On November 28, 2023 Coherus BioSciences, Inc. (Coherus, Nasdaq: CHRS) and Shanghai Junshi Biosciences Co., Ltd (Junshi Biosciences, HKEX: 1877; SSE: 688180) reported the publication of the final overall survival (OS) results from the pivotal JUPITER-02 study (NCT03581786), a randomized, double-blind, placebo-controlled, international, multi-center Phase 3 clinical trial evaluating the immune checkpoint inhibitor LOQTORZI (toripalimab-tpzi), in combination with the chemotherapy agents gemcitabine and cisplatin, as a first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma (NPC) in the Journal of the American Medical Association (JAMA) (Press release, Coherus Biosciences, NOV 28, 2023, View Source [SID1234638004]). As previously reported at the 2023 American Society of Clinical Oncologists (ASCO) (Free ASCO Whitepaper) Annual Meeting, the final analysis revealed a 37% reduction in the risk of death in NPC patients treated with toripalimab plus chemotherapy versus chemotherapy alone.

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In October, Coherus and Junshi announced the U.S. Food and Drug Administration (FDA) approval of LOQTORZI in combination with cisplatin and gemcitabine for the first-line treatment of adults with metastatic or recurrent locally advanced NPC, and as monotherapy for the treatment of adults with recurrent, unresectable, or metastatic NPC with disease progression on or after platinum-containing chemotherapy. Coherus plans to launch LOQTORZI in the United States in January 2024.

"There are limited options for patients living with this aggressive head and neck cancer. New treatment options are desperately needed for underserved cancer patients particularly ones with rare cancers," said Robert Ferris, M.D., Ph.D., director of UPMC Hillman Cancer Center in Pittsburgh, PA. "As these data demonstrate, toripalimab clearly has the potential to significantly extend both progression-free and overall survival for patients living with NPC, and I believe this approach will offer a new standard of care for patients."

"The final OS data published in JAMA demonstrates the potential of LOQTORZI to significantly extend survival while slowing the progression of NPC, an aggressive form of cancer which up until now has had no approved therapies and therefore represents an important unmet need for patients in the US living with NPC," said Rosh Dias, M.D., Chief Medical Officer at Coherus. "As a next-generation PD-1 monoclonal antibody showing both a statistically significant and clinically meaningful OS advantage, and as the first and only FDA approved treatment for NPC, LOQTORZI should quickly become the new standard of care when used in combination with chemotherapy to treat patients living with NPC."

Titled Toripalimab plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma, the paper highlights the addition of LOQTORZI to gemcitabine-cisplatin (GP) chemotherapy as first-line treatment for patients with recurrent or metastatic NPC provided superior OS compared to GP alone [HR=0.63 (95% CI: 0.45-0.89), two-sided p=0.008]. The median OS was not reached in the LOQTORZI arm and was 33.7 months in the placebo arm. The 2-year and 3-year OS rates were 78.0% vs. 65.1%, and 64.5% vs. 49.2% respectively. A consistent effect on OS, favoring the LOQTORZI arm, was observed in the majority of the subgroups, including PD-L1 expression and EBV copy number high and low subgroups. The addition of LOQTORZI to chemotherapy also provided superior progression-free survival (PFS) compared to chemotherapy alone, with a median PFS of 21.4 vs. 8.2 months [HR=0.52 (95% CI: 0.37, 0.73)]. The safety profile was consistent with that previously reported in other toripalimab clinical trials and consistent with the PD-1 inhibitor class. The full results can be found in the online edition of JAMA.

"From the oral presentation at the ASCO (Free ASCO Whitepaper) Annual meeting’s Plenary Session, to the cover article of Nature Medicine, and now publication in JAMA, the survival benefits of JUPITER-02 have become increasingly evident, gradually establishing the status of toripalimab plus chemotherapy as the first-line standard treatment for advanced NPC. We are extremely proud to contribute to the international advancement of the clinical diagnosis and treatment of NPC," said Professor Ruihua Xu, JUPITER-02’s principal investigator from Sun Yat-sen University Cancer Centre. "The latest 3-year follow-up data showed that the combination of toripalimab with GP chemotherapy significantly reduced the risk of death by 37% and the risk of disease progression by 48%, and the 3-year OS rate reached 64.5%, an encouraging result for the first-line treatment of advanced NPC. Moreover, the addition of toripalimab did not increase the incidence of grade≥3 adverse events, nor did it increase the incidence of fatal adverse events and displayed a manageable safety profile."

"Toripalimab in combination with chemotherapy is the world’s first and only first-line treatment for recurrent/metastatic NPC to achieve both statistically and clinically significant OS benefits in a Phase 3 study," said Dr. Jianjun Zou, Global Research and Development President of Junshi Biosciences. "At present, this innovative treatment has been approved in China and the U.S. And through extensive cooperation, we strive for toripalimab to reach other parts of the world to provide more patients with better treatment options."

About NPC
NPC is a type of aggressive cancer that starts in the nasopharynx, the upper part of the throat behind the nose and near the base of the skull. NPC is rare in the United States, with an annual incidence of fewer than one per 100,000. The five-year survival rate for all patients diagnosed with NPC is approximately 60%, however, those who are diagnosed with advanced disease have a five-year survival rate of approximately 49%.

Due to the location of the primary tumor, surgery is rarely an option, and patients with localized disease are treated primarily with radiation and chemotherapy. Patients treated with chemotherapy alone experience poor prognosis: only 20% experience one-year PFS; up to 50% developed distant metastasis during their disease course; and low median OS of 29 months.

LOQTORZI is the first FDA-approved therapy for NPC and will represent a new standard of care for treating the disease when used in combination with cisplatin and gemcitabine in the first line setting or as monotherapy in the second line or greater setting.

About LOQTORZI (toripalimab-tpzi)
LOQTORZI is a next generation anti-PD-1 monoclonal antibody that blocks PD-L1 binding to the PD⁠-⁠1 receptor at a unique site with high affinity and activates antitumor immunity demonstrating improvement in the overall survival of cancer patients in several tumor types.

INDICATIONS AND IMPORTANT SAFETY INFORMATION

INDICATIONS

LOQTORZI (toripalimab-tpzi) is indicated:

In combination with cisplatin and gemcitabine, for the first-line treatment of adults with metastatic or with recurrent, locally advanced nasopharyngeal carcinoma (NPC).
As a single agent, for the treatment of adults with recurrent unresectable or metastatic NPC with disease progression on or after a platinum-containing chemotherapy.
IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions. Immune-mediated adverse reactions, which can be severe or fatal, occur in any organ system or tissue, affect more than one body system simultaneously, and occur at any time after starting PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment, they can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue LOQTORZI based on severity and type of reaction (see Dosage and Administration in Prescribing Information). In general, If LOQTORZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis
LOQTORZI can cause immune-mediated pneumonitis.

In patients receiving LOQTORZI in combination with cisplatin and gemcitabine, immune-mediated pneumonitis occurred in 2.1% (3/146) of patients, including Grade 2 (1.4%) adverse reactions. Pneumonitis resolved in 67% (2/3) of these patients.
In patients receiving LOQTORZI monotherapy, immune-mediated pneumonitis occurred in 2.6% (22/851) of patients, including fatal (0.2%), Grade 3 (0.7%), and Grade 2 (1.1%) adverse reactions. Systemic corticosteroids were required in 82% (18/22) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of LOQTORZI in 1.2% (10/851) of patients. Pneumonitis resolved in 23% (5/22) of these patients.
Immune-Mediated Colitis
LOQTORZI can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving LOQTORZI monotherapy, immune-mediated colitis occurred in 0.4% (3/851) of patients, including Grade 3 (0.2%) and Grade 2 (0.1%) adverse reactions. Colitis resolved in all 3 patients.

Hepatotoxicity and Immune-Mediated Hepatitis
LOQTORZI can cause immune-mediated hepatitis.

In patients receiving LOQTORZI in combination with cisplatin and gemcitabine, immune-mediated hepatitis occurred in 0.7% (1/146) of patients, which was a Grade 3 (0.7%) adverse reaction. The patient with immune-mediated hepatitis required systemic corticosteroids.
In patients receiving LOQTORZI monotherapy, immune-mediated hepatitis occurred in 3.3% (28/851) of patients, including Grade 4 (0.8%), Grade 3 (2.1%), and Grade 2 (0.4%) adverse reactions. Hepatitis led to permanent discontinuation of LOQTORZI in 1.1% of patients and withholding of LOQTORZI in 0.8% of patients. Hepatitis resolved in 54% (15/28) of these patients.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
LOQTORZI can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue LOQTORZI depending on severity. In patients receiving LOQTORZI monotherapy, adrenal insufficiency occurred in 0.5% (4/851) of patients, including Grade 2 (0.4%) and Grade 1 (0.1%) adverse reactions. Systemic corticosteroids were required in 75% (3/4) of the patients with adrenal insufficiency. Adrenal insufficiency led to withholding of LOQTORZI in 0.1% (1/851) of patients. In the one patient in whom LOQTORZI was withheld, LOQTORZI was reinitiated after symptom improvement.

Hypophysitis
LOQTORZI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effects such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue LOQTORZI depending on severity. In patients receiving LOQTORZI monotherapy, hypophysitis occurred in 0.4% (3/851) of patients receiving LOQTORZI, including Grade 3 (0.2%) and Grade 2 (0.1%) adverse reactions. All three patients received systemic corticosteroids. Hypophysitis led to permanent discontinuation of LOQTORZI in 0.1% (1/851) of patients and withholding of LOQTORZI in 0.1% (1/851) of patients. The one patient in whom LOQTORZI was withheld reinitiated LOQTORZI.

Thyroid Disorders
LOQTORZI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue LOQTORZI depending on severity.

In patients receiving LOQTORZI in combination with cisplatin and gemcitabine, thyroiditis occurred in 2.1% (3/146) of patients receiving LOQTORZI, including Grade 2 (1.4%). Three patients required thyroid hormone replacement therapy. Thyroiditis resolved in one of the 3 patients. Hyperthyroidism occurred in 1.4% (2/146) of patients receiving LOQTORZI in combination with cisplatin and gemcitabine. Hyperthyroidism resolved in these 2 patients. Hypothyroidism occurred in 30% (44/146) of patients receiving LOQTORZI in combination with cisplatin and gemcitabine, including Grade 2 (24%) and Grade 1 (6%). Eighty percent of the 44 patients required thyroid hormone replacement therapy. LOQTORZI was withheld in 2.1% (3/146) of the patients. Of the 3 patients in whom LOQTORZI was withheld, 2 patients reinitiated LOQTORZI.
In patients receiving LOQTORZI monotherapy, thyroiditis occurred in 0.6% (5/851) patients receiving LOQTORZI, including Grade 2 (0.1%). Two of these 5 patients received systemic corticosteroids and 2 required thyroid hormone replacement therapy. Thyroiditis resolved in 2 of the 5 patients. Hyperthyroidism occurred in 7% (55/851) of patients receiving LOQTORZI, including Grade 2 (1.9%). Hyperthyroidism resolved in 85% (47/55) of the patients. Hypothyroidism occurred in 15% (128/851) of patients receiving LOQTORZI, including Grade 2 (8%). Sixty three percent of the 128 patients required thyroid hormone replacement therapy. LOQTORZI was withheld in 0.5% of patients. Of the 4 patients in whom LOQTORZI was withheld, 3 patients reinitiated LOQTORZI.
Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue LOQTORZI depending on severity. In patients receiving LOQTORZI monotherapy, diabetes mellitus occurred in 0.9% (8/851) of patients receiving LOQTORZI, including Grade 4 (0.1%), Grade 3 (0.7%), and Grade 2 (0.1%). Diabetes mellitus led to permanent discontinuation in 0.4% of patients. Six of the 8 (75%) patients with diabetes mellitus required long-term insulin therapy.

Immune-Mediated Nephritis with Renal Dysfunction
LOQTORZI can cause immune-mediated nephritis.

In patients receiving LOQTORZI in combination with cisplatin and gemcitabine, immune-mediated nephritis occurred in 0.7% (1/146) of patients receiving LOQTORZI. The one patient with immune-mediated nephritis (Grade 4) required systemic corticosteroids and nephritis led to discontinuation of LOQTORZI. Nephritis resolved in this patient.
In patients receiving LOQTORZI monotherapy, immune-mediated nephritis occurred in 0.5% (4/851) of patients, including Grade 3 (0.5%) adverse reactions. Nephritis resolved in 75% (3/4) of these patients.
Immune-Mediated Dermatologic Adverse Reactions
LOQTORZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue LOQTORZI depending on severity.

In patients receiving LOQTORZI in combination with cisplatin and gemcitabine, immune-mediated dermatologic adverse reactions occurred in 8% (12/146) of patients, including Grade 3 (3.4%) and Grade 2 (1.4%) adverse reactions. Systemic corticosteroids were required in 25% (3/12) of the patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions led to permanent discontinuation of LOQTORZI in 2.1% (3) of patients. Immune-mediated dermatologic adverse reactions resolved in 92% (11/12) of these patients.
In patients receiving LOQTORZI monotherapy, immune-mediated dermatologic adverse reactions occurred in 4% (34/851) of patients, including Grade 3 (0.4%) and Grade 2 (1.4%) adverse reactions. Immune-mediated dermatologic adverse reactions led to withholding of LOQTORZI in 0.4% (3) of the patients. Systemic corticosteroids were required in 12% (4/34) of the patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 71% (24/34) of these patients.
Other Immune-Mediated Adverse Reactions
The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received LOQTORZI or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Cardiac/Vascular: Myocarditis, pericarditis, vasculitis, pericardial effusion
Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy
Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.
Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis
Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis, polymyalgia rheumatica, dermatomyositis
Endocrine: Hypoparathyroidism
Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection
Infusion-Related Reactions
LOQTORZI can cause severe or life-threatening infusion-related reactions including hypersensitivity and anaphylaxis.

In patients receiving LOQTORZI in combination with cisplatin and gemcitabine, infusion-related reactions have been reported in 4.1% of patients, including Grade 2 (0.7%) reactions.
In patients receiving LOQTORZI monotherapy, infusion-related reactions occurred in 2% of 851 patients, including Grade 3 (0.1%) and Grade 2 (0.6%). LOQTORZI was withheld for one Grade 3 infusion related reaction. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue LOQTORZI.
Complications of Allogeneic Hematopoietic Stem Cell Transplant (HSCT)
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity
LOQTORZI can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LOQTORZI and for 4 months after the last dose.

Lactation
There are no data on the presence of toripalimab-tpzi in human milk; its effects on the breastfed child, or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to toripalimab-tpzi are unknown. Because of the potential for serious adverse reactions in breastfed children, advise lactating women not to breastfeed during treatment with LOQTORZI and for 4 months after the last dose.

Serious Adverse Reactions

In JUPITER-02, when LOQTORZI was administered in combination with cisplatin and gemcitabine for the first-line treatment of recurrent, locally advanced or metastatic nasopharyngeal carcinoma, serious adverse reactions occurred in 43% of patients. Serious adverse drug reactions in ≥2% were thrombocytopenia (14%), neutrophil count decreased (10%), pneumonia (10%), anemia (9%), abnormal hepatic function (2.7%), and rash (2.1%). There were three fatal adverse reactions (2.1%): one due to epistaxis; one due to intracranial hemorrhage associated with immune-related thrombocytopenia and coagulopathy; and one due to pneumonia. Permanent discontinuation of LOQTORZI, due to an adverse reaction occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation of LOQTORZI in ≥1% were pneumonia (2.1%), pulmonary tuberculosis (1.4%), rash (1.4%), and vomiting (1.4%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased neutrophils (58%), decreased lymphocytes (57%), decreased hemoglobin (50%) decreased platelets (33%), decreased potassium (10%), decreased sodium (9%), increased alanine aminotransferase (6%), increased or decreased magnesium (4.2% each), decreased calcium (3.5%), increased aspartate aminotransferase (2.7%), increased bilirubin (2.1%).
In POLARIS-02, when LOQTORZI was administered as a single agent to patients with previously treated, unresectable or metastatic nasopharyngeal carcinoma, serious adverse reactions occurred in 24% of patients. Serious adverse drug reactions in ≥2% were pneumonia (4.7%), abnormal hepatic function (2.6%), and hyperbilirubinemia (2.1%). Fatal adverse reactions occurred in 3.7% of patients who received LOQTORZI, including death not otherwise specified (1.6%), tumor hemorrhage (0.5%), hepatic failure and thrombocytopenia (0.5%), hyponatremia (0.5%), and sudden death (0.5%). Permanent discontinuation of LOQTORZI due to an adverse reaction occurred in 9% of patients. Adverse reaction resulting in permanent discontinuation of LOQTORZI in ≥1% included pneumonia (1.1%), abnormal hepatic function (1.1%), and hyperbilirubinemia (1.1%). The most common Grade 3 or 4 laboratory abnormalities (≥2%), were decreased sodium (11%), decreased lymphocytes (9%), decreased hemoglobin (6%), increased aspartate aminotransferase (3.8%), decreased phosphate (3.2%), and increased alkaline phosphatase (2.2%).
Common Adverse Reactions

In JUPITER-02, the most common adverse reactions (≥20%) were nausea (71%), vomiting (68%), decreased appetite (55%), constipation (39%), hypothyroidism (38%), rash (36%), pyrexia (32%), diarrhea (31%), peripheral neuropathy (30%), cough (26%), musculoskeletal pain (25%), upper respiratory infection (23%), insomnia (23%), dizziness (21%), and malaise (21%).
In POLARIS-02, in patients with previously treated, unresectable or metastatic nasopharyngeal carcinoma, the most common (≥20%) adverse reactions were hypothyroidism (27%), fatigue (22%), and cough (20%).
Please see Prescribing Information for LOQTORZI and Medication Guide

On November 28, 2023 C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company dedicated to advancing targeted protein degradation science to develop a new generation of small-molecule medicines and transform how disease is treated, reported that it will host a webcast on Tuesday, December 12, 2023 at 4:30 PM ET to present new Phase 1 dose escalation data for relapsed refractory multiple myeloma from the ongoing Phase 1/2 clinical trial of CFT7455, a MonoDAC degrader of IKZF1/3, for the potential treatment of relapsed/refractory multiple myeloma and relapsed/refractory non-Hodgkin’s lymphoma (Press release, C4 Therapeutics, NOV 28, 2023, View Source [SID1234638002]).

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To join the webcast, please visit this link or the "Events & Presentations" page of the Investors section on the company’s website at www.c4therapeutics.com. A replay of the webcast will be archived and available following the event.

On November 28, 2023 Alpha Tau Medical Ltd. ("Alpha Tau", or the "Company") (NASDAQ: DRTS, DRTSW), the developer of the innovative alpha-radiation cancer therapy Alpha DaRT, reported the release of interim results from treatment of the first five patients in the Company’s safety and feasibility trial examining the use of Alpha DaRT to treat advanced pancreatic cancer, currently underway at two university hospitals in Montreal, Canada (Press release, Alpha Tau Medical, NOV 28, 2023, View Source [SID1234638001]).

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The first five patients were treated at the Jewish General Hospital, an affiliated teaching hospital of McGill University, Faculty of Medicine in Montreal, Canada, in accordance with the study protocol calling for a pace of approximately one patient per month, pending results from the interim safety read-out from the first five patients. Levels of radium-224 activity were increased from one patient to the next. Tumor stages of the treated patients ranged from stage II to stage IV, and treated tumors were located in the pancreatic head or neck. Four of the five patients had been previously treated with chemotherapy before enrolling in the study.

With respect to primary outcome measures, the Alpha DaRT procedure was deemed technically successful in all five cases, with Alpha DaRT sources successfully inserted into the target tumor. In addition, there were no reported serious adverse events deemed related to the product. The only reported adverse events deemed possibly related to the product were of severity grade 1 (mild).

The first two patients, who had received the fewest number of Alpha DaRT sources, both died approximately three months after treatment, and the deaths were not related to Alpha DaRT treatment. The other three patients, who are still undergoing regular follow-up multiple months after treatment, all demonstrated stable disease responses at four weeks after treatment, i.e., neither material shrinkage nor material increase in the longest dimension of the treated tumor. The third patient treated, for whom the coverage of gross tumor volume at 16 Gy alpha radiation dose was estimated at 44% after treatment, was upgraded to partial response upon evaluation at 69 days after treatment, i.e., the treated tumor shrank by at least 30% on its longest dimension vs. the baseline measurement.

Alpha Tau CEO Uzi Sofer commented, "These initial results have surpassed our expectations, with complete success in delivery, minimal product-related side effects observed thus far, and our first patient with an overall response to the treatment, despite our conservative gradual step up of tumor coverage from minimal initial levels. This trial is a cornerstone of our overall strategy to broaden the use of the Alpha DaRT in hard-to-treat indications, and the promising results to date are very timely given that November is Pancreatic Cancer Awareness month. We look forward to completing this trial as well as generating important data in other cancers such as those of the brain, lung, vulva and breast, and future expansion into examination of Alpha DaRT in combination with systemic therapies in settings such as the pancreas."

Corey Miller, MD, CM, FRCPC, Director of Therapeutic Endoscopy of the Division of Gastroenterology of the JGH, Assistant Professor of Medicine at McGill University, Associate Researcher at the Lady Davis Institute, Associate Member of the McGill Centre for Translational Research in Cancer and principal investigator of the trial, noted, "We were excited to offer this treatment to some of our most advanced patients, as part of the on-going partnership between the departments of Gastroenterology and Radiation Oncology of the JGH, the McGill Centre for Translational Research in Cancer (MCTRC) of the Lady Davis Institute, MEDTEQ+ (the pan-Canadian consortium for research and innovation in medical technologies) and the Institute TransMedTech. We have been positively surprised by the ease of use and accuracy in delivering Alpha DaRT sources into the pancreas, with each procedure taking under an hour, and we continue to learn more about the delivery with each procedure. We are encouraged by the initial outcomes in this trial to date, and needless to say, these fantastic initial results only increase our interest to broaden our use of Alpha DaRT in patients with this deadly disease."

Alpha Tau Chief Medical Officer Dr. Robert Den added, "We are extremely pleased with our first release of clinical trial data from use of Alpha DaRT in treating internal organs. This procedure was enabled by a special-purpose applicator we designed for integration with existing equipment in the hospital, with limited need for additional specialized equipment and an intuitive method of delivery for the clinicians. Having observed strong initial results in the first five patients, we look forward to this trial progressing swiftly without the restriction of one patient per month, to allow us to generate a more complete dataset in 2024. In such a difficult setting, we would expect that any radiotherapy product demonstrating meaningful efficacy in treating pancreatic adenocarcinoma would be welcome news for patients and clinicians alike."

The trial seeks to recruit 37 participants who have Stage II to IV pancreatic adenocarcinoma which is deemed inoperable due to non-resectability, metastasis, or lack of fitness for surgery. The study primarily examines the safety and feasibility of placing the Alpha DaRT sources in the tumor utilizing endoscopic ultrasound, and the overall safety of the procedure by measuring adverse events. In addition, the study examines the efficacy of Alpha DaRT in terms of metrics such as overall response rate, overall survival and change in blood levels of CA19-9 (a blood-based biomarker often correlated with metrics such as disease progression). Additional information about the trial can be found at View Source

About Alpha DaRT

Alpha DaRT (Diffusing Alpha-emitters Radiation Therapy) is designed to enable highly potent and conformal alpha-irradiation of solid tumors by intratumoral delivery of radium-224 impregnated sources. When the radium decays, its short-lived daughters are released from the sources and disperse while emitting high-energy alpha particles with the goal of destroying the tumor. Since the alpha-emitting atoms diffuse only a short distance, Alpha DaRT aims to mainly affect the tumor, and to spare the healthy tissue around it.

On November 28, 2023 Imugene Limited (ASX: IMU), a clinical stage immuno-oncology company, reported that its MAST (Metastatic Advanced Solid Tumours) clinical program evaluating the safety and efficacy of novel cancer-killing virus CF33-hNIS (VAXINIA), has been granted Fast Track designation from the US Food and Drug Administration (FDA) (Press release, Imugene, NOV 28, 2023, https://mcusercontent.com/e38c43331936a9627acb6427c/files/d19332fd-bf6e-f62a-702e-599eab447f03/02746057.pdf [SID1234637979]).

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Imugene CEO and MD Ms Leslie Chong said, "The Fast Track process of drug development is designed to facilitate the development, and the review of drugs to treat serious conditions and fill an unmet medical need, with Fast Track status often leading to earlier drug approval and access by patients".

Benefits of Fast Track designation include:

Increased frequency of meetings with the FDA to discuss the drug’s development plan;
Eligibility for Accelerated Approval and Priority Review, if relevant criteria are met; and
Regular dialogue with the FDA known as a Rolling Review in support of a New Drug Application or Biologic License Application.
Imugene CMO Dr Paul Woodard said, "We are very encouraged to received Fast Track Designation by the FDA. We have received a high level of interest from clinicians in the emerging data from the difficult to treat bile duct cancer patient population".

FDA Fast Track was granted based on the promising data package from Imugene detailing Phase 1 efficacy and tolerability data in patients suffering with bile duct cancer. Bile duct cancer is a rare disease in which malignant (cancer) cells form in the bile ducts. Bile duct cancer is also called cholangiocarcinoma. Bile duct cancers are difficult to treat and typically respond poorly to immunotherapy drugs.

The multicenter Phase 1 MAST trial commenced by delivering a low dose of VAXINIA to patients with metastatic or advanced solid tumours who have had at least two prior lines of standard of care treatment. The City of Hope-developed oncolytic virus has been shown to shrink colon, lung, breast, ovarian and pancreatic cancer tumours in preclinical laboratory and animal models. Overall, the study aims to recruit cancer patients across approximately 12 trial sites in the United States and Australia.

The clinical trial is titled "A Phase I, Dose Escalation Safety and Tolerability Study of VAXINIA (CF33- hNIS), Administered Intratumorally or Intravenously as a Monotherapy or in Combination with Pembrolizumab in Adult Patients with Metastatic or Advanced Solid Tumours (MAST)." The trial commenced in May 2022 and is anticipated to run for approximately 24 months while being funded from existing budgets and resources.

Full study details can also be found on clinicaltrials.gov under study ID: NCT05346484.

On November 28, 2023 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global biotechnology company, reported the presentation of new data across a range of assets and blood cancers at the upcoming 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, taking place December 9-12 in San Diego, California (Press release, BeiGene, NOV 28, 2023, View Sourcenews/beigene-to-present-new-data-highlighting-hematology-portfolio-and-pipeline-strengths-at-ash-2023/294490e5-068a-482a-9c67-2a4d9f03a64a/" target="_blank" title="View Sourcenews/beigene-to-present-new-data-highlighting-hematology-portfolio-and-pipeline-strengths-at-ash-2023/294490e5-068a-482a-9c67-2a4d9f03a64a/" rel="nofollow">View Source [SID1234637971]). BeiGene has 24 abstracts accepted at ASH (Free ASH Whitepaper), with three abstracts scheduled for oral presentations.

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"Our data at ASH (Free ASH Whitepaper) showcase BeiGene’s leadership in the treatment of blood cancers, with promising clinical advances across our pipeline. Sonrotoclax, our BCL2 inhibitor, and BGB-16673, our BTK-degrader, both have very compelling results to date, and numerous presentations continue to underscore BRUKINSA as a potential best-in-class BTK inhibitor," said Mehrdad Mobasher, M.D., M.P.H., Chief Medical Officer, Hematology at BeiGene. "In addition to the sustained progression free survival benefit we see for BRUKINSA over ibrutinib with more than three years of follow-up for the ALPINE trial, we are sharing results of several studies that reinforce BRUKINSA’s safety and efficacy profile relative to other members of the class. At BeiGene, we are committed to advancing promising treatment options for patients living with blood cancers."

Furthering Leadership in BTK Inhibition with BRUKINSA

BRUKINSA continues to show sustained PFS benefit versus ibrutinib in the global Phase 3 ALPINE trial of patients with R/R CLL/SLL with this longer follow up. Durable PFS was observed across major subgroups, including in the high-risk 17p deletion/TP53 mutated patient population. In addition, the overall safety and tolerability profile was consistent with previous ALPINE analyses, including persistently lower rates of cardiovascular events reported with BRUKINSA. Based on these results among patients receiving more than three years of treatment, BRUKINSA continues to be a more efficacious and better-tolerated treatment than ibrutinib for patients with R/R CLL/SLL. (Abstract #202, oral presentation)

Data from Waldenström Macroglobulinemia patients treated with and tolerating ibrutinib on the Phase 3 ASPEN trial who switched to receive BRUKINSA on a long-term extension study demonstrate generally improved safety and deepening of responses with the switch to BRUKINSA. (Abstract #3043)

In an ongoing Phase 2 study, patients with B-cell malignancies experiencing intolerance to acalabrutinib were transitioned to BRUKINSA, with favorable results. The data suggest that for patients intolerant of acalabrutinib, switching to BRUKINSA leads to better tolerance (rare recurrence of adverse events) while maintaining or deepening response. (Abstract #3279)

Advancing BeiGene’s Pipeline of Next-Generation Blood Cancer Treatments

In an ongoing Phase 1/2 study, patients with treatment-naïve (TN) CLL/SLL were treated with sonrotoclax in combination with BRUKINSA. The combination was observed to be well tolerated; no cases of tumor lysis syndrome (TLS) were observed. There was a 100% response rate, including deep responses, and at time of follow-up no patient experienced disease progression (100% PFS). (Abstract #327, oral presentation) Based on these results, a Phase 3 study assessing a fixed duration combination of sonrotoclax and BRUKINSA is planned.

Sonrotoclax has also been well tolerated with high response rates as monotherapy in a continuing Phase 1 study in patients with R/R marginal zone lymphoma (MZL). (Abstract #3032)

Sonrotoclax was also evaluated in combination with dexamethasone in patients with R/R multiple myeloma (MM) harboring t(11;14) at doses up to 640 mg. Promising initial data indicate the combination is safe and efficacious, with the majority of patients across all dose levels achieving clinical response, including deep responses. Further investigations in this setting are ongoing. The US Food and Drug Administration recently granted Orphan Drug Designation to sonrotoclax for treatment of multiple myeloma. (Abstract #1011, oral presentation)

The first presentation of data from an ongoing, first-in-human study of BeiGene’s novel, orally available BTK-targeted chimeric degradation activation compound (CDAC), BGB-16673, demonstrates a tolerable safety profile and notable clinical responses that are durable at this clinical cut off in heavily pretreated patients with B-cell malignancies, including those with BTKi-resistant disease. (Abstract #4401)

More details on BeiGene’s abstracts are available in the ASH (Free ASH Whitepaper) program.

Raising Awareness Around the Importance of Mental Health and Cancer Care

BeiGene will host its second annual event at ASH (Free ASH Whitepaper) focused on the mental health of people with cancer. The event is titled "Mental Health First Aid: Bridging Cancer Centers and Community Partners to Help Meet Acute Needs," and it will take place on Friday, December 8 from 2:00 – 4:00 PM PT at the San Diego Wine and Culinary Center, Fallbrook Cellar, 200 Harbor Drive, San Diego, California. To learn more about this event and BeiGene’s "Talk About It" initiative, please visit View Source

BeiGene Presentation and Panel Event for Investors and Analysts

BeiGene will host an event in San Diego on Sunday, December 10 at 8:00 pm PST for investors and analysts attending ASH (Free ASH Whitepaper). BeiGene senior management and invited speakers will review BeiGene’s pipeline and highlights of the presented data, followed by a Q&A panel. The event can be accessed live from the Investors section of BeiGene’s website at View Source, View Source, or View Source Archived replays will be posted for 90 days following the event.

For more information on the BeiGene abstracts, see below:

Abstract Title

Abstract #

Presentation Time (PST)

Lead Author

BRUKINSA (zanubrutinib)

Extended Follow-up of ALPINE Randomized Phase 3 Study Confirms Sustained Superior Progression-Free Survival of Zanubrutinib Versus Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

202

Oral

Saturday, December 9, 2:00‑3:30 PM

J. Brown

Broad Superiority of Zanubrutinib Over Bendamustine + Rituximab Across Multiple High-Risk Factors: Biomarker Subgroup Analysis in the Phase 3 SEQUOIA Study in Patients with Treatment-Naive Chronic Lymphocytic Leukemia /Small Lymphocytic Lymphoma without del(17p)

1902

Poster

Saturday, December 9, 5:30‑7:30 PM

L. Xu

Acquired Mutations in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia That Progressed in the ALPINE Study

1890

Poster

Saturday, December 9, 5:30‑7:30 PM

J. Brown

Zanubrutinib in Acalabrutinib-Intolerant Patients with B-Cell Malignancies

3279

Poster

Sunday, December 10, 6:00‑8:00 PM

M. Shadman

Clinical Outcomes in Patients with Waldenström Macroglobulinemia Receiving Ibrutinib on the Phase 3 ASPEN Study ≥1 Year After Transitioning to Zanubrutinib

3043

Poster

Sunday, December 10, 6:00‑8:00 PM

R. Garcia‑Sanz

Indirect Comparison of Efficacy of Zanubrutinib Versus Orelabrutinib in Patients with Relapsed or Refractory Mantle Cell Lymphoma: An Updated Analysis with Long-Term Follow up

1682

Poster

Saturday, December 9, 5:30‑7:30 PM

Y. Song

A Phase 4, observational study evaluating the efficacy and safety of the Bruton tyrosine kinase inhibitor zanubrutinib in patients with Waldenström macroglobulinemia

6171

Online abstract

E. Kingsley

Genomic landscape of ibrutinib- and/or acalabrutinib-intolerant patients with B-cell malignancies treated with zanubrutinib in a Phase 2 study

6510

Online abstract

L. Xu

Sonrotoclax (BGB-11417)

Combination Treatment with Sonrotoclax (BGB-11417), a Second-Generation BCL2 Inhibitor, and Zanubrutinib, a Bruton Tyrosine Kinase (BTK) Inhibitor, Is Well Tolerated and Achieves Deep Responses in Patients with Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Data from an Ongoing Phase 1/2 Study

327

Oral

Saturday, December 9, 4:00‑5:30 PM

C. Tam

Sonrotoclax (BGB-11417) in Combination with Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma with t(11;14): Safety, Efficacy, and Determination of Recommended Phase 2 Dose

1011

Oral

Monday, December 11, 4:30‑6:00 PM

H. Quach

Monotherapy with Second-Generation BCL2 Inhibitor Sonrotoclax (BGB-11417) Is Well Tolerated with High Response Rates in Patients with Relapsed/Refractory Marginal Zone Lymphoma: Data from an Ongoing Phase 1 Study

3032

Poster

Sunday, December 10, 6:00‑8:00 PM

A. Tedeschi

BTK-CDAC (BGB-16673)

First Results from a Phase 1, First-in-Human Study of the Bruton’s Tyrosine Kinase Degrader Bgb-16673 in Patients with Relapsed or Refractory B-Cell Malignancies (BGB-16673-101)

4401

Poster

Monday, December 11, 6:00‑8:00 PM

J. Seymour

Tislelizumab (BGB-A317-210)

Tislelizumab, an Anti-PD1 Antibody, in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma in Tirhol BGB-A317-210: A Prospective Multicenter Lysa Phase 2 Study Conducted in Western Countries

1717

Poster

Saturday, December 9, 5:30‑7:30 PM

H. Ghesquières

Health Economics and Outcomes Research

Health-Related Quality of Life in Patients with Relapsed/Refractory Follicular Lymphoma Treated with Zanubrutinib+ Obinutuzumab Versus Obinutuzumab Monotherapy: The Rosewood Trial

1674

Poster

Saturday, December 9, 5:30‑7:30 PM

J. Trotman

Recent Patterns of Care with BTK Inhibitors and Distribution of Social Determinants of Health Among Patients with CLL/SLL in the US Community Setting

2413

Poster

Saturday, December 9, 5:30‑7:30 PM

D. Andorsky

Toxicity, Progression-Free Survival, and Quality of Life of Patients Treated with Zanubrutinib Versus Ibrutinib: A Q-TWiST Analysis from the ALPINE Study in Relapsed or Refractory Chronic Lymphocytic Leukemia

1909

Poster

Saturday, December 9, 5:30‑7:30 PM

V. Levy

Number Needed to Treat Analyses of Zanubrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia

2337

Poster

Saturday, December 9, 5:30‑7:30 PM

A. Chanan‑Khan

Similar Efficacy of Ibrutinib Arms across ALPINE and ELEVATE-RR Trials in Relapsed/Refractory Chronic Lymphocytic Leukemia: A Matching-Adjusted Indirect Comparison

4655

Poster

Monday, December 11, 6:00‑8:00 PM

M. Shadman

Impact of Real-World Treatment Sequencing Patterns on Time to Next Treatment among Patients with Chronic Lymphocytic Leukemia in the United States

5143

Poster

Monday, December 11, 6:00‑8:00 PM

A. Chanan‑Khan

Real-World Evaluation of Treatment Discontinuation and Healthcare Resource Utilization in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

5144

Poster

Monday, December 11, 6:00‑8:00 PM

A. Chanan‑Khan

Real-World Bruton Tyrosine Kinase Inhibitor Treatment Patterns Among Patients with Chronic or Small Lymphocytic Leukemia in US Community Oncology Practices

5163

Poster

Monday, December 11, 6:00‑8:00 PM

J.Z. Hou

Real-World Patterns of Care and Financial Burden of Patients with Follicular Lymphoma in the United States

5137

Poster

Monday, December 11, 6:00‑8:00 PM

B. Shah

Real-World Switching Pattern, Persistence, and Associated Healthcare Resource Utilization of Bruton Tyrosine Kinase Inhibitors for the Treatment of Mantle Cell Lymphoma in the United States

5155

Poster

Monday, December 11, 6:00‑8:00 PM

B. Shah

Zanubrutinib vs FCR in fit treatment-naive patients with chronic lymphocytic leukemia: A matching-adjusted indirect comparison

6522

Online abstract

T. Munir

About BRUKINSA (zanubrutinib)
BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared with other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease-relevant tissues.

About Sonrotoclax (BGB‑11417)
Sonrotoclax is an investigational small molecule B-cell lymphoma 2 (BCL2) inhibitor. It belongs to a class of BCL2 homology 3 (BH3) mimetics, and preclinical and IND-enabling studies have demonstrated potent activity and high selectivity of sonrotoclax against the antiapoptotic protein BCL2. Sonrotoclax is more potent and selective for BCL2 relative to BCLxL than venetoclax and shows the potential to overcome common BCL2 resistance mutations.

About BGB‑16673
BGB‑16673 is an orally available Bruton’s tyrosine kinase (BTK) targeting chimeric degradation activation compound (CDAC) designed to induce degradation of wildtype and multiple mutant forms of BTK, including those that commonly confer resistance to BTK inhibitors in patients who experience progressive disease.

About Tislelizumab
Tislelizumab is a humanized immunoglobulin G4 (IgG4) anti-programmed cell death protein 1 (PD‑1) monoclonal antibody with high affinity and binding specificity against PD‑1. It is designed to minimize binding to Fc-gamma (Fcγ) receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors.

U.S. Indications and Important Safety Information for BRUKINSA (zanubrutinib)

INDICATIONS
BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with:

Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
Waldenström’s macroglobulinemia (WM)
Mantle cell lymphoma (MCL) who have received at least one prior therapy
Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen
The MCL and MZL indications are approved under accelerated approval based on overall response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Hemorrhage
Fatal and serious hemorrhage has 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 3.6% of patients treated with BRUKINSA monotherapy in clinical trials, with fatalities occurring in 0.3% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 30% of patients.

Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Coadministration 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 infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 24% of patients, most commonly pneumonia (11%), with fatal infections occurring in 2.9% of patients. 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 (22%), thrombocytopenia (8%) and anemia (7%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy. Grade 4 neutropenia occurred in 11% of patients, and Grade 4 thrombocytopenia occurred in 2.8% 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 13% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer reported in 7% of patients. Other second primary malignancies included malignant solid tumors (5%), melanoma (1.2%), and hematologic malignancies (0.5%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

Cardiac Arrhythmias
Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 3.7% of 1550 patients treated with BRUKINSA monotherapy, including Grade 3 or higher cases in 1.7% of patients. Patients with cardiac risk factors, hypertension and acute infections may be at increased risk. Grade 3 or higher ventricular arrhythmias were reported in 0.2% of patients.

Monitor for signs and symptoms of cardiac arrhythmias (e.g. palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately, and consider the risks and benefits of continued BRUKINSA treatment.

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
In this pooled safety population, the most common adverse reactions, including laboratory abnormalities, in ≥30% of patients who received BRUKINSA (N=1550) included decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), 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 strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate 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 including U.S. Patient Information.