FDA Grant Accelerated Approval for Genentech’s Bispecific Antibody, Columvi in Relapsed or Refractory Diffuse Large B-Cell Lymphoma

FDA Approves Genentech’s Columvi, the First and Only Bispecific Antibody With a Fixed-Duration Treatment for People With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Pivotal study showed durable responses, with a 56% overall response rate, a 43% complete response (remission) rate, and a median duration of response of 1.5 years (18.4 months) Given over a fixed period of time, Columvi provides patients with a treatment end date and potential time off treatment Columvi is part of Genentech’s industry-leading portfolio of T-cell engaging bispecific antibodies in non-Hodgkin’s lymphoma, which also includes the recently approved Lunsumio to treat follicular lymphoma

South San Francisco, CA -- June 15, 2023 --

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced today that the U.S. Food and Drug Administration (FDA) has approved Columvi® (glofitamab-gxbm) for the treatment of adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not otherwise specified or large B-cell lymphoma (LBCL) arising from follicular lymphoma, after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and durability of response in the Phase I/II NP30179 study. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Columvi will be available in the United States in the coming weeks. 

“People with diffuse large B-cell lymphoma who have gone through multiple lines of therapy have a poor prognosis and desperately need additional treatment options,” said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. “As an off-the-shelf, fixed-duration treatment providing durable response rates, we believe Columvi could change the way this aggressive lymphoma is treated, reinforcing our dedication to bringing innovative treatment options to people with critical unmet needs.”  

DLBCL is an aggressive, hard-to-treat disease and is the most common form of non-Hodgkin’s lymphoma in the United States. While many people with DLBCL are responsive to treatment, the majority of those who relapse or are refractory to subsequent treatments have poor outcomes. 

“Patients with relapsed or refractory diffuse large B-cell lymphoma may experience rapid progression of their cancer and often urgently need an effective treatment option that can be administered without delay,” said Krish Patel, M.D., Director of the Lymphoma Program at the Swedish Cancer Institute in Seattle and investigator of the Columvi Phase I/II NP30179 study. “Experience from clinical trials demonstrates that Columvi can provide patients with relapsed or refractory diffuse large B-cell lymphoma a chance for complete remission with a fixed-duration immunotherapy and that such remissions can potentially be sustained after the end of their treatment.”

The FDA accelerated approval is based on positive results from the Phase I/II NP30179 study of Columvi given as a fixed course for 8.5 months in 132 patients with DLBCL who had relapsed or were refractory to prior therapies, including about one-third (30%) who had received prior CAR T-cell therapy. Additionally, 83% were refractory to their most recent therapy. Results showed patients treated with fixed-duration Columvi achieved durable remission, with 56% of patients achieving an overall response (OR; 74/132 [95% confidence interval (CI): 47-65]) and 43% of patients achieving a complete response (CR; 57/132 [95% CI: 35-52]). Over two-thirds of those who responded continued to respond for at least nine months (68.5% [95% CI: 56.7-80.3]). The OR rate is the combination of CR rate (a disappearance of all signs and symptoms of cancer) and partial response rate (a decrease in the amount of cancer in the body). The median duration of response was 1.5 years (18.4 months [95% CI: 11.4-not estimable]). Data from the NP30179 study were recently published in the New England Journal of Medicine. 

Among 145 patients who received Columvi in the study, the most common adverse events (AEs) were cytokine release syndrome (CRS; 70%), which may be serious or life-threatening, musculoskeletal pain (21%), fatigue (20%) and rash (20%). CRS was generally low grade (52% experienced Grade 1, and 14% experienced Grade 2). 

Columvi is the first and only CD20xCD3 T-cell engaging bispecific antibody for the treatment of R/R DLBCL that is given for a defined period of time. Unlike treat-to-progression approaches where treatment is given indefinitely until the cancer progresses or the therapy cannot be tolerated, Columvi is administered in 13 intravenous infusions over a maximum of 12 cycles (including step-up dosing) or until disease progression or the treatment cannot be tolerated, whichever occurs first. After Cycle 1, Columvi is administered once every three weeks. Designed to be completed in approximately 8.5 months, Columvi offers people with R/R DLBCL a target end date for their course of treatment and the possibility of a treatment-free period. Additionally, Columvi is a chemotherapy-free treatment option that is off-the-shelf and ready for infusion. Patients are pretreated with a single dose of obinutuzumab seven days prior to starting Columvi. Patients are also given a corticosteroid, an antipyretic (fever-reducing medicine) and an antihistamine as premedications to reduce the risk of CRS.

Columvi is part of Genentech’s broad and industry-leading CD20xCD3 T-cell-engaging bispecific antibody clinical development program. This includes the Phase III STARGLO study evaluating Columvi in combination with gemcitabine and oxaliplatin (GemOx) versus rituximab in combination with GemOx in patients with DLBCL who have been treated with one or more previous therapies and are ineligible for autologous stem cell transplant. Genentech’s hematology bispecific antibody portfolio also includes Lunsumio® (mosunetuzumab-axgb), which was granted accelerated approval by the FDA in December 2022 for the treatment of adult patients with R/R follicular lymphoma after two or more lines of systemic therapy. Genentech is exploring the potential of both Columvi and Lunsumio as monotherapies and in combination with other therapies, including Polivy® (polatuzumab vedotin-piiq), in earlier lines of treatment with the goal of providing patients with long-lasting outcomes. This robust development program includes two Phase III studies: CELESTIMO, investigating Lunsumio plus lenalidomide in second line plus (2L+) FL, and SUNMO, investigating Lunsumio plus Polivy in 2L+ DLBCL. Columvi received its first worldwide approval in Canada, and the European Medicines Agency’s Committee for Medicinal Products for Human Use recently granted a positive opinion recommending its approval.

Genentech is committed to helping people access the medicines they are prescribed and will be offering comprehensive services for people prescribed Columvi to help minimize barriers to access and reimbursement. For people who qualify, Genentech plans to offer patient assistance programs through Genentech Access Solutions. More information is also available at 866-4ACCESS/866-422-2377 or http://www.Genentech-Access.com. 

About the NP30179 Study
 The NP30179 study [NCT03075696] is a Phase I/II, multicenter, open-label, dose-escalation and expansion study evaluating the safety, efficacy and pharmacokinetics of Columvi® (glofitamab-gxbm) in people with relapsed or refractory diffuse large B-cell lymphoma. Outcome measures include complete response rate by an independent review committee (primary endpoint), overall response rate, duration of response, progression-free survival, safety and tolerability (secondary endpoints).

About Diffuse Large B-Cell Lymphoma 
 Diffuse large B-cell lymphoma (DLBCL) is an aggressive (fast-growing) blood cancer and is the most common form of non-Hodgkin’s lymphoma (NHL) in the U.S. While many people with DLBCL are responsive to treatment, the majority of those who relapse or are refractory to subsequent treatments have poor outcomes. DLBCL not otherwise specified is the most common category of large B-cell lymphoma (LBCL) and accounts for about 80% or more of cases. It applies to cases that do not fall into any specific disease subgroups of LBCL.

About Large B-Cell Lymphoma Arising from Follicular Lymphoma

Follicular lymphoma (FL) is the most common slow-growing (indolent) form of non-Hodgkin’s lymphoma (NHL), accounting for about one in five cases. It typically responds well to treatment but is often characterized by periods of remission and relapse. The disease typically becomes harder to treat each time a patient relapses, and early progression can be associated with poor long-term prognosis. As part of the natural history of FL, it can transform to more aggressive malignancies, including large B-cell lymphoma (LBCL), one of the most aggressive (fast-growing) blood cancers.

About Columvi® (glofitamab-gxbm)
 Columvi is a CD20xCD3 T-cell engaging bispecific antibody designed with a novel 2:1 structural format. Columvi targets both T cells, a type of immune cell, and B cells, which are cancerous in DLBCL. Columvi is engineered to have one region that binds to CD3, a protein on T cells, and two regions that bind to CD20, a protein on B cells, which can be healthy or cancerous. This dual-targeting brings the T cell in close proximity to the B cell, activating the release of cancer cell-killing proteins from the T cell that result in the death of B cells. A robust clinical development program for Columvi is ongoing, investigating the molecule as a monotherapy and in combination with other medicines for the treatment of people with B-cell non-Hodgkin’s lymphomas, including diffuse large B-cell lymphoma and other blood cancers.

Columvi U.S. Indication

Columvi (glofitamab-gxbm) is a prescription medicine to treat adults with certain types of diffuse large B-cell lymphoma (DLBCL) or large B-cell lymphoma (LBCL) that has come back (relapsed) or that did not respond to previous treatment (refractory), and who have received 2 or more prior treatments for their cancer.

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

The conditional approval of Columvi is based on response rate and durability of response. There are ongoing studies to establish how well the drug works.

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

Columvi can cause Cytokine Release Syndrome (CRS), a serious side effect that is common during treatment with Columvi, and can also be serious and lead to death. 

Call your healthcare provider or get emergency medical help right away if you develop any signs or symptoms of CRS, including:

• fever of 100.4°F (38°C) or higher

• chills or shaking

• fast or irregular heartbeat

• dizziness or light-headedness 

• trouble breathing

• shortness of breath

Due to the risk of CRS, you will receive Columvi on a “step-up dosing schedule”.

• A single dose of a medicine called obinutuzumab will be given to you on the first day of your first treatment cycle (Day 1 of Cycle 1). 

• You will start the Columvi step-up dosing schedule a week after the obinutuzumab dose. The step-up dosing schedule is when you receive smaller “step-up” doses of Columvi on Day 8 and Day 15 of Cycle 1. This is to help reduce your risk of CRS. You should be hospitalized during your infusion and for 24 hours after receiving the first step-up dose on Day 8. You should be hospitalized during your infusion and for 24 hours after receiving the second step-up dose on Day 15 if you experienced CRS during the first step-up dose.

• You will receive your first full dose of Columvi a week after the second step-up dose (this will be Day 1 of Cycle 2).

• If your dose of Columvi is delayed for any reason, you may need to repeat the “step-up dosing schedule”. 

• If you had more than mild CRS with your previous dose of Columvi, you should be hospitalized during and for 24 hours after receiving your next dose of Columvi.

• Before each dose of Columvi, you will receive medicines to help reduce your risk of CRS and infusion-related reactions.

Your healthcare provider will monitor you for CRS during treatment with Columvi and may treat you in a hospital if you develop signs and symptoms of CRS. Your healthcare provider may temporarily stop or completely stop your treatment with Columvi if you have severe side effects.

Carry the Columvi Patient Wallet Card with you at all times and show it to all of your healthcare providers. The Columvi Patient Wallet Card lists the signs and symptoms of CRS you should get emergency medical help for right away. 

What are the possible side effects of Columvi?

Columvi may cause serious side effects, including:            

• Cytokine Release Syndrome. 

• Neurologic problems. Columvi can cause serious neurologic problems that may lead to death. Your healthcare provider will monitor you for neurologic problems during treatment with Columvi. Your healthcare provider may also refer you to a healthcare provider who specializes in neurologic problems. Tell your healthcare provider right away if you develop any signs or symptoms of neurologic problems, including: 

  • headache

  • confusion and disorientation 

  • difficulty paying attention or understanding things

  • trouble speaking 

  • sleepiness

  • memory problems

  • numbness, tingling, or weakness of the hands or feet 

  • dizziness

  • shaking (tremors) 

• Serious Infections. Columvi can cause serious infections that may lead to death. Your healthcare provider will monitor you for signs and symptoms of infection and treat you as needed. Tell your health care provider right away if you develop any signs of an infection, including: fever, chills, weakness, cough, shortness of breath, or sore throat.

• Growth in your tumor or worsening of tumor related problems (tumor flare). Tell your healthcare provider if you get any of these signs or symptoms of tumor flare: 

  • tender or swollen lymph nodes

  • pain or swelling at the site of the tumor

  • chest pain

  • cough

  • trouble breathing

The most common side effects of Columvi include: CRS, muscle and bone pain, rash, and tiredness.

The most common severe abnormal lab test results with Columvi include: decreased white blood cells, decreased phosphate (an electrolyte), increased uric acid levels, and decreased fibrinogen (a protein that helps with blood clotting). 

Your healthcare provider may temporarily stop or completely stop treatment with Columvi if you develop certain side effects. 

Before receiving Columvi, tell your healthcare provider about all of your medical conditions, including if you:

• have an infection

• have kidney problems

• are pregnant or plan to become pregnant. Columvi may harm your unborn baby

Females who are able to become pregnant:

• Your healthcare provider should do a pregnancy test before you start treatment with Columvi. 

• You should use effective birth control (contraception) during treatment and for 1 month after your last dose of Columvi. Talk to your healthcare provider about what birth control method is right for you during this time.

• Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with Columvi.

• are breastfeeding or plan to breastfeed. Columvi may pass into your breast milk. Do not breastfeed during treatment and for 1 month after your last dose of Columvi.

Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

What should I avoid while receiving Columvi?

Do not drive, operate heavy machinery, or do other dangerous activities if you develop dizziness, confusion, shaking (tremors), sleepiness, or any other symptoms that impair consciousness until your signs and symptoms go away. These may be signs and symptoms of neurologic problems.

These are not all the possible side effects of Columvi. Talk to your health care provider for more information about the benefits and risks of Columvi. 

You may report side effects to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

Please see Important Safety Information, including Serious Side Effects, as well as the Columvi full Prescribing Information and Medication Guide or visit https://www.Columvi.com.

About Lunsumio® (mosunetuzumab-axgb)
 Lunsumio is a first-in-class CD20xCD3 T-cell engaging bispecific antibody designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells. A robust clinical development program for Lunsumio is ongoing, investigating the molecule as a monotherapy and in combination with other medicines, for the treatment of people with B-cell non-Hodgkin’s lymphomas, including follicular lymphoma and diffuse large B-cell lymphoma, and other blood cancers.

Lunsumio U.S. Indication

Lunsumio (mosunetuzumab-axgb) is a prescription medicine used to treat adults with follicular lymphoma whose cancer has come back or did not respond to previous treatment, and who have already received two or more treatments for their cancer. 

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

The conditional approval of Lunsumio is based on response rate. There are ongoing studies to establish how well the drug works.

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

Lunsumio may cause Cytokine Release Syndrome (CRS), a serious side effect that is common during treatment with Lunsumio and can also be severe or life-threatening.

Get medical help right away if you develop any signs or symptoms of CRS at any time, including: 

• fever of 100.4°F (38°C) or higher

• chills

• low blood pressure

• fast or irregular heartbeat

• tiredness or weakness

• difficulty breathing

• headache

• confusion

• feeling anxious

• dizziness or light-headedness

• nausea

• vomiting

Due to the risk of CRS, you will receive Lunsumio on a “step-up dosing schedule.”

• The step-up dosing schedule is when you receive smaller “step-up” doses of Lunsumio on Day 1 and Day 8 of your first cycle of treatment

• You will receive a higher dose of Lunsumio on Day 15 of your first cycle of treatment

• If your dose of Lunsumio is delayed for any reason, you may need to repeat the step-up dosing schedule

• Before each dose in Cycle 1 and Cycle 2, you will receive medicines to help reduce your risk of CRS

Your healthcare provider will check you for CRS during treatment with Lunsumio and may treat you in a hospital if you develop signs and symptoms of CRS. Your healthcare provider may temporarily stop or completely stop your treatment with Lunsumio, if you have severe side effects.

What are the possible side effects of Lunsumio?

Lunsumio may cause serious side effects, including:

• Neurologic problems. Your healthcare provider will check you for neurologic problems during treatment with Lunsumio. Your healthcare provider may also refer you to a healthcare provider who specializes in neurologic problems. Tell your healthcare provider right away if you develop any signs or symptoms of neurologic problems during or after treatment with Lunsumio, including:

  • headache

  • numbness and tingling of the arms, legs, hands, or feet

  • dizziness

  • confusion and disorientation

  • difficulty paying attention or understanding things

  • forgetting things or forgetting who or where you are

  • trouble speaking, reading, or writing

  • sleepiness or trouble sleeping

  • tremors

  • loss of consciousness

  • seizures

  • muscle problems or muscle weakness

  • loss of balance or trouble walking

• Serious infections. Lunsumio can cause serious infections that may lead to death. Your healthcare provider will check you for signs and symptoms of infection before and during treatment. Tell your healthcare provider right away if you develop any signs or symptoms of infection during treatment with Lunsumio, including:

  • fever of 100.4° F (38° C) or higher

  • chest pain

  • tiredness

  • shortness of breath

  • painful rash

  • sore throat

  • pain during urination

  • feeling weak or generally unwell

• Low blood cell counts. Low blood cell counts are common during treatment with Lunsumio and can also be severe. Your healthcare provider will check your blood cell counts during treatment with Lunsumio. Lunsumio may cause the following low blood cell counts:

  • low white blood cell counts (neutropenia). Low white blood cells can increase your risk for infection

  • low red blood cell counts (anemia). Low red blood cells can cause tiredness and shortness of breath

  • low platelet counts (thrombocytopenia). Low platelet counts can cause bruising or bleeding problems

• Growth in your tumor or worsening of tumor related problems (Tumor flare). Lunsumio may cause serious or severe worsening of your tumor. Tell your healthcare provider if you develop any of these signs or symptoms of tumor flare during your treatment with Lunsumio: tender or swollen lymph nodes, chest pain, cough, trouble breathing, and pain or swelling at the site of the tumor

Your healthcare provider may temporarily stop or permanently stop treatment with Lunsumio if you develop severe side effects.

The most common side effects of Lunsumio include: tiredness, rash, fever, and headache.

The most common severe abnormal lab test results with Lunsumio include: decreased phosphate, increased glucose, and increased uric acid levels.

Before receiving Lunsumio, tell your healthcare provider about all of your medical conditions, including if you:

• have ever had an infusion reaction after receiving Lunsumio

• have an infection, or have had an infection in the past which lasted a long time or keeps coming back

• have or have had Epstein-Barr Virus

• are pregnant or plan to become pregnant. Lunsumio may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with Lunsumio

Females who are able to become pregnant:

• your healthcare provider should do a pregnancy test before you start treatment with Lunsumio

• you should use an effective method of birth control during your treatment and for 3 months after the last dose of Lunsumio

• are breastfeeding or plan to breastfeed. It is not known if Lunsumio passes into your breast milk. Do not breastfeed during treatment and for 3 months after the last dose of Lunsumio

Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

What should I avoid while receiving Lunsumio?

Do not drive, operate heavy machinery, or do other dangerous activities if you develop dizziness, confusion, tremors, sleepiness, or any other symptoms that impair consciousness until your signs and symptoms go away. These may be signs and symptoms of CRS or neurologic problems.

These are not all the possible side effects of Lunsumio. Talk to your health care provider for more information about the benefits and risks of Lunsumio.

You may report side effects to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

Please see Important Safety Information, including Serious Side Effects, as well as the Lunsumio full Prescribing Information and Medication Guide or visit https://www.Lunsumio.com.

About Polivy® (polatuzumab vedotin-piiq)

Polivy is a first-in-class anti-CD79b antibody-drug conjugate (ADC). The CD79b protein is expressed specifically in the majority of B cells, an immune cell impacted in some types of non-Hodgkin’s lymphoma (NHL), making it a promising target for the development of new therapies. Polivy binds to cancer cells such as CD79b and destroys these B cells through the delivery of an anti-cancer agent, which is thought to minimize the effects on normal cells. Polivy is being developed by Genentech using Seagen ADC technology and is currently being investigated for the treatment of several types of NHL. 

Polivy U.S. Indication
 Polivy is a prescription medicine used with other medicines (a rituximab product, cyclophosphamide, doxorubicin, and prednisone) as a first treatment for adults who have moderate to high risk diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) or high-grade B-cell lymphoma (HGBL).

Polivy is a prescription medicine used with other medicines, bendamustine and a rituximab product, to treat DLBCL in adults who have progressed after at least 2 prior therapies.

Important Safety Information

Possible serious side effects

Everyone reacts differently to Polivy therapy, so it’s important to know what the side effects are. Some people who have been treated with Polivy have experienced serious to fatal side effects. Your doctor may stop or adjust your treatment if any serious side effects occur. Be sure to contact your healthcare team if there are any signs of these side effects.

• Nerve problems in your arms and legs: This may happen as early as after your first dose and may worsen with every dose. Your doctor will monitor for signs and symptoms, such as changes in your sense of touch, numbness or tingling in your hands or feet, nerve pain, burning sensation, any muscle weakness, or changes to your walking pattern

• Infusion-related reactions: You may experience fever, chills, rash, breathing problems, low blood pressure, or hives within 24 hours of your infusion

• Low Blood Cell Counts: Treatment with Polivy can cause severe low blood cell counts. Your doctor will monitor your blood counts throughout treatment with Polivy

• Infections: If you have a fever of 100.4°F (38°C) or higher, chills, cough, or pain during urination, contact your healthcare team. Your doctor may also give you medication before giving you Polivy, which may prevent some infections, and will monitor your blood counts throughout treatment with Polivy. Treatment with Polivy can cause severe low blood cell counts

• Rare and serious brain infections: Your doctor will monitor closely for signs and symptoms of these types of infections. Contact your doctor if you experience confusion, dizziness or loss of balance, trouble talking or walking, or vision changes

• Tumor lysis syndrome: Caused by the fast breakdown of cancer cells. Signs include nausea, vomiting, diarrhea, and lack of energy

• Potential harm to liver: Some signs include tiredness, weight loss, pain in the abdomen, dark urine, and yellowing of your skin or the white part of your eyes. You may be at higher risk if you already had liver problems or you are taking other medication

Side effects seen most often

The most common side effects of Polivy when used as a first treatment in DLBCL with the medicines rituximab product, cyclophosphamide, doxorubicin, and prednisone include

• Nerve problems in arms and legs

• Nausea

• Tiredness or lack of energy

• Diarrhea

• Constipation

• Hair Loss

• Redness and sores of the lining of the mouth, lips, throat, and digestive tract

Polivy may lower your red or white blood cell counts and increase uric acid levels.

The most common side effects of Polivy when used in DLBCL after at least 2 prior therapies with other medicines, bendamustine and a rituximab product include

• Low blood cell counts (platelets, red blood cells, white blood cells)

• Nerve problems in arms and legs

• Tiredness or lack of energy

• Diarrhea

• Nausea

• Fever

• Decreased appetite

• Infections

 Polivy may not be for everyone. Talk to your doctor if you are

• Pregnant or think you are pregnant: Data have shown that Polivy may harm your unborn baby

• Planning to become pregnant: Women should avoid getting pregnant while taking Polivy. Women should use effective contraception during treatment and for 3 months after their last Polivy treatment. Men taking Polivy should use effective contraception during treatment and for 5 months after their last Polivy treatment

• Breastfeeding: Women should not breastfeed while taking Polivy and for 2 months after the last dose

These may not be all the side effects. Talk to your healthcare provider for more information about the benefits and risks of Polivy treatment. 

You may report side effects to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

Please see the full Prescribing Information and visit https://www.Polivy.com for additional Important Safety Information.

About Genentech in Hematology

For more than 20 years, Genentech has been developing medicines with the goal to redefine treatment in hematology. Today, we’re investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. For more information visit http://www.gene.com/hematology. 

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer

On May 31, 2023, the Food and Drug Administration approved olaparib (Lynparza, AstraZeneca Pharmaceuticals LP) with abiraterone and prednisone (or prednisolone) for adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test.

View full prescribing information for Lynparza.

Efficacy was evaluated in the PROpel trial (NCT03732820) that enrolled 796 patients with mCRPC, Patients were randomized (1:1) to receive either olaparib with abiraterone or placebo with abiraterone and also received prednisone or prednisolone. Patients were required to have a prior orchiectomy and, if not performed, received gonadotropin-releasing hormone (GnRH) analogs. Patients with prior systemic therapy for mCRPC were excluded; however, prior docetaxel for metastatic hormone-sensitive prostate cancer was allowed. Randomization was stratified by site of metastases and prior docetaxel. All available clinical samples were retrospectively tested for BRCA mutational status with the FoundationOne CDx and FoundationOne Liquid CDx tests (Foundation Medicine, Inc.).

The major efficacy outcome measure was investigator-assessed radiological progression-free survival (rPFS) per RECIST version 1.1 for soft tissue and Prostate Cancer Working Group criteria for bone lesions. Overall survival (OS) was an additional endpoint.

A statistically significant improvement in rPFS for olaparib with abiraterone compared to placebo with abiraterone in the intent-to-treat (ITT) population was observed. An exploratory subgroup analysis in the 85 patients with BRCAm (11% of ITT population) demonstrated a median rPFS that was not reached in the olaparib with abiraterone arm compared to 8 months (95% CI: 6, 15) for those receiving placebo with abiraterone (hazard ratio [HR] 0.24 [95% CI: 0.12, 0.45]). The OS HR in these patients was 0.30 (95% CI: 0.15, 0.59). In the 711 patients (89% of ITT population) without BRCAm, the rPFS HR was 0.77 (95% CI: 0.63, 0.96) and the OS HR was 0.92 (95% CI: 0.74, 1.14), suggesting that the improvement in rPFS observed in the ITT population was primarily attributable to patients with BRCAm.

The most common adverse reactions (≥10%) in patients receiving olaparib plus abiraterone were anemia (48%), fatigue (38%), nausea (30%), diarrhea (19%), decreased appetite (16%), lymphopenia (14%), dizziness (14%), and abdominal pain (13%). Seventy-two patients (18%) required at least one blood transfusion and 46 (12%) required multiple transfusions.

The recommended olaparib dose is 300 mg taken orally twice daily with or without food. The recommended abiraterone dose is 1000 mg taken orally once daily. Abiraterone should be administered with prednisone or prednisolone 5 mg orally twice daily. Patients should also receive a GnRH analog concurrently or should have had a prior bilateral orchiectomy.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

FDA Approves AYVAKIT (avapritinib) as the First and Only Treatment for Indolent Systemic Mastocytosis

FDA Approve EPKINLY™ (epcoritamab-bysp) as the First Bispecific Antibody to Treat Adults with r/r DLBCL

EPKINLY™ (epcoritamab-bysp) Approved by U.S. Food and Drug Administration as the First and Only Bispecific Antibody to Treat Adults with Relapsed or Refractory (R/R) Diffuse Large B-cell Lymphoma (DLBCL)

May 19, 2023 at 6:34 PM CEST

Company Announcement

• Results from phase 2 clinical trial demonstrated EPKINLY™ (epcoritamab-bysp) delivered 61 percent overall response rate, 38 percent complete response, and 15.6-month median duration of response in challenging-to-treat R/R DLBCL patients

• EPKINLY represents the seventh approved medicine incorporating Genmab innovation and third created via Genmab’s DuoBody®technology platform

COPENHAGEN, Denmark; May 19, 2023 – Genmab A/S (Nasdaq: GMAB) today announced that the U.S. Food and Drug Administration (FDA) has approved EPKINLY™ (epcoritamab-bysp) as the first and only T-cell engaging bispecific antibody for the treatment of adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), including DLBCL arising from indolent lymphoma, and high-grade B‑cell lymphoma, after two or more lines of systemic therapy. EPKINLY was approved under accelerated approval based on response rate and durability of response. Continued approval for this indication is contingent upon verification and description of clinical benefit in a confirmatory trial(s). EPKINLY is being co-developed and co-commercialized by Genmab and AbbVie (NYSE: ABBV) as part of the companies’ oncology collaboration.

“The approval of EPKINLY in the U.S. is an incredibly important milestone for patients with relapsed or refractory DLBCL, who are in need of a new, innovative treatment option administered subcutaneously,” said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab. “As the first and only bispecific antibody approved in the U.S. to treat relapsed or refractory DLBCL, and the third approved medicine developed using Genmab’s DuoBody technology, EPKINLY is a testament to our dedication to turn novel science into medicine and develop innovative and differentiated antibody therapeutics with the goal of improving the lives of patients. Together with AbbVie, we are committed to further evaluating and developing epcoritamab as a potential future core therapy across B-cell malignancies.”   

EPKINLY features a dual-targeted approach continuously binding to T-cells and CD20+ lymphoma B-cells. In the pivotal Phase 2 clinical study, subcutaneous EPKINLY monotherapy demonstrated responses in challenging-to-treat, relapsed or refractory DLBCL patients who have received at least two prior treatments. An overall response (complete or partial response) was seen in 61 percent (90/148 [95 percent confidence interval (CI): 52.5-68.7]) of patients and 38 percent (56/148 [95 percent CI: 30.0-46.2]) achieved complete remission. The median duration of response was 15.6 months (95 percent CI: 9.7-Not reached). EPKINLY can cause serious side effects, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infections, and cytopenias. Please see additional Important Safety Information, including Important Warnings on CRS and ICANS, below.

“Patients with DLBCL who relapse or are refractory to currently available therapies have limited options. Generally, the prognosis for these patients is poor and management of this aggressive disease can be challenging,” said TycelPhillips, M.D., City of Hope Associate Professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation. “Epcoritamab is a subcutaneous bispecific antibody that offers an additional treatment option for this patient population. With this approval, patients who are in need of additional therapy may have the opportunity to receive epcoritamab after failure to respond or relapse after two or more prior systemic therapies.”

DLBCL is a fast-growing type of B-cell non-Hodgkin’s lymphoma (B-NHL), a cancer that develops in the lymphatic system and affects B-cell lymphocytes, a type of white blood cell. For many people living with DLBCL, their cancer either relapses, which means it may return after treatment, or becomes refractory, meaning it does not respond to treatment. Although new therapies have become available, treatment management can remain a challenge.i,ii

"Despite recent advances in treating advanced DLBCL, due to the aggressive nature and complexity of the disease, there remains a need for new options that can provide remission, are tolerable, and can be administered upon relapse. The approval of EPKINLY brings a new option – and with it – new hope to patients and the greater lymphoma community,” said Meghan Gutierrez, Chief Executive Officer, Lymphoma Research Foundation.

About the Phase 1/2 EPCORE NHL-1 trial
In the expansion cohort of the trial, 157 patients with large B-cell lymphoma (LBCL) were enrolled. Among them, 148 patients with DLBCL or high-grade B-cell lymphoma were enrolled, 89 percent of which were diagnosed with DLBCL NOS, including 28 percent with DLBCL transformed from indolent lymphoma, and 14 percent with high-grade B-cell lymphoma (HGBCL). The median number of prior therapies was three (range: 2 to 11), with 29 percent receiving two prior therapies, 32 percent receiving three prior therapies, and 39 percent receiving four or more prior therapies. Eighteen percent had prior autologous hematopoietic stem cell transplantation (HSCT), and 39 percent had prior chimeric antigen receptor (CAR) T-cell therapy. Eighty-two percent of patients had disease refractory to last therapy and 29 percent of patients were refractory to CAR T-cell therapy. 

The prescribing information has a Boxed Warning for serious or life-threatening cytokine release syndrome (CRS) and life-threatening or fatal immune effector cell-associated neurotoxicity syndrome (ICANS). Warnings and precautions include infections and cytopenias. The majority of treatment-emergent adverse events (TEAEs) occurred during the first 12 weeks of treatment and resolved. The most common (≥ 20 percent) adverse reactions were CRS, injection site reactions, fatigue, musculoskeletal pain, pyrexia, abdominal pain, nausea, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥10 percent) were decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, decreased hemoglobin, and decreased platelets. 

Helping Patients Access Care
Genmab strives to positively impact the lives of patients when our medicines reach the people who need them. We understand the impact that cancer can have, and so we empower patients and their care partners to take ownership of their treatment journey, offering support every step of the way. MyNavCare™ Patient Support by Genmab offers resources and services, from financial information to ongoing support, to help eligible patients access their Genmab medication. MyNavCare provides helpful information for patients, care partners and the healthcare providers who serve those patients throughout their treatment journey. MyNavCare is available now to patients who have been prescribed EPKINLY. Patients, care partners and healthcare providers interested in learning more about MyNavCare can visit www.MyNavCare.com or call 1-866-NAV-CAR1 (1-866-628-2271).

About Diffuse Large B-cell Lymphoma (DLBCL)
DLBCL is the most common type of NHL worldwide, accounting for approximately 30 percent of all NHL cases and comprising an estimated 30,400 U.S. cases in 2022. DLBCL can arise in lymph nodes as well as in organs outside of the lymphatic system, occurs more commonly in the elderly and is slightly more prevalent in men. i,iii

About EPKINLY™ (epcoritamab-bysp)
EPKINLY is an IgG1-bispecific antibody created using Genmab's proprietary DuoBody® technology and administered subcutaneously. Genmab's DuoBody-CD3 technology is designed to direct cytotoxic T-cells selectively to elicit an immune response towards target cell types. EPKINLY is designed to simultaneously bind to CD3 on T-cells and CD20 on B-cells and induces T-cell mediated killing of CD20+ cells.iv EPKINLY is being co-developed by Genmab and AbbVie as part of the companies' oncology collaboration.

What is EPKINLY?
EPKINLY is a prescription medicine used to treat adults with certain types of diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma that has come back (relapsed) or that did not respond to previous treatment (refractory), and who have received two or more treatments for their cancer. EPKINLY is approved in the U.S. based on patient response data. A study is ongoing to confirm the clinical benefit of EPKINLY. It is not known if EPKINLY is safe and effective in children.

Servier receives EU approval of Tibsovo® in IDH1-mutated AML and IDH1-mutated Cholangiocarcinoma

Servier receives European Commission approval of Tibsovo® (ivosidenib tablets) in IDH1-mutated Acute Myeloid Leukemia and IDH1-mutated Cholangiocarcinoma

• Marketing Authorization granted for Tibsovo® as the first and only approved IDH1 targeted therapy in Europe

• IDH1-mutated Acute Myeloid Leukemia and IDH1-mutated Cholangiocarcinoma, difficult and hard-to-treat cancer

Servier, a global pharmaceutical group, announced that the European Commission (EC) has approved Tibsovo® (ivosidenib tablets) as a targeted therapy in two indications: in combination with azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) R132 mutation who are not eligible to receive standard induction chemotherapy; as well as in monotherapy for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation who were previously treated by at least one prior line of systemic therapy.

Tibsovo® is the first and only IDH1 inhibitor approved in Europe. It has received orphan medicine designation recognizing the significant benefit brought to patients by Tibsovo® over available therapies for both CCA and AML.

“The prognosis for patients diagnosed with acute myeloid leukemia or cholangiocarcinoma has historically been poor with very limited treatment options. With today’s approval by the European Commission, Tibsovo® is now the first targeted IDH1 inhibitor approved in Europe. This further affirms our unparalleled scientific leadership in harnessing the IDH mutation and commitment to finding new therapeutic solutions for patients with difficult and hard-to-treat cancers,” said Arnaud Lallouette, M.D., Executive Vice President, Global Medical & Patient Affairs at Servier.

“IDH1 mutations are major drivers of disease progression in acute myeloid leukemia and cholangiocarcinoma, which are usually diagnosed at an advanced stage, highlighting the urgent need for a targeted therapeutic option. The development of new targeted therapies such as Tibsovo®, which works differently from traditional chemotherapies, is now providing treatment options that may increase the life expectancy and quality of life for patients,” said Philippe Gonnard, M.D., Executive Vice President, Global Product Strategy at Servier.

AML is a cancer of the blood and bone marrow marked by rapid disease progression. It is the most common acute leukemia in adults and affects 5/100,000 inhabitants in Europe, i.e., more than 20,000 new cases each year.[i] The two-year survival rate of 75 years-old patients with AML is below 10%.[ii]

The approval by the European Commission in AML is supported by data from the AGILE study, a global, Phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial published in the New England Journal of Medicine. Results demonstrated a statistically significant improvement in event-free survival (EFS) (hazard ratio [HR] 0.33; 95% CI [0.16, 0.69]) and overall survival (OS) (HR 0.44; 95% CI [0.27, 0.73] of patients with IDH1-mutated AML treated with Tibsovo® in combination with azacitidine compared to azacitidine plus placebo. The median OS (95% CI) for Tibsovo® + azacitidine and placebo + azacitidine was 24.0 (11.3, 34.1) and 7.9 (4.1, 11.3) months, respectively. In addition to the primary endpoint of EFS, the study met all key secondary endpoints, including complete remission (CR) rate, OS, and complete remission with partial hematologic recovery (CRh) rate, as well as objective response rate (ORR). These results prove that Tibsovo®, in combination with azacitidine, is an effective combination treatment option for patients with newly diagnosed IDH1-mutated AML. The most common adverse reactions were vomiting, neutropenia, thrombocytopenia, electrocardiogram QT prolonged, and insomnia.

Cholangiocarcinoma, a cancer of the bile duct, is a rare and aggressive tumor often linked to medical history such as cirrhosis or liver infection. Cholangiocarcinoma affects 1–3 in 100,000 people in Europe, with approximately 10,000 new cases each year.[iii] The five-year survival rate is 9%, but 0% if metastasized.[iv] Only surgery has been shown to cure patients, but this treatment option is only possible for a limited number of patients, and the risk of relapse remains high. Chemotherapy and immunotherapy are the standard therapy for patients with cholangiocarcinoma who are not eligible for surgery or whose disease has progressed after surgery.

The European Commission’s approval in cholangiocarcinoma is supported by data from the ClarIDHy trial, the first and only randomized Phase 3 trial for previously treated IDH1-mutated cholangiocarcinoma. Results from the ClarIDHy study demonstrated a statistically significant improvement in the primary endpoint of progression-free survival (PFS) by an independent review committee (HR 0.37; 95% CI [0.25, 0.54], p<0.001)[v]. The median PFS (95% CI) for Tibsovo® and placebo was 2.7 (1.6, 4.2) and 1.4 (1.4, 1.6) months, respectively. Thirty-two percent and 22% of patients randomized to Tibsovo® remained free of progression or death at 6 and 12 months, respectively, versus none on the placebo arm. The most common adverse reactions were fatigue, nausea, abdominal pain, diarrhea, decreased appetite, ascites, vomiting, anemia, and rash.

Tibsovo® is currently approved in the U.S. as monotherapy for the treatment of adults with IDH1-mutant relapsed or refractory AML and in monotherapy or in combination with azacitidine for adults with newly diagnosed IDH1-mutant AML who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. Tibsovo® has also been approved in the U.S. and Australia for patients with previously treated IDH1-mutated cholangiocarcinoma. Tibsovo® is also approved in China[vi] for the treatment of adult patients with relapsed or refractory AML who have a susceptible IDH1 mutation.

The Marketing Authorization covers the 27 countries[vii] of the European Union as well as Iceland, Liechtenstein and Norway.

Find out more about cholangiocarcinoma and acute myeloid leukemia on servier.com.

Press contacts

Group: presse@servier.com

USA: Nathan Mellor nathan.mellor@servier.com

About the AGILE Phase 3 AML Trial[viii]

The AGILE trial is a global, Phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial designed to evaluate the efficacy and safety of Tibsovo® in combination with azacitidine compared with placebo in combination with azacitidine, in adults with previously untreated IDH1-mutated acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy (≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy). The study’s primary endpoint is event-free survival (EFS), defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurs first. Treatment failure is defined as failure to achieve complete remission (CR) by Week 24.

Key secondary endpoints include CR rate, defined as the proportion of participants who achieve a CR; overall survival (OS), defined as the time from date of randomization to the date of death due to any cause; CR and complete remission with partial hematologic recovery (CRh) rate, defined as the proportion of participants who achieve a CR or CRh; and objective response rate (ORR), defined as the rate of CR, CR with incomplete hematologic recovery (CRi) (including CR with incomplete platelet recovery [CRp]), partial remission (PR), and morphologic leukemia-free state (MLFS).

About ClarlDHy Phase 3 cholangiocarcinoma trial

The ClarIDHy trial is a global, randomized Phase 3 trial in previously treated IDH1-mutant cholangiocarcinoma patients who have documented disease progression following one or two systemic therapies in the advanced setting. Patients were randomized 2:1 to receive either single-agent Tibsovo® 500 mg once daily or placebo with crossover to Tibsovo® permitted at the time of documented radiographic progression per RECIST 1.1. The primary endpoint of the ClarIDHy trial is progression-free survival (PFS) as evaluated by independent radiology review. Secondary endpoints include investigator-evaluated PFS, safety and tolerability, overall response rate, OS, duration of response, pharmacokinetics, pharmacodynamics and quality of life assessments.

About Servier

Founded to serve health, Servier is a global pharmaceutical group governed by a Foundation that aspires to have a meaningful social impact, both for patients and for a sustainable world. With its unique governance model, it can fully serve its vocation with a long-term vision: being committed to therapeutic progress to serve patient needs. The 21,400 employees of the Group are committed to this shared vocation, a source of inspiration every day.

As a world leader in cardiology, Servier’s ambition is to become a renowned, focused and innovative player in oncology by targeting difficult and hard-to-treat cancers. That is why the Group allocates over 50% of its R&D budget to Oncology.

Neuroscience and immuno-inflammatory diseases are the future growth drivers. In these areas, Servier is focused on a limited number of diseases in which accurate patient profiling makes it possible to offer a targeted therapeutic response through precision medicine.

To promote access to quality care for all at a lower cost, the Group also offers a range of quality generic drugs covering most pathologies, relying on strong brands in France, Eastern Europe, Brazil and Nigeria.

In all these areas, the Group includes the patient voice at each stage of the life cycle of a medicine.

Headquartered in France, Servier relies on a strong geographical footprint in over 150 countries and achieved a revenue of €4.9 billion in 2022.

More information on the new Group website: servier.com

European Commission Approves BMS CAR T Breyanzi r/r Large B-cell Lymphoma After One Prior Therapy

Approval of Breyanzi based on the pivotal Phase 3 TRANSFORM trial, in which Breyanzi significantly improved event-free survival compared to standard of care with a manageable and well-established safety profile

PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb (NYSE: BMY) today announced that the European Commission (EC) has granted approval for Breyanzi (lisocabtagene maraleucel; liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy, for the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL) and follicular lymphoma grade 3B (FL3B), who relapsed within 12 months from completion of, or are refractory to, first-line chemoimmunotherapy. This approval covers all European Union (EU) member states.*

The approval is based on results from the pivotal Phase 3 TRANSFORM trial in which Breyanzi demonstrated statistically significant and clinically meaningful improvements in the study’s primary endpoint of event-free survival (EFS), and key secondary endpoints of complete responses (CR) and progression-free survival (PFS) compared to standard therapy (consisting of salvage immunochemotherapy followed by high-dose chemotherapy and hematopoietic stem cell transplant [HSCT]), along with a manageable and well-established safety profile.

“With Breyanzi, people in Europe living with relapsed or refractory DLBCL now have a differentiated CAR T cell therapy option earlier in the treatment paradigm that provides long-term clinical benefit,” said Anne Kerber, senior vice president, head of Cell Therapy Development, Bristol Myers Squibb. “This marks the approval of our third indication in Europe for our CAR T cell therapy portfolio, underscoring our continued drive to deliver the promise of cell therapy with curative potential for more patients.”

In DLBCL, the most common form of non-Hodgkin lymphoma, up to 40% of patients have disease that is refractory to or relapses following initial therapy. The standard therapy for these patients consists of intensive salvage immunochemotherapy followed by high-dose chemotherapy and HSCT for those whose disease responds to the salvage therapy and are eligible for transplant. However, only an estimated 25% of patients are considered eligible for transplant and experience long-term clinical benefit, leaving a continued unmet need for second-line treatment options with curative potential.

“Based on results of the TRANSFORM trial, Breyanzi provides significantly improved outcomes compared to the standard of care that has been in place for decades, along with a well-established safety profile, demonstrating the benefit of using a CAR T cell therapy earlier for patients with relapsed or refractory DLBCL,” said Bertram Glass, M.D., TRANSFORM trial investigator and Chief Physician of the Department of Hematology and Stem Cell Transplantation, Helios Klinikum, Berlin, Germany. “This approval represents a significant milestone for patients with continued progress toward transforming second-line treatment practice to provide a personalized treatment option that offers the potential for durable remission.”

*Centralized Marketing Authorization does not include approval in Great Britain (England, Scotland and Wales).

TRANSFORM Clinical Trial Results

In the TRANSFORM study, Breyanzi more than quadrupled median EFS compared to standard therapy (10.1 months vs. 2.3 months [HR: 0.349; 95% CI (0.229-0.530) p<0.0001]) at the time of prespecified interim analysis with a median follow-up of 6.2 months. Results of the primary analysis, with a median follow-up of 17.5 months were consistent with the interim analysis, with median EFS not reached for Breyanzi (95% CI: 9.5-NR) vs. 2.4 months for standard therapy (95% CI: 2.2-4.9). With Breyanzi, the majority (73.9%) of patients achieved a CR compared to less than half (43.5%) of those who were treated with standard therapy. Median PFS was not reached (95% CI: 12.6-NR) with Breyanzi vs. 6.2 months (95% CI: 4.3-8.6) with standard therapy (HR: 0.400; 95% CI: 0.261-0.615; p<0.0001).

The safety profile of Breyanzi is well-established, and in the TRANSFORM study, occurrences of cytokine release syndrome (CRS) and neurologic events were generally low-grade, and mostly resolved quickly with standard protocols and without the use of prophylactic steroids. Any-grade CRS was reported in less than half of patients (48.9%), with Grade 3 CRS reported in 1% of patients. The median time to onset of CRS was five days (range: 1 to 63) and median duration of CRS was four days (range: 1 to 16). Any-grade neurologic events were reported in 10.9% of patients treated with Breyanzi, with Grade 3 neurologic events reported in 4.3% of patients. The median time to onset of neurologic events was 11 days (range: 7 to 17 days). The median duration of neurologic toxicities was 4.5 days (range: 1 to 30 days). For full details on the Special Warnings and Precautions for Use and Adverse Reactions (including appropriate management), please refer to the EU Summary of Product Characteristics (SmPC).

About TRANSFORM

TRANSFORM (NCT03575351) is a pivotal, global, randomized, multicenter Phase 3 trial evaluating Breyanzi compared to current standard of care (platinum-based salvage chemotherapy followed by high-dose chemotherapy and autologous hematopietic stem cell transplant [HSCT] in patients responding to salvage chemotherapy) in patients with large B-cell lymphoma that was primary refractory or relapsed within 12 months after CD20-antibody and anthracycline containing first-line therapy. Patients were randomized to receive Breyanzi or standard of care salvage therapy, including rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP), rituximab plus ifosfamide, carboplatin and etoposide (R-ICE), or rituximab plus gemcitabine, dexamethasone and cisplatin (R-GDP) per the investigators’ choice before proceeding to high-dose chemotherapy (HDCT) and auto-HSCT. The primary endpoint of the study was event-free survival, defined as time from randomization to death from any cause, progressive disease, failure to achieve complete response or partial response, or start of new antineoplastic therapy due to efficacy concerns, whichever occurs first. Complete response rate was a key secondary endpoint. Other efficacy endpoints included progression-free survival, overall survival, overall response rate and duration of response.

About Breyanzi

Breyanzi is a CD19-directed CAR T cell therapy with a 4-1BB costimulatory domain, which enhances the expansion and persistence of the CAR T cells. Breyanzi is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal LBCL, and follicular lymphoma grade 3B who have refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy, or refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant due to comorbidities or age, or relapsed or refractory disease after two or more lines of systemic therapy. Breyanzi is not indicated for the treatment of patients with primary central nervous system lymphoma. Please see the Important Safety Information section below, including Boxed WARNINGS for Breyanzi regarding cytokine release syndrome and neurotoxicity.

Breyanzi is also approved in Japan for the second-line treatment of relapsed or refractory LBCL, and in Japan, Europe, Switzerland and Canada for relapsed or refractory LBCL after two or more lines of systemic therapy. Bristol Myers Squibb’s clinical development program for Breyanzi includes clinical studies in earlier lines of treatment for patients with relapsed or refractory LBCL and other types of lymphomas and leukemia. For more information, visit clinicaltrials.gov.

Full European Summary of Product Characteristics for Breyanzi is available from the EMA website at www.ema.europa.eu .

U.S. Important Safety Information

BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

• Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI. Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.

• Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution or in the absence of CRS. Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed.

• BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.

Cytokine Release Syndrome (CRS)

CRS, including fatal or life-threatening reactions, occurred following treatment with BREYANZI. CRS occurred in 46% (122/268) of patients receiving BREYANZI, including ≥ Grade 3 (Lee grading system) CRS in 4% (11/268) of patients. One patient had fatal CRS and 2 had ongoing CRS at time of death. The median time to onset was 5 days (range: 1 to 15 days). CRS resolved in 119 of 122 patients (98%) with a median duration of 5 days (range: 1 to 17 days). Median duration of CRS was 5 days (range 1 to 30 days) in all patients, including those who died or had CRS ongoing at time of death.

Among patients with CRS, the most common manifestations of CRS include fever (93%), hypotension (49%), tachycardia (39%), chills (28%), and hypoxia (21%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI. Sixty-one of 268 (23%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of BREYANZI. Twenty-seven (10%) patients received tocilizumab only, 25 (9%) received tocilizumab and a corticosteroid, and 9 (3%) received corticosteroids only.

Neurologic Toxicities

Neurologic toxicities that were fatal or life-threatening, occurred following treatment with BREYANZI. CAR T cell-associated neurologic toxicities occurred in 35% (95/268) of patients receiving BREYANZI, including ≥ Grade 3 in 12% (31/268) of patients. Three patients had fatal neurologic toxicity and 7 had ongoing neurologic toxicity at time of death. The median time to onset of the first event was 8 days (range: 1 to 46 days). The onset of all neurologic events occurred within the first 8 weeks following BREYANZI infusion. Neurologic toxicities resolved in 81 of 95 patients (85%) with a median duration of 12 days (range: 1 to 87 days). Three of four patients with ongoing neurologic toxicity at data cutoff had tremor and one subject had encephalopathy. Median duration of neurologic toxicity was 15 days (range: 1 to 785 days) in all patients, including those with ongoing neurologic events at the time of death or at data cutoff.

Seventy-eight (78) of 95 (82%) patients with neurologic toxicity experienced CRS. Neurologic toxicity overlapped with CRS in 57 patients. The onset of neurologic toxicity was after onset of CRS in 30 patients, before CRS onset in 13 patients, same day as CRS onset in 7 patients, and same day as CRS resolution in 7 patients. Neurologic toxicity resolved in three patients before the onset of CRS. Eighteen patients experienced neurologic toxicity after resolution of CRS.

The most common neurologic toxicities included encephalopathy (24%), tremor (14%), aphasia (9%), delirium (7%), headache (7%), dizziness (6%), and ataxia (6%). Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, have occurred in patients treated with BREYANZI.

CRS and Neurologic Toxicities Monitoring

Monitor patients daily at a certified healthcare facility during the first week following infusion, for signs and symptoms of CRS and neurologic toxicities. Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion; evaluate and treat promptly. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.

BREYANZI REMS

Because of the risk of CRS and neurologic toxicities, BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. The required components of the BREYANZI REMS are:

• Healthcare facilities that dispense and administer BREYANZI must be enrolled and comply with the REMS requirements.

• Certified healthcare facilities must have on-site, immediate access to tocilizumab.

• Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after BREYANZI infusion, if needed for treatment of CRS.

• Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer BREYANZI are trained on the management of CRS and neurologic toxicities.

Further information is available at www.BreyanziREMS.com, or contact Bristol Myers Squibb at 1-888-423-5436.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO).

Serious Infections

Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion. Infections (all grades) occurred in 45% (121/268) of patients. Grade 3 or higher infections occurred in 19% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections occurred in 5%, and viral and fungal infections occurred in 1.5% and 0.4% of patients, respectively. Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines.

Febrile neutropenia has been observed in 9% (24/268) of patients after BREYANZI infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.

Avoid administration of BREYANZI in patients with clinically significant active systemic infections.

Viral reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Ten of the 11 patients in the TRANSCEND study with a prior history of HBV were treated with concurrent antiviral suppressive therapy to prevent HBV reactivation during and after treatment with BREYANZI. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias

Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion. Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 31% (84/268) of patients, and included thrombocytopenia (26%), neutropenia (14%), and anemia (3%). Monitor complete blood counts prior to and after BREYANZI administration.

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with BREYANZI. The adverse event of hypogammaglobulinemia was reported as an adverse reaction in 14% (37/268) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 21% (56/268) of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 32% (85/268) of patients. Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated.

Live vaccines: The safety of immunization with live viral vaccines during or following BREYANZI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during BREYANZI treatment, and until immune recovery following treatment with BREYANZI.

Secondary Malignancies

Patients treated with BREYANZI may develop secondary malignancies. Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol Myers Squibb at 1-888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing.

Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving BREYANZI are at risk for altered or decreased consciousness or impaired coordination in the 8 weeks following BREYANZI administration. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

Adverse Reactions

Serious adverse reactions occurred in 46% of patients. The most common nonlaboratory, serious adverse reactions (> 2%) were CRS, encephalopathy, sepsis, febrile neutropenia, aphasia, pneumonia, fever, hypotension, dizziness, and delirium. Fatal adverse reactions occurred in 4% of patients.

The most common nonlaboratory adverse reactions of any grade (≥ 20%) were fatigue, CRS, musculoskeletal pain, nausea, headache, encephalopathy, infections (pathogen unspecified), decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, and edema.

Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision—transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

Learn more about the science behind cell therapy and ongoing research at Bristol Myers Squibb here.

FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma

On April 3, 2023, the Food and Drug Administration granted accelerated approval to enfortumab vedotin-ejfv (Padcev, Astellas Pharma) with pembrolizumab (Keytruda, Merck) for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.

View full prescribing information for Padcev and Keytruda. 

Efficacy was evaluated in EV-103/KEYNOTE-869 (NCT03288545), a multi-cohort (dose escalation cohort, Cohort A, Cohort K) study. The dose escalation cohort and Cohort A were single-arm cohorts treating patients with enfortumab vedotin-ejfv plus pembrolizumab while patients on Cohort K were randomized to either the combination or to enfortumab vedotin-ejfv alone. Patients had not received prior systemic therapy for locally advanced or metastatic disease and were ineligible for cisplatin-containing chemotherapy. A total of 121 patients received enfortumab vedotin-ejfv plus pembrolizumab.

The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR) determined by blinded independent central review using RECIST v1.1. The confirmed ORR in 121 patients was 68% (95% CI: 59, 76), including 12% with complete responses. The median DoR for the dose escalation cohort + Cohort A was 22 months (range: 1+ to 46+) and for Cohort K was not reached (range: 1 to 24+). 

The most common adverse reactions (>20%), including laboratory abnormalities, were increased glucose, increased aspartate aminotransferase, rash, decreased hemoglobin, increased creatinine, peripheral neuropathy, decreased lymphocytes, fatigue, increased alanine aminotransferase, decreased sodium, increased lipase, decreased albumin, alopecia, decreased phosphate, decreased weight, diarrhea, pruritus, decreased appetite, nausea, dysgeusia, decreased potassium, decreased neutrophils, urinary tract infection, constipation, potassium increased, calcium increased, peripheral edema, dry eye, dizziness, arthralgia, and dry skin.  

The recommended enfortumab vedotin-ejfv dose when given with pembrolizumab is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) administered as an intravenous infusion over 30 minutes on Days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity. The recommended pembrolizumab dose, administered after enfortumab vedotin on the same day, is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months. 

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. 

This application was granted priority review and breakthrough designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

FDA approves dabrafenib with trametinib for pediatric patients with low-grade glioma with a BRAF V600E mutation

On March 16, 2023, the Food and Drug Administration approved dabrafenib (Tafinlar, Novartis) with trametinib (Mekinist, Novartis) for pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. The FDA also approved new oral formulations of both drugs suitable for patients who cannot swallow pills.

This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAF V600E mutation.

View full prescribing information for Tafinlar and Mekinist.

Efficacy was evaluated in Study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in patients with LGG (WHO grades 1 and 2) requiring first systemic therapy. Patients were randomized 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). BRAF mutation status was identified prospectively by local or central laboratory tests. Retrospective testing of available tumor samples by the central laboratory was also performed to evaluate mutation status. Patients received age- and weight-based dosing of D+T until they were no longer deriving benefit or experienced unacceptable toxicity. C+V were dosed based on body surface area at 175 mg/m2 and 1.5 mg/m2 (0.05 mg/kg for patients < 12 kg), respectively, as one 10-week induction course, followed by eight 6-week cycles of maintenance therapy.

The major efficacy outcome measure was overall response rate (ORR) by independent review based on RANO LGG (2017) criteria. Additional efficacy outcome measures were progression- free survival (PFS) and overall survival (OS). The primary analysis was performed when all patients had completed at least 32 weeks of therapy.

In the LGG cohort, 110 patients were randomized to D+T (n=73) or C+V (n=37). ORR was 46.6% (95% CI: 34.8, 58.6) in the D+T arm and 10.8% (95% CI: 3.0, 25.4) for those receiving C+V (p= <0.001). DOR was 23.7 months (95% CI: 14.5, not estimable) in the D+T arm and not estimable (95% CI: 6.6, not estimable) in the C+V arm. PFS was 20.1 months (95% CI: 12.8, not estimable) and 7.4 months (95% CI: 3.6, 11.8) (HR=0.31 [95% CI: 0.17, 0.55]; p= <0.001) in the D+T and C+V arms, respectively. At the time of the interim analysis of OS conducted when all patients had completed at least 32 weeks of treatment or had discontinued earlier, there was one death on the C+V arm. The OS results at the interim analysis did not reach statistical significance.

In the pooled safety population of pediatric patients receiving D+T (N=166), the most common (>20%) adverse reactions were pyrexia (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%), and dermatitis acneiform (23%). The most common (>2%) Grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and aspartate aminotransferase increased (3.1%).

The recommended doses for dabrafenib and trametinib in pediatric patients are based on body weight; dabrafenib is administered orally twice daily and trametinib is administered orally once daily. Dabrafenib and trametinib are administered until disease progression or unacceptable toxicity.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, breakthrough designation and orphan drug designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.