On June 11, 2021 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, reported updated data from its ongoing Phase 1/2 open-label, single arm, dose escalation and expansion trial of CA-4948, a novel, small molecule IRAK4 kinase inhibitor, in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) at the European Hematology Association (EHA) (Free EHA Whitepaper) 2021 Virtual Congress (EHA) (Free EHA Whitepaper) (Press release, Curis, JUN 11, 2021, View Source [SID1234583875]).

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"As we have observed increasingly mature sets of data, we continue to be pleased by the steady progression of clinical activity demonstrated by CA-4948 monotherapy in this historically difficult-to-treat late-line population," said James Dentzer, President and Chief Executive Officer of Curis. "We believe these updated data further support the growing body of evidence that CA-4948’s anti-cancer activity continues to deepen the longer patients remain on drug, which is enabled by its safety and durability profile to date. Further, after backfilling patient cohorts and evaluating additional data after the April 30, 2021 cut-off date for today’s presentation, we have concluded 300mg BID is the optimal dose to take into Phase 2 studies."

Mr. Dentzer added, "We are especially pleased with the outcomes seen to date for patients with spliceosome or FLT3 mutations. All three patients with a spliceosome mutation achieved an objective response. The FLT3 patient also achieved an objective response and, after two cycles of CA-4948, the patient’s FLT3 mutation was found to be completely eradicated. While these are early days, and we have a limited set of patient data, we are very encouraged about the potential CA-4948 may have to become a disease-modifying alternative for these late-line patients, where no approved therapies currently exist."

Mr. Dentzer continued, "In addition to the updated clinical data presented today, we are also excited by the preclinical combination synergy data announced, demonstrating that CA-4948 increases anti-cancer activity in AML cell lines resistant to clinically relevant concentrations of azacitidine and venetoclax, as well as synergistic antileukemic activity in combination with venetoclax and azacitidine. We look forward to initiating dosing in the Phase 1/2 combination study of CA-4948 plus azacitidine and CA-4948 plus venetoclax in patients with R/R AML and MDS later this year."

"As a clinician for patients with high-risk MDS or AML, I am acutely aware of the challenges of these diseases and the limitations of existing treatments. I continue to be very encouraged by the data coming out of this study," said Dr. Guillermo Garcia-Manero, Chief of the Section of Myelodysplastic Syndromes within the Department of Leukemia at The University of Texas MD Anderson Cancer Center and a lead investigator in the study. "This is a late-line population, in which patients have few options following repeated treatment failures and as a result, have deeply damaged and dysfunctional marrow, which severely limits their odds of hematologic recovery. Having an effective, non-myelosuppressive drug that does not further damage their already fragile marrow is of critical importance. The fact that some hematologic recovery has been observed and appears to continue while patients remain on therapy is an indication that CA-4948 may have the potential to provide, for the first time, a well-tolerated and clinically active treatment for this subset of heavily diseased patients."

The reported data are from Curis’s ongoing open-label, single arm Phase 1/2 dose escalation 3+3 study of orally administered CA-4948 monotherapy in adult patients with AML or high-risk MDS. A total of 22 patients (11 with high-risk MDS, 11 with AML) were enrolled across dose cohorts of 200 mg BID, 300 mg BID, 400 mg BID, and 500 mg BID. The primary objective of the study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for CA-4948 based on safety and tolerability, dose-limiting toxicities (DLT), and any biologic activity, pharmacokinetic (PK), and pharmacodynamic (PD) findings from the trial population. Additional objectives include characterization of CA-4948’s pharmacokinetic parameters and biomarker correlations.

Key findings from an oral presentation today at EHA (Free EHA Whitepaper) presented by Dr. Garcia-Manero from an April 30, 2021 cutoff in 17 evaluable patients (9 MDS and 8 AML), include:

Bone marrow blast reductions observed at all tested doses in 10 of 12 patients who were evaluable for bone marrow response (elevated blast count at baseline and at least one malignancy assessment following first cycle).
5 objective responses observed included:
1 patient experiencing a full hematologic recovery CR
1 patient with CRi with negative minimal residual disease
1 patient with partial response
2 patients with marrow CRs
3 patients had SF3B1 or U2AF1 spliceosome mutation and all 3 achieved marrow CR or better.
All patients with objective responses also saw signs of hematologic recovery.
Genomic analyses from multiple patients show disease modification by CA-4948:
DNA sequencing demonstrates disease modification with the reduction of cancer-associated variant allele frequency after CA-4948 treatment
RNA sequencing demonstrates disease modification with the reduction of long/short ratio of IRAK4 after CA-4948 treatment
No significant myeloid suppressive adverse events were observed.
Key findings from additional information included in today’s management’s KOL presentation:

An AML patient with spliceosome mutation SF3B1 who has experienced a durable objective response has been on study for over 8 months. In December 2020, this patient was reported as having a Marrow CR and has since improved to a CRi with negative minimal residual disease.
An AML patient with a FLT3 mutation, whose disease had relapsed after prior treatment with decitabine and venetoclax and was refractory to subsequent treatment with gilteritinib, experienced a partial response (90% decrease in marrow blast count, from 60% to 6%) as well as elimination of detectable FLT3 mutation based on genomic analysis post-treatment with CA-4948.
An AML patient with 4 prior lines of chemotherapy treatment showed reduction of IRAK4-L expression following CA-4948 treatment as well as a full recovery of hematologic parameters and has been on study for over 7 months.
Key findings in determining 300mg BID to be the Recommended Phase 2 Dose include:

Safety: No DLTs observed
PK/PD: PK exposure correlates with 98% target inhibition
Efficacy: 12 evaluable patients in the study had elevated blasts at baseline;
4 of these patients were dosed at 300mg BID;
All 4 patients achieved blast reductions, including CRi and negative MRD
Including additional patients enrolled after the April 30, 2021 cut-off at doses higher than the Recommended Phase 2 Dose, a total of 4 DLTs were observed:
400mg: 13% of patients experienced DLT (2 Grade 3 rhabdomyolysis)
500mg: 66% of patients experienced DLT (1 Grade 3 rhabdomyolysis and 1 Grade 3 syncope)
All three rhabdomyolysis cases were quickly detected by elevated CPK and resolved after dosing interruption; no cases involved renal dysfunction.
Key findings from a poster presentation today at EHA (Free EHA Whitepaper) of preclinical data in AML cell lines:

Combination with CA-4948 increased the antitumor effect of azacitidine
Combination with CA-4948 increased the antitumor effect of venetoclax
Combination with CA-4948 increased the antitumor effect of venetoclax + azacitidine
We believe synergistic activity observed in leukemia cells provides a rationale for clinical testing of CA-4948 + azacitidine, CA-4948 + venetoclax, and the triplet combination of all three agents together in patients with AML.
Webcast Event Information

Curis management will host a virtual KOL event today, June 11, 2021 at 8:00 am ET to discuss these results with Dr. Guillermo Garcia-Manero. To access the webcast, please visit the Events & Presentations section of the Curis website at www.curis.com.

About CA-4948

CA-4948 is an IRAK4 kinase inhibitor and IRAK4 plays an essential role in the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways, which are frequently dysregulated in patients with AML and MDS. Third parties have recently discovered that the long form of IRAK4 (IRAK4-L) is oncogenic and preferentially expressed in over half of patients with AML and MDS. The overexpression of IRAK4-L is believed to be driven by a variety of factors, including specific spliceosome mutations such as SF3B1 and U2AF1.

On June 11, 2021 Celyad Oncology SA (Euronext & Nasdaq: CYAD), a clinical-stage biotechnology company focused on the discovery and development of chimeric antigen receptor T cell (CAR T) therapies for cancer, reported preliminary data from the Phase 1 IMMUNICY-1 trial of CYAD-211 for the treatment of relapsed/refractory multiple myeloma (r/r MM) patients were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2021 Virtual Congress (Press release, Celyad, JUN 11, 2021, View Source [SID1234583874]).

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Filippo Petti, Chief Executive Officer of Celyad Oncology, commented, "We believe the initial data presented today are meaningful beyond the demonstrated clinical activity of CYAD-211. This is the first clinical trial evaluating the potential of shRNA as an allogeneic technology to underpin off-the-shelf CAR T candidates for the treatment of cancer, and today’s data continue to demonstrate the potential value of non-gene edited technology to generate allogeneic CAR T cells. We are extremely encouraged by the cell kinetic, clinical activity and tolerability data for CYAD-211. As we work to establish shRNA as a platform for developing allogeneic CAR T therapies, these early data from the IMMUNICY-1 trial are key. In addition, we believe our future ability to employ multiple shRNAs in our CAR T candidates while leveraging our streamlined All-in-One Vector approach could be fundamental to the allogeneic CAR T landscape."

Dr. Sébastien Anguille, IMMUNICY-1 trial investigator and professor in the Division of Hematology of the Antwerp University Hospital said, "Even with great strides made in recent years, multiple myeloma remains largely incurable, creating a need for new therapeutic options. Unfortunately, most patients eventually relapse and we observe shorter duration and depth of responses to treatments over time. We are pleased with the encouraging initial data from the IMMUNICY-1 trial and we’re eager to move forward with higher doses and continue to evaluate CYAD-211 in treating myeloma patients."

CYAD-211 and IMMUNICY-1 Phase 1 Trial Update

Background:

CYAD-211 is an allogeneic CAR T candidate engineered to co-express a BCMA targeting chimeric antigen receptor and a single short hairpin RNA (shRNA), which interferes with the expression of the CD3ζ component of the T cell receptor complex.
IMMUNICY-1 is a first-in-human, open-label, dose-escalation Phase 1 trial to determine the recommended dose of CYAD-211 in patients with r/r MM following preconditioning with cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²) given three consecutive days.
The trial is designed to evaluate proof-of-concept that shRNA-mediated knockdown of the CD3ζ can generate allogeneic CAR T cells.
Safety and tolerability data:

Of the six patients dosed at the first two dose levels (30×106 and 100×106 cells per infusion):

No dose limiting toxicity (DLT), Graft-versus Host disease (GvHD) or CAR T-cell-related encephalopathy syndrome (CRES) were observed in the first two dose cohorts.
One cytokine release syndrome (CRS) Grade 1 (fever) requiring hospitalization occurred 10 days post CYAD-211 administration in patient 1 (dose level 1) who achieved a partial response (PR).
One patient experienced an anemia adverse event (Grade 3) and neutropenia (Grade 4) possibly related to CYAD-211.
Clinical activity:

Of the five evaluable patients at the first two dose levels (30×106 and 100×106 cells per infusion):

Two patients achieved a PR. Both patients were ‘triple-therapy exposed’ (previously treated with an immunomodulator (IMiD), a proteasome inhibitor and an anti-CD38 antibody).
The three additional patients had stable disease (SD).
Cell kinetics:

CYAD-211 cells were detected by PCR-based methods in all six patients from dose cohorts 1 and 2.
Cell engraftment was seen in all three patients at dose level 2 at a similar magnitude. In addition, preliminary data suggest that all patients in dose level 2 showed deep lymphodepletion. Across dose level 1, the depth of lymphodepletion appears to correlate with the degree of observed systemic CAR T engraftment.
Next steps:

Enrollment in dose cohort 3 (300×106 cells per infusion) is ongoing.
Additional clinical data from the dose escalation trial are expected during second half 2021.
shRNA technology platform to be highlighted at upcoming virtual R&D Day in Q3 2021.
Conference Call and Webcast Details

Celyad Oncology will host a conference call to discuss the update from EHA (Free EHA Whitepaper) on Friday, June 11, 2021 at 2 p.m. CET / 8 a.m. ET. The conference call can be accessed through the following numbers:

United States: #1 877-407-9208

International: #1 201-493-6784

The conference call will be webcast live and can be accessed here. The event will also be archived and available on the "Events " section of the company’s website. Please visit the website several minutes prior to the start of the broadcast to ensure adequate time for registration to the webcast.

On June 11, 2021 BerGenBio ASA (OSE:BGBIO), BerGenBio ASA (OSE: BGBIO), a clinical-stage biopharmaceutical company developing novel, selective AXL kinase inhibitors for severe unmet medical need, reported that it will present updated preliminary survival data from the ongoing Phase II study of bemcentinib (BGBC003) in combination with low dose cytarabine (LDAC) in elderly relapsed Acute Myeloid Leukaemia (AML) patients at the European Haematology Association (EHA) (Free EHA Whitepaper) 2021 Virtual Meeting, taking place from 9-17 June 2021 (Press release, BerGenBio, JUN 11, 2021, View Source [SID1234583872]).

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An update will be provided from an expansion cohort of 27 relapsed/refractory AML patients, who were assessed to explore safety and efficacy together with translational analysis.

The data indicate that the combination of bemcentinib, a once-daily oral AXL-inhibitor and LDAC is efficacious and well tolerated in the elderly and unfit relapsed AML population. Durable responses were observed in the relapsed AML setting, with an overall response rate of 31% (5/16) and median overall survival of 13.3 months, currently still immature and potentially subject to change.

In a subset of eleven relapsed AML patients, who received two or more cycles of the combination, an increased clinical benefit was demonstrated; a CR/CRi rate of 36% (4/11) was observed, coupled with encouraging overall survival to date (median OS not reached at >16 months) with several subjects continuing on the study. In contrast, historic controls of LDAC monotherapy suggest CR/CRi rates of 13-17% with median survival rates of 4.1-5.6 months, as reported by Sarkozy et al. (2015) and Wei et al. (2020).

An in-depth translational research program to identify predictive molecular and biological factors associated with response is ongoing.

Ongoing dialogue continues with the FDA and EMA regulatory agencies to align on a pathway for a pivotal registration trial for the combination of bemcentinib and LDAC in relapsed elderly AML patients unfit for intensive chemotherapy.

Dr. Sonja Loges, Principal Investigator of the trial, commented: "We were impressed to see these positive responses in relapsed AML patients, for whom treatment options are very limited under the current standard of care. Interestingly, the first complete responses were reported at a relatively late stage in the trial, between week 13 and 15. These later onset responses could reflect the importance of AXL mechanisms in disease development as well as the potential immune promoting benefits of bemcentinib treatment. Further clinical investigation of this promising combination is therefore warranted."

Richard Godfrey, CEO of BerGenBio, commented: "We are very encouraged by this promising preliminary response and survival data from the combination of bemcentinib and LDAC in this patient population. Effective treatments with meaningful survival benefit for relapsed AML patients is acknowledged as a critical unmet medical need, this being a significant and rapidly growing patient population as the first line treatment options improve. We continue to work closely with the regulators in Europe and the US to align on the way forward to embark on late-stage pivotal trial of bemcentinib in this combination and patient population."

The e-poster presentations are now available to watch online for registered attendees here: View Source

Details of the e-poster presentation are below:

E-poster title: The combination of AXL inhibitor bemcentinib and low-dose cytarabine is well tolerated and efficacious in elderly relapsed AML patients: Update from the ongoing BGBC003 Phase II trial (NCT02488408)

Session: 04. Acute Myeloid Leukaemia – Clinical

Abstract Number: EHA (Free EHA Whitepaper)-2859

Date/Time: Friday, June 11, 2021 at 9:00 AM (CEST)

About AXL

AXL kinase is a cell membrane receptor and an essential mediator of the biological mechanisms underlying life-threatening diseases.

In COVID-19, AXL has two synergistic mechanisms of action, it acts a co-receptor to ACE2, to which the spike protein of the SARS-CoV-2 virus attaches and enters the host cell, and AXL expression is upregulated that leads to suppression of the Type 1 Interferon immune response by host cells and in their environment.

Research data confirms bemcentinib inhibits SARS-CoV-2 host cell entry and promotes the anti-viral Type I interferon response. Data from a Phase II in human clinical trial has shown that treatment with AXL inhibitor bemcentinib increased the rate ventilator free survival in hospitalised COVID-19 patients.

In cancer, increase in AXL expression has been linked to key mechanisms of drug resistance and immune escape by tumour cells, leading to aggressive metastatic cancers. AXL suppresses the body’s immune response to tumours and drives treatment failure across many cancers. High AXL expression defines a very poor prognosis subgroup in most cancers. AXL inhibitors, such as bemcentinib, therefore, have potential high value as monotherapy and as the cornerstone of cancer combination therapy, addressing significant unmet medical needs and multiple high-value market opportunities. Research has also shown that AXL mediates other aggressive diseases including fibrosis.

About Bemcentinib

Bemcentinib (formerly known as BGB324), is a potential first-in-class, potent and highly selective AXL inhibitor, currently in a broad phase II clinical development programme. It is administered as an oral capsule and taken once per day. Ongoing clinical trials are investigating bemcentinib in COVID-19, and multiple solid and haematological tumours, in combination with current and emerging therapies (including immunotherapies, targeted therapies and chemotherapy), and as a single agent. Bemcentinib targets and binds to the intracellular catalytic kinase domain of AXL receptor tyrosine kinase and inhibits its activity.

On June 11, 2021 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a global biotechnology company focused on developing and commercializing innovative medicines worldwide, reported long-term follow-up results from three pivotal trials in its hematology program at the 26th European Hematology Association (EHA) (Free EHA Whitepaper) 2021 (EHA2021) Virtual Congress, including a pivotal Phase 2 trial of its anti-PD-1 antibody tislelizumab in relapsed or refractory (R/R) classical Hodgkin’s lymphoma (cHL) in an oral presentation, and two pivotal Phase 2 trials of its BTK inhibitor BRUKINSA (zanubrutinib) in R/R mantle cell lymphoma (MCL) and in R/R chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in poster presentations (Press release, BeiGene, JUN 11, 2021, View Source [SID1234583866]).

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"We are excited to see the long-term clinical benefits tislelizumab and BRUKINSA provided for patients in these pivotal trials, which supported the approvals in the relapsed or refractory setting of cHL and CLL or SLL in China, and MCL in both the U.S. and China," said Jane Huang, M.D., Chief Medical Officer, Hematology at BeiGene. "With additional treatment exposure, tislelizumab achieved a higher complete response rate with no new safety signals identified, and the deep responses translated to impressive progression-free survival outcomes. And in the two BRUKINSA trials, our selective next-generation BTK inhibitor showed sustained deep responses and remained well-tolerated in these patients. As BeiGene continues to expand our global footprint, we plan to work to bring these important therapies to more patients in need."

Long-Term Follow-up Results of Tislelizumab in R/R cHL

Oral presentation; Abstract code: S207

The 34-month follow-up results from the single-arm, multicenter, pivotal Phase 2 trial (NCT03209973) demonstrated that tislelizumab was active and generally well-tolerated as a treatment for patients with R/R cHL. Results from this pivotal Phase 2 trial supported the conditional approval of tislelizumab for the treatment of patients with cHL who received at least two prior therapies in China in December 2019.

"Despite the progress made by previous checkpoint inhibitors in R/R cHL treatment, only a minority of patients can achieve a CR," said Yuqin Song, M.D., Ph.D., chief physician and deputy director of the Lymphoma Department at Beijing Cancer Hospital and a principal investigator of the trial. "As demonstrated in the 34-month follow-up results, tislelizumab achieved deep, durable, and consistent responses in these patients regardless of subgroup characteristics, and nearly 70% of patients reached complete remission. We are hopeful that this NMPA-approved immunotherapy can bring continued clinical benefits to patients with R/R cHL in China."

With a median follow-up time of 34 months, tislelizumab demonstrated deep and durable responses in patients with R/R cHL across all patient subgroups. The IRC-assessed overall response rate (ORR) was 87.1% (95% CI: 77.0, 93.9) and the complete response (CR) rate was 67.1% (95% CI: 54.9, 77.9). The median progression-free survival (PFS) was 31.5 months (95% CI: 16.53, not estimable [NE]), and the PFS rate at 24 months and 36 months was 55.4% (95% CI: 42.2, 66.8) and 40.8% (95% CI: 25.2, 55.8), respectively. The median overall survival (OS) was not reached, and the OS rate at 24 months and 36 months was 93.9% (95% CI: 84.5, 97.7) and 84.8% (95% CI: 70.5, 92.6), respectively.

Tislelizumab remained generally well-tolerated with long-term exposure. Most adverse events were Grade 1-2 and no new safety signals were identified. Treatment-emergent adverse events (TEAEs) of any grade were reported in 97.1% of patients, and Grade ≥3 TEAEs occurred in 41.4% of patients. Treatment discontinuation due to TEAEs occurred in 8.6% of patients.

Long-Term Follow-up Results of BRUKINSA in R/R MCL

Poster; Abstract code: EP789

The 35-month follow-up results from the single-arm, open-label, multicenter pivotal Phase 2 trial (NCT03206970) demonstrated BRUKINSA’s long-term benefit and tolerability for patients with R/R MCL. Results from this pivotal Phase 2 trial were part of the data package that supported the accelerated approval of BRUKINSA in this indication in the U.S. in November 2019 and the conditional approval in China in June 2020.

"With nearly three years of patient follow-up, BRUKINSA sustained a high response rate in patients with R/R MCL, and the safety profile remained largely unchanged with longer treatment exposure," said Yuqin Song, M.D., Ph.D., chief physician and deputy director of the Lymphoma Department at Beijing Cancer Hospital and a principal investigator of the trial. "We hope these encouraging results will further establish this highly selective BTK inhibitor as a preferred treatment for patients with R/R MCL in the approved geographies."

With a median follow-up time of 35.3 months and a median duration of exposure of 27.6 months, BRUKINSA demonstrated high, deep, and sustained efficacy in patients with R/R MCL, and responses were generally consistent across patient subgroups. The investigator-assessed ORR was 83.7% (95% CI: 74.2, 90.8), including 67 patients who achieved a CR (77.9%). The median PFS was 33.0 months (95% CI: 19.4, NE) and the estimated 36-month PFS rate was 47.6% (95% CI: 36.2, 58.1).

In long-term follow-up, the safety profile of BRUKINSA largely remained the same. Most adverse events occurred during the early stage of BRUKINSA treatment, with no additional dose reduction, treatment discontinuation, or death due to TEAEs. Grade ≥3 TEAEs occurred in 50.0% of patients.

Long-Term Follow-up Results of BRUKINSA in R/R CLL or SLL

Poster; Abstract code: EP639

Based on the 34-month follow-up results from the single-arm, open-label, multicenter pivotal Phase 2 trial (NCT03206918), BRUKINSA continued to demonstrate deep and durable responses in patients with R/R CLL, regardless of subgroup characteristics, and was well-tolerated with no new safety signals identified. Results from this pivotal Phase 2 trial supported the conditional approval of BRUKINSA in China in June 2020 for the treatment of adult patients with CLL or SLL who have received at least one prior therapy.

"With an additional 19-month follow-up time, BRUKINSA continued to demonstrate promising efficacy and tolerability, as deeper responses were observed in more patients and no new safety signals were identified," Wei Xu, M.D., Ph.D., professor at the First Affiliated Hospital of Nanjing Medical University and a principal investigator of the trial. "High-risk patients with del (11q), del (17p), and/or TP53 mutation were also able to achieve deep and durable responses, and PFS among patients with a prolonged PR-L was on par with patients who achieved a CR or PR."

After a median follow-up time of 34 months, responses to BRUKINSA increased and deepened over time and were consistent across all subgroups. The IRC-assessed ORR was 87.9%, including six patients who achieved a CR (6.6%), 63 patients who achieved a PR (69.2%), and 11 patients who achieved a PR with lymphocytosis (PR-L; 12.1%).

With a longer follow-up, BRUKINSA continued to be generally well-tolerated in patients with R/R CLL, similar to the previously reported data, with no new safety signals identified. TEAEs of any grade were reported in all patients (100%), and Grade ≥3 TEAEs occurred in 83.5% of patients. Treatment discontinuation due to TEAEs occurred in 15.4% of patients and fatal TEAEs occurred in 6.6% of patients.

To learn more about BeiGene’s research and development and activities around EHA (Free EHA Whitepaper)2021, please visit View Source

BeiGene EHA (Free EHA Whitepaper)2021 Investor Conference Call and Webcast Information

BeiGene will host an investor and analyst conference call and webcast to discuss results from the interim analysis of the ALPINE trial, other data presented at EHA (Free EHA Whitepaper)2021, and the BRUKINSA clinical program, today Friday, June 11, at 12:00 p.m. (noon) ET (18:00 CEST).

A live webcast of the conference call can be accessed from the investors section of BeiGene’s website at View Source or View Source An archived replay will be available two hours after the event for 90 days.

About Tislelizumab

Tislelizumab (BGB-A317) is a 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 from BeiGene’s immuno-oncology biologics program and is being developed internationally as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers.

The China National Medical Products Administration (NMPA) has granted tislelizumab approval in three indications, including full approval for first-line treatment of patients with advanced squamous non-small cell lung cancer (NSCLC) in combination with chemotherapy; and conditional approval for the treatment of patients with classical Hodgkin’s lymphoma (cHL) who received at least two prior therapies and for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) with PD-L1 high expression whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Full approval for these indications is contingent upon results from ongoing randomized, controlled confirmatory clinical trials.

In addition, four supplemental Biologics License Applications for tislelizumab have been accepted by the Center for Drug Evaluation (CDE) of the NMPA and are under review for first-line treatment of patients with advanced non-squamous NSCLC in combination with chemotherapy, for second- or third-line treatment of patients with locally advanced or metastatic NSCLC who progressed on prior platinum-based chemotherapy, for patients with previously treated unresectable hepatocellular carcinoma, and for the treatment of patients with previously treated, locally advanced unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors.

BeiGene has initiated or completed 17 potentially registration-enabling clinical trials in China and globally, including 13 Phase 3 trials and four pivotal Phase 2 trials.

In January 2021, BeiGene and Novartis entered into a collaboration and license agreement granting Novartis rights to develop, manufacture, and commercialize tislelizumab in North America, Europe, and Japan.

Tislelizumab is not approved for use outside of China.

About BRUKINSA

BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by BeiGene scientists that is currently being evaluated globally in a broad clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. Because new BTK is continuously synthesized, BRUKINSA was specifically designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared to other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease relevant tissues.

BRUKINSA is approved in the following indications and regions:

For the treatment of mantle cell lymphoma (MCL) in adult patients who have received at least one prior therapy (United States, November 2019)*;
For the treatment of MCL in adult patients who have received at least one prior therapy (China, June 2020)**;
For the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) in adult patients who have received at least one prior therapy (China, June 2020)**;
For the treatment of relapsed or refractory MCL (United Arab Emirates, February 2021); and
For the treatment of Waldenström’s macroglobulinemia (WM) in adult patients (Canada, March 2021).
To-date, more than 30 marketing authorization applications in multiple indications have been submitted outside of the United States and China, covering countries in the European Union and more than 20 other countries.

* This indication was 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.

** This indication was approved under conditional approval. Complete approval for this indication may be contingent upon results from ongoing randomized, controlled confirmatory clinical trials.

IMPORTANT U.S. 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%).

Of the 118 patients with MCL treated with BRUKINSA, 8 (7%) patients discontinued treatment due to adverse reactions in the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumonia (3.4%). One (0.8%) patient experienced an adverse reaction leading to dose reduction (hepatitis B).

Drug Interactions

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

CYP3A Inducers: Avoid co-administration 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 U.S. Prescribing Information at www.beigene.com/PDF/BRUKINSAUSPI.pdf and Patient Information at www.beigene.com/PDF/BRUKINSAUSPPI.pdf.

BeiGene Oncology

BeiGene is committed to advancing best and first-in-class clinical candidates internally or with like-minded partners to develop impactful and affordable medicines for patients across the globe. We have a growing R&D team of approximately 2,300 colleagues dedicated to advancing more than 90 clinical trials involving more than 13,000 patients and healthy volunteers. Our expansive portfolio is directed by a predominantly internalized clinical development team supporting trials in more than 40 countries. Hematology-oncology and solid tumor targeted therapies and immuno-oncology are key focus areas for the Company, with both mono- and combination therapies prioritized in our research and development. The Company currently markets three medicines discovered and developed in our labs: BTK inhibitor BRUKINSA in the United States, China, Canada, and additional international markets; and non-FC-gamma receptor binding anti-PD-1 antibody tislelizumab and PARP inhibitor pamiparib in China.

BeiGene also partners with innovative companies who share our goal of developing therapies to address global health needs. We commercialize a range of oncology medicines in China licensed from Amgen and Bristol Myers Squibb. We also plan to address greater areas of unmet need globally through our collaborations including with Amgen, Bio-Thera, EUSA Pharma, Mirati Therapeutics, Seagen, and Zymeworks. BeiGene has also entered into a collaboration with Novartis granting Novartis rights to develop, manufacture, and commercialize tislelizumab in North America, Europe, and Japan.

On June 11, 2021 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a global biotechnology company focused on developing and commercializing innovative medicines worldwide, reported results from the interim analysis of the Phase 3 ALPINE trial comparing its BTK inhibitor BRUKINSA (zanubrutinib) to ibrutinib in adult patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), including superiority in the primary endpoint of investigator-assessed overall response rate (ORR) and superiority in a key secondary endpoint of atrial fibrillation or flutter (Press release, BeiGene, JUN 11, 2021, View Source [SID1234583865]).

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These results were reported in an oral presentation as part of the Presidential Symposium and featured during the congress press briefing at the 26th European Hematology Association (EHA) (Free EHA Whitepaper) 2021 (EHA2021) Virtual Congress, taking place virtually on June 9-17, 2021.

"While ibrutinib has transformed the outlook for patients with chronic lymphocytic leukemia, or CLL, not all patients respond to treatment and toxicities associated with prolonged exposure remain an issue," commented Peter Hillmen, MBChB, Ph.D., Professor of Experimental Haematology at University of Leeds and principal investigator of the ALPINE trial. "The ALPINE trial is the only head-to-head study in CLL to demonstrate an efficacy advantage for a more selective BTK inhibitor over ibrutinib. Compared to ibrutinib, BRUKINSA demonstrated superiority in investigator-assessed overall response rate in patients with relapsed or refractory CLL. Additionally, the event rate of atrial fibrillation or flutter, an important indicator of cardiac toxicity, was also significantly lower with BRUKINSA."

"The positive data from the interim analysis of the ALPINE trial, including a superior overall response rate by investigator assessment, supportive initial data in progression-free survival and overall survival, and a significantly lower rate of atrial fibrillation of any grade, reinforce our belief that the differentiated profile of BRUKINSA can provide clinical benefits for patients with CLL," said Jane Huang, M.D., Chief Medical Officer, Hematology at BeiGene. "As evidenced in ALPINE and ASPEN, our head-to-head trials of BRUKINSA against the first-generation BTK inhibitor ibrutinib, this potentially best-in-class molecule can provide meaningful responses and consistent safety advantages for these patients. In addition to ALPINE, we are evaluating BRUKINSA in the Phase 3 SEQUOIA trial in treatment-naïve CLL, and expect to share topline results as early as later this year."

Interim Analysis of the ALPINE Trial Comparing BRUKINSA to Ibrutinib in R/R CLL

Oral presentation; Abstract code: LB1900

Results from the planned interim analysis presented at EHA (Free EHA Whitepaper) were based on the first 415 patients enrolled in the ALPINE trial, including 207 on BRUKINSA treatment and 208 on ibrutinib treatment.

In the interim analysis, with a median follow-up time of 15.3 months, the trial met the primary endpoint with BRUKINSA demonstrating superiority in ORR, defined as the combined rate of complete responses (CRs) and partial responses (PRs), per investigator assessment. In the ORR analysis conducted by independent review committee (IRC), BRUKINSA demonstrated non-inferiority in the interim analysis. Efficacy results included:

As assessed by investigator, BRUKINSA achieved an ORR of 78.3% (95% CI: 72.0, 83.7), a statistically significant improvement compared to 62.5% (95% CI: 55.5, 69.1) with ibrutinib (p=0.0006);
As assessed by IRC, BRUKINSA achieved an ORR of 76.3%, numerically higher but not statistically significant compared to 64.4% with ibrutinib (p=0.0121 compared to the pre-specified stringent statistical boundary of p<0.0099 set for the interim analysis);
In patients whose tumor exhibited chromosome 17p deletion (del[17p]), the ORR was 83.3% in the BRUKINSA arm, compared to 53.8% in the ibrutinib arm, as assessed by investigator;
PFS data were early at the time of interim analysis and formal analysis will be performed when the target number of events is reached. The PFS rate at 12 months was 94.9% in the BRUKINSA arm, compared to 84.0% in the ibrutinib arm (descriptive p=0.0007; descriptive hazard ratio [HR]=0.40 [95% CI: 0.23, 0.69]), as assessed by investigator; and
OS data were early at the time of interim analysis. The OS rate at 12 months was 97.0% in the BRUKINSA arm, compared to 92.7% in the ibrutinib arm (descriptive p=0.1081; descriptive HR=0.54 [95% CI: 0.25, 1.16]).
In the interim analysis, the ALPINE trial also met a pre-specified key secondary endpoint related to safety, with BRUKINSA demonstrating a statistically significant lower risk of atrial fibrillation or flutter and advantages in the overall cardiac safety profile, compared to ibrutinib. Treatment discontinuation was more common in the ibrutinib arm. Safety results included:

195 patients (95.6%) in the BRUKINSA arm experienced at least one adverse event (AE) of any grade, compared to 205 patients (99.0%) in the ibrutinib arm, and the most common (≥10%) AEs included anemia (BRUKINSA vs. ibrutinib: 13.2% vs. 15.0%), arthralgia (9.3% vs. 14.0%), contusion (10.3% vs. 8.7%), cough (12.7% vs. 6.3%), diarrhea (16.7% vs. 19.3%), hypertension (15.7% vs. 13.0%), muscle spasm (2.9% vs. 11.1%), neutropenia (19.6% vs. 15.5%), upper respiratory tract infection (21.6% vs. 14.0%), and urinary tract infection (10.8% vs. 8.2%);
114 patients (55.9%) in the BRUKINSA arm experienced Grade ≥3 AEs, compared to 106 patients (51.2%) in the ibrutinib arm;
56 patients (27.5%) in the BRUKINSA arm experienced serious AEs, compared to 67 patients (32.4%) in the ibrutinib arm;
Dose reduction and interruption due to AEs occurred in 23 patients (11.3%) and 81 patients (39.7%) in the BRUKINSA arm, respectively, compared to 25 patients (12.1%) and 84 patients (40.6%) in the ibrutinib arm;
16 patients (7.8%) discontinued BRUKINSA treatment due to AEs, with none caused by cardiac disorders; in comparison, 27 patients (13.0%) discontinued ibrutinib treatment due to AEs, with seven caused by cardiac disorders, including two of atrial fibrillation, and one each of cardiac arrest, cardiac failure, myocardial infarction, palpitations, and ventricular fibrillation;
Fatal AEs were reported in eight patients (3.9%) in the BRUKINSA arm, compared to 12 patients (5.8%) in the ibrutinib arm;
A key secondary endpoint of atrial fibrillation or flutter of any grade occurred in five patients (2.5%) in the BRUKINSA arm, significantly lower than the 21 patients (10.1%) in the ibrutinib arm (p=0.0014);
Grade ≥3 atrial fibrillation or flutter occurred in two patients (1.0%) in the BRUKINSA arm, compared to four patients (1.9%) in the ibrutinib arm;
Additional AEs of special interest of any grade included cardiac disorders (BRUKINSA vs. ibrutinib: 13.7% vs. 25.1%), hemorrhage (35.8% vs. 36.2%), major hemorrhage (2.9% vs. 3.9%), hypertension (16.7% vs. 16.4%), infections (59.8% vs. 63.3%), neutropenia (28.4% vs. 21.7%), secondary primary malignancies (8.3% vs. 6.3%), skin cancers (3.4% vs. 4.8%), and thrombocytopenia (9.3% vs. 12.6%); and
Grade ≥3 AEs of special interest included cardiac disorders (BRUKINSA vs. ibrutinib: 2.5% vs. 6.8%), hemorrhage (2.9% vs. 2.9%), major hemorrhage (2.9% vs. 2.9%), hypertension (10.8% vs. 10.6%), infections (12.7% vs. 17.9%), neutropenia (18.6% vs. 15.0%), secondary primary malignancies (4.9% vs. 1.9%), skin cancers (1.5% vs. 1.0%), and thrombocytopenia (3.4% vs. 3.4%).
Summary of ALPINE Interim Results

ALPINE
Summary

BRUKINSA
(n=207)

Ibrutinib
(n=208)

Efficacy Results

Investigator-
Assessed ORR
(Primary Endpoint)

78.3%
(95% CI: 72.0, 83.7)

62.5%
(95% CI: 55.5, 69.1)

p=0.0006

IRC-Assessed ORR

76.3%

64.4%

p=0.0121 compared to the pre-specified stringent
statistical boundary of p<0.0099

ORR in del(17p)

83.3%

53.8%

12-Month PFS Rate*

94.9%

84.0%

descriptive p=0.0007;
descriptive HR=0.40 (95% CI: 0.23, 0.69)

* PFS data were early at the time of interim analysis and formal analysis will be performed when the target number of events is reached.

Overall Safety Results

AEs of any grade

95.6%

99.0%

Grade ≥3 AEs

55.9%

51.2%

Serious AEs

27.5%

32.4%

AEs leading to treatment discontinuation

7.8%

13.0%

Fatal AEs

3.9%

5.8%

Adverse Events of Special Interest (Any Grade)

Atrial Fibrillation
or Flutter
(Key Secondary Endpoint)

2.5%

10.1%

p=0.0014

Cardiac Disorders

13.7%

25.1%

Hemorrhage

35.8%

36.2%

Major Hemorrhage

2.9%

3.9%

Hypertension

16.7%

16.4%

Infections

59.8%

63.3%

Neutropenia

28.4%

21.7%

Secondary Primary Malignancies

8.3%

6.3%

Skin Cancers

3.4%

4.8%

Thrombocytopenia

9.3%

12.6%

To learn more about BeiGene’s research and development and activities around EHA (Free EHA Whitepaper)2021, please visit View Source

BeiGene EHA (Free EHA Whitepaper)2021 Investor Conference Call and Webcast Information

BeiGene will host an investor and analyst conference call and webcast to discuss results from the interim analysis of the ALPINE trial, other data presented at EHA (Free EHA Whitepaper)2021, and the BRUKINSA clinical program, today Friday, June 11, at 12:00 p.m. (noon) ET (18:00 CEST).

A live webcast of the conference call can be accessed from the investors section of BeiGene’s website at View Source or View Source An archived replay will be available two hours after the event for 90 days.

About Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults, with a global incidence of approximately 114,000 new cases in 2017.1,2 CLL affects white blood cells or lymphocytes in the bone marrow.1 Proliferation of cancer cells (leukemia) in the marrow result in reduced ability to fight infection and spread into the blood, which affects other parts of the body including the lymph nodes, liver and spleen.1,3 The BTK pathway is a known route that signals malignant B cells and contributes to the onset of CLL.4 Small lymphocytic lymphoma (SLL) is a non-Hodgkin’s lymphoma affecting the B-lymphocytes of the immune system, which shares many similarities to CLL but with cancer cells found mostly in lymph nodes.5

About ALPINE

ALPINE is a randomized, global Phase 3 trial (NCT03734016) comparing BRUKINSA against ibrutinib in previously treated patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

In the trial, a total of 652 patients were randomized into two arms, with the first receiving BRUKINSA (160 mg orally twice daily) and the second receiving ibrutinib (420 mg orally once daily) until disease progression or unacceptable toxicity. The primary analysis of overall response rate (ORR), defined by pre-specified non-inferiority of BRUKINSA versus ibrutinib, was assessed by investigator and independent review committee (IRC) using the modified 2008 iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL, and per Lugano Classification for non-Hodgkin’s lymphoma for patients with SLL. There was hierarchical testing of non-inferiority followed by superiority in ORR as assessed by investigator and IRC. Key secondary endpoints include progression-free survival (PFS) and event rate of atrial fibrillation or flutter; other secondary endpoints include duration of response, overall survival, and incidence of adverse events. The study is ongoing, with pre-specified final analysis of ORR superiority by IRC assessment and formal analysis of PFS when the target number of events is reached. Results are expected in 2022.

About BRUKINSA

BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by BeiGene scientists that is currently being evaluated globally in a broad clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. Because new BTK is continuously synthesized, BRUKINSA was specifically designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared to other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease relevant tissues.

BRUKINSA is approved in the following indications and regions:

For the treatment of mantle cell lymphoma (MCL) in adult patients who have received at least one prior therapy (United States, November 2019)*;
For the treatment of MCL in adult patients who have received at least one prior therapy (China, June 2020)**;
For the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) in adult patients who have received at least one prior therapy (China, June 2020)**;
For the treatment of relapsed or refractory MCL (United Arab Emirates, February 2021); and
For the treatment of Waldenström’s macroglobulinemia (WM) in adult patients (Canada, March 2021).
To-date, more than 30 marketing authorization applications in multiple indications have been submitted outside of the United States and China, covering countries in the European Union and more than 20 other countries.

* This indication was 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.

** This indication was approved under conditional approval. Complete approval for this indication may be contingent upon results from ongoing randomized, controlled confirmatory clinical trials.

IMPORTANT U.S. 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%).

Of the 118 patients with MCL treated with BRUKINSA, 8 (7%) patients discontinued treatment due to adverse reactions in the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumonia (3.4%). One (0.8%) patient experienced an adverse reaction leading to dose reduction (hepatitis B).

Drug Interactions

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

CYP3A Inducers: Avoid co-administration 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.