On March 7, 2024 Bristol Myers Squibb (NYSE: BMY) reported that the U.S. Food and Drug Administration (FDA) approved Opdivo (nivolumab), in combination with cisplatin and gemcitabine, for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma (UC), the most common type of bladder cancer (Press release, Bristol-Myers Squibb, MAR 7, 2024, View Source;nivolumab-in-Combination-with-Cisplatin-and-Gemcitabine-for-First-Line-Treatment-of-Adult-Patients-with-Unresectable-or-Metastatic-Urothelial-Carcinoma/default.aspx [SID1234640916]). This approval is based on results from the Phase 3 CheckMate –901 trial which evaluated Opdivo in combination with cisplatin and gemcitabine followed by Opdivo monotherapy (n=304), compared to cisplatin-gemcitabine alone (n=304), for patients with previously untreated unresectable or metastatic UC.1,3 The primary efficacy endpoints were overall survival (OS) and progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR).1

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In the trial, with a median follow-up of approximately 33 months, treatment with Opdivo in combination with cisplatin and gemcitabine reduced the risk of death by 22%, demonstrating a median OS of 21.7 months versus 18.9 months with cisplatin-gemcitabine alone (Hazard Ratio [HR] 0.78; 95% Confidence Interval [CI]: 0.63, 0.96; p=0.0171).1,4 Patients receiving Opdivo in combination with cisplatin and gemcitabine had their risk of disease progression or death reduced by 28%, with a median PFS of 7.9 months compared to 7.6 months with cisplatin-gemcitabine alone (HR 0.72; 95% CI: 0.59, 0.88; p=0.0012).1

Additionally, in exploratory analyses, treatment with Opdivo in combination with cisplatin and gemcitabine resulted in an objective response rate (ORR) of 57.6% (n=175) (95% CI: 51.8, 63.2) versus 43.1% (n=131) (95% CI: 37.5, 48.9) with cisplatin-gemcitabine alone.1,4 The complete response (CR) rate and partial response (PR) rate seen in patients treated with Opdivo in combination with cisplatin and gemcitabine was 22% (n=66) and 36% (n=109), respectively, versus 12% (n=36) and 31% (n=95) with cisplatin-gemcitabine alone.1

"This approval marks an important advancement in a historically difficult-to-treat setting, where there has been a need for new and differentiated first-line approaches that may offer patients a chance to live longer,"5 said Guru P. Sonpavde, MD, Medical Director of Genitourinary Oncology and the Phase I Clinical Research Unit and Christopher K. Glanz Chair for Bladder Cancer Research at the AdventHealth Cancer Institute, Orlando, Florida. "Based on outcomes and the safety profile seen in the CheckMate -901 clinical trial, the approval of Opdivo in combination with cisplatin and gemcitabine has the potential to change how metastatic or unresectable UC is treated for certain patients and offers them new hope."1

Opdivo is associated with the following Warnings & Precautions: severe and fatal immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, dermatologic adverse reactions, nephritis with renal dysfunction, other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when Opdivo is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials. Please see Important Safety Information below.1

"Bringing Opdivo to the first-line setting in UC with chemotherapy is the latest realization of our history of research and progress in immunotherapy, which has helped transform the treatment landscape for many cancers, including bladder cancer,"1,6 said Wendy Short Bartie, senior vice president and general manager, U.S. Hematology and Oncology at Bristol Myers Squibb. "This milestone adds a meaningful expansion to our portfolio of Opdivo-based treatments in genitourinary cancers, where we now have offerings in UC spanning three indications across stages of disease and treatment needs."1

The FDA previously approved Opdivo for the adjuvant treatment of adult patients with UC who are at high risk of recurrence after undergoing radical resection of UC; it also previously approved Opdivo for the treatment of adult patients with locally advanced or metastatic UC who have had disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.1

Bristol Myers Squibb’s supplemental Biologics License Application (sBLA) leading to today’s approval was granted Priority Review status by the FDA, and was approved under the FDA’s Real-Time Oncology Review (RTOR) pilot program, which aims to ensure that safe and effective treatments are available to patients as early as possible.7 The review was also conducted under the FDA’s Project Orbis initiative, which enables concurrent review by the health authorities in several other countries where the application remains under review.

About CheckMate -901

CheckMate -901 is a Phase 3, randomized, open-label trial evaluating Opdivo in combination with cisplatin and gemcitabine followed by Opdivo monotherapy compared to cisplatin-gemcitabine alone, in patients with previously untreated unresectable or metastatic urothelial cancer.3

In the CheckMate -901 study, a total of 608 cisplatin-eligible patients were randomized to receive either Opdivo 360 mg in combination with cisplatin-gemcitabine every three weeks for up to six cycles followed by Opdivo monotherapy 480 mg every 4 weeks until disease progression or unacceptable toxicity up to a maximum of two years, or cisplatin-gemcitabine alone every three weeks for up to six cycles.1 The primary endpoints of this study were overall survival (OS) and progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR).1,3 The OS and PFS outcomes for cisplatin-eligible patients are based on the final efficacy analyses of these endpoints.4

Select Safety Profile from CheckMate -901

Serious adverse reactions occurred in 48% of patients receiving Opdivo with chemotherapy.1 The most frequent serious adverse reactions reported in ≥2% of patients who received Opdivo with chemotherapy were urinary tract infection (4.9%), acute kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and platelet count decreased (2.3%).1 The most common adverse reactions (reported in ≥20% of patients) were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy.1 Fatal adverse reactions occurred in 3.6% patients who received Opdivo with chemotherapy; these included sepsis (1%).1 Opdivo and/or chemotherapy were discontinued in 30% of patients and were delayed in 67% of patients for an adverse reaction.1

About Urothelial Carcinoma

Bladder cancer is the sixth most common cancer in the U.S., with an estimated 83,190 new cases expected to be diagnosed in 2024.2,8 Urothelial carcinoma, which most frequently begins in the cells that line the inside of the bladder, accounts for approximately 90% of bladder cancer cases.2,8 In addition to the bladder, urothelial carcinoma can occur in other parts of the urinary tract, including the ureters and renal pelvis.2 The majority of urothelial carcinomas are diagnosed at an early stage, but approximately 50% of patients who undergo radical surgery will experience disease progression and recurrence, generally within two years post-surgery.9,10,11,12,13 Approximately 20% to 25% of patients with urothelial carcinoma present with metastatic disease, and treatment challenges have historically persisted in the first- and second-line settings, in part due to limited therapeutic options.13,14,15

INDICATION

OPDIVO (nivolumab), in combination with cisplatin and gemcitabine, is indicated as first-line treatment for adult patients with unresectable or metastatic urothelial carcinoma.

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 may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO. Early identification and management are essential to ensure safe use of OPDIVO. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment with OPDIVO. 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 OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO interruption or discontinuation is required, 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. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. A common symptom included in the definition of colitis was 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 OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%).

Immune-Mediated Endocrinopathies

OPDIVO can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%).

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%).

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%).

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 OPDIVO monotherapy 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; 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; 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; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.

Some ocular IMAR 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, which has been observed in patients receiving OPDIVO, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO can cause severe infusion-related reactions. Discontinue OPDIVO in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO. 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 OPDIVO and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of OPDIVO in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

In Checkmate 901, serious adverse reactions occurred in 48% of patients receiving OPDIVO in combination with chemotherapy. The most frequent serious adverse reactions reporting in ≥2% of patients who received OPDIVO with chemotherapy were urinary tract infection (4.9%), acute kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and platelet count decreased (2.3%). Fatal adverse reactions occurred in 3.6% of patients who received OPDIVO in combination with chemotherapy; these included sepsis (1%). OPDIVO and/or chemotherapy were discontinued in 30% of patients and were delayed in 67% of patients for an adverse reaction.

Common Adverse Reactions

In Checkmate 901, the most common adverse reactions (≥20%) were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy.

Please see US Full Prescribing Information for OPDIVO.

On March 7, 2024 BeiGene, Ltd. (Nasdaq: BGNE; HKEX: 06160; SSE: 688235), a global oncology company, reported that the U.S. Food and Drug Administration (FDA) has granted accelerated approval to BRUKINSA (zanubrutinib) for the treatment of adult patients with relapsed or refractory (R/R) follicular lymphoma (FL), in combination with the anti-CD20 monoclonal antibody obinutuzumab, after two or more lines of systemic therapy (Press release, BeiGene, MAR 7, 2024, View Source [SID1234640915]). The indication is approved under accelerated approval based on response rate and durability of response, marking BRUKINSA’s fifth indication in B-cell malignancies in the U.S.

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"This accelerated approval of BRUKINSA represents an important advancement, offering the first and only BTK inhibitor treatment for follicular lymphoma patients in the U.S. who have either not responded to initial therapies or have experienced relapse," said Mehrdad Mobasher, M.D., M.P.H., Chief Medical Officer, Hematology at BeiGene. "BRUKINSA is the only BTK inhibitor to date that shows efficacy with this type of malignancy and now has the broadest label, including five oncology indications, of any medication in its class globally. This is a testament to BRUKINSA’s differentiated clinical profile and our continued commitment to bringing this much-needed treatment option to patients around the world."

BRUKINSA was approved for the treatment of R/R FL under the FDA’s accelerated approval program based on the overall response rate (ORR) from the ROSEWOOD trial (NCT03332017), as assessed by an independent review committee (IRC). Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory MAHOGANY (NCT05100862) trial, which is underway. The application for R/R FL was also granted Fast Track Designation and Orphan Drug Designation by the FDA.

The ROSEWOOD trial is a global, randomized, open-label Phase 2 study of BRUKINSA plus obinutuzumab compared with obinutuzumab alone in 217 patients with R/R FL who received at least two prior lines of systemic therapy. In the study, the ORR by IRC was 69% in the BRUKINSA plus obinutuzumab arm versus 46% in the obinutuzumab arm (P=0.0012), with a median follow-up of approximately 20 months. Responses were durable, with an 18-month landmark duration of response (DOR) of 69% in the BRUKINSA combination arm.i

BRUKINSA plus obinutuzumab was generally well-tolerated, with safety results consistent with previous studies of both medicines.i Serious adverse reactions occurred in 35% of patients who received BRUKINSA in combination with obinutuzumab. Adverse reactions led to permanent discontinuation of BRUKINSA in 17% of patients.

Christopher Flowers, M.D., Division Head of Cancer Medicine and Chair of the Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center commented, "Patients living with follicular lymphoma often experience relapse or do not respond to treatment and need options for treatment during the course of their illness. The findings from the ROSEWOOD trial highlight the significant clinical advantage of treating patients who experience relapse or have refractory follicular lymphoma with zanubrutinib plus obinutuzumab."

"Follicular lymphoma can significantly impact patients’ lives and prove to be challenging, especially for those whose condition has advanced despite undergoing prior treatment or experienced relapse," said the Follicular Lymphoma Foundation. "However, the emergence of new treatment options which have been shown to be effective and well-tolerated, including second generation BTK inhibitors such as zanubrutinib in combination with existing therapies, brings hope to those dealing with advanced follicular lymphoma."

In addition to R/R FL, BRUKINSA is also approved in the U.S. as a treatment for adult patients with Waldenström’s macroglobulinemia; mantle cell lymphoma, who have received at least one prior therapy, R/R marginal zone lymphoma, who have received at least one anti-CD20-based regimen; and most recently chronic lymphocytic leukemia or small lymphocytic lymphoma. BRUKINSA is the first and only BTK inhibitor to demonstrate PFS superiority in a head-to-head clinical trial versus ibrutinib in patients with R/R CLL in the global Phase 3 ALPINE trial. In a recent presentation, BRUKINSA showed sustained PFS benefit versus ibrutinib in a longer term follow up. Durable PFS was observed across major subgroups, including in the high-risk 17p deletion/TP53 mutated patient population.

BRUKINSA is approved in 70 markets, including the U.S., EU, Great Britain, Canada, Australia, China, South Korea and Switzerland in selected indications, and it is under development for additional indications globally. The global BRUKINSA development program includes more than 5,000 subjects enrolled to date in 29 countries and regions.

About Follicular Lymphoma

Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL), accounting for 22% of all NHL cases.ii Approximately 15,000 cases are diagnosed in the U.S. each year.iii While FL remains incurable, people with the condition can live a long time. The five-year survival rate is about 90%, and approximately half of people diagnosed with FL can live with the disease for nearly 20 years.iv

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.

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.
Relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy.
The MCL, MZL and FL indications are approved under accelerated approval based on overall response rate and durability of response. 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. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax was reported in 3.8% of patients treated with BRUKINSA in clinical trials, with fatalities occurring in 0.2% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 32% 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 before and after 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. Grade 3 or higher infections occurred in 26% of patients, most commonly pneumonia (7.9%), with fatal infections occurring in 3.2% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jirovecii 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 (21%), thrombocytopenia (8%) and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA. Grade 4 neutropenia occurred in 10% of patients, and Grade 4 thrombocytopenia occurred in 2.5% 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. The most frequent second primary malignancy was non-melanoma skin cancers (8%), followed by other solid tumors in 7% of the patients (including melanoma in 1% of patients) and hematologic malignancies (0.7%). 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 4.4% patients treated with BRUKINSA, including Grade 3 or higher cases in 1.9% 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 0.3% 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

The most common adverse reactions (≥30%), including laboratory abnormalities, in patients who received BRUKINSA (N=1729) are decreased neutrophil count (51%), decreased platelet count (41%), upper respiratory tract infection (38%), hemorrhage (32%), and musculoskeletal pain (31%).

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.

On March 7, 2024 ALX Oncology Holdings Inc., ("ALX Oncology" or "the Company") (Nasdaq: ALXO), an immuno-oncology company developing therapies that block the CD47 immune checkpoint pathway, reported financial results for the fourth quarter and full year ended December 31, 2023, and provided a corporate update (Press release, ALX Oncology, MAR 7, 2024, View Source [SID1234640914]).

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"This past year proved to be a profound growth period for ALX Oncology highlighted by evorpacept’s positive results in the prespecified randomized interim analysis of the ASPEN-06 Phase 2 clinical trial in advanced HER2-positive gastric/GEJ cancer," said Jason Lettmann, Chief Executive Officer ("CEO") of ALX Oncology. "Notably, this outcome is particularly important as it represents the first promising activity in a randomized trial in solid tumors in the CD47 space and further underscores evorpacept’s differentiation. Over the next 12-18 months, we expect to report multiple value inflection datapoints, with the goal of advancing evorpacept’s potential beyond anti-cancer antibodies through ongoing combination studies with ADCs and checkpoint inhibitors. With nine ongoing trials, our goal is to expand evorpacept’s value to other tumor types including breast, NHL, multiple myeloma and urothelial cancers as well as accelerate our efforts to identify new indications around this highly differentiated asset."

Fourth Quarter 2023 Highlights

Appointed long-standing board member, Jason Lettmann to CEO, while co-founder and previous CEO, Jaume Pons, Ph.D., transitioned to Chief Scientific Officer in September.
Reported positive results from a prespecified interim analysis of the Phase 2 randomized multi-center international clinical trial of ASPEN-06 for the treatment of advanced HER2-positive gastric/gastroesophageal junction ("GEJ") cancer in October.
Key findings from the 54 randomized subjects, which included those previously treated with ENHERTU (fam-trastuzumab deruxtecan-nxki) and/or immune checkpoint inhibitors, reported a confirmed overall response rate ("ORR") of 52 percent in the evorpacept combination treatment arm compared to 22 percent for the control group of trastuzumab + CYRAMZA (ramucirumab) + paclitaxel ("TRP").
Median duration of response ("mDOR") was not reached for the evorpacept TRP combination treatment arm compared to 7.4 months for the control group of TRP.
The safety profile of evorpacept was consistent with the Company’s previous clinical trials and remained well-tolerated in this reported treatment combination.
The interim results compared favorably to the efficacy results reported for CYRAMZA + paclitaxel in the RAINBOW study (ORR of 28 percent and mDOR of 4.4 months), which currently serves as the regulatory benchmark and global standard-of-care for second-line gastric/GEJ cancer.
Executed an oversubscribed underwritten public offering that generated gross proceeds of approximately $63.2 million during October, which helps to extend the Company’s expected cash runway into early 2026. The follow-on offering closely followed the report of the positive interim analysis of the Phase 2 ASPEN-06 clinical trial in advanced HER2-positive gastric/GEJ cancer.
ALX Oncology sold 8,663,793 shares of common stock, which included 1,293,103 shares of common stock pursuant to the full exercise of the underwriters’ option to purchase additional shares and, in lieu of common stock to certain investors, pre-funded warrants to purchase 1,250,000 shares of common stock in the offering. The shares of common stock were sold at a public offering price of $6.38 per share (the closing price on October 4, 2023), and the pre-funded warrants were sold at a public offering price of $6.379 per pre-funded warrant.
Anticipated 2024 Clinical Milestones for Evorpacept’s Maturing Pipeline Development

Non-Hodgkin Lymphoma – Data from a Phase 1b IST with rituximab + lenalidomide will be presented in an oral presentation in a Clinical Trials Minisymposium session at the AACR (Free AACR Whitepaper) Annual Meeting 2024 on Tuesday, April 9, 2024, from 2:30 pm – 4:30 pm PT.
Urothelial Carcinoma – Data from a Phase 1b ASPEN-07 clinical trial with PADCEV (enfortumab vedotin-ejfv) (Q2 2024)
Gastric/GEJ Cancer – Top line results from all 122 subjects in a Phase 2 randomized clinical trial of ASPEN-06 (June-July 2024)
Breast Cancer – Top line results from a Phase 1b I-SPY TRIAL with ENHERTU (Q4 2024)
Head and Neck Squamous Cell Carcinoma – Top line results from a Phase 2 randomized clinical trial of ASPEN-03 with KEYTRUDA (pembrolizumab) (Q4 2024/Q1 2025)
Head and Neck Squamous Cell Carcinoma – Top line results from a Phase 2 randomized clinical trial of ASPEN-04 with KEYTRUDA and chemotherapy (Q4 2024/Q1 2025)
Gastric/GEJ Cancer – Initiation of Phase 3 registrational randomized clinical trial for evorpacept (Q4 2024)
2023 Full Year and Fourth Quarter Financial Results:

Cash, Cash Equivalents and Investments: Cash, cash equivalents and investments as of December 31, 2023, were $218.1 million. The Company believes its cash, cash equivalents, and investments along with the ability to draw down an additional $40 million of its term loan are sufficient to fund planned operations into early 2026.
Research and Development ("R&D") Expenses: R&D expenses consist primarily of pre-clinical, clinical and manufacturing expenses related to the development of the Company’s current lead product candidate, evorpacept, and R&D employee-related expenses. These expenses for the three months ended December 31, 2023, were $41.8 million, compared to $25.2 million for the prior-year period. The increase was primarily attributable to an increase of $13.6 million in clinical costs from an increase in the number of active trials and patient enrollment as well as manufacturing of clinical trial materials to support a higher number of active clinical trials and future expected patient enrollment related to the advancement of evorpacept. R&D expenses for the year ended December 31, 2023 were $141.8 million, compared to $98.4 million for the prior-year period.
General and Administrative ("G&A") Expenses: G&A expenses consist primarily of administrative employee-related expenses, legal and other professional fees, patent filing and maintenance fees, and insurance. These expenses for the three months ended December 31, 2023, were $6.2 million, compared to $7.0 million for the prior year period. G&A expenses for the year ended December 31, 2023 were $28.5 million, compared to $29.0 million for the prior-year period.
Net loss: GAAP net loss was $45.5 million for the fourth quarter ended December 31, 2023, or ($0.93) per basic and diluted share, as compared to a GAAP net loss of $30.7 million for the fourth quarter ended December 31, 2022, or ($0.75) per basic and diluted share. GAAP net loss was $160.8 million for the year ended December 31, 2023, or ($3.74) per basic and diluted share, as compared to a GAAP net loss of $123.5 million for the year ended December 31, 2022, or ($3.03) per basic and diluted share. Non-GAAP net loss was $38.7 million for the fourth quarter ended December 31, 2023, as compared to a non-GAAP net loss of $24.4 million for the fourth quarter ended December 31, 2022. Non-GAAP net loss was $134.3 million for the year ended December 31, 2023, as compared to a non-GAAP net loss of $99.6 million for the year ended December 31, 2022. A reconciliation of GAAP to non-GAAP financial results can be found at the end of this news release.

On March 7, 2024 Alpha Tau Medical Ltd. ("Alpha Tau", or the "Company") (NASDAQ: DRTS, DRTSW), the developer of the innovative alpha-radiation cancer therapy Alpha DaRT, reported full year 2023 financial results and provided a corporate update (Press release, Alpha Tau Medical, MAR 7, 2024, View Source [SID1234640913]).

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"2023 was an incredibly productive year, as we launched our ReSTART pivotal U.S. multi-center trial in recurrent cutaneous squamous cell carcinoma, which is expected to complete recruitment in the second half of 2024, and as we initiated a number of feasibility trials in difficult-to-treat internal organ tumors with high unmet need," stated Alpha Tau CEO Uzi Sofer. "We saw meaningful inflection points delivered by the end of 2023, including strong interim safety and feasibility data from our pancreatic cancer trial in Montreal, with initial signs of dose response, and our PMDA submission in Japan for pre-market approval. In parallel, we continue to advance our commercial planning activities and to solidify our supply chain, which was recently bolstered by both a valuable land grant in Jerusalem that is expected to increase our future manufacturing capacity, as well as by the leasing of a second manufacturing site in the United States. In 2024, we are focused on completing patient recruitment in our U.S. pivotal ReSTART study and our pancreatic cancer pilot study in Canada, and on beginning to treat patients in studies targeting a number of other internal organs. We are also exploring the addition of new clinical trials in the U.S., based upon recent positive regulatory feedback. We expect to begin work on the construction of our second U.S. facility, in Hudson, NH, and on the construction plans for our second facility in Jerusalem. Alpha Tau expects to remain adequately capitalized to support all of these programs over the coming years."

Recent Corporate Highlights:

● In October, the Company announced that it had entered into a long-term lease agreement for a standalone building of over 14,000 rentable square feet in Hudson, NH, with the intention of erecting the Company’s second U.S. manufacturing site, alongside its first site in nearby Lawrence, MA.

● In October, the Company announced that Dr. Stephen Hahn, a former commissioner of the U.S. Food and Drug Administration ("FDA") and a distinguished expert in the field of radiation oncology and translational clinical research, joined its Scientific Advisory Board.

● In November, the Company announced that Japan’s Pharmaceuticals and Medical Devices Agency ("PMDA") accepted Alpha Tau’s submission requesting shonin pre-market approval of Alpha DaRT in patients with recurrent head and neck cancer, following multiple pre-submission consultation meetings with the PMDA per common practice in Japan.

● In November, the Company announced interim results from treatment of the first five patients in the Company’s safety and feasibility trial in Montreal, Canada, examining the use of Alpha DaRT to treat advanced pancreatic cancer. The Alpha DaRT procedure was deemed technically successful in all five cases, with Alpha DaRT sources successfully inserted into the target tumors. There were no reported serious adverse events deemed related to the product, and the only reported adverse events deemed possibly related to the product were of severity grade 1 (mild). In addition, despite the conservative and gradual step-up of tumor coverage from minimal initial levels, three of the five patients demonstrated stable disease responses at four weeks after treatment, and one was upgraded to partial response at 69 days after treatment.

Upcoming Milestones

● Planning treatment of the first patient in the Canadian liver metastases safety and feasibility trial in H1 2024. The trial is currently open for recruitment; for more information please see here: View Source

● Planning treatment of the first patient in the Israeli recurrent lung cancer safety and feasibility trial in H1 2024. The trial is currently open for recruitment; for more information please see here: View Source

● Targeting first brain cancer treatment in H2 2024.

● Targeting completion of patient recruitment in the ReSTART pivotal U.S. multi-center trial in recurrent cutaneous squamous cell carcinoma in H2 2024. For more information please see here: View Source

● Targeting completion of patient recruitment in the Canadian advanced inoperable pancreatic cancer study in Montreal in H2 2024. For more information please see here: View Source

● Anticipating response from PMDA in Japan by year-end 2024 for pre-market approval for Alpha DaRT in patients with recurrent head and neck cancer.

Financial results for the full year ended December 31, 2023

R&D expenses for the year ended December 31, 2023 were $26.4 million, compared to $20.9 million in 2022, due to increased employee headcount, compensation and benefits, including share-based compensation, increased operating costs, and increased pre-clinical study and clinical trial expenses, particularly in our U.S. ReSTART trial, with a smaller offset through government grants from the Israel Innovation Authority.

Marketing expenses for the year ended December 31, 2023 were $1.9 million, compared to $1.0 million for 2022 due to increased employee compensation and benefits, including share-based compensation, and the hiring of our chief commercial officer.

G&A expenses for the year ended December 31, 2023 were $7.3 million, compared to $10.3 million for 2022, due to to decreased professional fees (including D&O insurance), and costs associated with our financing transaction in the first quarter of 2022.

Financial expenses (income), net, for the year ended December 31, 2023 were $(6.5) million, compared to $1.6 million for 2022, due to revaluation of warrants and an increase in interest from bank deposits, offset by changes in foreign exchange rates.

For the year ended December 31, 2023, the Company had a net loss of $29.2 million, or $0.42 per share, compared to a net loss of $33.8 million, or $0.53 per share, in 2022.

Balance Sheet Highlights

As of December 31, 2023, the Company had cash and cash equivalents, restricted cash and deposits in the amount of $84.9 million, compared to $105.4 million as of December 31, 2022 and $90.1 million as of September 30, 2023. The Company expects that this cash balance will be sufficient to fund operations for at least two years.

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 March 7, 2024 Alligator Bioscience AB ("Alligator") (Nasdaq Stockholm: ATORX) and Aptevo Therapeutics ("Aptevo") (Nasdaq: APVO) reported positive interim data from the dose escalation phase of their Phase 1 trial evaluating ALG.APV-527 for the treatment of solid tumors likely to express the tumor antigen 5T4 (Press release, Alligator Bioscience, MAR 7, 2024, View Source [SID1234640912]).

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The multi-center, dose escalation trial is now more than 50% enrolled, and preliminary results include:

Treatment was overall well-tolerated, and a maximum tolerated dose has not yet been determined, dose-escalation in higher-dose cohorts is ongoing
ALG.APV-527 could be measured in all patients with plasma concentration of ALG.APV-527 consistent with the administered dose
Biomarker analyses indicate the expression of the targets (4-1BB and 5T4) in tumor biopsies and confirm biological activity of ALG.APV-527
Of particular interest, signs of clinical activity were observed for both enrolled patients with heavily pre-treated breast cancer. These patients demonstrated measurable level of drug in circulation (pharmacokinetics) and reproducible elevation of serum pharmacodynamic markers with dosing, suggesting the drug is biologically active. One patient remained on study for seven months and a second remains on study beyond nine months. Both patients achieved best overall response of stable disease.

"I am pleased to share that we are now dosing cohort four, heading into higher dose ranges where we believe there is potential for increased signs of clinical activity based on preclinical models. We have treated patients with multiple tumor types including breast, pancreatic, non-small cell lung cancer and colorectal cancer. It is our belief that continued analysis of this cross section of tumor types will offer important insights about ALG.APV-527 that can be used to increase our success in later stage development," said Dirk Huebner, MD, Chief Medical Officer at Aptevo. "Additionally, as the trial has progressed, we have seen growing enthusiasm among our clinical sites, evidenced by a long and growing waiting list of patients who would like to participate in the study. We look forward to announcing additional data later in the year."
"We’re thrilled to share positive interim Phase 1 data from our trial with ALG.APV-527, a testament to our dedicated collaboration with Aptevo. The presence of both targets in tumor biopsies is a particularly encouraging finding, which underlines the potential of our novel bispecific antibody to treat multiple indications," said Sumeet Ambarkhane, MD, CMO at Alligator Bioscience. "We very much look forward to continuing this journey together, to make a meaningful impact in the fight against cancer."
About the Trial
The ALG.APV-527 Phase 1 trial is a multi-center, multi-cohort, open-label trial that will include six cohorts (dose levels) in a 3+3 design*. The trial will be conducted at up to 10 sites in the U.S. among adult patients with multiple solid tumor types/histologies likely to express the 5T4 antigen. ALG.APV-527 will be given intravenously once every two weeks. The trial will assess the safety and tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of ALG.APV-527.

*The 3+3 design proceeds in cohorts of three patients treated at increasing dose levels. Dose escalation stops when at least two out of three or six patients experience dose limiting toxicities (DLTs) at that dose level.

About ALG.APV-527
ALG.APV-527 is a bispecific conditional 4-1BB agonist, only active upon simultaneous binding to 4-1BB and 5T4. This has the potential to be clinically important because 4-1BB can stimulate the immune cells (antitumor-specific T cells and NK cells) involved in tumor control, making 4-1BB a particularly compelling target for cancer immunotherapy. 5T4 is an oncofetal tumor associated antigen overexpressed on numerous solid tumors including non-small-cell lung carcinoma (NSCLC), breast, head and neck, cervical, renal, gastric, and colorectal cancer.

Preclinical studies, highlighting the differentiated design of the molecule that minimizes systemic immune activation, allowing for highly efficacious tumor-specific responses as demonstrated by potent activity in preclinical models, were recently published in the peer-reviewed publication, Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper).