a high rate of durable complete responses achieved in heavily pre-treated patients, including patients who have failed ibrutinib and venetoclax. We are encouraged by the potential of liso-cel to treat second-line relapsed or refractory large B-cell NHL patients who are not able to undergo a stem cell transplant. Finally, the analysis evaluating liso-cel administered in the outpatient setting demonstrates that not all patients require hospitalization and that the safety and efficacy profile across a variety of types of clinical sites is consistent."

TRANSCEND CLL 004

In the phase 1/2 TRANSCEND CLL 004 study, at the data cutoff, 23 patients with CLL/SLL who had received at least three (standard-risk disease) or two (high-risk disease) prior treatments were evaluable for safety, with 22 patients evaluable for efficacy. Patients had a median of 5 prior lines of therapy (range 2-11). All patients (23/23) had received prior ibrutinib and most (21/23) were refractory to or had relapsed on the BTK inhibitor. There were nine patients (39%) that had failed both a BTK inhibitor (progressed on treatment) and venetoclax (did not achieve a response after at least 3 months). Most patients (83%) had high-risk features including deletion 17p (35%, 8/23) and TP53 mutation (61%, 14/23). Patients received liso-cel target doses of either 50 × 106 (n=9) or 100 × 106 (n=14) CAR+ T cells following lymphodepletion.

Treatment-emergent adverse events (TEAE) of any grade occurred in 100% (23/23) of patients with 96% (22/23) of patients experiencing a grade 3 or higher TEAE. The most common grade 3 or higher TEAEs occurring in at least 25% of patients were anemia (78%, 18/23), thrombocytopenia (70%, 16/23), neutropenia (56.5%, 13/23), leukopenia (43.5%, 10/23), febrile neutropenia (26%, 6/23), lymphopenia (26%, 6/23) and cytokine release syndrome (9%, 2/23).

Seventy-four percent (17/23) of patients had cytokine release syndrome (CRS) of any grade with 9% of patients (2/23) experiencing grade 3 CRS. Thirty-nine percent (9/23) of patients had neurological events (NE) of any grade, while 22% (5/23) of patients had grade 3 or higher NE. Median time to onset of CRS was 4 days (range 1-10 days) and of NE was 4 days (range 2-21). Incidence and severity of CRS and NEs were similar for patients who failed a BTK inhibitor and venetoclax. Seventy-four percent (17/23) of patients received tocilizumab and/or corticosteroids. There were no grade 5 events.

At a median follow-up of 11 months, the overall response rate (ORR) for patients receiving liso-cel was 81.5% (18/22, 95% CI: 59.7 – 94.8) with 45.5% (10/22) of patients achieving a complete response (CR). In patients that had failed a BTK inhibitor and venetoclax, the ORR was 89% (8/9, 95% CI: 51.8 – 99.7) with 67% (6/9) achieving a CR. By day 30 following treatment, 68% (15/22) of patients had achieved an early objective response with 10 of 12 responders at 6 months remaining progression-free after at least 9 months, and eight patients in response at 12 months or longer. Among 20 patients evaluable for minimal residual disease (MRD), the majority achieved undetectable MRD in the blood (75%) and bone marrow (65%) by next-generation sequencing. All patients who achieved undetectable MRD have maintained this status at last follow-up.

PILOT

In the phase 2 PILOT study, patients had relapsed/refractory large B-cell NHL, had received only 1 prior line of immunochemotherapy and had been deemed ineligible for HSCT due to patient factors including age, comorbidities or performance status. Patients received liso-cel at a target dose of 100 × 106 CAR+ T cells following lymphodepletion and could be treated in the outpatient setting at the investigator’s discretion.

At the time of data cutoff, 19 patients had been leukapheresed, with 13 patients receiving lymphodepletion followed by liso-cel.

Of the 13 patients, eight (61.5%) had at least one grade 3 or higher TEAE and these were primarily cytopenias. Four patients (31%) had prolonged grade 3 or higher cytopenias at day 29. No patients had grade 3 or higher CRS and no patients experienced NE of any grade. Grade 1-2 CRS occurred in 3 (23%) patients. There were no grade 5 TEAEs. Finally, of the 6 patients treated in the outpatient setting, none were admitted to the hospital in the first 29 days following liso-cel infusion.

All 12 (100%) patients eligible for response evaluation achieved a response with 6 (50%) patients achieving a CR. Seven of 12 (58%) patients maintained response levels at 3 months following liso-cel infusion.

Outpatient Administration

A report of the safety and efficacy of liso-cel in patients with relapsed/refractory large B-cell NHL treated in the outpatient treatment setting was also presented. The analysis encompassed three studies including OUTREACH (n=13), the only trial evaluating CAR T-cell therapy in an outpatient setting at non-university centers, including treatment sites not accredited by the Foundation for the Accreditation of Cellular Therapy. The analysis also included TRANSCEND NHL 001 (n=25) and PILOT (n=6).

Outpatient treatment required patient education regarding CAR T-cell therapy, a caregiver and proximity to the treatment location. Additionally, each site was required to have specific readiness plans for patient care and monitoring for AEs, such as CRS and NE, in the outpatient setting.

In the analysis, at data cutoff, 44 patients treated in the outpatient setting from across the studies were evaluated and received liso-cel on day 1. Seventeen (39%) patients had CRS of any grade, while 13 (30%) patients had NE (n=13) of any grade. There was 1 case of grade 3 or higher CRS and 2 cases of grade 3 or higher NE and these were reversible. A total of 9 patients received supportive tocilizumab and/or corticosteroids. Fifty-five percent (24/44) of patients required hospitalization at some point and these were all from TRANSCEND or OUTREACH. Of these patients, 9 (20%) were admitted on study day 4 or earlier. Two (5%) patients required intensive care unit-level care lasting a median of 4 days. No patients from PILOT were admitted to hospital in the first 29 days. Following treatment, the median time to hospitalization was 5 days (range 2-22) and the median length of stay was 6.5 days (range 1-23). TEAEs of any grade reported in at least 20% of patients included fatigue, neutropenia, decreased appetite, CRS, anemia, constipation, nausea, headache, cough, dizziness, hypotension, thrombocytopenia, vomiting, back pain, diarrhea hypomagnesemia and tremor.

Across the studies, the ORR was 80% (35/44) with 55% (24/44) of patients achieving a complete response.

Liso-cel is not approved for any indication in any country.

Bristol-Myers Squibb: Advancing Cancer Research

At Bristol-Myers Squibb, patients are at the center of everything we do. The goal of our cancer research is to increase quality, long-term survival and make cure a possibility. We harness our deep scientific experience, cutting-edge technologies and discovery platforms to discover, develop and deliver novel treatments for patients.

Building upon our transformative work and legacy in hematology and Immuno-Oncology that has changed survival expectations for many cancers, our researchers are advancing a deep and diverse pipeline across multiple modalities. In the field of immune cell therapy, this includes registrational chimeric antigen receptor (CAR) T-cell agents for numerous diseases, and a growing early-stage pipeline that expands cell and gene therapy targets, and technologies. We are developing cancer treatments directed at key biological pathways using our protein homeostasis platform, a research capability that has been the basis of our approved therapies for multiple myeloma and several promising compounds in early to mid-stage development. Our scientists are targeting different immune system pathways to address interactions between tumors, the microenvironment and the immune system to further expand upon the progress we have made and help more patients respond to treatment. Combining these approaches is key to delivering new options for the treatment of cancer and addressing the growing issue of resistance to immunotherapy. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines a reality for patients.

About Lisocabtagene Maraleucel (liso-cel)

Liso-cel is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, which is a surface glycoprotein expressed during normal B-cell development and maintained following malignant transformation of B cells. Liso-cel CAR T cells aim to target CD19 expressing cells through a CAR construct that includes an anti-CD19 single-chain variable fragment (scFv) targeting domain for antigen specificity, a transmembrane domain, a 4-1BB costimulatory domain hypothesized to increase T-cell proliferation and persistence, and a CD3-zeta T-cell activation domain. The defined composition of CD4+ and CD8+ CAR T cells in liso-cel may limit product variability; however, the clinical significance of defined composition is unknown.

On December 8, 2019 Eli Lilly and Company (NYSE: LLY) reported interim clinical data from the LOXO-305 global Phase 1/2 BRUIN dose escalation trial. LOXO-305 is an investigational, highly selective, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor (Press release, Eli Lilly, DEC 8, 2019, View Source [SID1234552043]). These data were presented today at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando (abstract 501). At all doses studied, LOXO-305 delivered objective responses in patients who had received diverse prior therapies and had exhibited varied molecular mechanisms of acquired resistance.

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"We are excited to report that LOXO-305 is active in patients resistant and intolerant to covalent BTK inhibitors, as well as in patients resistant to BCL2 inhibition," said Anthony Mato, M.D., director of the CLL Program at Memorial Sloan Kettering Cancer Center and the presenting author. "We observed compelling response rates in both CLL and MCL. Interestingly, we reported responses regardless of C481 status, a putative mechanism of resistance to the covalent BTK class. We saw objective responses in dose cohort 1 and have not identified a maximum tolerated dose. These data suggest that LOXO-305 has the required selectivity profile and human target coverage to maximize the full potential of this molecular target, combine well with other agents, and perhaps, even move to earlier lines of therapy."

"Put simply, LOXO-305 has exceeded our expectations," said Jacob Van Naarden, chief operating officer of Loxo Oncology at Lilly. "LOXO-305’s wide therapeutic index allows us to plan and implement an ambitious comprehensive development program, one that includes combination regimens that exploit the drug’s selectivity profile. We look forward to working closely with global regulators to position LOXO-305 in the most appropriate patient populations. It will be exciting to combine Lilly’s resources and talent with Loxo’s focus and agility for the benefit of this program within Loxo Oncology at Lilly."

Trial Background
The BRUIN Phase 1/2 trial, which began enrolling patients in March 2019, contains a dose escalation phase and a dose expansion phase. The dose escalation phase follows a "3+3" design. LOXO-305 is dosed orally in 28-day cycles. As dose cohorts are cleared, additional patients can enroll in cleared cohorts and intra-patient dose escalation is permitted. The primary endpoint of the trial is the determination of the maximum tolerated dose (MTD) or recommended dose for further study. Secondary endpoints include safety, overall response rate (by disease-specific criteria) and duration of response. The dose expansion phase is designed to further characterize the overall response rate, durability of response, and safety of LOXO-305 in predefined groups of patients with B-cell leukemias and lymphomas.

Key Data Presented at ASH (Free ASH Whitepaper)
The data presented at ASH (Free ASH Whitepaper) were based on patients treated as of September 27, 2019, with follow-up as of November 5, 2019. Twenty-eight total patients had been enrolled to five dose escalation cohorts: 25 mg QD (n=5), 50 mg QD (n=6), 100 mg QD (n=9), 150 mg QD (n=5), and 200 mg QD (n=3). There were 16 patients with CLL, eight patients with MCL, two patients with Waldenstrom macroglobulinemia, one patient with diffuse large B-cell lymphoma (DLBCL), and one patient with marginal zone lymphoma (MZL). The CLL patients had received a median of four prior systemic therapy regimens and 75% had received at least one prior BTK inhibitor. The MCL patients had received a median of three prior systemic therapy regimens and 88% had received at least one prior BTK inhibitor.

Pharmacokinetic analyses during the dose escalation phase demonstrated dose-dependent and linear increases in LOXO-305 exposure with increasing dose. Starting at the 50 mg QD dose, LOXO-305 delivered >IC90 target coverage for wild-type and C481S-mutated BTK, based on estimates from cell-based potencies.

The efficacy data presented at ASH (Free ASH Whitepaper) are based on investigator response assessments. Responses were observed across all dose levels.

Of 16 CLL patients enrolled, there were 10 responders (8 partial responses, 2 partial response with ongoing lymphocytosis) among 13 patients eligible for response assessment, resulting in a 77% ORR. All patients with CLL have demonstrated tumor reduction, with evidence of deepening response over time. Responses were observed in patients with acquired resistance to prior BTK therapy (those with and without C481S mutations), in patients who were intolerant to prior BTK therapy, and in patients with acquired resistance to prior BCL2 therapy (including one with a known BCL G101V mutation). As expected, LOXO-305 treatment causes acute lymphocytosis, which resolves over time—a well described pharmacodynamic response associated with effective BTK inhibition. Of the three CLL patients not yet eligible for response assessment (one with the BTK C481S mutation), all three have demonstrated lymphocytosis early in cycle 1. All CLL responding patients remain in response and all CLL patients remain on study.
Of eight MCL patients enrolled, there were three responses (1 complete response, 2 partial responses) among six patients eligible for response assessment, resulting in a 50% ORR. Two of the responders had progressed on prior BTK therapy (but without a documented C481x mutation). All MCL responding patients remain in response and on study. Three MCL patients discontinued therapy in cycle 1 due to progressive disease.
Most treatment-emergent adverse events were Grade 1 in severity with the most commonly reported events, regardless of attribution, being fatigue (25% total: 21% Grade 1, 4% Grade 2) and diarrhea (18% total: 14% Grade 1, 4% Grade 2). Two adverse events ≥Grade 3 were attributed to LOXO-305 (Grade 3 leukocytosis and Grade 3 transient neutropenia). No dose limiting toxicities were reported and an MTD had not been reached.

About LOXO-305
LOXO-305 is an investigational, highly selective, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation and survival of normal white blood cells, known as B-cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, mantle cell lymphoma and marginal zone lymphoma. Currently available BTK inhibitors irreversibly inhibit BTK and the long-term efficacy of these therapies has been limited by acquired resistance, most commonly through BTK C481 mutations, and intolerance, due to off target inhibition of other cellular targets. LOXO-305 was designed to reversibly bind BTK, preserve activity in the presence of the C481 acquired resistance mutations, and avoid off-target kinases that have complicated the development of both covalent and investigational non-covalent BTK inhibitors. Interested patients and physicians can contact the Loxo Oncology Physician and Patient BTK Clinical Trial Hotline at 1-855-LOXO-305 or email [email protected].

About the BRUIN Trial
This first-in-human, global, multi-center Phase 1/2 trial evaluates LOXO-305 as a single agent in patients with previously treated chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or non-Hodgkin’s lymphomas (NHL). The primary objective of the Phase 1 portion of the trial is to determine the maximum tolerated dose or recommended Phase 2 dose. Key secondary objectives include measures of safety, pharmacokinetics, and anti-tumor activity (i.e. Overall Response Rate and Duration of Response, as determined by appropriate histology-specific response criteria). The trial includes a Phase 1 dose escalation phase and a Phase 2 dose expansion phase. The Phase 1 dose escalation enrolls patients with CLL/SLL or NHL who have received at least two prior lines of therapy and have progressed or are intolerant to standard of care. In the Phase 2 dose expansion phase, six cohorts are planned to allow for the characterization of the preliminary anti-tumor activity of LOXO-305: 1) CLL/SLL failed prior BTK inhibitor with BTK C481 mutation; 2) CLL/SLL failed prior BTK inhibitor without BTK C481 mutation; 3) Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL) or marginal zone lymphoma (MZL) failed prior BTK inhibitor with BTK C481 mutation; 4) WM, MCL or MZL failed prior BTK inhibitor without BTK C481 mutation; 5) CLL/SLL, WM, MCL or MZL intolerant to prior BTK inhibitor; 6) CLL/SLL, WM, MCL or MZL failed prior BTK inhibitor with unknown BTK C481 mutation status and other CLL/SLL, WM, CML, MZL or other NHL patients not meeting the definitions of Cohorts 1 through 5.

About Lilly Oncology
For more than 50 years, Lilly has been dedicated to delivering life-changing medicines and support to people living with cancer and those who care for them. Lilly is determined to build on this heritage and continue making life better for all those affected by cancer around the world. To learn more about Lilly’s commitment to people with cancer, please visit www.LillyOncology.com.