On December 11, 2021 Neoleukin Therapeutics, Inc., "Neoleukin" (NASDAQ:NLTX), a biopharmaceutical company utilizing sophisticated computational methods to design de novo protein therapeutics, reported the presentation of preclinical data on NL-201 in multiple myeloma at the 63RD American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place virtually and in person December 11-14, 2021 (Press release, Neoleukin Therapeutics, DEC 11, 2021, View Source [SID1234596845]). Additionally, a published abstract in Blood reports on NL-201 antitumor activity in preclinical studies of non-Hodgkin lymphoma.

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NL-201 is a de novo agonist of the IL-2 and IL-15 receptors, designed to expand cancer-fighting CD8 T cells and natural killer (NK) cells without a bias toward cells expressing the IL-2 receptor alpha subunit (CD25). NL-201 is currently in a Phase 1 clinical trial for patients with solid tumors.

The preclinical multiple myeloma data, to be presented in a poster session by Simone A. Minnie, PhD, Fred Hutchinson Cancer Research Center, demonstrate the ability of NL-201 to prevent relapse in murine myeloma models following autologous stem cell transplant. Experimental results indicate that anti-myeloma activity is mediated by expansion of cytotoxic memory CD8 T cells and a decrease in T-regulatory CD4 cells in the bone marrow. Furthermore, NL-201 treated mice had an increase in bone marrow T-cells expressing granzyme B and a decrease in the T-cell exhaustion phenotype.

"These data, generated by our collaborators at the Fred Hutchinson Cancer Research Center, demonstrate robust immune effects and anti-myeloma activity in a challenging setting," said Priti Patel M.D., Chief Medical Officer of Neoleukin. "Together with our published results on the preclinical activity of NL-201 against B-cell lymphoma, we believe that a clinical trial of NL-201 in patients with hematologic malignancies is warranted. We expect to initiate a Phase 1 trial in 2022 to evaluate NL-201 in patients with these indications."

Further details as follows:

Abstract number: 1609
The IL-2/IL-15 Mimetic NL-201 Prevents Myeloma Relapse after ASCT by Expanding Highly Cytolytic T Cells in the Bone Marrow that are Resistant to Exhaustion

Abstract number: 4560
NL-201, a De Novo Agonist of IL-2 and IL-15 Receptors, Demonstrates Synergistic Antitumor Activity with Anti-PD-1 Checkpoint Inhibitor Therapy in a Preclinical Non-Hodgkin Lymphoma Model

The ASH (Free ASH Whitepaper) poster and abstract link are available on the Neoleukin website publications page: View Source

About NL-201
NL-201 is a de novo agonist of the IL-2 and IL-15 receptors, designed to expand cancer-fighting CD8 T cells and natural killer (NK) cells without any bias toward cells expressing the alpha receptor subunit (CD25). Previously presented preclinical data has demonstrated the ability of NL-201 to stimulate and expand CD8+ and NK cells at low doses with minimal impact on immunosuppressive regulatory T cells. Furthermore, NL-201 has demonstrated both monotherapy and combination activity across a wide range of preclinical syngeneic tumor models.

On December 11, 2021 Novartis reported new 48-week data from the Phase III ASCEMBL trial of Scemblix (asciminib) demonstrating that the results observed in the primary analysis (24 weeks) vs. Bosulif* (bosutinib) were maintained in longer-term follow up for patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) previously treated with two or more tyrosine kinase inhibitors (TKIs)1-4 (Press release, Novartis, DEC 11, 2021, View Source [SID1234596843]).

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In this analysis, presented at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (ASH) (Free ASH Whitepaper), the major molecular response (MMR) rate at 48 weeks was 29.3% for patients treated with Scemblix vs. 13.2% for patients in the Bosulif arm, which is consistent with a doubling of the efficacy at 24 weeks (25% vs. 13% [P=0.029])1-4. The proportion of patients treated with Scemblix who experienced adverse reactions leading to discontinuation was more than three times lower than those in the Bosulif arm (7.1% vs. 25%)1.

Scemblix is the first FDA-approved CML treatment that works by binding to the ABL myristoyl pocket2. This novel mechanism of action, also known in scientific literature as a STAMP inhibitor, can help address resistance to TKI therapy in patients with CML and overcome mutations at the defective BCR-ABL1 gene, which is associated with the over-production of leukemic cells2-4. Scemblix continues to be studied across multiple lines of treatment for CML-CP3-12.

"We often see that sequential use of TKI treatments can be associated with increased failure rates and greater concerns regarding potential treatment side effects as patients move to later lines. Scemblix offers an increasingly proven option for patients living with CML who have previously tried two or more TKIs, and takes a different approach to targeted inhibition to better manage CML," said Dr. Michael J. Mauro**, Hematologist and Myeloproliferative Neoplasms Program Leader at Memorial Sloan Kettering Cancer Center (MSK).

In this updated analysis, responses were also durable, with 60 out of 62 patients on Scemblix maintaining MMR at time of their last assessment1. Scemblix continued to deliver more favorable deep molecular responses (MRs) with MR4 and MR4.5 rates at 48 weeks of 10.8% and 7.6%, compared to 3.9% and 1.3% in patients treated with Bosulif, respectively1. Additionally, the cumulative proportion of patients achieving a level of BCR-ABL1IS ≤1% at 48 weeks – a predictor of better long-term outcomes in this heavily pretreated patient population – was higher in the Scemblix arm than in the Bosulif arm (50.8% vs 33.7%)1.

The most common reason for treatment discontinuation was lack of efficacy in 37 (23.6%) patients treated with Scemblix and 27 (35.5%) patients treated with Bosulif1. Median duration of exposure was 15.4 months (range, 0.0–37.3 months) for Scemblix and 6.8 months (range, 0.2–34.3 months) for Bosulif1. With a longer duration of exposure, the safety and tolerability profile remains consistent with the primary analysis of the ASCEMBL trial1-4. The most common (incidence ≥ 20%) adverse reactions reported in this analysis were thrombocytopenia (29.5%) and neutropenia (23.1%) in the Scemblix arm; and diarrhea (71.1%), nausea (46.1%), increased ALT (28.9%), vomiting (26.3%), rash (23.7%), increased AST (21.1%) and neutropenia (21.1%) in the Bosulif arm1.

"We are excited to see the continued benefit with Scemblix for this long-underserved patient population," said Jeff Legos, Executive Vice President, Global Head of Oncology & Hematology Development at Novartis. "These data are encouraging as we continue to challenge the current standard of care in CML by exploring if and how Scemblix can help more patients living with this disease."

Scemblix received FDA approval in October 2021 and is currently available for physicians to prescribe to appropriate patients in the US2. Scemblix is also being evaluated in studies across multiple treatment lines and indications for CML-CP, including the ASC4FIRST Phase III study for newly diagnosed adult patients, as well as in a Phase Ib/II dose assessment study in pediatric patients with Ph+ CML-CP. Trial-in-progress posters for both are being presented at ASH (Free ASH Whitepaper)13-22.

To learn more about our long-standing commitment to transforming the lives of patients with CML with bold science, the latest information from Novartis and access to our ASH (Free ASH Whitepaper) 2021 scientific presentations, visit the Novartis Oncology Congress Hub at View Source

About Scemblix (asciminib)
Scemblix (asciminib) is indicated for the treatment of adult patients with Ph+ CML-CP pre-treated with two or more TKIs, as well as adult patients with Ph+ CML-CP with the T315I mutation. The first indication is approved under the US FDA Accelerated Approval Program based on MMR rate at 24 weeks; continued approval for the first indication may be contingent upon verification and description of clinical benefit from confirmatory evidence2.

Scemblix is the first FDA-approved CML treatment that binds to the ABL myristoyl pocket2. This novel mechanism of action, also known in scientific literature as a STAMP inhibitor, can help address resistance in patients with CML previously treated with two or more TKIs and overcome mutations at the defective BCR-ABL1 gene, which is associated with the over-production of leukemic cells3-12.

Novartis has initiated regulatory filings for Scemblix in multiple countries and regions across the globe.

Scemblix represents an important development for patients who experience resistance and/or intolerance to currently available TKI therapies, and it is being studied across multiple treatment lines for CML-CP3-20. Specifically, the ASC4FIRST Phase III study (NCT04971226) evaluates Scemblix as a first-line treatment and is in the recruitment phase14,21.

About Novartis Commitment to CML
Novartis has a long-standing scientific commitment to patients living with CML. For more than 20 years, our bold science has helped transform CML into a chronic disease for many patients. Despite these advancements, we’re not standing still. We continue to research ways to target the disease, seeking to address the challenges with treatment resistance and/or intolerance that many patients face. Novartis also continues to reimagine CML care through its commitment to sustainable access for patients and collaboration with the global CML community.

Indication
SCEMBLIX (asciminib) tablets is a prescription medicine used to treat adults with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with 2 or more tyrosine kinase inhibitor (TKI) medicines. The effectiveness of SCEMBLIX in these patients is based on a study that measured major molecular response (MMR) rates. No clinical information is available to show if these patients treated with SCEMBLIX live longer or if their symptoms improve. Ongoing studies exist to find out how SCEMBLIX works over a longer period of time.

SCEMBLIX is also approved for use in adults with Ph+ CML in CP with the T315I mutation.

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

Important Safety Information
SCEMBLIX (asciminib) tablets may cause low platelet counts (thrombocytopenia), low white blood cell counts (neutropenia), and low red blood cell counts (anemia). Patients should tell their doctor right away if they have unexpected bleeding or easy bruising; blood in their urine or stools; fever; or any signs of an infection. SCEMBLIX may increase enzymes in the patient’s blood called amylase and lipase, which may be a sign of inflammation of the pancreas (pancreatitis). Patients should tell their doctor right away if they have sudden stomach-area pain or discomfort, nausea, or vomiting. During treatment with SCEMBLIX, doctors may check their patients’ blood pressure and treat any high blood pressure as needed. Patients should tell their doctor if they develop elevated blood pressure or symptoms of high blood pressure including confusion, headaches, dizziness, chest pain, or shortness of breath.

If a patient has an allergic reaction while on SCEMBLIX, they should stop taking SCEMBLIX and get medical help right away. Signs or symptoms of an allergic reaction include trouble breathing or swallowing; feeling dizzy or faint; swelling of the face, lips, or tongue; fever; skin rash or flushing; or a fast heartbeat. SCEMBLIX may cause heart and blood vessel problems, including heart attack; stroke; blood clots or blockage of patient’s arteries; heart failure; and abnormal heartbeat which can be serious and may sometimes lead to death. These heart and blood vessel problems can happen in people with risk factors or a history of these problems and/or previously treated with multiple TKI medicines. Patients should tell their doctor right away if they get shortness of breath; chest pain or pressure; a feeling like their heart is beating too fast or they feel abnormal heartbeats; swelling in their ankles or feet; dizziness; weight gain; numbness or weakness on one side of their body; decreased vision or loss of vision; trouble talking; pain in their arms, legs, back, neck, or jaw; headache; or severe stomach-area pain.

Before taking SCEMBLIX, patients should tell their doctor about all of their medical conditions, including if they have a history of pancreatitis; a history of heart problems; or blood clots in their arteries and veins (types of blood vessels). SCEMBLIX can harm an unborn baby. Women should tell their doctor right away if they become pregnant or think they may be pregnant during treatment with SCEMBLIX. Women who are able to become pregnant should have a pregnancy test before they start SCEMBLIX and should use effective birth control during treatment and for 1 week after the last dose of SCEMBLIX. Women should not breastfeed during treatment and for 1 week after their last dose of SCEMBLIX.

Patients should tell their doctor about all the medicines they take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. SCEMBLIX and other medicines may affect each other, causing side effects. The most common side effects of SCEMBLIX include nose, throat, or sinus (upper respiratory tract) infections; muscle, bone, or joint pain; rash; tiredness; nausea; and diarrhea. The most common blood test abnormalities include decreased blood counts of platelets, white blood cells, and red blood cells; and increased blood levels of triglycerides, creatine kinase, liver enzymes, or pancreas enzymes (amylase and lipase).

Please see full Prescribing Information for SCEMBLIX, available at View Source

On December 11, 2021 Novartis reported that Kymriah (tisagenlecleucel) demonstrated strong efficacy in high-risk patients with relapsed or refractory (r/r) follicular lymphoma (FL) based on a subgroup analysis from an approximately 17-month median follow-up of the pivotal Phase II ELARA study1 (Press release, Novartis, DEC 11, 2021, View Source [SID1234596842]). These results were presented in an oral session at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (ASH) (Free ASH Whitepaper) (Abstract #131).

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In the subgroup analysis, results showed high rates of durable responses were induced by Kymriah in patients for the majority of high-risk disease subgroups, who typically have a poor prognosis. Complete response rate (CRR), overall response rate (ORR), and durability of response (DOR) were maintained in most patients in the high-risk subgroups, with the exception of those in three of the nine subgroups analyzed: those with progression-of-disease within two years (POD24), high total metabolic tumor volume (TMTV) and patients who had received five or more prior lines of therapy1.

"It’s truly exciting to see that after treatment with Kymriah in patients with difficult-to-treat, high-risk follicular lymphoma, patients are experiencing long-lasting responses with a low risk of severe adverse events," said Catherine Thieblemont, MD, PhD, Professor of Hematology in the Paris VII- University, France and Head of the Hemato-Oncology Unit of St-Louis Hospital in Paris.

High and durable responses were seen in the overall population of the ELARA study in which 94 patients were evaluable for efficacy with a median follow-up of approximately 17 months. The CRR was 69% (95% CI, 60-78), ORR was 86% (95% CI, 78-92), 12-month progression-free survival (PFS) was 67% (95% CI, 56-76) and nine-month DOR was 76% (95% CI, 65-84). For patients who had a complete response (CR), 12-month PFS was 86% (95% CI, 74-92) and the estimated DOR rate was 87% (95% CI, 75-93). In the safety analysis (n=97), the safety profile of Kymriah continued to reflect the remarkable results seen in earlier ELARA analyses. Within eight weeks of infusion, 48% of patients experienced cytokine release syndrome (CRS), with no patients experiencing CRS of grade 3 or higher as defined by the Lee scale, 37% had neurological events (3% were greater than or equal to grade 3) and there were no treatment-related deaths1.

A separate analysis of hospitalization and intensive care unit patterns for patients treated in the inpatient and outpatient settings in the ELARA trial suggest Kymriah may reduce healthcare resource utilization for patients with r/r FL treated in the outpatient setting (Abstract #3533). Among patients treated in the outpatient setting (n=17), 35% did not require hospitalization during the first two months of the post-infusion period; those who did had a lower median average length of stay than the patients infused in an inpatient setting (4 days [n=17] vs 12 days [n=80]). Additionally, the mean hospitalization costs in the post-infusion period were substantially lower in the outpatient versus inpatient setting2.

"The ability to administer Kymriah, a potentially definitive treatment, in the outpatient setting may reduce the burden of therapy for patients and their care teams," said Jeff Legos, Executive Vice President, Global Head of Oncology & Hematology Development, Novartis. "The breadth of follicular lymphoma data presented at this year’s ASH (Free ASH Whitepaper) demonstrate the potential for Kymriah to provide transformative results and a positive impact on health systems overall."

Novartis is committed to bringing the benefits of Kymriah to more patients with advanced blood cancers worldwide, with regulatory submissions for follicular lymphoma in the US and EU complete in October 2021. If approved in this indication, Novartis will look to confirm these results of the ELARA trial and related analyses in the real-world setting.

About follicular lymphoma
Follicular lymphoma (FL), the second most common form of non-Hodgkin lymphoma (NHL), is an indolent lymphoma, and represents approximately 22% of NHL cases3,4. It is often an unrelenting malignancy with a relapsing and remitting pattern5,6. Throughout the lifetime of a patient with relapsing FL, he or she may be exposed to a median of five lines of prior treatment, with an upper range of 13 lines7,8. Although patients in third or later line treatment for FL have multiple systemic therapies available, the efficacy of these regimens drops off rapidly in later lines5. Additionally, because of this relapsing and remitting pattern, patients who are refractory to treatment or relapse may exhaust available treatment options5.

About the ELARA trial
ELARA is a Phase II, single-arm, multicenter, open-label trial investigating the efficacy and safety of Kymriah in adult patients with r/r FL after at least two prior therapies. This international trial has enrolled patients from over 30 sites in 12 countries worldwide. The primary endpoint is complete response rate (CRR) based on best response by central review (Lugano 2014 criteria). Patients evaluable for efficacy had measurable disease at infusion and more than six months of follow-up from infusion or discontinued early. After infusion, disease assessments were performed every three months. In a high-risk subgroup analysis, patients evaluated included those with prior hematopoietic stem cell transplant, double-refractory disease, high Follicular Lymphoma International Prognostic Index at study entry, high lactate dehydrogenase at baseline, high C-reactive protein prior to infusion, radiological bulky disease, progression-of-disease within two years (POD24), high total metabolic tumor volume (TMTV), and patients who had received five or more prior lines of therapy1. Secondary endpoints include overall response rate, duration of response, progression-free survival, overall survival and safety. Primary analysis data announced at ASCO (Free ASCO Whitepaper) 2021 showed Kymriah led to responses for the majority of patients treated, with 66% achieving a complete response (95% CI, 56-75). The overall response rate was 86% (95% CI, 78-92)9. Importantly, no patients in ELARA trial experienced grade 3 or higher cytokine release syndrome related to Kymriah within the first 8 weeks following infusion, the most common side effect associated with CAR-T therapy9.

About Novartis commitment to Oncology Cell Therapy
Novartis has a mission to reimagine medicine by bringing curative cell therapies to patients worldwide. Novartis has a deep CAR-T pipeline and ongoing investment in manufacturing and supply chain process improvements. With active research underway to broaden the impact of cell and gene therapy in oncology, Novartis is going deeper in hematological malignancies, reaching patients with other cancer types and evaluating next-generation CAR-T cell therapies that focus on new targets and utilize new technologies.

Novartis was the first pharmaceutical company to significantly invest in pioneering CAR-T research and initiate global CAR-T trials. Kymriah, the first approved CAR-T cell therapy, developed in collaboration with the Perelman School of Medicine at the University of Pennsylvania, is the foundation of Novartis’ commitment to CAR-T cell therapy.

Kymriah is currently approved for use in at least one indication in 30 countries and at more than 350 certified treatment centers, with the ambition for further expansion to help fulfill the ultimate goal of bringing CAR-T cell therapy to every patient in need.

Novartis has a global CAR-T manufacturing footprint that includes both Novartis-owned and contract manufacturing sites. This comprehensive, integrated footprint strengthens the flexibility, resilience and sustainability of the Novartis manufacturing and supply chain.

US FDA approved indications for Kymriah
Kymriah (tisagenlecleucel) is a CD19-directed genetically modified autologous T cell immunotherapy, which is indicated for:

The treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.
The treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma (FL). Limitations of Use: Kymriah is not indicated for treatment of patients with primary central nervous system lymphoma.
Kymriah (tisagenlecleucel) US Important Safety Information
KYMRIAH may cause side effects that are severe or life-threatening, such as Cytokine Release Syndrome (CRS) or neurological toxicities. Patients with CRS may experience symptoms including difficulty breathing, fever (100.4◦F/38◦C or higher), chills/shaking chills, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, or dizziness/lightheadedness. Patients may be admitted to the hospital for CRS and treated with other medications.

Patients with neurological toxicities may experience symptoms such as altered or decreased consciousness, headaches, delirium, confusion, agitation, anxiety, seizures, difficulty speaking and understanding, or loss of balance. Patients should be advised to call their healthcare provider or get emergency help right away if they experience any of these signs and symptoms of CRS or neurological toxicities.

Because of the risk of CRS and neurological toxicities, KYMRIAH is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS.

Serious allergic reactions, including anaphylaxis, may occur after KYMRIAH infusion. KYMRIAH can increase the risk of life-threatening infections that may lead to death. Patients should be advised to tell their healthcare provider right away if they develop fever, chills, or any signs or symptoms of an infection.

Patients may experience prolonged low blood cell counts (cytopenia), where one or more types of blood cells (red blood cells, white blood cells, or platelets) are decreased. The patient’s healthcare provider will do blood tests to check all their blood cell counts after treatment with KYMRIAH. Patients should be advised to tell their healthcare provider right away if they get a fever, are feeling tired, weak, or short of breath, or have bruising or bleeding.

Patients may experience hypogammaglobulinemia, a condition in which the level of immunoglobulins (antibodies) in the blood is low and the risk of infection is increased. It is expected that patients may develop hypogammaglobulinemia with KYMRIAH and may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with KYMRIAH. Patients should tell their healthcare provider about their treatment with KYMRIAH before receiving a live vaccine.

After treatment with KYMRIAH, patients will be monitored lifelong by their healthcare provider, as they may develop secondary cancers or recurrence of their cancer.

Patients should not drive, operate heavy machinery, or do other dangerous activities for eight weeks after receiving KYMRIAH because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, weakness, dizziness, and seizures.

Some of the most common side effects of KYMRIAH are difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, confusion, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, dizziness/lightheadedness, and headache. However, these are not all the possible side effects of KYMRIAH. Patients should talk to their healthcare provider for medical advice about side effects.

Prior to a female patient starting treatment with KYMRIAH, their healthcare provider may do a pregnancy test. No information is available for KYMRIAH use in pregnant or breast-feeding women. Therefore, KYMRIAH is not recommended for women who are pregnant or breast feeding. Patients should talk to their healthcare provider about birth control and pregnancy.

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

After receiving KYMRIAH, patients should be advised that some commercial HIV tests may cause a false-positive test result. Patients should also be advised not to donate blood, organs, tissues, sperm, oocytes, and other cells after receiving KYMRIAH.

On December 11, 2021 Kite, a Gilead Company (Nasdaq: GILD), reported updated two-year results from ZUMA-5, a global, multicenter, single-arm, open-label Phase 2 study evaluating Yescarta (axicabtagene ciloleucel) in adult patients with relapsed or refractory indolent non-Hodgkin lymphoma (NHL) after at least two prior lines of therapy (Press release, Kite Pharma, DEC 11, 2021, View Source [SID1234596841]). The data were presented in an oral session during the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (Abstract #93).

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At the time of data cut-off, 110 patients (86 with follicular lymphoma (FL); 24 with marginal zone lymphoma (MZL)) were eligible for efficacy analyses. FL patients had at least two years of follow-up time, and the minimum requirement for MZL was four weeks. Among eligible patients with FL, median follow-up was 30.9 months (range, 24.7-44.3). The objective response rate (ORR) in FL was 94%, with a complete response (CR) rate of 79%. Fifty-seven percent of eligible FL patients had ongoing responses. The estimated median duration of response (DOR) and progression-free survival (PFS) was 38.6 months and 39.6 months, respectively. Among eligible FL patients, median time to next treatment was 39.6 months. Median overall survival (OS) was not reached, with an estimated 24-month OS rate of 81%.

Among eligible patients with MZL, median follow-up was 23.8 months (range, 7.4-39.4). Eighty-three percent of patients achieved ORR, including 63% with a CR. Fifty percent of patients were in ongoing response at the time of data cut-off. Median DOR and time to next treatment were not yet reached among eligible patients, and median PFS was 17.3 months. Median OS was not yet reached, with an estimated 24-month OS rate of 70%.

"When treating patients with indolent non-Hodgkin lymphomas including follicular lymphoma, we try to reduce the frequency of relapses and slow progression to more aggressive disease," said Sattva S. Neelapu, MD, Professor, Department of Lymphoma-Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "Relapse among these patients is most likely to take place within two years of treatment, so to see high rates of response, an estimated median PFS of almost 40 months, and no evidence of progressive events after the two-year mark is highly encouraging of the potential for axicabtagene ciloluecel to redefine treatment for these patients."

Among all evaluable patients (n=149), safety observations were consistent with the known safety profile for Yescarta. Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in 7% (6% FL; 8% MZL) and 19% (15% FL; 36% MZL) of patients, respectively. Most CRS cases (120/121) and neurologic events (82/87) of any grade resolved by the time of data cut-off.

"The continued durable response to a single infusion of Yescarta in a patient population that tends to experience frequent relapses is impressive," said Frank Neumann, MD, PhD, Kite’s Global Head of Clinical Development. "With these longer-term data, we believe Yescarta is truly practice-changing for patients with indolent NHLs like follicular lymphoma, and we’re working diligently to bring this therapy to patients across the globe who may benefit."

Yescarta received accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy in March 2021. The Yescarta U.S. Prescribing Information has a BOXED WARNING for the risks of CRS and neurologic toxicities, and Yescarta is approved with a Risk Evaluation and Mitigation Strategy (REMS) due to these risks; see below for Important Safety Information.

Yescarta is currently under review in the European Union for the treatment of adult patients with relapsed or refractory FL. Yescarta has not been approved by any regulatory agency for the treatment of MZL.

About ZUMA-5
ZUMA-5 is an ongoing, single-arm, open-label, multicenter trial evaluating 146 patients (≥18 years old) with relapsed or refractory iNHL including FL, who received at least two prior lines of systemic therapy, including the combination of an anti-CD20 monoclonal antibody and an alkylating agent. Efficacy was established on the basis of objective response rate (ORR) and duration of response (DoR) as assessed by an independent review committee per the 2014 Lugano Classification.

About Indolent Non-Hodgkin Lymphoma and Follicular Lymphoma
Follicular lymphoma (FL) is a form of indolent non-Hodgkin lymphoma (iNHL) in which malignant tumours slowly grow but can become more aggressive over time. FL is the most common form of indolent non-Hodgkin lymphoma and the second most common type of lymphoma globally. It accounts for approximately 22% of all lymphomas diagnosed worldwide. Currently, there are limited options for the treatment of relapsed or refractory indolent FL after two or more lines of therapy.

About Yescarta

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

Yescarta is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

Adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Limitations of Use: Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.
Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
U.S. IMPORTANT SAFETY INFORMATION
BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed.
Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS Program.
CYTOKINE RELEASE SYNDROME (CRS), including fatal or life-threatening reactions, occurred. CRS occurred in 88% (224/254) of all patients with non-Hodgkin lymphoma (NHL), including Grade ≥3 in 10%. CRS occurred in 94% (101/108) of patients with large B-cell lymphoma (LBCL), including Grade ≥3 in 13%. Among patients with LBCL who died after receiving Yescarta, 4 had ongoing CRS events at the time of death. The median time to onset of CRS was 2 days (range: 1-12 days) and the median duration was 7 days (range: 2-58 days) for patients with LBCL. CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL), including Grade ≥3 in 8% (11/146). Among patients with iNHL who died after receiving Yescarta, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and median duration was 6 days (range: 1-27 days) for patients with iNHL. Key manifestations of CRS (≥10%) in all patients combined included fever (80%), hypotension (38%), tachycardia (29%), hypoxia (21%), chills (21%), and headache (13%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, multi-organ failure and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. In a subsequent cohort of LBCL patients, tocilizumab and/or corticosteroids were administered for ongoing Grade 1 events. CRS occurred in 93% (38/41) of these patients and 2% (1/41) had Grade 3 CRS, with no patients experiencing a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1 to 8 days) and the median duration of CRS was 7 days (range: 2 to 16 days). Key manifestations of CRS (>5%) included pyrexia, hypotension, chills, headache, nausea, tachycardia, C-reactive protein increased, fatigue, hypoxia, and vomiting. Ensure that 2 doses of tocilizumab are available prior to Yescarta infusion. Following infusion, monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES that were fatal or life-threatening occurred. Neurologic toxicities occurred in 81% (206/254) of all patients with NHL receiving Yescarta, including Grade ≥3 in 26%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL, including Grade ≥3 in 31%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including Grade ≥3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days for patients with iNHL. 98% of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of Yescarta infusion. Neurologic toxicities occurred within the first 7 days of infusion for 89% of affected patients with LBCL and 74% of affected patients with iNHL. The most common neurologic toxicities (≥10%) in all patients combined included encephalopathy (53%), headache (45%), tremor (31%), dizziness (20%), delirium (16%), aphasia (15%), and insomnia (11%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including leukoencephalopathy and seizures, as well as fatal and serious cases of cerebral edema, have occurred. In a subsequent cohort of LBCL patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) of these patients and 20% (8/41) had Grade 3 neurologic toxicities with no patients experiencing a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). The most common neurologic toxicities were consistent with the overall LBCL population treated with Yescarta. Following Yescarta infusion, monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS: Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program called the Yescarta and Tecartus REMS Program which requires that: Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after Yescarta infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer Yescarta are trained about the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS: Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of Yescarta.

SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 47% (119/254) of all patients with NHL. Grade ≥3 infections occurred in 19% of patients, Grade ≥3 infections with an unspecified pathogen occurred in 15%, bacterial infections in 5%, viral infections in 2%, and fungal infections in 1%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 40% of all patients with NHL and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated. In immunosuppressed patients, including those who have received Yescarta, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. Grade ≥3 cytopenias not resolved by Day 30 following Yescarta infusion occurred in 30% of all patients with NHL and included neutropenia (22%), thrombocytopenia (13%), and anemia (5%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA and B-cell aplasia can occur. Hypogammaglobulinemia occurred in 17% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following Yescarta treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS: The most common adverse reactions (incidence ≥20%) in patients with LBCL included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias. The most common non-laboratory adverse reactions (incidence ≥20%) in patients with iNHL included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with pathogen unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

On December 11, 2021 BeiGene (NASDAQ: BGNE; HKEX: 06160), a global, science-driven biotechnology company focused on developing innovative and affordable medicines, reported that additional safety and efficacy results from an ongoing Phase 2 trial evaluating BRUKINSA (zanubrutinib) in patients with previously treated B-cell malignancies who were intolerant to ibrutinib and/or acalabrutinib (Press release, BeiGene, DEC 11, 2021, View Source [SID1234596839]). These data were reported in a mini-oral presentation today at the 63rd American Society for Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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"We are highly encouraged by these results, providing further evidence of BRUKINSA’s potential to benefit patients with a variety of advanced B-cell malignancies who experience intolerable adverse events on other BTK inhibitors," said Jane Huang, M.D., Chief Medical Officer, Hematology at BeiGene. "BRUKINSA was purposefully designed by BeiGene scientists to deliver sustained inhibition of the BTK protein and address certain tolerability concerns by optimizing kinase selectivity to reduce off-target effects. The updated results from this trial in patients who discontinued treatment with other BTK inhibitors due to adverse events complements previously reported findings from our two Phase 3 head-to-head trials comparing BRUKINSA to ibrutinib, where BRUKINSA demonstrated certain safety advantages over ibrutinib."

For more information on BeiGene’s clinical program and company updates, please visit BeiGene’s virtual booth at this year’s ASH (Free ASH Whitepaper) Annual Meeting at View Source

Phase 2 Trial of BRUKINSA in BTK Inhibitor-Intolerant Patients with R/R B-cell Malignancies

Mini Oral Presentation; Abstract #1410

This single-arm, open-label, multicenter Phase 2 trial in the U.S. (NCT04116437) evaluated the safety and efficacy of BRUKINSA in patients with previously treated B-cell malignancies who were intolerant to prior BTK inhibitor therapy, with preliminary results presented at the 62nd ASH (Free ASH Whitepaper) Annual Meeting in December 2020. The primary endpoint of safety was assessed by the recurrence and the change in severity of adverse events (AEs) compared to patients’ intolerance AE profile to ibrutinib and/or acalabrutinib. Secondary endpoints included investigator-assessed disease control rate (DCR), overall response rate (ORR), investigator-assessed progression-free survival (PFS) and patient-reported outcomes.

A total of 67 patients were enrolled in the trial, with 57 patients intolerant to ibrutinib (Cohort 1) and 10 patients intolerant to acalabrutinib and/or ibrutinib (Cohort 2), including 43 patients with chronic lymphocytic leukemia (CLL; 38 in Cohort 1 and five in Cohort 2), 11 patients with Waldenström’s Macroglobulinemia (WM; nine in Cohort 1 and two in Cohort 2), seven patients with small lymphocytic lymphoma (SLL; six in Cohort 1 and one in Cohort 2), three patients with mantle cell lymphoma (MCL; two in Cohort 1 and one in Cohort 2), and three patients with marginal zone lymphoma (MZL; two in Cohort 1 and one in Cohort 2). Patients were considered intolerant if they developed significant or persistent toxicities while on ibrutinib and/or acalabrutinib despite optimal care.

"Tolerability of BTK inhibitors continues to be a significant challenge for patients and their physicians, as treatment disruption or discontinuation may impact clinical outcomes. These data demonstrated that treatment with BRUKINSA was well-tolerated and unlikely to lead to recurrence of intolerant AEs experienced with prior BTK inhibitor therapy," commented Mazyar Shadman, M.D., MPH, Associate Professor of Clinical Research Division at Fred Hutchinson Cancer Research Center and Assistant Professor of Oncology at University of Washington, and a principal investigator of the trial. "Additionally, BRUKINSA was effective in at least maintaining or improving treatment responses from baseline, suggesting BRUKINSA may be a treatment option for patients intolerant to other BTK inhibitor therapy across hematologic malignancies."

At the data cutoff on September 8, 2021, with a median BRUKINSA exposure of 11.1 months (11.6 months in Cohort 1 and 9.8 months in Cohort 2), more than a majority of the ibrutinib and acalabrutinib intolerance events did not recur with BRUKINSA treatment and none of the intolerance events recurred at a higher severity. Safety results included:

34 out of 57 patients (59.6%) who took ibrutinib and seven out of 10 patients (70.0%) who took acalabrutinib did not have recurrence of any intolerance event with BRUKINSA treatment;
Of the 115 ibrutinib intolerance events, 81 (70.4%) did not recur on BRUKINSA; of the 34 recurrent events, 26 (76.5%) recurred at a lower severity, and eight (23.5%) recurred at the same severity;
Of the 18 acalabrutinib intolerance events, 15 (83.3%) did not recur on BRUKINSA; of the three recurrent events, one (33.3%) recurred at a lower severity, and two (66.6%) recurred at the same severity;
Of the 38 Grade 3 ibrutinib intolerance events, 25 (65.8%) did not recur on BRUKINSA, 12 (31.6%) recurred at a lower severity, and one (2.6%) recurred at the same severity;
Of the four Grade 3 acalabrutinib intolerance events, three (75.0%) did not recur on BRUKINSA and one (25.0%) recurred at a lower severity;
All four Grade 4 intolerance events (neutropenia [n=2], ALT increase [n=1], AST increase [n=1]) did not recur on BRUKINSA; and
One patient (1.5%) discontinued BRUKINSA due to recurrence of a prior intolerant event (myalgia; acalabrutinib).
In 67 patients across both cohorts, BRUKINSA was tolerable with additional safety results including:

AEs leading to BRUKINSA treatment discontinuation occurred in five patients (7.5%), including four in Cohort 1 and one in Cohort 2);
64 patients (95.5%) experienced at least one AE of any grade with BRUKINSA treatment, including 54 in Cohort 1 and 10 in Cohort 2, with the most common (≥10%) being confusion or bruising (22.4%), fatigue (20.9%), myalgia (14.9%), arthralgia (13.4%), diarrhea (13.4%), hypertension (11.9%), dizziness (10.4%), and nausea (10.4%);
20 patients (29.9%) experienced at least one Grade ≥3 AE with BRUKINSA treatment, including 17 in Cohort 1 and three in Cohort 2, with the most common (in more than one patient) being neutropenia (7.5%) and decreased neutrophil count (4.5%);
Eight patients (11.9%) experienced at least one serious AE with BRUKINSA treatment, including six in Cohort 1 and two in Cohort 2; and
AEs leading to dose interruption, reduction, and death with BRUKINSA treatment occurred in 20 patients (29.9%; 16 in Cohort 1 and four in Cohort 2), six patients (9.0%; five in Cohort 1 and one in Cohort 2), and one patient (1.5%; Cohort 1), respectively.
Efficacy results were assessed by investigators in patients who were on treatment for more than 90 days across both cohorts. BRUKINSA was effective in at least maintaining response in 60 patients (93.8% in all patients, with 94.7% in Cohort 1 and 85.7% in Cohort 2) or improving response from baseline in 41 patients (64.1% in all patients, with 63.2% in Cohort 1 and 71.4% in Cohort 2); the median time to first response was 2.96 months in all patients, with 2.92 months in Cohort 1 and 3.02 months in Cohort 2.

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 has received 12 approvals covering 40 countries 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 (CLL) or small lymphocytic lymphoma (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);
For the treatment of Waldenström’s macroglobulinemia (WM) in adult patients (Canada, March 2021);
For the treatment of adult patients with WM who have received at least one prior therapy (China, June 2021)**;
For the treatment of MCL in adult patients who have received at least one prior therapy (Canada, July 2021);
For the treatment of MCL in adult patients who have received at least one prior therapy (Chile, July 2021);
For the treatment of adult patients with MCL who have received at least one previous therapy (Brazil, August 2021);
For the treatment of adult patients with WM (United States, August 2021);
For the treatment of adult patients with marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen (United States, September 2021)*;
For the treatment of adult patients with MCL who have received at least one previous therapy (Singapore, October 2021);
For the treatment of MCL in patients who have received at least one prior therapy (Israel, October 2021);
For the treatment of adult patients with WM who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy (Australia, October 2021);
For the treatment of adult patients with MCL who have received at least one prior therapy (Australia, October 2021);
For the treatment of adult patients with MCL who have received at least one previous therapy (Russia, October 2021);
For the treatment of adult patients with MCL who have received at least one previous therapy (Saudi Arabia, November 2021); and
For the treatment of adult patients with WM who have received at least one prior therapy or first-line treatment of patients unsuitable for chemo-immunotherapy (European Union plus Iceland and Norway, November 2021).
To date, more than 20 marketing authorization applications have been submitted for BRUKINSA for various indications.

* 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 hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 3.4% of patients treated with BRUKINSA monotherapy. Hemorrhage events of any grade occurred in 35% 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 27% of patients, most commonly 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 (26%), thrombocytopenia (11%) and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy. Grade 4 neutropenia occurred in 13% of patients, and Grade 4 thrombocytopenia occurred in 3.6% of patients.

Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted. Treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 8% of patients. Other second primary malignancies included malignant solid tumors (4.0%), melanoma (1.7%) and hematologic malignancies (1.2%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

Cardiac Arrhythmias

Atrial fibrillation and atrial flutter were reported in 3.2% 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 1.1% 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 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 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, including laboratory abnormalities, in ≥ 30% of patients who received BRUKINSA (N = 847) included decreased neutrophil count (54%), upper respiratory tract infection (47%), decreased platelet count (41%), hemorrhage (35%), decreased lymphocyte count (31%), rash (31%) and musculoskeletal pain (30%).

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.

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 2,750 colleagues dedicated to advancing more than 90 ongoing or planned clinical trials that have involved more than 14,000 patients and healthy volunteers. Our expansive portfolio is directed predominantly by our internal colleagues supporting clinical trials in more than 45 countries and regions. 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. BeiGene currently has three approved medicines discovered and developed in our own labs: BTK inhibitor BRUKINSA in the United States, China, the EU, Canada, Australia and additional international markets; and the non-FC-gamma receptor binding anti-PD-1 antibody tislelizumab as well as the 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.